Transient Exposure to Ethanol during Zebrafish Embryogenesis Results in Defects in Neuronal Differentiation: An Alternative Model System to Study FASD

PubMed Central

Joya, Xavier; Garcia-Algar, Oscar; Vall, Oriol; Pujades, Cristina

2014-01-01

Background The exposure of the human embryo to ethanol results in a spectrum of disorders involving multiple organ systems, including the impairment of the development of the central nervous system (CNS). In spite of the importance for human health, the molecular basis of prenatal ethanol exposure remains poorly understood, mainly to the difficulty of sample collection. Zebrafish is now emerging as a powerful organism for the modeling and the study of human diseases. In this work, we have assessed the sensitivity of specific subsets of neurons to ethanol exposure during embryogenesis and we have visualized the sensitive embryonic developmental periods for specific neuronal groups by the use of different transgenic zebrafish lines. Methodology/Principal Findings In order to evaluate the teratogenic effects of acute ethanol exposure, we exposed zebrafish embryos to ethanol in a given time window and analyzed the effects in neurogenesis, neuronal differentiation and brain patterning. Zebrafish larvae exposed to ethanol displayed small eyes and/or a reduction of the body length, phenotypical features similar to the observed in children with prenatal exposure to ethanol. When neuronal populations were analyzed, we observed a clear reduction in the number of differentiated neurons in the spinal cord upon ethanol exposure. There was a decrease in the population of sensory neurons mainly due to a decrease in cell proliferation and subsequent apoptosis during neuronal differentiation, with no effect in motoneuron specification. Conclusion Our investigation highlights that transient exposure to ethanol during early embryonic development affects neuronal differentiation although does not result in defects in early neurogenesis. These results establish the use of zebrafish embryos as an alternative research model to elucidate the molecular mechanism(s) of ethanol-induced developmental toxicity at very early stages of embryonic development. PMID:25383948

Exposure to Endocrine Disruptor Induces Transgenerational Epigenetic Deregulation of MicroRNAs in Primordial Germ Cells

PubMed Central

Brieño-Enríquez, Miguel A.; García-López, Jesús; Cárdenas, David B.; Guibert, Sylvain; Cleroux, Elouan; Děd, Lukas; Hourcade, Juan de Dios; Pěknicová, Jana; Weber, Michael; del Mazo, Jesús

2015-01-01

In mammals, germ cell differentiation is initiated in the Primordial Germ Cells (PGCs) during fetal development. Prenatal exposure to environmental toxicants such as endocrine disruptors may alter PGC differentiation, development of the male germline and induce transgenerational epigenetic disorders. The anti-androgenic compound vinclozolin represents a paradigmatic example of molecule causing transgenerational effects on germ cells. We performed prenatal exposure to vinclozolin in mice and analyzed the phenotypic and molecular changes in three successive generations. A reduction in the number of embryonic PGCs and increased rate of apoptotic cells along with decrease of fertility rate in adult males were observed in F1 to F3 generations. Blimp1 is a crucial regulator of PGC differentiation. We show that prenatal exposure to vinclozolin deregulates specific microRNAs in PGCs, such as miR-23b and miR-21, inducing disequilibrium in the Lin28/let-7/Blimp1 pathway in three successive generations of males. As determined by global maps of cytosine methylation, we found no evidence for prominent changes in DNA methylation in PGCs or mature sperm. Our data suggest that embryonic exposure to environmental endocrine disruptors induces transgenerational epigenetic deregulation of expression of microRNAs affecting key regulatory pathways of germ cells differentiation. PMID:25897752

Sexually Dimorphic Responses to Early Adversity: Implications for Affective Problems and Autism Spectrum Disorder

PubMed Central

Davis, Elysia Poggi; Pfaff, Donald

2014-01-01

During gestation, development proceeds at a pace that is unmatched by any other stage of the lifecycle. For these reason the human fetus is particularly susceptible not only to organizing influences, but also to pathogenic disorganizing influences. Growing evidence suggests that exposure to prenatal adversity leads to neurological changes that underlie lifetime risks for mental illness. Beginning early in gestation, males and females show differential developmental trajectories and responses to stress. It is likely that sex-dependent organization of neural circuits during the fetal period influences differential vulnerability to mental health problems. We consider in this review evidence that sexually dimorphic responses to early life stress are linked to two developmental disorders: affective problems (greater female prevalence) and autism spectrum disorder (greater male prevalence). Recent prospective studies illustrating the neurodevelopmental consequences of fetal exposure to stress and stress hormones for males and females are considered here. Plausible biological mechanisms including the role of the sexually differentiated placenta are discussed. We consider in this review evidence that sexually dimorphic responses to early life stress are linked to two sets of developmental disorders: affective problems (greater female prevalence) and autism spectrum disorders (greater male prevalence). PMID:25038479

Arsenic inhibits hedgehog signaling during P19 cell differentiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Jui Tung; Bain, Lisa J., E-mail: lbain@clemson.edu; Department of Biological Sciences, Clemson University, 132 Long Hall, Clemson, SC 29634

Arsenic is a toxicant found in ground water around the world, and human exposure mainly comes from drinking water or from crops grown in areas containing arsenic in soils or water. Epidemiological studies have shown that arsenic exposure during development decreased intellectual function, reduced birth weight, and altered locomotor activity, while in vitro studies have shown that arsenite decreased muscle and neuronal cell differentiation. The sonic hedgehog (Shh) signaling pathway plays an important role during the differentiation of both neurons and skeletal muscle. The purpose of this study was to investigate whether arsenic can disrupt Shh signaling in P19 mousemore » embryonic stem cells, leading to changes muscle and neuronal cell differentiation. P19 embryonic stem cells were exposed to 0, 0.25, or 0.5 μM of sodium arsenite for up to 9 days during cell differentiation. We found that arsenite exposure significantly reduced transcript levels of genes in the Shh pathway in both a time and dose-dependent manner. This included the Shh ligand, which was decreased 2- to 3-fold, the Gli2 transcription factor, which was decreased 2- to 3-fold, and its downstream target gene Ascl1, which was decreased 5-fold. GLI2 protein levels and transcriptional activity were also reduced. However, arsenic did not alter GLI2 primary cilium accumulation or nuclear translocation. Moreover, additional extracellular SHH rescued the inhibitory effects of arsenic on cellular differentiation due to an increase in GLI binding activity. Taken together, we conclude that arsenic exposure affected Shh signaling, ultimately decreasing the expression of the Gli2 transcription factor. These results suggest a mechanism by which arsenic disrupts cell differentiation. - Highlights: • Arsenic exposure decreases sonic hedgehog pathway-related gene expression. • Arsenic decreases GLI2 protein levels and transcriptional activity in P19 cells. • Arsenic exposure does not alter the levels of SHH expression and GLI2 primary cilum accumulation. • Induction of the Shh pathway rescues arsenic's inhibitory effects on cell differentiation.« less

Reduction of adult hippocampal neurogenesis is amplified by aluminum exposure in a model of type 2 diabetes

PubMed Central

Nam, Sung Min; Kim, Jong Whi; Yoo, Dae Young; Jung, Hyo Young; Choi, Jung Hoon; Hwang, In Koo; Seong, Je Kyung

2016-01-01

In this study, we investigated the effects of chronic aluminum (Al) exposure for 10 weeks on cell proliferation and neuroblast differentiation in the hippocampus of type 2 diabetic rats. Six-week-old Zucker diabetic fatty (ZDF) and Zucker lean control (ZLC) rats were selected and randomly divided into Al- and non-Al-groups. Al was administered via drinking water for 10 weeks, after which the animals were sacrificed at 16 weeks of age. ZDF rats in both Al- and non-Al-groups showed increases in body weight and blood glucose levels compared to ZLC rats. Al exposure did not significantly affect body weight, blood glucose levels or pancreatic β-cells and morphology of the pancreas in either ZLC or ZDF rats. However, exposure to Al reduced cell proliferation and neuroblast differentiation in both ZLC and ZDF rats. Exposure to Al resulted in poor development of the dendritic processes of neuroblasts in both ZLC and ZDF rats. Furthermore, onset and continuation of diabetes reduced cell proliferation and neuroblast differentiation, and Al exposure amplified reduction of these parameters. These results suggest that Al exposure via drinking water aggravates the impairment in hippocampal neurogenesis that is typically observed in type 2 diabetic animals. PMID:27051335

Fitness Trade-Offs in Competence Differentiation of Bacillus subtilis

PubMed Central

Yüksel, Melih; Power, Jeffrey J.; Ribbe, Jan; Volkmann, Thorsten; Maier, Berenike

2016-01-01

In the stationary phase, Bacillus subtilis differentiates stochastically and transiently into the state of competence for transformation (K-state). The latter is associated with growth arrest, and it is unclear how the ability to develop competence is stably maintained, despite its cost. To quantify the effect differentiation has on the competitive fitness of B. subtilis, we characterized the competition dynamics between strains with different probabilities of entering the K-state. The relative fitness decreased with increasing differentiation probability both during the stationary phase and during outgrowth. When exposed to antibiotics inhibiting cell wall synthesis, transcription, and translation, cells that differentiated into the K-state showed a selective advantage compared to differentiation-deficient bacteria; this benefit did not require transformation. Although beneficial, the K-state was not induced by sub-MIC concentrations of antibiotics. Increasing the differentiation probability beyond the wt level did not significantly affect the competition dynamics with transient antibiotic exposure. We conclude that the competition dynamics are very sensitive to the fraction of competent cells under benign conditions but less sensitive during antibiotic exposure, supporting the picture of stochastic differentiation as a fitness trade-off. PMID:27375604

Fitness Trade-Offs in Competence Differentiation of Bacillus subtilis.

PubMed

Yüksel, Melih; Power, Jeffrey J; Ribbe, Jan; Volkmann, Thorsten; Maier, Berenike

2016-01-01

In the stationary phase, Bacillus subtilis differentiates stochastically and transiently into the state of competence for transformation (K-state). The latter is associated with growth arrest, and it is unclear how the ability to develop competence is stably maintained, despite its cost. To quantify the effect differentiation has on the competitive fitness of B. subtilis, we characterized the competition dynamics between strains with different probabilities of entering the K-state. The relative fitness decreased with increasing differentiation probability both during the stationary phase and during outgrowth. When exposed to antibiotics inhibiting cell wall synthesis, transcription, and translation, cells that differentiated into the K-state showed a selective advantage compared to differentiation-deficient bacteria; this benefit did not require transformation. Although beneficial, the K-state was not induced by sub-MIC concentrations of antibiotics. Increasing the differentiation probability beyond the wt level did not significantly affect the competition dynamics with transient antibiotic exposure. We conclude that the competition dynamics are very sensitive to the fraction of competent cells under benign conditions but less sensitive during antibiotic exposure, supporting the picture of stochastic differentiation as a fitness trade-off.

Differential effect of exposure-based therapy and cognitive therapy on post-traumatic stress disorder symptom clusters: A randomized controlled trial.

PubMed

Horesh, Danny; Qian, Meng; Freedman, Sara; Shalev, Arieh

2017-06-01

A question remains regarding differential effects of exposure-based versus non-exposure-based therapies on specific post-traumatic stress disorder (PTSD) symptom clusters. Traumatized emergency room patients were randomized to receive prolonged exposure (PE) or cognitive therapy (CT) without exposure. PE/CT had no differential effect on individual symptom clusters, and change in total PTSD score remained significant even after controlling for the reductions in all three symptom clusters. In addition, baseline levels of PTSD avoidance/intrusion/hyperarousal did not moderate the effects of PE and CT on total PTSD symptom scores. Taken together, these findings challenge the notion that PE and CT are specifically, and differentially, useful in treating one particular PTSD symptom cluster. Despite their different theoretical backgrounds and techniques, the notion that PE and CT (without exposure) target different PTSD symptoms was not confirmed in this study. Thus, both interventions may in fact be equally effective for treating intrusion, avoidance and hyperarousal symptoms. Baseline levels of avoidance, intrusion and hyperarousal may not be good a priori indicators for PTSD treatment selection. The effect of PE and CT on PTSD as a whole does not seem to depend on a reduction in any specific symptom cluster. These findings indicate that exposure and non-exposure interventions may lead to similar results in terms of reductions in specific PTSD symptoms. It is quite possible that individual PTSD clusters may respond to therapy in an inter-related fashion, with one cluster affecting the other. © 2016 The British Psychological Society.

In Utero Alcohol Exposure, Epigenetic Changes, and Their Consequences

PubMed Central

Ungerer, Michelle; Knezovich, Jaysen; Ramsay, Michele

2013-01-01

Exposure to alcohol has serious consequences for the developing fetus, leading to a range of conditions collectively known as fetal alcohol spectrum disorders (FASD). Most importantly, alcohol exposure affects the development of the brain during critical periods of differentiation and growth, leading to cognitive and behavioral deficits. The molecular mechanisms and processes underlying the teratogenic effects of alcohol exposure remain poorly understood and are complex, because the specific effects depend on the timing, amount, and duration of exposure as well as genetic susceptibility. Accumulating evidence from studies on DNA methylation and histone modification that affect chromatin structure, as well as on the role of microRNAs in regulating mRNA levels supports the contribution of epigenetic mechanisms to the development of FASD. These epigenetic effects are difficult to study, however, because they often are cell-type specific and transient in nature. Rodent models play an important role in FASD research. Although recent studies using these models have yielded some insight into epigenetic mechanisms affecting brain development, they have generated more questions than they have provided definitive answers. Researchers are just beginning to explore the intertwined roles of different epigenetic mechanisms in neurogenesis and how this process is affected by exposure to alcohol, causing FASD. PMID:24313163

In utero exposure to low doses of environmental pollutants disrupts fetal ovarian development in sheep

PubMed Central

Fowler, Paul A.; Dorà, Natalie J.; McFerran, Helen; Amezaga, Maria R.; Miller, David W.; Lea, Richard G.; Cash, Phillip; McNeilly, Alan S.; Evans, Neil P.; Cotinot, Corinne; Sharpe, Richard M.; Rhind, Stewart M.

2008-01-01

Epidemiological studies of the impact of environmental chemicals on reproductive health demonstrate consequences of exposure but establishing causative links requires animal models using ‘real life’ in utero exposures. We aimed to determine whether prolonged, low-dose, exposure of pregnant sheep to a mixture of environmental chemicals affects fetal ovarian development. Exposure of treated ewes (n = 7) to pollutants was maximized by surface application of processed sewage sludge to pasture. Control ewes (n = 10) were reared on pasture treated with inorganic fertilizer. Ovaries and blood were collected from fetuses (n = 15 control and n = 8 treated) on Day 110 of gestation for investigation of fetal endocrinology, ovarian follicle/oocyte numbers and ovarian proteome. Treated fetuses were 14% lighter than controls but fetal ovary weights were unchanged. Prolactin (48% lower) was the only measured hormone significantly affected by treatment. Treatment reduced numbers of growth differentiation factor (GDF9) and induced myeloid leukaemia cell differentiation protein (MCL1) positive oocytes by 25–26% and increased pro-apoptotic BAX by 65% and 42% of protein spots in the treated ovarian proteome were differently expressed compared with controls. Nineteen spots were identified and included proteins involved in gene expression/transcription, protein synthesis, phosphorylation and receptor activity. Fetal exposure to environmental chemicals, via the mother, significantly perturbs fetal ovarian development. If such effects are replicated in humans, premature menopause could be an outcome. PMID:18436539

Noise exposure of immature rats can induce different age-dependent extra-auditory alterations that can be partially restored by rearing animals in an enriched environment.

PubMed

Molina, S J; Capani, F; Guelman, L R

2016-04-01

It has been previously shown that different extra-auditory alterations can be induced in animals exposed to noise at 15 days. However, data regarding exposure of younger animals, that do not have a functional auditory system, have not been obtained yet. Besides, the possibility to find a helpful strategy to restore these changes has not been explored so far. Therefore, the aims of the present work were to test age-related differences in diverse hippocampal-dependent behavioral measurements that might be affected in noise-exposed rats, as well as to evaluate the effectiveness of a potential neuroprotective strategy, the enriched environment (EE), on noise-induced behavioral alterations. Male Wistar rats of 7 and 15 days were exposed to moderate levels of noise for two hours. At weaning, animals were separated and reared either in standard or in EE cages for one week. At 28 days of age, different hippocampal-dependent behavioral assessments were performed. Results show that rats exposed to noise at 7 and 15 days were differentially affected. Moreover, EE was effective in restoring all altered variables when animals were exposed at 7 days, while a few were restored in rats exposed at 15 days. The present findings suggest that noise exposure was capable to trigger significant hippocampal-related behavioral alterations that were differentially affected, depending on the age of exposure. In addition, it could be proposed that hearing structures did not seem to be necessarily involved in the generation of noise-induced hippocampal-related behaviors, as they were observed even in animals with an immature auditory pathway. Finally, it could be hypothesized that the differential restoration achieved by EE rearing might also depend on the degree of maturation at the time of exposure and the variable evaluated, being younger animals more susceptible to environmental manipulations. Copyright © 2016 Elsevier B.V. All rights reserved.

Developmental effects of tobacco smoke exposure during human embryonic stem cell differentiation are mediated through the transforming growth factor-β superfamily member, Nodal

PubMed Central

Liszewski, Walter; Ritner, Carissa; Aurigui, Julian; Wong, Sharon S. Y.; Hussain, Naveed; Krueger, Winfried; Oncken, Cheryl; Bernstein, Harold S.

2012-01-01

While the pathologies associated with in utero smoke exposure are well established, their underlying molecular mechanisms are incompletely understood. We differentiated human embryonic stem cells in the presence of physiological concentrations of tobacco smoke and nicotine. Using post hoc microarray analysis, quantitative PCR, and immunoblot analysis, we demonstrated that tobacco smoke has lineage- and stage-specific effects on human embryonic stem cell differentiation, through both nicotine-dependent and -independent pathways. We show that three major stem cell pluripotency/differentiation pathways, Notch, canonical Wnt, and transforming growth factor-β, are affected by smoke exposure, and that Nodal signaling through SMAD2 is specifically impacted by effects on Lefty1, Nodal, and FoxH1. These events are associated with upregulation of microRNA-302a, a post-transcriptional silencer of Lefty1. The described studies provide insight into the mechanisms by which tobacco smoke influences fetal development at the cellular level, and identify specific transcriptional, post-transcriptional, and signaling pathways by which this likely occurs. PMID:22381624

Bisphenol A Exposure Disrupts Genomic Imprinting in the Mouse

PubMed Central

Susiarjo, Martha; Sasson, Isaac; Mesaros, Clementina; Bartolomei, Marisa S.

2013-01-01

Exposure to endocrine disruptors is associated with developmental defects. One compound of concern, to which humans are widely exposed, is bisphenol A (BPA). In model organisms, BPA exposure is linked to metabolic disorders, infertility, cancer, and behavior anomalies. Recently, BPA exposure has been linked to DNA methylation changes, indicating that epigenetic mechanisms may be relevant. We investigated effects of exposure on genomic imprinting in the mouse as imprinted genes are regulated by differential DNA methylation and aberrant imprinting disrupts fetal, placental, and postnatal development. Through allele-specific and quantitative real-time PCR analysis, we demonstrated that maternal BPA exposure during late stages of oocyte development and early stages of embryonic development significantly disrupted imprinted gene expression in embryonic day (E) 9.5 and 12.5 embryos and placentas. The affected genes included Snrpn, Ube3a, Igf2, Kcnq1ot1, Cdkn1c, and Ascl2; mutations and aberrant regulation of these genes are associated with imprinting disorders in humans. Furthermore, the majority of affected genes were expressed abnormally in the placenta. DNA methylation studies showed that BPA exposure significantly altered the methylation levels of differentially methylated regions (DMRs) including the Snrpn imprinting control region (ICR) and Igf2 DMR1. Moreover, exposure significantly reduced genome-wide methylation levels in the placenta, but not the embryo. Histological and immunohistochemical examinations revealed that these epigenetic defects were associated with abnormal placental development. In contrast to this early exposure paradigm, exposure outside of the epigenetic reprogramming window did not cause significant imprinting perturbations. Our data suggest that early exposure to common environmental compounds has the potential to disrupt fetal and postnatal health through epigenetic changes in the embryo and abnormal development of the placenta. PMID:23593014

Methylmercury exposure causes a persistent inhibition of myogenin expression and C2C12 myoblast differentiation.

PubMed

Prince, Lisa M; Rand, Matthew D

2018-01-15

Methylmercury (MeHg) is a ubiquitous environmental toxicant, best known for its selective targeting of the developing nervous system. MeHg exposure has been shown to cause motor deficits such as impaired gait and coordination, muscle weakness, and muscle atrophy, which have been associated with disruption of motor neurons. However, recent studies have suggested that muscle may also be a target of MeHg toxicity, both in the context of developmental myogenic events and of low-level chronic exposures affecting muscle wasting in aging. We therefore investigated the effects of MeHg on myotube formation, using the C2C12 mouse myoblast model. We found that MeHg inhibits both differentiation and fusion, in a concentration-dependent manner. Furthermore, MeHg specifically and persistently inhibits myogenin (MyoG), a transcription factor involved in myocyte differentiation, within the first six hours of exposure. MeHg-induced reduction in MyoG expression is contemporaneous with a reduction of a number of factors involved in mitochondrial biogenesis and mtDNA transcription and translation, which may implicate a role for mitochondria in mediating MeHg-induced change in the differentiation program. Unexpectedly, inhibition of myoblast differentiation with MeHg parallels inhibition of Notch receptor signaling. Our research establishes muscle cell differentiation as a target for MeHg toxicity, which may contribute to the underlying etiology of motor deficits with MeHg toxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

Excess Imidacloprid Exposure Causes the Heart Tube Malformation of Chick Embryos.

PubMed

Gao, Lin-Rui; Li, Shuai; Zhang, Jing; Liang, Chang; Chen, En-Ni; Zhang, Shi-Yao; Chuai, Manli; Bao, Yong-Ping; Wang, Guang; Yang, Xuesong

2016-11-30

As a neonicotinoid pesticide, imidacloprid is widely used to control sucking insects on agricultural planting and fleas on domestic animals. However, the extent to which imidacloprid exposure has an influence on cardiogensis in early embryogenesis is still poorly understood. In vertebrates, the heart is the first organ to be formed. In this study, to address whether imidacloprid exposure affects early heart development, the early chick embryo has been used as an experimental model because of its accessibility at its early developmental stage. The results demonstrate that exposure of the early chick embryo to imidacloprid caused malformation of heart tube. Furthermore, the data reveal that down-regulation of GATA4, NKX2.5, and BMP4 and up-regulation of Wnt3a led to aberrant cardiomyocyte differentiation. In addition, imidacloprid exposure interfered with basement membrane breakdown, E-cadherin/laminin expression, and mesoderm formation during the epithelial-mesenchymal transition (EMT) in gastrula chick embryos. Finally, the DiI-labeled cell migration trajectory indicated that imidacloprid restricted the cell migration of cardiac progenitors to primary heart field in gastrula chick embryos. A similar observation was also obtained from the cell migration assay of scratch wounds in vitro. Additionally, imidacloprid exposure negatively affected the cytoskeleton structure and expression of corresponding adhesion molecules. Taken together, these results reveal that the improper EMT, cardiac progenitor migration, and differentiation are responsible for imidacloprid exposure-induced malformation of heart tube during chick embryo development.

In utero exposure to dietheylhexyl phthalate differentially affects fetal testosterone and insl3 levels in the testes of male Sprague Dawley and Wistar rats: A dose response study

EPA Science Inventory

We previously reported that 750 mg/kg/day of diethylhexyl phthalate (DEHP) administered in utero during the period of sex differentiation resulted in a higher prevalence of gubernacular lesions in male Wistar offspring than in the male Sprague Dawley (SD) rat offspring, whereas D...

Radiation-induced gene expression in the nematode Caenorhabditis elegans

NASA Technical Reports Server (NTRS)

Nelson, Gregory A.; Jones, Tamako A.; Chesnut, Aaron; Smith, Anna L.

2002-01-01

We used the nematode C. elegans to characterize the genotoxic and cytotoxic effects of ionizing radiation in a simple animal model emphasizing the unique effects of charged particle radiation. Here we demonstrate by RT-PCR differential display and whole genome microarray hybridization experiments that gamma rays, accelerated protons and iron ions at the same physical dose lead to unique transcription profiles. 599 of 17871 genes analyzed (3.4%) showed differential expression 3 hrs after exposure to 3 Gy of radiation. 193 were up-regulated, 406 were down-regulated and 90% were affected only by a single species of radiation. A novel statistical clustering technique identified the regulatory relationships between the radiation-modulated genes and showed that genes affected by each radiation species were associated with unique regulatory clusters. This suggests that independent homeostatic mechanisms are activated in response to radiation exposure as a function of track structure or ionization density.

Sex-Dependent Effects of Developmental Lead Exposure on the Brain.

PubMed

Singh, Garima; Singh, Vikrant; Sobolewski, Marissa; Cory-Slechta, Deborah A; Schneider, Jay S

2018-01-01

The role of sex as an effect modifier of developmental lead (Pb) exposure has until recently received little attention. Lead exposure in early life can affect brain development with persisting influences on cognitive and behavioral functioning, as well as, elevated risks for developing a variety of diseases and disorders in later life. Although both sexes are affected by Pb exposure, the incidence, manifestation, and severity of outcomes appears to differ in males and females. Results from epidemiologic and animal studies indicate significant effect modification by sex, however, the results are not consistent across studies. Unfortunately, only a limited number of human epidemiological studies have included both sexes in independent outcome analyses limiting our ability to draw definitive conclusions regarding sex-differentiated outcomes. Additionally, due to various methodological differences across studies, there is still not a good mechanistic understanding of the molecular effects of lead on the brain and the factors that influence differential responses to Pb based on sex. In this review, focused on prenatal and postnatal Pb exposures in humans and animal models, we discuss current literature supporting sex differences in outcomes in response to Pb exposure and explore some of the ideas regarding potential molecular mechanisms that may contribute to sex-related differences in outcomes from developmental Pb exposure. The sex-dependent variability in outcomes from developmental Pb exposure may arise from a combination of complex factors, including, but not limited to, intrinsic sex-specific molecular/genetic mechanisms and external risk factors including sex-specific responses to environmental stressors which may act through shared epigenetic pathways to influence the genome and behavioral output.

Sex-Dependent Effects of Developmental Lead Exposure on the Brain

PubMed Central

Singh, Garima; Singh, Vikrant; Sobolewski, Marissa; Cory-Slechta, Deborah A.; Schneider, Jay S.

2018-01-01

The role of sex as an effect modifier of developmental lead (Pb) exposure has until recently received little attention. Lead exposure in early life can affect brain development with persisting influences on cognitive and behavioral functioning, as well as, elevated risks for developing a variety of diseases and disorders in later life. Although both sexes are affected by Pb exposure, the incidence, manifestation, and severity of outcomes appears to differ in males and females. Results from epidemiologic and animal studies indicate significant effect modification by sex, however, the results are not consistent across studies. Unfortunately, only a limited number of human epidemiological studies have included both sexes in independent outcome analyses limiting our ability to draw definitive conclusions regarding sex-differentiated outcomes. Additionally, due to various methodological differences across studies, there is still not a good mechanistic understanding of the molecular effects of lead on the brain and the factors that influence differential responses to Pb based on sex. In this review, focused on prenatal and postnatal Pb exposures in humans and animal models, we discuss current literature supporting sex differences in outcomes in response to Pb exposure and explore some of the ideas regarding potential molecular mechanisms that may contribute to sex-related differences in outcomes from developmental Pb exposure. The sex-dependent variability in outcomes from developmental Pb exposure may arise from a combination of complex factors, including, but not limited to, intrinsic sex-specific molecular/genetic mechanisms and external risk factors including sex-specific responses to environmental stressors which may act through shared epigenetic pathways to influence the genome and behavioral output. PMID:29662502

Beetle Exoskeleton May Facilitate Body Heat Acting Differentially across the Electromagnetic Spectrum.

PubMed

Carrascal, Luis M; Ruiz, Yolanda Jiménez; Lobo, Jorge M

Exoskeletons of beetles and their associated morphological characteristics can serve many different functions, including thermoregulation. We study the thermal role of the exoskeleton in 13 Geotrupidae dung beetle species using heating experiments under controlled conditions. The main purpose was to measure the influence of heating sources (solar radiance vs. infrared), animal position (dorsal exposure vs. ventral exposure), species identity, and phylogenetic relationships on internal asymptotic temperatures and heating rates. The thermal response was significantly influenced by phylogenetic relatedness, although it was not affected by the apterous condition. The asymptotic internal temperature of specimens was not affected by the thoracic volume but was significantly higher under simulated sunlight conditions than under infrared radiation and when exposed dorsally as opposed to ventrally. There was thus a significant interaction between heating source and body position. Heating rate was negatively and significantly influenced by thoracic volume, and, although insignificantly slower under simulated sunlight, it was significantly affected by body position, being faster under dorsal exposure. The results constitute the first evidence supporting the hypothesis that the beetle exoskeleton acts differentially across the electromagnetic spectrum determining internal body temperatures. This interesting finding suggests the existence of a kind of passive physiology imposed by the exoskeleton and body size, where interspecific relationships play a minor role.

Pollution and Infant Health.

PubMed

Currie, Janet

2013-12-01

In this article, I review recent research showing that even relatively low levels of pollution can affect infants' health. This research attempts to go beyond documenting correlations by using sharp changes in pollution levels, carefully selecting control groups (including unexposed siblings as controls for exposed children), and considering behavioral responses to pollution such as maternal mobility. Poor and minority children are more likely to be affected and differential exposure could be responsible for some of the observed group-level differences in health at birth. Policymakers concerned about the roots of inequality should consider the role played by environmental exposures of pregnant mothers.

Effects of Violent-Video-Game Exposure on Aggressive Behavior, Aggressive-Thought Accessibility, and Aggressive Affect Among Adults With and Without Autism Spectrum Disorder.

PubMed

Engelhardt, Christopher R; Mazurek, Micah O; Hilgard, Joseph; Rouder, Jeffrey N; Bartholow, Bruce D

2015-08-01

Recent mass shootings have prompted the idea among some members of the public that exposure to violent video games can have a pronounced effect on individuals with autism spectrum disorder (ASD). Empirical evidence for or against this claim has been missing, however. To address this issue, we assigned adults with and without ASD to play a violent or nonviolent version of a customized first-person shooter video game. After they played the game, we assessed three aggression-related outcome variables (aggressive behavior, aggressive-thought accessibility, and aggressive affect). Results showed strong evidence that adults with ASD, compared with typically developing adults, are not differentially affected by acute exposure to violent video games. Moreover, model comparisons provided modest evidence against any effect of violent game content whatsoever. Findings from this experiment suggest that societal concerns that exposure to violent games may have a unique effect on adults with autism are not supported by evidence. © The Author(s) 2015.

What Works in Gifted Education Mathematics Study: Impact of Pre-Differentiated and Enriched Curricula on General Education Teachers and Their Students. Research Monograph Series. RM13242

ERIC Educational Resources Information Center

Gubbins, E. Jean; McCoach, D. Betsy; Foreman, Jennifer L.; Gilson, Cindy M.; Bruce-Davis, Micah N.; Rubenstein, Lisa DaVia; Savino, Jennifer; Rambo, Karen; Waterman, Craig

2013-01-01

The present study seeks to determine how exposure to pre-differentiated and enriched curricula incorporating educative curriculum materials affects students' achievement as well as teacher and administrator responses to the intervention. A 2-year multi-site cluster randomized control trial study recruited a national sample of 4,530 grade 3…

Low-dose/dose-rate γ radiation depresses neural differentiation and alters protein expression profiles in neuroblastoma SH-SY5Y cells and C17.2 neural stem cells.

PubMed

Bajinskis, Ainars; Lindegren, Heléne; Johansson, Lotta; Harms-Ringdahl, Mats; Forsby, Anna

2011-02-01

The effects of low doses of ionizing radiation on cellular development in the nervous system are presently unclear. The focus of the present study was to examine low-dose γ-radiation-induced effects on the differentiation of neuronal cells and on the development of neural stem cells to glial cells. Human neuroblastoma SH-SY5Y cells were exposed to (137)Cs γ rays at different stages of retinoic acid-induced neuronal differentiation, and neurite formation was determined 6 days after exposure. When SH-SY5Y cells were exposed to low-dose-rate γ rays at the onset of differentiation, the number of neurites formed per cell was significantly less after exposure to either 10, 30 or 100 mGy compared to control cells. Exposure to 10 and 30 mGy attenuated differentiation of immature C17.2 mouse-derived neural stem cells to glial cells, as verified by the diminished expression of glial fibrillary acidic protein. Proteomic analysis of the neuroblastoma cells by 2D-PAGE after 30 mGy irradiation showed that proteins involved in neuronal development were downregulated. Proteins involved in cell cycle and proliferation were altered in both cell lines after exposure to 30 mGy; however, the rate of cell proliferation was not affected in the low-dose range. The radiation-induced attenuation of differentiation and the persistent changes in protein expression is indicative of an epigenetic rather than a cytotoxic mechanism.

High salt-induced excess reactive oxygen species production resulted in heart tube malformation during gastrulation.

PubMed

Gao, Lin-Rui; Wang, Guang; Zhang, Jing; Li, Shuai; Chuai, Manli; Bao, Yongping; Hocher, Berthold; Yang, Xuesong

2018-09-01

An association has been proved between high salt consumption and cardiovascular mortality. In vertebrates, the heart is the first functional organ to be formed. However, it is not clear whether high-salt exposure has an adverse impact on cardiogenesis. Here we report high-salt exposure inhibited basement membrane breakdown by affecting RhoA, thus disturbing the expression of Slug/E-cadherin/N-cadherin/Laminin and interfering with mesoderm formation during the epithelial-mesenchymal transition(EMT). Furthermore, the DiI + cell migration trajectory in vivo and scratch wound assays in vitro indicated that high-salt exposure restricted cell migration of cardiac progenitors, which was caused by the weaker cytoskeleton structure and unaltered corresponding adhesion junctions at HH7. Besides, down-regulation of GATA4/5/6, Nkx2.5, TBX5, and Mef2c and up-regulation of Wnt3a/β-catenin caused aberrant cardiomyocyte differentiation at HH7 and HH10. High-salt exposure also inhibited cell proliferation and promoted apoptosis. Most importantly, our study revealed that excessive reactive oxygen species(ROS)generated by high salt disturbed the expression of cardiac-related genes, detrimentally affecting the above process including EMT, cell migration, differentiation, cell proliferation and apoptosis, which is the major cause of malformation of heart tubes. © 2018 Wiley Periodicals, Inc.

Differential gene expression induced by exposure of captive mink to fuel oil: A model for the sea otter

USGS Publications Warehouse

Bowen, Lizabeth; Riva, F.; Mohr, C.; Aldridge, B.; Schwartz, J.; Miles, A. Keith; Stott, J.L.

2007-01-01

Free-ranging sea otters are subject to hydrocarbon exposure from a variety of sources, both natural and anthropogenic. Effects of direct exposure to unrefined crude oil, such as that associated with the Exxon Valdez oil spill, are readily apparent. However, the impact of subtle but pathophysiologically relevant concentrations of crude oil on sea otters is difficult to assess. The present study was directed at developing a model for assessing the impact of low concentrations of fuel oil on sea otters. Quantitative PCR was used to identify differential gene expression in American mink that were exposed to low concentrations of bunker C fuel oil. A total of 23 genes, representing 10 different physiological systems, were analyzed for perturbation. Six genes with immunological relevance were differentially expressed in oil-fed mink. Interleukin-18 (IL-18), IL-10, inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and complement cytolysis inhibitor (CLI) were down-regulated while IL-2 was up-regulated. Expression of two additional genes was affected; heat shock protein 70 (HSP70) was up-regulated and thyroid hormone receptor (THR) was down-regulated. While the significance of each perturbation is not immediately evident, we identified differential expression of genes that would be consistent with the presence of immune system-modifying and endocrine-disrupting compounds in fuel oil. Application of this approach to identify effects of petroleum contamination on sea otters should be possible following expansion of this mink model to identify a greater number of affected genes in peripheral blood leukocytes.

Fasciola gigantica: cercarial shedding pattern from Lymnaea natalensis after long-term exposure to cadmium at different temperatures.

PubMed

Soliman, Maha F M

2009-04-01

Little is known about the response of Fasciola spp., inside its snail host to pollutant toxicity. The effect of long-term exposure of Lymnaea natalensis to 0.1 microg/l, 10 microg/l, or 100 microg/l cadmium (Cd) on the infection rates with F. gigantica, percentage of cercariae-shedding snails and cercariae shedding pattern was investigated. The snails were exposed to Cd for 7 days either pre-infection with single Fasciola miracidium or during the late pre-patent period of the infection. The possible interaction between metal exposure and acclimatization temperature was also studied in three ranges; 16-18 degrees C, 23-25 degrees C and 30-32 degrees C. Results clearly showed that host exposure to 100 microg/l Cd significantly affected the pattern of Fasciola development inside its snail host, and that the acclimatization temperature was a key factor affecting the role played by Cd. Pre-infection exposure to Cd caused a significant reduction in the infection rates where the effect was temperature-dependent. Post-infection exposure to Cd significantly increased the percentage of cercariae-shedding snails; the effect was temperature-independent. Interestingly, post-infection exposure significantly altered the differential cercarial output pattern, while no clear impact on the total was found. The alteration in the differential cercarial output was represented as a significantly higher proportion of floating metacercaria as compared to fixed ones and also higher proportion of dead cercariae which may directly reduce the transmission of Fasciola to the final host. The mechanisms of cadmium impact are briefly discussed.

Comparative cardiopulmonary effects of size-fractionated airborne particulate matter.

PubMed

Amatullah, Hajera; North, Michelle L; Akhtar, Umme S; Rastogi, Neeraj; Urch, Bruce; Silverman, Frances S; Chow, Chung-Wai; Evans, Greg J; Scott, Jeremy A

2012-02-01

Strong epidemiological evidence exists linking particulate matter (PM) exposures with hospital admissions of individuals for cardiopulmonary symptoms. The PM size is important in influencing the extent of infiltration into the respiratory tract and systemic circulation and directs the differential physiological impacts. To investigate the differential effects of the quasi-ultrafine (PM(0.2)), fine (PM(0.15-2.5)), and coarse PM (PM(2.5-10)) size fractions on pulmonary and cardiac function. Female BALB/c mice were exposed to HEPA-filtered laboratory air or concentrated coarse, fine, or quasi-ultrafine PM using Harvard Ambient Particle Concentrators in conjunction with our nose-only exposure system. These exposures were conducted as part of the "Health Effects of Aerosols in Toronto (HEAT)" campaign. Following a 4 h exposure, mice underwent assessment of respiratory function and recording of electrocardiograms using the flexiVent® system. Exposure to coarse and fine PM resulted in a significant reduction in quasistatic compliance of the lung. Baseline total respiratory resistance and maximum responsiveness to methacholine were augmented after coarse PM exposures but were not affected by quasi-ultrafine PM exposures. In contrast, quasi-ultrafine PM alone had a significant effect on heart rate and in reducing heart rate variability. These findings indicate that coarse and fine PM influence lung function and airways responsiveness, while ultrafine PM can perturb cardiac function. This study supports the hypothesis that coarse and fine PM exerts its predominant physiologic effects at the site of deposition in the airways, whereas ultrafine PM likely crosses the alveolar epithelial barrier into the systemic circulation to affect cardiovascular function.

Quantifying Exposure and Risk Disproportionality in Environmental Justice Populations

EPA Science Inventory

Disproportionate risk suggests a predisposition within an individual or population to be either differentially exposed or affected by a given stressor or combination of stressors, which are especially prevalent in Environmental Justice (EJ) communities. Research gaps remain in ac...

Identification of Differential Gene Expression Patterns after Acute Exposure to High and Low Doses of Low-LET Ionizing Radiation in a Reconstituted Human Skin Tissue

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tilton, Susan C.; Markillie, Lye Meng; Hays, Spencer

Our goal here was to identify dose and temporal dependent radiation responses in a complex tissue, reconstituted human skin. Direct sequencing of RNA (RNA-seq) was used to quantify altered transcripts following exposure to 0.1, 2 and 10 Gy of ionizing radiation at 3 and 8 hours. These doses include a low dose in the range of some medical diagnostic procedures (0.1 Gy), a dose typically received during radiotherapy (2.0 Gy) and a lethal dose (10 Gy). These doses could be received after an intentional or accidental radiation exposure and biomarkers are needed to rapidly and accurately triage exposed individuals. Amore » total of 1701 genes were deemed to be significantly affected by high dose radiation exposure with the majority of genes affected at 10 Gy. A group of 29 genes including GDF15, BBC3, PPM1D, FDXR, GADD45A, MDM2, CDKN1A, TP53INP1, CYCSP27, SESN1, SESN2, PCNA, and AEN were similarly altered at both 2 and 10 Gy, but not 0.1 Gy, at multiple time points. A much larger group of up regulated genes, including those involved in inflammatory responses, was significantly altered only after a 10 Gy exposure. At high doses, down regulated genes were associated with cell cycle regulation and exhibited an apparent linear response between 2 and 10 Gy. While only a handful of genes were significantly affected by 0.1 Gy exposure using stringent statistical filters, groups of related genes regulating cell cycle progression and inflammatory responses consistently exhibited opposite trends in their regulation compared to the high dose exposures. Differential regulation of PLK1 signaling at low and high doses was confirmed using qRT-PCR. These results indicate that some alterations in gene expression are qualitatively different at low and high doses of radiation in this model system.« less

Cigarette smoke differentially affects IL-13-induced gene expression in human airway epithelial cells.

PubMed

Mertens, Tinne C J; van der Does, Anne M; Kistemaker, Loes E; Ninaber, Dennis K; Taube, Christian; Hiemstra, Pieter S

2017-07-01

Allergic airways inflammation in asthma is characterized by an airway epithelial gene signature composed of POSTN , CLCA1 , and SERPINB2 This Th2 gene signature is proposed as a tool to classify patients with asthma into Th2-high and Th2-low phenotypes. However, many asthmatics smoke and the effects of cigarette smoke exposure on the epithelial Th2 gene signature are largely unknown. Therefore, we investigated the combined effect of IL-13 and whole cigarette smoke (CS) on the Th2 gene signature and the mucin-related genes MUC5AC and SPDEF in air-liquid interface differentiated human bronchial (ALI-PBEC) and tracheal epithelial cells (ALI-PTEC). Cultures were exposed to IL-13 for 14 days followed by 5 days of IL-13 with CS exposure. Alternatively, cultures were exposed once daily to CS for 14 days, followed by 5 days CS with IL-13. POSTN , SERPINB2 , and CLCA1 expression were measured 24 h after the last exposure to CS and IL-13. In both models POSTN , SERPINB2 , and CLCA1 expression were increased by IL-13. CS markedly affected the IL-13-induced Th2 gene signature as indicated by a reduced POSTN , CLCA1 , and MUC5AC expression in both models. In contrast, IL-13-induced SERPINB2 expression remained unaffected by CS, whereas SPDEF expression was additively increased. Importantly, cessation of CS exposure failed to restore IL-13-induced POSTN and CLCA1 expression. We show for the first time that CS differentially affects the IL-13-induced gene signature for Th2-high asthma. These findings provide novel insights into the interaction between Th2 inflammation and cigarette smoke that is important for asthma pathogenesis and biomarker-guided therapy in asthma. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Predator odor exposure of rat pups has opposite effects on play by juvenile males and females

PubMed Central

Stockman, Sara L.; McCarthy, Margaret M.

2017-01-01

Juvenile social play behavior is one of the earliest sexually differentiated behaviors to emerge. In rats, as with most other species that play, males engage in more rough-and-tumble play compared to females. Exposure to early life adversity is a major driver of adult health and can manifest differently in males and females. However, the effects of adverse early life exposure on play behavior in the juvenile period are poorly understood. To address this, male and female neonatal rats were exposed to predator odor (PO), for 5 min/day on PN1-PN3. At the time of exposure to PO, both male and female pups suppressed ultrasonic vocalization and displayed more freezing behavior. Circulating corticosterone increased in males immediately following PO exposure but not in females. The enduring effects of PO exposure were opposite in males compared to females in that PO exposed males decreased social play, while PO exposed females increased play behavior compared to same sex controls. PO exposure did not significantly affect cell genesis in the neonatal dentate gyrus of either sex. PO exposure did not affect anxiety-like behavior assessed in the juvenile period or in adulthood, nor did it affect social interactions in adulthood. This work provides new insight into how sex may interact with adverse early life events to contribute to development of the social consequences of such exposures. PMID:27569603

An Evolutionary Perspective on Family Studies: Differential Susceptibility to Environmental Influences.

PubMed

Hartman, Sarah; Belsky, Jay

2016-12-01

An evolutionary perspective of human development provides the basis for the differential-susceptibility hypothesis which stipulates that individuals should differ in their susceptibility to environmental influences, with some being more affected than others by both positive and negative developmental experiences and environmental exposures. This paper reviews evidence consistent with this claim while revealing that temperamental and genetic characteristics play a role in distinguishing more and less susceptible individuals. The differential-susceptibility framework under consideration is contrasted to the traditional diathesis-stress view that "vulnerability" traits predispose some to being disproportionately affected by (only) adverse experiences. We raise several issues stimulated by the literature that need to be clarified in further research. Lastly, we suggest that therapy may differ in its effects depending on an individual's susceptibility. © 2015 Family Process Institute.

Effect of a 2.45-GHz radiofrequency electromagnetic field on neutrophil chemotaxis and phagocytosis in differentiated human HL-60 cells.

PubMed

Koyama, Shin; Narita, Eijiro; Suzuki, Yoshihisa; Taki, Masao; Shinohara, Naoki; Miyakoshi, Junji

2015-01-01

The potential public health risks of radiofrequency (RF) fields have been discussed at length, especially with the use of mobile phones spreading extensively throughout the world. In order to investigate the properties of RF fields, we examined the effect of 2.45-GHz RF fields at the specific absorption rate (SAR) of 2 and 10 W/kg for 4 and 24 h on neutrophil chemotaxis and phagocytosis in differentiated human HL-60 cells. Neutrophil chemotaxis was not affected by RF-field exposure, and subsequent phagocytosis was not affected either compared with that under sham exposure conditions. These studies demonstrated an initial immune response in the human body exposed to 2.45-GHz RF fields at the SAR of 2 W/kg, which is the maximum value recommended by the International Commission for Non-Ionizing Radiation Protection (ICNIRP) guidelines. The results of our experiments for RF-field exposure at an SAR under 10 W/kg showed very little or no effects on either chemotaxis or phagocytosis in neutrophil-like human HL-60 cells. © The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Differential effects of 5-HTTLPR genotypes on mood, memory, and attention bias following acute tryptophan depletion and stress exposure.

PubMed

Firk, Christine; Markus, C Rob

2009-05-01

Polymorphisms of the serotonin transporter gene (5-HTTLPR) may be associated with increased vulnerability to acute tryptophan depletion (ATD) and depression vulnerability especially following stressful life events. The aim of the present study was to investigate the effects of ATD in subjects with different 5-HTTLPR profiles before and after stress exposure on affective and cognitive-attentional changes. Eighteen subjects with homozygotic short alleles (S'/S') and 17 subjects with homozygotic long alleles (L'/L') of the 5-HTTLPR participated in a double-blind, placebo-controlled, crossover design to measure the effects of ATD on mood, memory, and attention before and after acute stress exposure. ATD lowered mood in all subjects independent of genotype. In S'/S' genotypes, mild acute stress increased depressive mood and in L'/L' genotypes increased feelings of vigor. Furthermore, S'/S' genotypes differed from L'/L' genotypes on measures of attention independent of treatment and memory following ATD. Polymorphisms of the 5-HTTLPR differentially affect responses to mild stress and ATD, suggesting greater vulnerability of S'/S' carriers to serotonergic manipulations and supporting increased depression vulnerability.

DNA methylation differentially regulates cytokine secretion in gingival epithelia in response to bacterial challenges.

PubMed

Drury, Jeanie L; Chung, Whasun Oh

2015-03-01

Epigenetic modifications are changes in gene expression without altering DNA sequence. We previously reported that bacteria-specific innate immune responses are regulated by epigenetic modifications. Our hypothesis is that DNA methylation affects gingival cytokine secretion in response to bacterial stimulation. Gingival epithelial cells (GECs) were treated with DNMT-1 inhibitors prior to Porphyromonas gingivalis (Pg) or Fusobacterium nucleatum (Fn) exposure. Protein secretion was assessed using ELISA. Gene expression was quantified using qRT-PCR. The ability of bacteria to invade inhibitor pretreated GECs was assessed utilizing flow cytometry. Changes were compared to unstimulated GECs. GEC upregulation of IL-6 and CXCL1 by Pg or Fn stimulation was significantly diminished by inhibitor pretreatment. Pg stimulated IL-1α secretion and inhibitor pretreatment significantly enhanced this upregulation, while Fn alone or with inhibitor pretreatment had no effect on IL-1α expression. GEC upregulation of human beta-definsin-2 in response to Pg and Fn exposure was enhanced following the inhibitor pretreatment. GEC susceptibility to bacterial invasion was unaltered. These results suggest that DNA methylation differentially affects gingival cytokine secretion in response to Pg or Fn. Our data provide basis for better understanding of how epigenetic modifications, brought on by exposure to oral bacteria, will subsequently affect host susceptibility to oral diseases. © FEMS 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Methoprene and Temperature Effects on Caste Differentiation and Protein Composition in the Formosan Subterranean Termite, Coptotermes formosanus

PubMed Central

Tarver, Matthew R.; Florane, Christopher B.; Zhang, Dunhua; Grimm, Casey; Lax, Alan R.

2012-01-01

The utilization of multiple castes is a shared feature of social insects. In termites, multiple extrinsic factors have been shown to impact caste differentiation; for example, increased temperature has been shown to increase soldier production. Also, application of exogenous methoprene has also been demonstrated to increase soldier production. The objective of this investigation was to examine and correlate the effects of temperature variation and methoprene treatments on termite caste differentiation, and identify the resulting changes in protein levels. Our results indicate that worker—to—soldier differentiation is modulated by temperature, where a greater number of soldiers developed at a higher rate at higher temperatures compared to lower temperatures. We analyzed total protein by sodium dodecyl sulfate Polyacrylamide gel electrophoresis and N-terminal sequencing and found several changes. Specifically, four proteins affected by temperature change were identified: Hexamerin-1, Hexamerin-2, Endo-beta 1,4 glucanase, and myosin. These proteins were further examined for their response to temperature, assay length (time), and exposure to the juvenile hormone analog methoprene. Hexamerin-1 protein showed a temperature—and assay length—dependent effect, while Hexamerin-2, Endo-beta 1, 4 glucanase, and myosin protein levels were all affected by temperature, assay length, and exposure to methoprene. Our analysis allows the correlation of temperature, assay length, and presence of methoprene with specific changes in protein levels that occur during caste differentiation. These results can be directly applied to better understand the complex developmental factors that control termite differentiation and guide the use of juvenile hormone analogs to maximize efficiency of termite eradication in the field. PMID:22943185

Sub-toxic concentrations of nano-ZnO and nano-TiO2 suppress neurite outgrowth in differentiated PC12 cells.

PubMed

Irie, Tomohiko; Kawakami, Tsuyoshi; Sato, Kaoru; Usami, Makoto

2017-01-01

Nanomaterials have been extensively used in our daily life, and may also induce health effects and toxicity. Nanomaterials can translocate from the outside to internal organs, including the brain. For example, both nano-ZnO and nano-TiO 2 translocate into the brain via the olfactory pathway in rodents, possibly leading to toxic effects on the brain. Although the effects of nano-ZnO and nano-TiO 2 on neuronal viability or neuronal excitability have been studied, no work has focused on how these nanomaterials affect neuronal differentiation and development. In this study, we investigated the effects of nano-ZnO and nano-TiO 2 on neurite outgrowth of PC12 cells, a useful model system for neuronal differentiation. Surprisingly, the number, length, and branching of differentiated PC12 neurites were significantly suppressed by the 7-day exposure to nano-ZnO (in the range of 1.0 × 10 -4 to 1.0 × 10 -1 µg/mL), at which the cell viability was not affected. The number and length were also significantly inhibited by the 7-day exposure to nano-TiO 2 (1.0 × 10 -3 to 1.0 µg/mL), which did not have cytotoxic effects. These results demonstrate that the neurite outgrowth in differentiated PC12 cells was suppressed by sub-cytotoxic concentrations of nano-ZnO or nano-TiO 2 .

Sex-based differences in gene expression in hippocampus following postnatal lead exposure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schneider, J.S., E-mail: jay.schneider@jefferson.edu; Anderson, D.W.; Sonnenahalli, H.

The influence of sex as an effect modifier of childhood lead poisoning has received little systematic attention. Considering the paucity of information available concerning the interactive effects of lead and sex on the brain, the current study examined the interactive effects of lead and sex on gene expression patterns in the hippocampus, a structure involved in learning and memory. Male or female rats were fed either 1500 ppm lead-containing chow or control chow for 30 days beginning at weaning.Blood lead levels were 26.7 {+-} 2.1 {mu}g/dl and 27.1 {+-} 1.7 {mu}g/dl for females and males, respectively. The expression of 175more » unique genes was differentially regulated between control male and female rats. A total of 167 unique genes were differentially expressed in response to lead in either males or females. Lead exposure had a significant effect without a significant difference between male and female responses in 77 of these genes. In another set of 71 genes, there were significant differences in male vs. female response. A third set of 30 genes was differentially expressed in opposite directions in males vs. females, with the majority of genes expressed at a lower level in females than in males. Highly differentially expressed genes in males and females following lead exposure were associated with diverse biological pathways and functions. These results show that a brief exposure to lead produced significant changes in expression of a variety of genes in the hippocampus and that the response of the brain to a given lead exposure may vary depending on sex. - Highlights: > Postnatal lead exposure has a significant effect on hippocampal gene expression patterns. > At least one set of genes was affected in opposite directions in males and females. > Differentially expressed genes were associated with diverse biological pathways.« less

Combined effect of pulsed electromagnetic field and sound wave on In vitro and In vivo neural differentiation of human mesenchymal stem cells.

PubMed

Choi, Yun-Kyong; Urnukhsaikhan, Enerelt; Yoon, Hee-Hoon; Seo, Young-Kwon; Cho, Hyunjin; Jeong, Jong-Seob; Kim, Soo-Chan; Park, Jung-Keug

2017-01-01

Biophysical wave stimulus has been used as an effective tool to promote cellular maturation and differentiation in the construction of engineered tissue. Pulsed electromagnetic fields (PEMFs) and sound waves have been selected as effective stimuli that can promote neural differentiation. The aim of this study was to investigate the synergistic effect of PEMFs and sound waves on the neural differentiation potential in vitro and in vivo using human bone marrow mesenchymal stem cells (hBM-MSCs). In vitro, neural-related genes in hBM-MSCs were accelerated by the combined exposure to both waves more than by individual exposure to PEMFs or sound waves. The combined wave also up-regulated the expression of neural and synaptic-related proteins in a three-dimensional (3-D) culture system through the phosphorylation of extracellular signal-related kinase. In a mouse model of photochemically induced ischemia, exposure to the combined wave reduced the infarction volume and improved post-injury behavioral activity. These results indicate that a combined stimulus of biophysical waves, PEMFs and sound can enhance and possibly affect the differentiation of MSCs into neural cells. Our study is meaningful for highlighting the potential of combined wave for neurogenic effects and providing new therapeutic approaches for neural cell therapy. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:201-211, 2017. © 2016 American Institute of Chemical Engineers.

High frequency electromagnetic fields (GSM signals) affect gene expression levels in tumor suppressor p53-deficient embryonic stem cells.

PubMed

Czyz, Jaroslaw; Guan, Kaomei; Zeng, Qinghua; Nikolova, Teodora; Meister, Armin; Schönborn, Frank; Schuderer, Jürgen; Kuster, Niels; Wobus, Anna M

2004-05-01

Effects of electromagnetic fields (EMF) simulating exposure to the Global System for Mobile Communications (GSM) signals were studied using pluripotent embryonic stem (ES) cells in vitro. Wild-type ES cells and ES cells deficient for the tumor suppressor p53 were exposed to pulse modulated EMF at 1.71 GHz, lower end of the uplink band of GSM 1800, under standardized and controlled conditions, and transcripts of regulatory genes were analyzed during in vitro differentiation. Two dominant GSM modulation schemes (GSM-217 and GSM-Talk), which generate temporal changes between GSM-Basic (active during talking phases) and GSM-DTX (active during listening phases thus simulating a typical conversation), were applied to the cells at and below the basic safety limits for local exposures as defined for the general public by the International Commission on Nonionizing Radiation Protection (ICNIRP). GSM-217 EMF induced a significant upregulation of mRNA levels of the heat shock protein, hsp70 of p53-deficient ES cells differentiating in vitro, paralleled by a low and transient increase of c-jun, c-myc, and p21 levels in p53-deficient, but not in wild-type cells. No responses were observed in either cell type after EMF exposure to GSM-Talk applied at similar slot-averaged specific absorption rates (SAR), but at lower time-averaged SAR values. Cardiac differentiation and cell cycle characteristics were not affected in embryonic stem and embryonic carcinoma cells after exposure to GSM-217 EMF signals. Our data indicate that the genetic background determines cellular responses to GSM modulated EMF. Bioelectromagnetics 25:296-307, 2004. Copyright 2004 Wiley-Liss, Inc.

Contaminant loading in remote Arctic lakes affects cellular stress-related proteins expression in feral charr.

USGS Publications Warehouse

Wiseman, Steve; Jorgensen, Even H.; Maule, Alec G.; Vijayan, Mathilakath M.

2011-01-01

The remote Arctic lakes on Bjornoya Island, Norway, offer a unique opportunity to study possible affect of lifelong contaminant exposure in wild populations of landlocked Arctic charr (Salvelinus alpinus). This is because Lake Ellasjoen has persistent organic pollutant (POP) levels that are significantly greater than in the nearby Lake Oyangen. We examined whether this differential contaminant loading was reflected in the expression of protein markers of exposure and effect in the native fish. We assessed the expressions of cellular stress markers, including cytochrome P4501A (Cyp1A), heat shock protein 70 (hsp70), and glucocorticoid receptor (GR) in feral charr from the two lakes. The average polychlorinated biphenyl (PCB) load in the charr liver from Ellasjoen was approximately 25-fold higher than in individuals from Oyangen. Liver Cyp1A protein expression was significantly higher in individuals from Ellasjoen compared with Oyangen, confirming differential PCB exposure. There was no significant difference in hsp70 protein expression in charr liver between the two lakes. However, brain hsp70 protein expression was significantly elevated in charr from Ellasjoen compared with Oyangen. Also, liver GR protein expression was significantly higher in the Ellasjoen charr compared with Oyangen charr. Taken together, our results suggest changes to cellular stress-related protein expression as a possible adaptation to chronic-contaminant exposure in feral charr in the Norwegian high-Arctic.

Predator odor exposure of rat pups has opposite effects on play by juvenile males and females.

PubMed

Stockman, Sara L; McCarthy, Margaret M

2017-01-01

Juvenile social play behavior is one of the earliest sexually differentiated behaviors to emerge. In rats, as with most other species that play, males engage in more rough-and-tumble play compared to females. Exposure to early life adversity is a major driver of adult health and can manifest differently in males and females. However, the effects of adverse early life exposure on play behavior in the juvenile period are poorly understood. To address this, male and female neonatal rats were exposed to predator odor (PO), for 5min/day on PN1-PN3. At the time of exposure to PO, both male and female pups suppressed ultrasonic vocalization and displayed more freezing behavior. Circulating corticosterone increased in males immediately following PO exposure but not in females. The enduring effects of PO exposure were opposite in males compared to females in that PO exposed males decreased social play, while PO exposed females increased play behavior compared to same sex controls. PO exposure did not significantly affect cell genesis in the neonatal dentate gyrus of either sex. PO exposure did not affect anxiety-like behavior assessed in the juvenile period or in adulthood, nor did it affect social interactions in adulthood. This work provides new insight into how sex may interact with adverse early life events to contribute to development of the social consequences of such exposures. Copyright © 2016 Elsevier Inc. All rights reserved.

Differential ultrasonic indices of separation distress in the presence and absence of maternal cues in infant rats bred for high and low positive social affect.

PubMed

Iacobucci, Paolo; Colonnello, Valentina; Fuchs, Thomas; D'Antuono, Laura; Panksepp, Jaak

2013-10-01

Preclinical models of human mood disorders commonly focus on the study of negative affectivity, without comparably stressing the role of positive affects and their ability to promote resilient coping styles. We evaluated the role of background constitutional affect of rats by studying the separation and reunion responses of infants from low and high positive affect genetic lines (i.e., differentially selected for High and Low 50 kHz ultrasonic vocalisations (USVs). Infants from Low and High 50 kHz USV breeding lines were isolated from mothers and exposed to either social (familiar or unfamiliar bedding) or neutral (clean bedding) odour cues between two short isolation periods, and tested in homeothermic and hypothermic ambient temperatures. Negative affect was estimated by monitoring separation distress calls (35-45 kHz USVs). Low Line pups called at higher rates than High Line, and their rates were stable regardless of odour cue. In contrast, High Line pups increased vocalisations during the second compared with the first isolation periods and during exposure to both familiar and unfamiliar odour cues, but not to neutral odour. Furthermore, the greatest increase in USV emission was seen in the second isolation period following exposure to the unfamiliar odour. However, both lines showed comparable elevated distress USVs to the thermal stressor. High Line animals, selected for a positive affective phenotype (50 kHz USVs), exhibited reduced separation anxiety responses in infancy, making this a promising animal model for the role of constitutional affective states in emotional responsivity and potential resilience against emotional disorders.

Effect of fetal or neonatal exposure to monobutyl phthalate (MBP) on testicular development and function in the marmoset

PubMed Central

McKinnell, Chris; Mitchell, Rod T.; Walker, Marion; Morris, Keith; Kelnar, Chris J.H.; Wallace, W. Hamish; Sharpe, Richard M.

2009-01-01

BACKGROUND Fetal exposure of male rats to some phthalates induces reproductive abnormalities, raising concerns for similar effects in humans. In order to address this in a more appropriate animal model, the aim of the present studies was to investigate the effect of fetal/neonatal exposure to monobutyl phthalate (MBP) in a non-human primate, the marmoset. In particular, to determine if exposure resulted in effects at birth, or in adulthood, similar to those in male rats, and whether there was evidence for induction of carcinoma-in-situ (CIS) or testicular germ cell tumours (TGCT). METHODS Pregnant female marmosets were dosed from ∼7–15 weeks gestation with 500 mg/kg/day MBP and male offspring studied at birth (1–5 days; n = 6) or in adulthood (n = 5). In another study, newborn males (n = 5 co-twins) were dosed with 500 mg/kg/day MBP for 14 days, commencing at ∼4 days of age. RESULTS Fetal exposure of marmosets to MBP did not affect gross testicular morphology, reproductive tract development or testosterone levels at birth, nor were germ cell number and proliferation, Sertoli cell number or germ:Sertoli cell ratio affected. In two of six MBP-exposed animals, unusual clusters of undifferentiated germ cells were found, but their significance is unclear. Neonatal MBP treatment did not affect germ cell numbers or differentiation. Fetal exposure to MBP did not affect testis size/morphology, germ cell numbers or fertility in adulthood. There was no evidence for CIS or TGCT. CONCLUSIONS Fetal exposure of marmosets to MBP does not measurably affect testis development/function or cause testicular dysgenesis, and no effects emerge by adulthood. Some effects on germ cell development were found, but these were inconsistent and of uncertain significance. PMID:19491204

BIOLOGIC EFFECTS OF INHALED DIESEL EXHAUST IN YOUNG AND OLD MICE: A PILOT PROJECT

EPA Science Inventory

The investigators hypothesis is that TNF-a production will be shown to be impaired in old animals exposed to diesel exhaust. The investigators extend  their hypothesis to suggest that exposure to diesel exhaust may differentially affect molecules involved in i...

Does differential growth affect the distribution and recovery of Listeria spp. in pasture-raised broiler farm soils?

USDA-ARS?s Scientific Manuscript database

Listeria spp. represent an important foodborne pathogen, but relatively little is known about its environmental prevalence on poultry farms. Considering the environmental exposure inherent with pasture-raised production systems, these types of alternative poultry management systems represent an idea...

Measures of Affect and Nicotine Dependence Predict Differential Response to Smoking Cessation Treatments.

ERIC Educational Resources Information Center

Zelman, Diane C.; And Others

1992-01-01

Randomly assigned smokers (n=126) to six-session smoking cessation treatments consisting of skills training or support counseling strategies and nicotine gum or rapid smoking nicotine exposure strategies. Counseling and nicotine strategies were completely crossed; all four combinations resulted in equivalent one-year abstinence rates. Treatments…

THE AORTA, BUT NOT LUNG OR HEART, IS THE TARGET OF SUBCHRONIC DIESEL-INDUCED INJURY AND INFLAMMATION

EPA Science Inventory

Recently cardiovascular abnormalities have been noted in individuals exposed to diesel exhaust (DE) or traffic generated air pollution; however, the mechanisms are unknown. We postulated that long-term episodic exposure of rats to DE would differentially affect three target orga...

The effect of obesity and repeated exposure on pharmacokinetic response to grape polyphenols in humans

USDA-ARS?s Scientific Manuscript database

Obesity is associated with lower circulating nutrients, though the reason is unclear. Since obesity may affect intestinal function, differential absorption may play a role. We investigated the pharmacokinetic response of polyphenols in obese/overweight and lean individuals from a dose of grape poly...

Domains of environmental quality are differentially associated with adverse birth outcomes by levels of urban-rural status

EPA Science Inventory

Human health is affected by exposures operating from multiple domains across level of urbanicity. To accommodate this, we constructed an environmental quality index(EQI) using data from five domains (air, water, land, built, sociodemographic) for each United States (U.S.) county;...

Whole and particle-free diesel exhausts differentially affect cardiac electrophysiology, blood pressure, and autonomic balance in heart failure-prone rats

EPA Science Inventory

Epidemiologic studies strongly link short-term exposures to vehicular traffic and particulate matter (PM) air pollution with adverse cardiovascular events, especially in those with preexisting cardiovascular disease. Diesel engine exhaust (DE) is a key contributor to urban ambien...

Spatiotemporally‐Resolved Air Exchange Rate as a Modifier of Acute Air Pollution‐Related Morbidity in AtlantaMorbidity in Atlanta

EPA Science Inventory

Epidemiological studies frequently use central site concentrations as surrogates of exposure to air pollutants. Variability in air pollutant infiltration due to differential air exchange rates (AERs) is potentially a major factor affecting the relationship between central site c...

Cellular Effects of Perfluorinated Fatty Acids (PFDA).

DTIC Science & Technology

This is a proposal to investigate the effects of perfluorinated decanoic acid ( PFDA ) on the cell surface of liver cells and tissue. The major method...summarized as follows: (a) differentiated liver tissue culture cells in vitro do have the membrane fluidity affected by PFDA whereas undifferentiated, non...d) the effect on mobility occurs within 24 hours of exposure without further increase with time of exposure; (e) scanning EM demonstrates no gross structural abnormality of the surface as a result of the non-toxic levels of PFDA .

Early life ethanol exposure causes long-lasting disturbances in rat mesenchymal stem cells via epigenetic modifications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leu, Yu-Wei; Chu, Pei-Yi; Chen, Chien-Min

Highlights: • Ethanol exposure alters proliferation and differentiation of MSCs. • Ethanol exposure suppresses osteogenesis and adipogenesis of MSCs. • H3K27me3-associated genes/pathways are affected in ethanol-exposed MSCs. • Expression of lineage-specific genes is dysregulated in ethanol-exposed MSCs. - Abstract: Fetal alcohol syndrome (FAS) is a birth defect due to maternal alcohol consumption during pregnancy. Because mesenchymal stem cells (MSCs) are the main somatic stem cells in adults and may contribute to tissue homeostasis and repair in adulthood, we investigated whether early life ethanol exposure affects MSCs and contributes to the propensity for disease onset in later life. Using a rodentmore » model of FAS, we found that ethanol exposure (5.25 g/kg/day) from postnatal days 4 to 9 in rat pups (mimic of human third trimester) caused long-term anomalies in bone marrow-derived MSCs. MSCs isolated from ethanol-exposed animals were prone to neural induction but resistant to osteogenic and adipogenic inductions compared to their age-matched controls. The altered differentiation may contribute to the severe trabecular bone loss seen in ethanol-exposed animals at 3 months of age as well as overt growth retardation. Expression of alkaline phosphatase, osteocalcin, aP2, and PPARγ were substantially inhibited, but BDNF was up-regulated in MSCs isolated from ethanol-exposed 3 month-old animals. Several signaling pathways were distorted in ethanol-exposed MSCs via altered trimethylation at histone 3 lysine 27. These results demonstrate that early life ethanol exposure can have long-term impacts in rat MSCs by both genetic and epigenetic mechanisms.« less

Perfluoroalkyl substances in human bone: concentrations in bones and effects on bone cell differentiation.

PubMed

Koskela, A; Koponen, J; Lehenkari, P; Viluksela, M; Korkalainen, M; Tuukkanen, J

2017-07-28

Perfluoroalkyl substances (PFAS), including two most commonly studied compounds perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), are widely distributed environmental pollutants, used extensively earlier. Due to their toxicological effects the use of PFAS is now regulated. Based on earlier studies on PFOA's distribution in bone and bone marrow in mice, we investigated PFAS levels and their possible link to bone microarchitecture of human femoral bone samples (n = 18). Soft tissue and bone biopsies were also taken from a 49-year old female cadaver for PFAS analyses. We also studied how PFOA exposure affects differentiation of human osteoblasts and osteoclasts. PFAS were detectable from all dry bone and bone marrow samples, PFOS and PFOA being the most prominent. In cadaver biopsies, lungs and liver contained the highest concentrations of PFAS, whereas PFAS were absent in bone marrow. Perfluorononanoic acid (PFNA) was present in the bones, PFOA and PFOS were absent. In vitro results showed no disturbance in osteogenic differentiation after PFOA exposure, but in osteoclasts, lower concentrations led to increased resorption, which eventually dropped to zero after increase in PFOA concentration. In conclusion, PFAS are present in bone and have the potential to affect human bone cells partly at environmentally relevant concentrations.

Toxic effects of prenatal exposure to alcohol, tobacco and other drugs.

PubMed

Scott-Goodwin, A C; Puerto, M; Moreno, I

2016-06-01

Tobacco, alcohol, cannabis and cocaine are the most consumed psychoactive drugs throughout the population. Prenatal exposure to these drugs could alter normal foetal development and could threaten future welfare. The main changes observed in prenatal exposure to tobacco are caused by nicotine and carbon monoxide, which can impede nutrient and oxygen exchange between mother and foetus, restricting foetal growth. Memory, learning processes, hearing and behaviour can also be affected. Alcohol may cause physical and cognitive alterations in prenatally exposed infants, fundamentally caused by altered NMDAR and GABAR activity. Tetrahydrocannabinol, the psychoactive compound of cannabis, is capable of activating CB1R, inducing connectivity deficits during the foetal brain development. This fact could be linked to behavioural and cognitive deficits. Many of the effects from prenatal cocaine exposure are caused by altered cell proliferation, migration, differentiation and dendritic growth processes. Cocaine causes long term behavioural and cognitive alterations and also affects the uteroplacental unit. Copyright © 2016 Elsevier Inc. All rights reserved.

Adulthood stress responses in rats are variably altered as a factor of adolescent stress exposure.

PubMed

Moore, Nicole L T; Altman, Daniel E; Gauchan, Sangeeta; Genovese, Raymond F

2016-05-01

Stress exposure during development may influence adulthood stress response severity. The present study investigates persisting effects of two adolescent stressors upon adulthood response to predator exposure (PE). Rats were exposed to underwater trauma (UWT) or PE during adolescence, then to PE after reaching adulthood. Rats were then exposed to predator odor (PO) to test responses to predator cues alone. Behavioral and neuroendocrine assessments were conducted to determine acute effects of each stress experience. Adolescent stress altered behavioral response to adulthood PE. Acoustic startle response was blunted. Bidirectional changes in plus maze exploration were revealed as a factor of adolescent stress type. Neuroendocrine response magnitude did not predict severity of adolescent or adult stress response, suggesting that different adolescent stress events may differentially alter developmental outcomes regardless of acute behavioral or neuroendocrine response. We report that exposure to two different stressors in adolescence may differentially affect stress response outcomes in adulthood. Acute response to an adolescent stressor may not be consistent across all stressors or all dependent measures, and may not predict alterations in developmental outcomes pertaining to adulthood stress exposure. Further studies are needed to characterize factors underlying long-term effects of a developmental stressor.

The Effects of Low-Dose Bisphenol A and Bisphenol F on Neural Differentiation of a Fetal Brain-Derived Neural Progenitor Cell Line.

PubMed

Fujiwara, Yuki; Miyazaki, Wataru; Koibuchi, Noriyuki; Katoh, Takahiko

2018-01-01

Environmental chemicals are known to disrupt the endocrine system in humans and to have adverse effects on several organs including the developing brain. Recent studies indicate that exposure to environmental chemicals during gestation can interfere with neuronal differentiation, subsequently affecting normal brain development in newborns. Xenoestrogen, bisphenol A (BPA), which is widely used in plastic products, is one such chemical. Adverse effects of exposure to BPA during pre- and postnatal periods include the disruption of brain function. However, the effect of BPA on neural differentiation remains unclear. In this study, we explored the effects of BPA or bisphenol F (BPF), an alternative compound for BPA, on neural differentiation using ReNcell, a human fetus-derived neural progenitor cell line. Maintenance in growth factor-free medium initiated the differentiation of ReNcell to neuronal cells including neurons, astrocytes, and oligodendrocytes. We exposed the cells to BPA or BPF for 3 days from the period of initiation and performed real-time PCR for neural markers such as β III-tubulin and glial fibrillary acidic protein (GFAP), and Olig2. The β III-tubulin mRNA level decreased in response to BPA, but not BPF, exposure. We also observed that the number of β III-tubulin-positive cells in the BPA-exposed group was less than that of the control group. On the other hand, there were no changes in the MAP2 mRNA level. These results indicate that BPA disrupts neural differentiation in human-derived neural progenitor cells, potentially disrupting brain development.

Proteomic changes during adult stage in pre-optic, hypothalamus, hippocampus and pituitary regions of female rat brain following neonatal exposure to estradiol-17β.

PubMed

Govindaraj, Vijayakumar; Shridharan, Radhika Nagamangalam; Rao, Addicam Jagannadha

2018-05-16

Although neonatal exposure to estrogen or estrogenic compounds results in irreversible changes in the brain function and reproductive abnormalities during adulthood but the underlying mechanisms are still largely unknown. The present study has attempted to compare the protein profiles of sexually dimorphic brain regions of adult female rats which were exposed to estradiol- 17β during neonatal period. The total proteins extracted from pre-optic area (POA), hypothalamus, hippocampus and pituitary of control and neonatally E2 treated female rats was subjected to 2D-SDS-PAGE and differentially expressed proteins were identified by MALDI TOF/TOF-MS. Our results revealed that a total of 21 protein spots which were identified as differentially expressed in all the four regions analyzed; the differential expression was further validated by RT-PCR and western blotting. The differentially expressed proteins such as 14-3-3 zeta/delta (POA), LMNA (hippocampus), Axin2 (hypothalamus), Syntaxin-7 (hippocampus), prolactin and somatotropin (pituitary) which have very important functions in the process of neuronal differentiation, migration, axon outgrowth, formation of dendritic spine density and synaptic plasticity and memory have not been previously reported in association with neonatal estrogen exposure. The affected brain functions are very important for the establishment of sex specific brain morphology and behavior. Our results suggest that the differentially expressed proteins may play an important role in irreversible changes in the brain function as well as reproductive abnormalities observed in the female rats during adulthood. Copyright © 2018 Elsevier Inc. All rights reserved.

THE INFLUENCE OF EXTRINSIC REINFORCEMENT ON CHILDREN WITH HEAVY PRENATAL ALCOHOL EXPOSURE

PubMed Central

Graham, Diana M.; Glass, Leila; Mattson, Sarah N.

2016-01-01

Background Prenatal alcohol exposure affects inhibitory control and other aspects of attention and executive function. However, the efficacy of extrinsic reinforcement on these behaviors has not been tested. Methods Alcohol-exposed children (AE; n=34), children with ADHD (ADHD; n=23), and controls (CON; n=31) completed a flanker task with four reward conditions (no reward, reward, reward+occasional response cost, equal probability of reward+response cost). Inhibitory control was tested in the no reward conditions using a 3(group) x 2(flanker type) ANCOVA. Response to reinforcement was tested using 3(group) x 4(reward condition) x 4(flanker type) ANCOVA. Response time (RT) and accuracy were tested independently. Results Groups did not differ on demographic variables. The flanker task was successful in taxing interference control, an aspect of executive attention (i.e., responses to incongruent stimuli were slower than to congruent stimuli) and the AE group demonstrated impaired executive control over the other groups. Overall, the AE group had significantly slower response times compared to the CON and ADHD groups, which did not differ. However, reinforcement improved RT in all groups. While occasional response cost had the greatest benefit in the CON group, the type of reinforcement did not differentially affect the AE and ADHD groups. Accuracy across reward conditions did not differ by group, but was dependent on flanker type and reward condition. Conclusions Alcohol-exposed children, but not children with ADHD, had impaired interference control in comparison to controls, supporting a differential neurobehavioral profile in these two groups. Both clinical groups were equally affected by introduction of reinforcement, although the type of reinforcement did not differentially affect performance as it did in the control group, suggesting that reward or response cost could be used interchangeably to result in the same benefit. PMID:26842253

Rearing Conditions Differentially Affect the Locomotor Behavior of Larval Zebrafish, but not their Response to Valproate-Induced Developmental Neurotoxicity

EPA Science Inventory

Zebrafish (Dania rerio) are widely used in developmental research, but little is known about the role environment may play in their development. Zebrafish are a highly social organism; thus exposure to or isolation from social environments may have profound effects. Details of re...

Rearing Conditions Differentially Affect the Locomotor Behavior of Larval Zebrafish, but not Their Response to Valproate-Induced Developmental Neurotoxicity*

EPA Science Inventory

Zebrafish (Danio rerio) are widely used in developmental research, but still not much is known about the role of the environment in their development. Zebrafish are a highly social organism; thus exposure to, or isolation from, social environments may have profound developmental ...

Location restrictions on smoking: assessing their differential impacts and consequences in the workplace.

PubMed

Bell, Kirsten; McCullough, Lucy; Devries, Karen; Jategaonkar, Natasha; Greaves, Lorraine; Richardson, Lindsay

2009-01-01

To analyze existing evidence on the impact of two types of location restrictions on smoking: workplace bans and bans in hospitality settings, and to assess the extent to which they differentially affect subpopulations. A review of international studies on location restrictions on smoking published between 1990-2007. Although workplace smoking bans reduce exposure to second-hand smoke (SHS) at work, their effects on overall cigarette consumption and smoking prevalence may be uneven across the population. Bans in hospitality settings reduce SHS exposure among workers, but have potentially uneven effects based on the interactions between gender, socio-economic status (SES) and ethnicity. The unintended consequences of smoking bans are also more likely to be experienced by low SES groups. Although location restrictions on smoking reduce SHS exposure and may serve to positively impact smoking behaviours, there is preliminary evidence that they may have a reduced impact on subpopulations such as low-income groups, although further research is needed.

Transcriptional response of mysid crustacean, Americamysis bahia, is affected by subchronic exposure to nonylphenol.

PubMed

Uchida, Masaya; Hirano, Masashi; Ishibashi, Hiroshi; Kobayashi, Jun; Kagami, Yoshihiro; Koyanagi, Akiko; Kusano, Teruhiko; Koga, Minoru; Arizono, Koji

2016-11-01

Nonylphenol (NP) has been classified as an endocrine-disrupting chemical. In this study, we conducted mysid DNA microarray analysis with which has 2240 oligo DNA probes to observe differential gene expressions in mysid crustacean (Americamysis bahia) exposed to 1, 3, 10 and 30 μg/l of NP for 14 days. As a result, we found 31, 27, 39 and 68 genes were differentially expressed in the respective concentrations. Among these genes, the expressions of five particular genes were regulated in a similar manner at all concentrations of the NP exposure. So, we focused on one gene encoding cuticle protein, and another encoding cuticular protein analogous to peritrophins 1-H precursor. These genes were down-regulated by NP exposure in a dose-dependent manner, and it suggested that they were related in a reduction of the number of molting in mysids. Thus, they might become useful molecular biomarker candidates to evaluate molting inhibition in mysids. Copyright © 2016 Elsevier Inc. All rights reserved.

Transgenerational Actions of Environmental Compounds on Reproductive Disease and Identification of Epigenetic Biomarkers of Ancestral Exposures

PubMed Central

Tracey, Rebecca; Haque, Md. M.; Skinner, Michael K.

2012-01-01

Environmental factors during fetal development can induce a permanent epigenetic change in the germ line (sperm) that then transmits epigenetic transgenerational inheritance of adult-onset disease in the absence of any subsequent exposure. The epigenetic transgenerational actions of various environmental compounds and relevant mixtures were investigated with the use of a pesticide mixture (permethrin and insect repellant DEET), a plastic mixture (bisphenol A and phthalates), dioxin (TCDD) and a hydrocarbon mixture (jet fuel, JP8). After transient exposure of F0 gestating female rats during the period of embryonic gonadal sex determination, the subsequent F1–F3 generations were obtained in the absence of any environmental exposure. The effects on the F1, F2 and F3 generations pubertal onset and gonadal function were assessed. The plastics, dioxin and jet fuel were found to promote early-onset female puberty transgenerationally (F3 generation). Spermatogenic cell apoptosis was affected transgenerationally. Ovarian primordial follicle pool size was significantly decreased with all treatments transgenerationally. Differential DNA methylation of the F3 generation sperm promoter epigenome was examined. Differential DNA methylation regions (DMR) were identified in the sperm of all exposure lineage males and found to be consistent within a specific exposure lineage, but different between the exposures. Several genomic features of the DMR, such as low density CpG content, were identified. Exposure-specific epigenetic biomarkers were identified that may allow for the assessment of ancestral environmental exposures associated with adult onset disease. PMID:22389676

Effect of poverty on the relationship between personal exposures and ambient concentrations of air pollutants in Ho Chi Minh City

NASA Astrophysics Data System (ADS)

Mehta, Sumi; Sbihi, Hind; Dinh, Tuan Nguyen; Xuan, Dan Vu; Le Thi Thanh, Loan; Thanh, Canh Truong; Le Truong, Giang; Cohen, Aaron; Brauer, Michael

2014-10-01

Socioeconomic factors often affect the distribution of exposure to air pollution. The relationships between health, air pollution, and poverty potentially have important public health and policy implications, especially in areas of Asia where air pollution levels are high and income disparity is large. The objective of the study was to characterize the levels, determinants of exposure, and relationships between children personal exposures and ambient concentrations of multiple air pollutants amongst different socioeconomic segments of the population of Ho Chi Minh City, Vietnam. Using repeated (N = 9) measures personal exposure monitoring and determinants of exposure modeling, we compared daily average PM2.5, PM10, PM2.5 absorbance and NO2 concentrations measured at ambient monitoring sites to measures of personal exposures for (N = 64) caregivers of young children from high and low socioeconomic groups in two districts (urban and peri-urban), across two seasons. Personal exposures for both PM sizes were significantly higher among the poor compared to non-poor participants in each district. Absolute levels of personal exposures were under-represented by ambient monitors with median individual longitudinal correlations between personal exposures and ambient concentrations of 0.4 for NO2, 0.6 for PM2.5 and PM10 and 0.7 for absorbance. Exposures of the non-poor were more highly correlated with ambient concentrations for both PM size fractions and absorbance while those for NO2 were not significantly affected by socioeconomic position. Determinants of exposure modeling indicated the importance of ventilation quality, time spent in the kitchen, air conditioner use and season as important determinant of exposure that are not fully captured by the differences in socioeconomic position. Our results underscore the need to evaluate how socioeconomic position affects exposure to air pollution. Here, differential exposure to major sources of pollution, further influenced by characteristics of Ho Chi Minh City's rapidly urbanizing landscape, resulted in systematically higher PM exposures among the poor.

Effect of low-level ozone fumigations on crown rust of oats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Heagle, A.S.

1970-02-01

Exposure of crown rust differential varieties of Avena spp. to 10 pphm ozone for 6 hr in the light for 10 days after infection with Puccinia coronata significantly reduced the growth of uredia. Urediospores produced on the plants exposed to ozone germinated as well, produced as many appressoria, and resulted in as much infection as spores produced on unexposed leaves. Exposure on dry leaves to 20 pphm ozone for 3 hr for 1-5 days did not affect urediospore germination, appressoria formation, or penetration. 9 references, 1 figure, 3 tables.

Ionizing Radiation Perturbs Cell Cycle Progression of Neural Precursors in the Subventricular Zone Without Affecting Their Long-Term Self-Renewal

PubMed Central

Chen, Hongxin; Goodus, Matthew T; de Toledo, Sonia M; Azzam, Edouard I; Levison, Steven W

2015-01-01

Damage to normal human brain cells from exposure to ionizing radiation may occur during the course of radiotherapy or from accidental exposure. Delayed effects may complicate the immediate effects resulting in neurodegeneration and cognitive decline. We examined cellular and molecular changes associated with exposure of neural stem/progenitor cells (NSPs) to 137Cs γ-ray doses in the range of 0 to 8 Gy. Subventricular zone NSPs isolated from newborn mouse pups were analyzed for proliferation, self-renewal, and differentiation, shortly after irradiation. Strikingly, there was no apparent increase in the fraction of dying cells after irradiation, and the number of single cells that formed neurospheres showed no significant change from control. Upon differentiation, irradiated neural precursors did not differ in their ability to generate neurons, astrocytes, and oligodendrocytes. By contrast, progression of NSPs through the cell cycle decreased dramatically after exposure to 8 Gy (p < .001). Mice at postnatal day 10 were exposed to 8 Gy of γ rays delivered to the whole body and NSPs of the subventricular zone were analyzed using a four-color flow cytometry panel combined with ethynyl deoxyuridine incorporation. Similar flow cytometric analyses were performed on NSPs cultured as neurospheres. These studies revealed that neither the percentage of neural stem cells nor their proliferation was affected. By contrast, γ-irradiation decreased the proliferation of two classes of multipotent cells and increased the proliferation of a specific glial-restricted precursor. Altogether, these results support the conclusion that primitive neural precursors are radioresistant, but their proliferation is slowed down as a consequence of γ-ray exposure. PMID:26056396

Repeated Cocaine Experience Facilitates Sucrose-Reinforced Operant Responding in Enriched and Isolated Rats

ERIC Educational Resources Information Center

Klein, Emily D.; Gehrke, Brenda J.; Green, Thomas A.; Zentall, Thomas R.; Bardo, Michael T.

2007-01-01

The purpose of the present experiment was to determine whether repeated cocaine exposure differentially affects sucrose-reinforced operant responding in rats raised in an enriched condition (EC) or an isolated condition (IC). Specifically, the performance of EC and IC rats pressing a lever for sucrose under a high fixed-ratio schedule (FR 30)…

Do Pharmacological and Behavioral Interventions Differentially Affect Treatment Outcome for Children with Social Phobia?

ERIC Educational Resources Information Center

Scharfstein, Lindsay A.; Beidel, Deborah C.; Rendon Finnell, Laura; Distler, Aaron; Carter, Nathan T.

2011-01-01

In a randomized trial for children with social phobia (SP), Social Effectiveness Therapy for Children (SET-C; a treatment consisting of exposure and social skills training) and fluoxetine were more effective than pill placebo in reducing social distress and behavioral avoidance, but only SET-C demonstrated significantly improved overall social…

Exposure to social defeat stress in adolescence improves the working memory and anxiety-like behavior of adult female rats with intrauterine growth restriction, independently of hippocampal neurogenesis.

PubMed

Furuta, Miyako; Ninomiya-Baba, Midori; Chiba, Shuichi; Funabashi, Toshiya; Akema, Tatsuo; Kunugi, Hiroshi

2015-04-01

Intrauterine growth restriction (IUGR) is a risk factor for memory impairment and emotional disturbance during growth and adulthood. However, this risk might be modulated by environmental factors during development. Here we examined whether exposing adolescent male and female rats with thromboxane A2-induced IUGR to social defeat stress (SDS) affected their working memory and anxiety-like behavior in adulthood. We also used BrdU staining to investigate hippocampal cellular proliferation and BrdU and NeuN double staining to investigate neural differentiation in female IUGR rats. In the absence of adolescent stress, IUGR female rats, but not male rats, scored significantly lower in the T-maze test of working memory and exhibited higher anxiety-like behavior in the elevated-plus maze test compared with controls. Adolescent exposure to SDS abolished these behavioral impairments in IUGR females. In the absence of adolescent stress, hippocampal cellular proliferation was significantly higher in IUGR females than in non-IUGR female controls and was not influenced by adolescent exposure to SDS. Hippocampal neural differentiation was equivalent in non-stressed control and IUGR females. Neural differentiation was significantly increased by adolescent exposure to SDS in controls but not in IUGR females. There was no significant difference in the serum corticosterone concentrations between non-stressed control and IUGR females; however, adolescent exposure to SDS significantly increased serum corticosterone concentration in control females but not in IUGR females. These results demonstrate that adolescent exposure to SDS improves behavioral impairment independent of hippocampal neurogenesis in adult rats with IUGR. Copyright © 2015 Elsevier Inc. All rights reserved.

Psychotic disorder and educational achievement: a family-based analysis.

PubMed

Frissen, Aleida; Lieverse, Ritsaert; Marcelis, Machteld; Drukker, Marjan; Delespaul, Philippe

2015-10-01

Early social and cognitive alterations in psychotic disorder, associated with familial liability and environmental exposures, may contribute to lower than expected educational achievement. The aims of the present study were to investigate (1) how differences in educational level between parents and their children vary across patients, their healthy siblings, and healthy controls (effect familial liability), and across two environmental risk factors for psychotic disorder: childhood trauma and childhood urban exposure (effect environment) and (2) to what degree the association between familial liability and educational differential was moderated by the environmental exposures. Patients with a diagnosis of non-affective psychotic disorder (n = 629), 552 non-psychotic siblings and 326 healthy controls from the Netherlands and Belgium were studied. Participants reported their highest level of education and that of their parents. Childhood trauma was assessed with the Dutch version of the Childhood Trauma Questionnaire-Short Form. Urban exposure, expressed as population density, was rated across five levels. Overall, participants had a higher level of education than their parents. This difference was significantly reduced in the patient group, and the healthy siblings displayed intergenerational differences that were in between those of controls and patients. Higher levels of childhood urban exposure were also associated with a smaller intergenerational educational differential. There was no evidence for differential sensitivity to childhood trauma and childhood urbanicity across the three groups. Intergenerational difference in educational achievements is decreased in patients with psychotic disorder and to a lesser extent in siblings of patients with psychotic disorder, and across higher levels of childhood urban exposure. More research is required to better understand the dynamics between early social and cognitive alterations in those at risk in relation to progress through the educational system and to understand the interaction between urban environment and educational outcomes.

Consequences of adolescent ethanol exposure in male Sprague-Dawley rats on fear conditioning and extinction in adulthood

NASA Astrophysics Data System (ADS)

Broadwater, Margaret A.

Some evidence suggests that adolescents are more vulnerable than adults to alcohol-induced cognitive deficits and that these deficits may persist into adulthood. Five experiments were conducted to assess long-term consequences of ethanol exposure on tone and context Pavlovian fear conditioning in male Sprague-Dawley rats. Experiment 1 examined age-related differences in sensitivity to ethanol-induced disruptions of fear conditioning to a pre-conditioning ethanol challenge. Experiments 2 examined fear conditioning 22 days after early-mid adolescent (P28-48) or adult (P70-90) exposure to 4 g/kg i.g. ethanol or water given every other day (total of 11 exposures). In Experiment 3, mid-late adolescents (P35-55) were exposed in the same manner to assess whether timing of ethanol exposure within the adolescent period would differentially affect later fear conditioning. Experiment 4 assessed the influence of prior adolescent or adult ethanol exposure on the disrupting effects of a pre-conditioning ethanol challenge. In Experiment 5, neurogenesis (doublecortin---DCX) and cholinergic (choline acetyltransferase---ChAT) markers were measured to assess potential long-term ethanol-induced changes in neural mechanisms important for learning and memory. Results indicated that the long-lasting behavioral effects of ethanol exposure varied depending on exposure age, with early-mid adolescent exposed animals showing attenuated context fear retention (a relatively hippocampal-dependent task), whereas mid-late adolescent and adult exposed animals showed slower context extinction (thought to be reliant on the mPFC). Early-mid adolescent ethanol-exposed animals also had significantly less DCX and ChAT expression than their water-exposed counterparts, possibly contributing to deficits in context fear. Tone fear was not influenced by prior ethanol exposure at any age. In terms of age differences in ethanol sensitivity, adolescents were less sensitive than adults to ethanol-induced disruption of context fear retention; however, acute ethanol-induced disruptions of context fear did not differ as a function of prior ethanol exposure at either exposure age in adulthood. Together these results reflect differential influence of ethanol on the brain as it changes throughout ontogeny, with the hippocampus seemingly vulnerable to early adolescent exposure, whereas the mPFC may be more affected by ethanol exposure in mid-adolescence through adulthood. These data have implications for alcohol use not only throughout adolescence, but also in adulthood.

Diverse effects of lead nitrate on the proliferation, differentiation, and gene expression of stem cells isolated from a dental origin.

PubMed

Abdullah, Mariam; Rahman, Fazliny Abd; Gnanasegaran, Nareshwaran; Govindasamy, Vijayendran; Abu Kasim, Noor Hayaty; Musa, Sabri

2014-01-01

Lead (Pb(2+)) exposure continues to be a significant public health problem. Therefore, it is vital to have a continuous epidemiological dataset for a better understanding of Pb(2+) toxicity. In the present study, we have exposed stem cells isolated from deciduous and permanent teeth, periodontal ligament, and bone marrow to five different types of Pb(2+) concentrations (160, 80, 40, 20, and 10 µM) for 24 hours to identify the adverse effects of Pb(2+) on the proliferation, differentiation, and gene expression on these cell lines. We found that Pb(2+) treatment altered the morphology and adhesion of the cells in a dose-dependent manner. There were no significant changes in terms of cell surface phenotypes. Cells exposed to Pb(2+) continued to differentiate into chondrogenesis and adipogenesis, and a severe downregulation was observed in osteogenesis. Gene expression studies revealed a constant expression of key markers associated with stemness (Oct 4, Rex 1) and DNA repair enzyme markers, but downregulation occurred with some ectoderm and endoderm markers, demonstrating an irregular and untimely differentiation trail. Our study revealed for the first time that Pb(2+) exposure not only affects the phenotypic characteristics but also induces significant alteration in the differentiation and gene expression in the cells.

Pulsed electromagnetic fields promote the proliferation and differentiation of osteoblasts by reinforcing intracellular calcium transients.

PubMed

Tong, Jie; Sun, Lijun; Zhu, Bin; Fan, Yun; Ma, Xingfeng; Yu, Liyin; Zhang, Jianbao

2017-10-01

Pulsed electromagnetic fields (PEMF) can be used to treat bone-related diseases, but the underlying mechanism remains unclear, especially the process by which PEMFs initiate biological effects. In this study, we demonstrated the effects of PEMF on proliferation and differentiation of osteoblasts using the model of calcium transients induced by high extracellular calcium. Our results showed that PEMF can increase both the percentage of responding cells and amplitude of intracellular calcium transients induced by high extracellular calcium stimulation. Compared with corresponding extracellular calcium levels, PEMF stimulation increased proliferation and differentiation of osteoblasts and related gene expressions, such as insulin-like growth factor 1 (IGF-1), alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), and osteocalcin (OCN), which can be completely abolished by BAPTA-AM. Moreover, PEMF did not affect proliferation and differentiation of osteoblasts if no intracellular calcium transient was present in osteoblasts during PEMF exposure. Our results revealed that PEMF affects osteoblast proliferation and differentiation through enhanced intracellular calcium transients, which provided a cue to treat bone-related diseases with PEMF. Bioelectromagnetics. 38:541-549, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Chronic schistosomiasis during pregnancy epigenetically reprograms T-cell differentiation in offspring of infected mothers.

PubMed

Klar, Kathrin; Perchermeier, Sophie; Bhattacharjee, Sonakshi; Harb, Hani; Adler, Thure; Istvanffy, Rouzanna; Loffredo-Verde, Eva; Oostendorp, Robert A; Renz, Harald; Prazeres da Costa, Clarissa

2017-05-01

Schistosomiasis is a nontransplacental helminth infection. Chronic infection during pregnancy suppresses allergic airway responses in offspring. We addressed the question whether in utero exposure to chronic schistosome infection (Reg phase) in mice affects B-cell and T-cell development. Therefore, we focused our analyses on T-cell differentiation capacity induced by epigenetic changes in promoter regions of signature cytokines in offspring. Here, we show that naïve T cells from offspring of schistosome infected female mice had a strong capacity to differentiate into T H 1 cells, whereas T H 2 differentiation was impaired. In accordance, reduced levels of histone acetylation of the IL-4 promoter regions were observed in naïve T cells. To conclude, our mouse model revealed distinct epigenetic changes within the naïve T-cell compartment affecting T H 2 and T H 1 cell differentiation in offspring of mothers with chronic helminth infection. These findings could eventually help understand how helminths alter T-cell driven immune responses induced by allergens, bacterial or viral infections, as well as vaccines. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Transcription profile analysis of Lycopersicum esculentum leaves, unravels volatile emissions and gene expression under salinity stress.

PubMed

Zhang, Jihong; Zeng, Li; Chen, Shaoyang; Sun, Helong; Ma, Shuang

2018-05-01

Salinity stress can impede development and plant growth adversely. However, there is very little molecular information on NaCl resistance and volatile emissions in Lycopersicum esculentum. In order to investigate the effects of salt stress on the release of volatile compounds, we quantified and compared transcriptome changes by RNA-Seq analysis and volatile constituents with gas chromatography/mass spectrometry (GC/MS) coupled with solid-phase microextraction (SPME) after exposure to continuous salt stress. Chemical analysis by GC-MS analysis revealed that NaCl stress had changed species and quantity of volatile compounds released. In this research, 21,578 unigenes that represented 44,714 assembled unique transcripts were separated from tomato leaves exposed to NaCl stress based on de novo transcriptome assembly. The total number of differentially expressed genes was 7210 after exposure to NaCl, including 6200 down-regulated and 1208 up-regulated genes. Among these differentially expressed genes (DEGs), there were eighteen differentially expressed genes associated with volatile biosynthesis. Of the unigenes, 3454 were mapped to 131 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, mainly those are involved in RNA transport, plant-pathogen interactions, and plant hormone signal transduction. qRT-PCR analysis showed that NaCl exposure affected the expression profiles of the biosynthesis genes for eight volatile compounds (IPI, GPS, and TPS, etc.), which corresponded well with the RNA-Seq analysis and GC-MS results. Our results suggest that NaCl stress affects the emission of volatile substances from L. esculentum leaves by regulating the expression of genes that are involved in volatile organic compounds' biosynthesis. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Anabolic/androgenic steroid administration during adolescence and adulthood differentially modulates aggression and anxiety.

PubMed

Morrison, Thomas R; Ricci, Lesley A; Melloni, Richard H

2015-03-01

Anabolic/androgenic steroid (AAS) use remains high in both teens and adults in the U.S. and worldwide despite studies showing that AAS use is associated with a higher incidence of aggression and anxiety. Recently we showed that chronic exposure to AAS through adolescence increases aggression and decreases anxious behaviors, while during AAS-withdrawal aggression is lowered to species-normative levels and anxiety increases. AAS exposure is known to differentially alter behaviors and their underlying neural substrates between adults and adolescents and thus the current study investigated whether exposure to AAS during adulthood affects the relationship between aggression and anxiety in a manner similar to that previously observed in adolescents. Male hamsters were administered a moderate dose of AAS (5.0mg/kg/day×30days) during adolescence (P27-56) or young adulthood (P65-P94) and then tested for aggression and anxiety during AAS exposure (i.e., on P57 or P95) and during AAS withdrawal (i.e., 30days later on P77 or P115). Adolescent exposure to AAS increased aggressive responding during the AAS exposure period and anxiety-like responding during AAS withdrawal. Neither behavior was similarly influenced by adult exposure to AAS. Adult AAS exposure produced no difference in aggressive responding during AAS exposure (P95) or AAS withdrawal (P115); however, while AAS exposure during adulthood produced no difference in anxiety-like responding during AAS exposure, adult hamsters administered AAS were less anxious than vehicle control animals following AAS withdrawal. Together these data suggest that the aggression and anxiety provoking influence of AAS are likely a developmental phenomenon and that adult exposure to AAS may be anxiolytic over the long term. Copyright © 2015 Elsevier Inc. All rights reserved.

Prolonged exposure to bacterial toxins downregulated expression of toll-like receptors in mesenchymal stromal cell-derived osteoprogenitors

PubMed Central

Mo, Irene Fung Ying; Yip, Kevin Hak Kong; Chan, Wing Keung; Law, Helen Ka Wai; Lau, Yu Lung; Chan, Godfrey Chi Fung

2008-01-01

Background Human mesenchymal stromal cells (MSCs, also known as mesenchymal stem cells) are multipotent cells with potential therapeutic value. Owing to their osteogenic capability, MSCs may be clinically applied for facilitating osseointegration in dental implants or orthopedic repair of bony defect. However, whether wound infection or oral microflora may interfere with the growth and osteogenic differentiation of human MSCs remains unknown. This study investigated whether proliferation and osteogenic differentiation of MSCs would be affected by potent gram-positive and gram-negative derived bacterial toxins commonly found in human settings. Results We selected lipopolysaccharide (LPS) from Escherichia coli and lipoteichoic acid (LTA) from Streptococcus pyogenes as our toxins of choice. Our findings showed both LPS and LTA did not affect MSC proliferation, but prolonged LPS challenge upregulated the osteogenic differentiation of MSCs, as assessed by alkaline phosphatase activity and calcium deposition. Because toll-like receptors (TLRs), in particularly TLR4 and TLR2, are important for the cellular responsiveness to LPS and LTA respectively, we evaluated their expression profiles serially from MSCs to osteoblasts by quantitative PCR. We found that during osteogenic differentiation, MSC-derived osteoprogenitors gradually expressed TLR2 and TLR4 by Day 12. But under prolonged incubation with LPS, MSC-derived osteoprogenitors had reduced TLR2 and TLR4 gene expression. This peculiar response to LPS suggests a possible adaptive mechanism when MSCs are subjected to continuous exposure with bacteria. Conclusion In conclusion, our findings support the potential of using human MSCs as a biological graft, even under a bacterial toxin-rich environment. PMID:18799018

Effects of tributyltin on early life-stage, reproduction, and gonadal sex differentiation in Japanese medaka (Oryzias latipes).

PubMed

Horie, Yoshifumi; Yamagishi, Takahiro; Shintaku, Yoko; Iguchi, Taisen; Tatarazako, Norihisa

2018-07-01

Tributyltin, an organotin compound, was used worldwide as an antifouling agent in aquatic environments and there has been much concern about the toxicological and ecotoxicological properties of organotin compounds. Even though it has been prohibited worldwide, tributyltin is still detected at low concentrations in aquatic environments. Here we investigated the effects of tributyltin on the early life-stage, reproduction, and gonadal sex differentiation in Japanese medaka (Oryzias latipes). In adults, exposure to tributyltin at 3.82 μg/L suppressed fecundity and fertility and increased mortality. At 10.48 μg/L all medaka died by the sixth day of exposure. Exposure to tributyltin during early life-stages induced no significant differences in mortality or embryonic development, but growth was suppressed in groups exposed to 0.13 and 0.68 μg/L. Furthermore, there was no abnormal gonadal development in Japanese medaka exposed to tributyltin. These results provide evidence of the negative effects of tributyltin on reproduction in a teleost fish. Tributyltin did not affect gonadal sex differentiation in Japanese medaka, but fecundity and fertility were suppressed, although it is not clear whether this suppression resulted from the endocrine-disrupting action of tributyltin or its toxicity. Copyright © 2018 Elsevier Ltd. All rights reserved.

The mammalian respiratory system and critical windows of exposure for children's health.

PubMed Central

Pinkerton, K E; Joad, J P

2000-01-01

The respiratory system is a complex organ system composed of multiple cell types involved in a variety of functions. The development of the respiratory system occurs from embryogenesis to adult life, passing through several distinct stages of maturation and growth. We review embryonic, fetal, and postnatal phases of lung development. We also discuss branching morphogenesis and cellular differentiation of the respiratory system, as well as the postnatal development of xenobiotic metabolizing systems within the lungs. Exposure of the respiratory system to a wide range of chemicals and environmental toxicants during perinatal life has the potential to significantly affect the maturation, growth, and function of this organ system. Although the potential targets for exposure to toxic factors are currently not known, they are likely to affect critical molecular signals expressed during distinct stages of lung development. The effects of exposure to environmental tobacco smoke during critical windows of perinatal growth are provided as an example leading to altered cellular and physiological function of the lungs. An understanding of critical windows of exposure of the respiratory system on children's health requires consideration that lung development is a multistep process and cannot be based on studies in adults. Images Figure 1 Figure 4 PMID:10852845

Targeting premeal anxiety in eating disordered clients and normal controls: a preliminary investigation into the use of mindful eating vs. distraction during food exposure.

PubMed

Marek, Ryan J; Ben-Porath, Denise D; Federici, Anita; Wisniewski, Lucene; Warren, Mark

2013-09-01

Studies have demonstrated that negative affect increases prior to food intake in individuals diagnosed with an eating disorder. Mindfulness has been supported empirically to treat experiential avoidance stemming from anxiety. Thus, the current objective in this study is to empirically compare mindfulness vs. thought suppression invention during a food exposure in both clinical and nonclinical samples. In a 2 (Group: clinical vs. nonclinical) × 2 (INTERVENTION: mindfulness vs. distraction) counterbalanced within treatment design, the current investigation sought to determine the differential effectiveness of a brief mindfulness intervention vs. a brief distraction intervention in women diagnosed with AN and BN in a clinical and nonclinical sample during a food exposure. Results indicated that the eating disorder group reported a significant increase in negative affect after the mindfulness intervention as compared to the distraction intervention, whereas the nonclinical group reported a significant decrease in negative affect after the mindfulness intervention as compared to the distraction intervention. Preliminary findings suggest that clinicians may want to proceed cautiously when using mindful eating in those with severe eating disorders during the early stages of food exposure. Limitations and future directions are discussed. Copyright © 2013 Wiley Periodicals, Inc.

The effect of low-frequency electromagnetic field on human bone marrow stem/progenitor cell differentiation

PubMed Central

Ross, Christina L.; Siriwardane, Mevan; Almeida-Porada, Graça; Porada, Christopher D.; Brink, Peter; Christ, George J.; Harrison, Benjamin S.

2015-01-01

Human bone marrow stromal cells (hBMSCs, also known as bone marrow-derived mesenchymal stem cells) are a population of progenitor cells that contain a subset of skeletal stem cells (hSSCs), able to recreate cartilage, bone, stroma that supports hematopoiesis and marrow adipocytes. As such, they have become an important resource in developing strategies for regenerative medicine and tissue engineering due to their self-renewal and differentiation capabilities. The differentiation of SSCs/BMSCs is dependent on exposure to biophysical and biochemical stimuli that favor early and rapid activation of the in vivo tissue repair process. Exposure to exogenous stimuli such as an electromagnetic field (EMF) can promote differentiation of SSCs/BMSCs via ion dynamics and small signaling molecules. The plasma membrane is often considered to be the main target for EMF signals and most results point to an effect on the rate of ion or ligand binding due to a receptor site acting as a modulator of signaling cascades. Ion fluxes are closely involved in differentiation control as stem cells move and grow in specific directions to form tissues and organs. EMF affects numerous biological functions such as gene expression, cell fate, and cell differentiation, but will only induce these effects within a certain range of low frequencies as well as low amplitudes. EMF has been reported to be effective in the enhancement of osteogenesis and chondrogenesis of hSSCs/BMSCs with no documented negative effects. Studies show specific EMF frequencies enhance hSSC/BMSC adherence, proliferation, differentiation, and viability, all of which play a key role in the use of hSSCs/BMSCs for tissue engineering. While many EMF studies report significant enhancement of the differentiation process, results differ depending on the experimental and environmental conditions. Here we review how specific EMF parameters (frequency, intensity, and time of exposure) significantly regulate hSSC/BMSC differentiation in vitro. We discuss optimal conditions and parameters for effective hSSC/BMSC differentiation using EMF treatment in an in vivo setting, and how these can be translated to clinical trials. PMID:26042793

Differential roles of vascular endothelial growth factor receptors 1 and 2 in dendritic cell differentiation.

PubMed

Dikov, Mikhail M; Ohm, Joyce E; Ray, Neelanjan; Tchekneva, Elena E; Burlison, Jared; Moghanaki, Drew; Nadaf, Sorena; Carbone, David P

2005-01-01

Impaired Ag-presenting function in dendritic cells (DCs) due to abnormal differentiation is an important mechanism of tumor escape from immune control. A major role for vascular endothelial growth factor (VEGF) and its receptors, VEGFR1/Flt-1 and VEGFR2/KDR/Flk-1, has been documented in hemopoietic development. To study the roles of each of these receptors in DC differentiation, we used an in vitro system of myeloid DC differentiation from murine embryonic stem cells. Exposure of wild-type, VEGFR1(-/-), or VEGFR2(-/-) embryonic stem cells to exogenous VEGF or the VEGFR1-specific ligand, placental growth factor, revealed distinct roles of VEGF receptors. VEGFR1 is the primary mediator of the VEGF inhibition of DC maturation, whereas VEGFR2 tyrosine kinase signaling is essential for early hemopoietic differentiation, but only marginally affects final DC maturation. SU5416, a VEGF receptor tyrosine kinase inhibitor, only partially rescued the mature DC phenotype in the presence of VEGF, suggesting the involvement of both tyrosine kinase-dependent and independent inhibitory mechanisms. VEGFR1 signaling was sufficient for blocking NF-kappaB activation in bone marrow hemopoietic progenitor cells. VEGF and placental growth factor affect the early stages of myeloid/DC differentiation. The data suggest that therapeutic strategies attempting to reverse the immunosuppressive effects of VEGF in cancer patients might be more effective if they specifically targeted VEGFR1.

Dose-response assessment of fetal testosterone production and gene expression levels in rat testes following in utero exposure to diethylhexyl phthalate, diisobutyl phthalate, diisoheptyl phthalate and diisononyl phthalate

EPA Science Inventory

Several phthalate esters have been linked to the Phthalate Syndrome, affecting male reproductive development when administered to pregnant rats during in utero sexual differentiation. The goal of the current study was to enhance understanding of this class of compounds in the Spr...

Social Memory Formation Rapidly and Differentially Affects the Motivation and Performance of Vocal Communication Signals in the Bengalese Finch (Lonchura striata var. domestica).

PubMed

Toccalino, Danielle C; Sun, Herie; Sakata, Jon T

2016-01-01

Cognitive processes like the formation of social memories can shape the nature of social interactions between conspecifics. Male songbirds use vocal signals during courtship interactions with females, but the degree to which social memory and familiarity influences the likelihood and structure of male courtship song remains largely unknown. Using a habituation-dishabituation paradigm, we found that a single, brief (<30 s) exposure to a female led to the formation of a short-term memory for that female: adult male Bengalese finches were significantly less likely to produce courtship song to an individual female when re-exposed to her 5 min later (i.e., habituation). Familiarity also rapidly decreased the duration of courtship songs but did not affect other measures of song performance (e.g., song tempo and the stereotypy of syllable structure and sequencing). Consistent with a contribution of social memory to the decrease in courtship song with repeated exposures to the same female, the likelihood that male Bengalese finches produced courtship song increased when they were exposed to a different female (i.e., dishabituation). Three consecutive exposures to individual females also led to the formation of a longer-term memory that persisted over days. Specifically, when courtship song production was assessed 2 days after initial exposures to females, males produced fewer and shorter courtship songs to familiar females than to unfamiliar females. Measures of song performance, however, were not different between courtship songs produced to familiar and unfamiliar females. The formation of a longer-term memory for individual females seemed to require at least three exposures because males did not differentially produce courtship song to unfamiliar females and females that they had been exposed to only once or twice. Taken together, these data indicate that brief exposures to individual females led to the rapid formation and persistence of social memories and support the existence of distinct mechanisms underlying the motivation to produce and the performance of courtship song.

Monoethylhexyl Phthalate Elicits an Inflammatory Response in Adipocytes Characterized by Alterations in Lipid and Cytokine Pathways.

PubMed

Manteiga, Sara; Lee, Kyongbum

2017-04-01

A growing body of evidence links endocrine-disrupting chemicals (EDCs) with obesity-related metabolic diseases. While it has been shown that EDCs can predispose individuals toward adiposity by affecting developmental processes, little is known about the chemicals' effects on adult adipose tissue. Our aim was to study the effects of low, physiologically relevant doses of EDCs on differentiated murine adipocytes. We combined metabolomics, proteomics, and gene expression analysis to characterize the effects of mono-ethylhexyl phthalate (MEHP) in differentiated adipocytes. Repeated exposure to MEHP over several days led to changes in metabolite and enzyme levels indicating elevated lipogenesis and lipid oxidation. The chemical exposure also increased expression of major inflammatory cytokines, including chemotactic factors. Proteomic and gene expression analysis revealed significant alterations in pathways regulated by peroxisome proliferator activated receptor-γ (PPARγ). Inhibiting the nuclear receptor's activity using a chemical antagonist abrogated not only the alterations in PPARγ-regulated metabolic pathways, but also the increases in cytokine expression. Our results show that MEHP can induce a pro-inflammatory state in differentiated adipocytes. This effect is at least partially mediated PPARγ.

Temperature gradient affects differentiation of gene expression and SNP allele frequencies in the dominant Lake Baikal zooplankton species.

PubMed

Bowman, Larry L; Kondrateva, Elizaveta S; Timofeyev, Maxim A; Yampolsky, Lev Y

2018-06-01

Local adaptation and phenotypic plasticity are main mechanisms of organisms' resilience in changing environments. Both are affected by gene flow and are expected to be weak in zooplankton populations inhabiting large continuous water bodies and strongly affected by currents. Lake Baikal, the deepest and one of the coldest lakes on Earth, experienced epilimnion temperature increase during the last 100 years, exposing Baikal's zooplankton to novel selective pressures. We obtained a partial transcriptome of Epischura baikalensis (Copepoda: Calanoida), the dominant component of Baikal's zooplankton, and estimated SNP allele frequencies and transcript abundances in samples from regions of Baikal that differ in multiyear average surface temperatures. The strongest signal in both SNP and transcript abundance differentiation is the SW-NE gradient along the 600+ km long axis of the lake, suggesting isolation by distance. SNP differentiation is stronger for nonsynonymous than synonymous SNPs and is paralleled by differential survival during a laboratory exposure to increased temperature, indicating directional selection operating on the temperature gradient. Transcript abundance, generally collinear with the SNP differentiation, shows samples from the warmest, less deep location clustering together with the southernmost samples. Differential expression is more frequent among transcripts orthologous to candidate thermal response genes previously identified in model arthropods, including genes encoding cytoskeleton proteins, heat-shock proteins, proteases, enzymes of central energy metabolism, lipid and antioxidant pathways. We conclude that the pivotal endemic zooplankton species in Lake Baikal exists under temperature-mediated selection and possesses both genetic variation and plasticity to respond to novel temperature-related environmental pressures. © 2018 John Wiley & Sons Ltd.

Synergistic effects of tributyltin and 2,3,7,8-tetrachlorodibenzo-p-dioxin on differentiating osteoblasts and osteoclasts.

PubMed

Koskela, Antti; Viluksela, Matti; Keinänen, Meeri; Tuukkanen, Juha; Korkalainen, Merja

2012-09-01

The purpose of this study was to examine the effects of the persistent and accumulative environmental pollutants tributyltin (TBT) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) individually and in combination on differentiating bone cells. TBT and TCDD are chemically distinct compounds with different mechanisms of toxicity, but they typically have the same sources of exposure and both have been shown to affect bone development at low exposure levels. Bone marrow stem cells were isolated from femurs and tibias of C57BL/6J mice, differentiated in culture into osteoblasts or osteoclasts and exposed to 0.1-10nM TBT, 0.01-1nM TCDD or 10nM TBT+ 1nM TCDD. In osteoblasts, the combined exposure to TBT and TCDD significantly decreased the mRNA expression of alkaline phosphatase and osteocalcin more than TBT or TCDD alone. PCR array showed different gene expression profiles for TBT and TCDD individually, and the combination evoked several additional alterations in gene expression. Expression of aryl hydrocarbon receptor repressor (AHRR) was increased by TCDD as expected, but simultaneous exposure to TBT prevented the increase thus potentially strengthening AHR-mediated effects of TCDD. The number of osteoclasts was reduced by TCDD alone and in combination with TBT, but TBT alone had no effect. However, the total area of resorbed bone was remarkably lower after combined exposure than after TBT or TCDD alone. In conclusion, very low concentrations of TBT and TCDD have synergistic deleterious effects on bone formation and additive effects on bone resorption. Copyright © 2012 Elsevier Inc. All rights reserved.

Seed storage conditions change the germination pattern of clonal growth plants in Mediterranean salt marshes

USGS Publications Warehouse

Espinar, J.L.; Garcia, L.V.; Clemente, L.

2005-01-01

The effect of salinity level and extended exposure to different salinity and flooding conditions on germination patterns of three saltmarsh clonal growth plants (Juncus subulatus, Scirpus litoralis, and S. maritimus) was studied. Seed exposure to extended flooding and saline conditions significantly affected the outcome of the germination process in a different, though predictable, way for each species, after favorable conditions for germination were restored. Tolerance of the germination process was related to the average salinity level measured during the growth/germination season at sites where established individuals of each species dominated the species cover. No relationship was found between salinity tolerance of the germination process and seed response to extended exposure to flooding and salinity conditions. The salinity response was significantly related to the conditions prevailing in the habitats of the respective species during the unfavorable (nongrowth/nongermination) season. Our results indicate that changes in salinity and hydrology while seeds are dormant affect the outcome of the seed-bank response, even when conditions at germination are identical. Because these environmental-history-dependent responses differentially affect seed germination, seedling density, and probably sexual recruitment in the studied and related species, these influences should be considered for wetland restoration and management.

Early endocrine disruptors exposure acts on 3T3-L1 differentiation and endocrine activity

PubMed Central

Boudalia, Sofiane; Belloir, Christine; Miller, Marie-Louise; Canivenc-Lavier, Marie-Chantal

2017-01-01

Introduction: Data from last years suggested that early exposure to endocrine disruptors (EDs) can predispose newborns to endocrine dysfunction of adipocytes, obesity, and associated disorders. The implication of EDs at low doses on adipocyte development has been poorly investigated. For instance, vinclozolin (V) is a dicarboximide fungicide widely used in agriculture since the 90's, alone or in mixture with genistein (G), an isoflavonoid from Leguminosae. This study aims to identify the effect of vinclozolin alone or with genistein, on adipose tissue properties using cell culture. Methods: In steroid-free conditions, 3T3-L1 pre-adipocytes were induced to differentiate in the presence of EDs, singularly or in mixtures, for 2 days. DNA and triglyceride (TG) levels were measured on days 0, 2 and 8 of differentiation. Leptin secretion was measured only on the eighth day. Results: We show that low doses of G (25 µM) and V (0.1 µM) inhibit pre-adipocytes differentiation. This inhibition has been represented by a decreasing in DNA content (µg/well) and decreasing in TG accumulation (mg/mL) in 3T3-L1 cells. Nevertheless, V increased the anti-adipogenic properties of G. Conclusion: This study confirms that EDs singularly or in mixtures, introduced during early stages of life, could affect the differentiation and the endocrine activity of adipocytes, and can act as potential factors for obesity. PMID:28752072

Chronic Exposure to Bisphenol A Affects Uterine Function During Early Pregnancy in Mice

PubMed Central

Davila, Juanmahel; Kannan, Athilakshmi; Flaws, Jodi A.; Bagchi, Milan K.

2016-01-01

Environmental and occupational exposure to bisphenol A (BPA), a chemical widely used in polycarbonate plastics and epoxy resins, has received much attention in female reproductive health due to its widespread toxic effects. Although BPA has been linked to infertility and recurrent miscarriage in women, the impact of its exposure on uterine function during early pregnancy remains unclear. In this study, we addressed the effect of prolonged exposure to an environmental relevant dose of BPA on embryo implantation and establishment of pregnancy. Our studies revealed that treatment of mice with BPA led to improper endometrial epithelial and stromal functions thus affecting embryo implantation and establishment of pregnancy. Upon further analyses, we found that the expression of progesterone receptor (PGR) and its downstream target gene, HAND2 (heart and neural crest derivatives expressed 2), was markedly suppressed in BPA-exposed uterine tissues. Previous studies have shown that HAND2 controls embryo implantation by repressing fibroblast growth factor and the MAPK signaling pathways and inhibiting epithelial proliferation. Interestingly, we observed that down-regulation of PGR and HAND2 expression in uterine stroma upon BPA exposure was associated with enhanced activation of fibroblast growth factor and MAPK signaling in the epithelium, thus contributing to aberrant proliferation and lack of uterine receptivity. Further, the differentiation of endometrial stromal cells to decidual cells, an event critical for the establishment and maintenance of pregnancy, was severely compromised in response to BPA. In summary, our studies revealed that chronic exposure to BPA impairs PGR-HAND2 pathway and adversely affects implantation and the establishment of pregnancy. PMID:27022677

Electromagnetic field and brain development.

PubMed

Kaplan, Suleyman; Deniz, Omur Gulsum; Önger, Mehmet Emin; Türkmen, Aysın Pınar; Yurt, Kıymet Kübra; Aydın, Işınsu; Altunkaynak, Berrin Zuhal; Davis, Devra

2016-09-01

Rapid advances in technology involve increased exposures to radio-frequency/microwave radiation from mobile phones and other wireless transmitting devices. As cell phones are held close to the head during talking and often stored next to the reproductive organs, studies are mostly focused on the brain. In fact, more research is especially needed to investigate electromagnetic field (EMF)'s effects on the central nervous system (CNS). Several studies clearly demonstrate that EMF emitted by cell phones could affect a range of body systems and functions. Recent work has demonstrated that EMF inhibit the formation and differentiation of neural stem cells during embryonic development and also affect reproductive and neurological health of adults that have undergone prenatal exposure. The aim of this review is to discuss the developing CNS and explain potential impacts of EMF on this system. Copyright © 2015 Elsevier B.V. All rights reserved.

Early prenatal androgen exposure reduces testes size and sperm concentration in sheep without altering neuroendocrine differentiation and masculine sexual behavior.

PubMed

Scully, C M; Estill, C T; Amodei, R; McKune, A; Gribbin, K P; Meaker, M; Stormshak, F; Roselli, C E

2018-01-01

Prenatal androgens are largely responsible for growth and differentiation of the genital tract and testis and for organization of the control mechanisms regulating male reproductive physiology and behavior. The aim of the present study was to evaluate the impact of inappropriate exposure to excess testosterone (T) during the first trimester of fetal development on the reproductive function, sexual behavior, and fertility potential of rams. We found that biweekly maternal T propionate (100 mg) treatment administered from Day 30-58 of gestation significantly decreased (P < 0.05) postpubertal scrotal circumference and sperm concentration. Prenatal T exposure did not alter ejaculate volume, sperm motility and morphology or testis morphology. There was, however, a trend for more T-exposed rams than controls to be classified as unsatisfactory potential breeders during breeding soundness examinations. Postnatal serum T concentrations were not affected by prenatal T exposure, nor was the expression of key testicular genes essential for spermatogenesis and steroidogenesis. Basal serum LH did not differ between treatment groups, nor did pituitary responsiveness to GnRH. T-exposed rams, like control males, exhibited vigorous libido and were sexually attracted to estrous females. In summary, these results suggest that exposure to exogenous T during the first trimester of gestation can negatively impact spermatogenesis and compromise the reproductive fitness of rams. Copyright © 2017 Elsevier Inc. All rights reserved.

Inducible growth mode switches influence Valonia rhizoid differentiation.

PubMed

Elvira, Paul Rommel; Sekida, Satoko; Okuda, Kazuo

2013-02-01

Cell differentiation and cell type commitment are an integral part of plant growth and development. Investigations on how environmental conditions affect the formation of shoots, roots, and rhizoids can help illustrate how plants determine cell fate and overall morphology. In this study, we evaluated the role of substratum and light on rhizoid differentiation in the coenocytic green alga, Valonia aegagropila. Elongating rhizoids displayed varying growth modes and cell shape upon exposure to different substrata and light conditions. It was found that soft substrata and dark incubation promoted rhizoid elongation via tip growth while subsequent exposure to light prevented tip growth and instead induced swelling in the apical region of rhizoids. Swelling was accompanied by the accumulation of protoplasm in the rhizoid tip through expansion of the cell wall and uninhibited cytoplasmic streaming. Subsequent diffuse growth led to the transformation from slender, rod-shaped rhizoids into spherical thallus-like structures that required photosynthesis. Further manipulation of light regimes caused vacillating cell growth redirections. An elongating V. aegagropila rhizoid cell thus appears capable of growth mode switching that is regulated by immediate environmental conditions thereby influencing ultimate cell shape and function. This is the first description of inducible, multiple growth mode shifts in a single intact plant cell that directly impact its differentiation.

Disturbances in Maternal Steroidogenesis and Appearance of Intrauterine Growth Retardation at High-Altitude Environments Are Established from Early Pregnancy. Effects of Treatment with Antioxidant Vitamins

PubMed Central

Parraguez, Victor H.; Mamani, Sandra; Cofré, Eileen; Castellaro, Giorgio; Urquieta, Bessie; De los Reyes, Mónica; Astiz, Susana; Gonzalez-Bulnes, Antonio

2015-01-01

Pregnancies at high-altitudes are influenced by hypoxia and oxidative stress and frequently affected by IUGR. However, a common thought is that early pregnant women visiting altitude have no major complications for gestation development, since IUGR is developed during the second half of pregnancy. Thus, using a well-characterized sheep-model, we aimed to determine whether long- and/or short-term exposure to high-altitude may affect maternal steroidogenesis and therefore embryo-fetal growth from conception. The second aim was to differentiate the relative role of hypoxia and oxidative stress by assessing the effects of supplementation with antioxidant agents during this early-pregnancy stage, which were previously found to be useful to prevent IUGR. The results indicate that both long- and short-term exposure to high-altitude causes disturbances in maternal ovarian steroidogenesis and negatively affects embryo-fetal growth already during the very early stages of gestation, with the consequences being even worsened in newcomers to high-altitude. The supply of antioxidant during this period only showed discrete effects for preventing IUGR. In conclusion, the present study gives a warning for clinicians about the risks for early-pregnant women when visiting high-altitude regions and suggests the need for further studies on the effects of the length of exposure and on the interaction of the exposure with the pregnancy stage. PMID:26560325

Phosphoproteomics profiling of human skin fibroblast cells reveals pathways and proteins affected by low doses of ionizing radiation.

PubMed

Yang, Feng; Waters, Katrina M; Miller, John H; Gritsenko, Marina A; Zhao, Rui; Du, Xiuxia; Livesay, Eric A; Purvine, Samuel O; Monroe, Matthew E; Wang, Yingchun; Camp, David G; Smith, Richard D; Stenoien, David L

2010-11-30

High doses of ionizing radiation result in biological damage; however, the precise relationships between long-term health effects, including cancer, and low-dose exposures remain poorly understood and are currently extrapolated using high-dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose-dependent responses to radiation. We have identified 7117 unique phosphopeptides (2566 phosphoproteins) from control and irradiated (2 and 50 cGy) primary human skin fibroblasts 1 h post-exposure. Semi-quantitative label-free analyses were performed to identify phosphopeptides that are apparently altered by radiation exposure. This screen identified phosphorylation sites on proteins with known roles in radiation responses including TP53BP1 as well as previously unidentified radiation-responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatic analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role for MAP kinase and protein kinase A (PKA) signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provide a basis for the systems-level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at different radiation doses and elucidate the impact of low-dose radiation exposure on human health.

Phosphoproteomics Profiling of Human Skin Fibroblast Cells Reveals Pathways and Proteins Affected by Low Doses of Ionizing Radiation

PubMed Central

Yang, Feng; Waters, Katrina M.; Miller, John H.; Gritsenko, Marina A.; Zhao, Rui; Du, Xiuxia; Livesay, Eric A.; Purvine, Samuel O.; Monroe, Matthew E.; Wang, Yingchun; Camp, David G.; Smith, Richard D.; Stenoien, David L.

2010-01-01

Background High doses of ionizing radiation result in biological damage; however, the precise relationships between long-term health effects, including cancer, and low-dose exposures remain poorly understood and are currently extrapolated using high-dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose-dependent responses to radiation. Principal Findings We have identified 7117 unique phosphopeptides (2566 phosphoproteins) from control and irradiated (2 and 50 cGy) primary human skin fibroblasts 1 h post-exposure. Semi-quantitative label-free analyses were performed to identify phosphopeptides that are apparently altered by radiation exposure. This screen identified phosphorylation sites on proteins with known roles in radiation responses including TP53BP1 as well as previously unidentified radiation-responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatic analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role for MAP kinase and protein kinase A (PKA) signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. Conclusions Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provide a basis for the systems-level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at different radiation doses and elucidate the impact of low-dose radiation exposure on human health. PMID:21152398

Neurotoxicogenomic investigations to assess mechanisms of action of the munitions constituents RDX and 2,6-DNT in Northern bobwhite (Colinus virginianus).

PubMed

Gust, Kurt A; Pirooznia, Mehdi; Quinn, Michael J; Johnson, Mark S; Escalon, Lynn; Indest, Karl J; Guan, Xin; Clarke, Joan; Deng, Youping; Gong, Ping; Perkins, Edward J

2009-07-01

Munitions constituents (MCs) including hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), 2,4,6-trinitrotoluene (TNT), and TNT derivatives are recognized to elicit aberrant neuromuscular responses in many species. The onset of seizures resulting in death was observed in the avian model Northern bobwhite after oral dosing with RDX beginning at 8 mg/kg/day in subacute (14 days) exposures, whereas affective doses of the TNT derivative, 2,6-dinitrotoluene (2,6-DNT), caused gastrointestinal impacts, lethargy, and emaciation in subacute and subchronic (60 days) exposures. To assess and contrast the potential neurotoxicogenomic effects of these MCs, a Northern bobwhite microarray was developed consisting of 4119 complementary DNA (cDNA) features enriched for differentially-expressed brain transcripts from exposures to RDX and 2,6-DNT. RDX affected hundreds of genes in brain tissue, whereas 2,6-DNT affected few (

Exposure to altered gravity during specific developmental periods differentially affects growth, development, the cerebellum and motor functions in male and female rats

NASA Astrophysics Data System (ADS)

Nguon, K.; Ladd, B.; Sajdel-Sulkowska, E. M.

2006-01-01

We previously reported that perinatal exposure to hypergravity affects cerebellar structure and motor coordination in rat neonates. In the present study, we explored the hypothesis that neonatal cerebellar structure and motor coordination may be particularly vulnerable to the effects of hypergravity during specific developmental stages. To test this hypothesis, we compared neurodevelopment, motor behavior and cerebellar structure in rat neonates exposed to 1.65 G on a 24-ft centrifuge during discrete periods of time: the 2nd week of pregnancy [gestational day (G) 8 through G15; group A], the 3rd week of pregnancy (G15 through birth on G22/G23; group B), the 1st week of nursing [birth through postnatal day (P) 6; group C], the 2nd and 3rd weeks of nursing (P6 through P21; group D), the combined 2nd and 3rd weeks of pregnancy and nursing (G8 through P21; group E) and stationary control (SC) neonates (group F). Prenatal exposure to hypergravity resulted in intrauterine growth retardation as reflected by a decrease in the number of pups in a litter and lower average mass at birth. Exposure to hypergravity immediately after birth impaired the righting response on P3, while the startle response in both males and females was most affected by exposure during the 2nd and 3rd weeks after birth. Hypergravity exposure also impaired motor functions, as evidenced by poorer performance on a rotarod; while both males and females exposed to hypergravity during the 2nd and 3rd weeks after birth performed poorly on P21, male neonates were most dramatically affected by exposure to hypergravity during the second week of gestation, when the duration of their recorded stay on the rotarod was one half that of SC males. Cerebellar mass was most reduced by later postnatal exposure. Thus, for the developing rat cerebellum, the postnatal period that overlaps the brain growth spurt is the most vulnerable to hypergravity. However, male motor behavior is also affected by midpregnancy exposure to hypergravity, suggesting discrete and sexually dimorphic windows of vulnerability of the developing central nervous system to environmental perturbations.

Bilobalide induces neuronal differentiation of P19 embryonic carcinoma cells via activating Wnt/β-catenin pathway.

PubMed

Liu, Mei; Guo, Jingjing; Wang, Juan; Zhang, Luyong; Pang, Tao; Liao, Hong

2014-08-01

Bilobalide, a natural product extracted from Ginkgo biloba leaf, is known to exhibit a number of pharmacological activities. So far, whether it could affect embryonic stem cell differentiation is still unknown. The main aim of this study was to investigate the effect of bilobalide on P19 embryonic carcinoma cells differentiation and the underlying mechanisms. Our results showed that bilobalide induced P19 cells differentiation into neurons in a concentration- and time-dependent manner. We also found that bilobalide promoted neuronal differentiation through activation of Wnt/β-catenin signaling pathway. Exposure to bilobalide increased inactive GSK-3β phosphorylation, further induced the nuclear accumulation of β-catenin, and also up-regulated the expression of Wnt ligands Wnt1 and Wnt7a. Neuronal differentiation induced by bilobalide was totally abolished by XAV939, an inhibitor of Wnt/β-catenin pathway. These results revealed a novel role of bilobalide in neuronal differentiation from P19 embryonic cells acting through Wnt/β-catenin signaling pathway, which would provide a better insight into the beneficial effects of bilobalide in brain diseases.

Simulation of the geomagnetic field experienced by the International Space Station in its revolution around the Earth: Effects on psychophysiological responses to affective picture viewing

NASA Astrophysics Data System (ADS)

Del Seppia, C.; Mezzasalma, L.; Messerotti, M.; Cordelli, A.; Ghione, S.

2006-02-01

There is evidence suggesting that exposure to an abnormal magnetic environment may produce psychophysiological effects related to abnormalities in responses to stress. This may be of relevance for space medicine where astronauts are exposed to a magnetic field different from that exerted by the Earth. Aim of this study was to assess how the exposure of the head to a magnetic field simulating the one encountered by the International Space Station (ISS) during a single orbit (90 min) around the Earth affects the cardiovascular and psychophysiological parameters. Twenty-four human volunteers were studied double blindly in random order under sham and magnetic exposure. During exposure, the persons were shown a set of pictures of different emotional content while subjective self-rating, skin conductance (SC), blood pressure (BP), and heart rate (HR) were measured. In addition, BP, HR, and tooth pain threshold were assessed before and after exposure. While subjects were under magnetic exposure, skin conductance was strongly differentiated (F|2,36 = 22.927; p = 0.0001), being high during emotionally involving (positive and negative) pictures and low during neutral pictures. Conversely, when subjects were under sham exposure, no significant differences were observed. There was, however, a trend for higher heart rate during picture viewing under magnetic exposure as compared to sham exposure. No effects were found for the other variables. These results suggest that an abnormal magnetic field that simulates the one encountered by ISS orbiting around the Earth may enhance autonomic response to emotional stimuli.

Molecular insights into the progression of crystalline silica-induced pulmonary toxicity in rats.

PubMed

Sellamuthu, Rajendran; Umbright, Christina; Roberts, Jenny R; Cumpston, Amy; McKinney, Walter; Chen, Bean T; Frazer, David; Li, Shengqiao; Kashon, Michael; Joseph, Pius

2013-04-01

Identification of molecular target(s) and mechanism(s) of silica-induced pulmonary toxicity is important for the intervention and/or prevention of diseases associated with exposure to silica. Rats were exposed to crystalline silica by inhalation (15 mg m(-3), 6 h per day, 5 days) and global gene expression profile was determined in the lungs by microarray analysis at 1, 2, 4, 8 and 16 weeks following termination of silica exposure. The number of significantly differentially expressed genes (>1.5-fold change and <0.01 false discovery rate P-value) detected in the lungs during the post-exposure time intervals analyzed exhibited a steady increase in parallel with the progression of silica-induced pulmonary toxicity noticed in the rats. Quantitative real-time PCR analysis of a representative set of 10 genes confirmed the microarray findings. The number of biological functions, canonical pathways and molecular networks significantly affected by silica exposure, as identified by the bioinformatics analysis of the significantly differentially expressed genes detected during the post-exposure time intervals, also exhibited a steady increase similar to the silica-induced pulmonary toxicity. Genes involved in oxidative stress, inflammation, respiratory diseases, cancer, and tissue remodeling and fibrosis were significantly differentially expressed in the rat lungs; however, unresolved inflammation was the single most significant biological response to pulmonary exposure to silica. Excessive mucus production, as implicated by significant overexpression of the pendrin coding gene, SLC26A4, was identified as a potential novel mechanism for silica-induced pulmonary toxicity. Collectively, the findings of our study provided insights into the molecular mechanisms underlying the progression of crystalline silica-induced pulmonary toxicity in the rat. Published 2012. This article is a US Government work and is in the public domain in the USA. Published 2012. This article is a US Government work and is in the public domain in the USA.

Prenatal exposure of mice to diethylstilbestrol disrupts T-cell differentiation by regulating Fas/Fas ligand expression through estrogen receptor element and nuclear factor-κB motifs.

PubMed

Singh, Narendra P; Singh, Udai P; Nagarkatti, Prakash S; Nagarkatti, Mitzi

2012-11-01

Prenatal exposure to diethylstilbestrol (DES) is known to cause altered immune functions and increased susceptibility to autoimmune disease in humans. In the current study, we investigated the effect of prenatal exposure to DES on thymocyte differentiation involving apoptotic pathways. Prenatal DES exposure caused thymic atrophy, apoptosis, and up-regulation of Fas and Fas ligand (FasL) expression in thymocytes. To examine the mechanism underlying DES-mediated regulation of Fas and FasL, we performed luciferase assays using T cells transfected with luciferase reporter constructs containing full-length Fas or FasL promoters. There was significant luciferase induction in the presence of Fas or FasL promoters after DES exposure. Further analysis demonstrated the presence of several cis-regulatory motifs on both Fas and FasL promoters. When DES-induced transcription factors were analyzed, estrogen receptor element (ERE), nuclear factor κB (NF-κB), nuclear factor of activated T cells (NF-AT), and activator protein-1 motifs on the Fas promoter, as well as ERE, NF-κB, and NF-AT motifs on the FasL promoter, showed binding affinity with the transcription factors. Electrophoretic mobility-shift assays were performed to verify the binding affinity of cis-regulatory motifs of Fas or FasL promoters with transcription factors. There was shift in mobility of probes (ERE or NF-κB2) of both Fas and FasL in the presence of nuclear proteins from DES-treated cells, and the shift was specific to DES because these probes failed to shift their mobility in the presence of nuclear proteins from vehicle-treated cells. Together, the current study demonstrates that prenatal exposure to DES triggers significant alterations in apoptotic molecules expressed on thymocytes, which may affect T-cell differentiation and cause long-term effects on the immune functions.

Prenatal Exposure of Mice to Diethylstilbestrol Disrupts T-Cell Differentiation by Regulating Fas/Fas Ligand Expression through Estrogen Receptor Element and Nuclear Factor-κB Motifs

PubMed Central

Singh, Narendra P.; Singh, Udai P.; Nagarkatti, Prakash S.

2012-01-01

Prenatal exposure to diethylstilbestrol (DES) is known to cause altered immune functions and increased susceptibility to autoimmune disease in humans. In the current study, we investigated the effect of prenatal exposure to DES on thymocyte differentiation involving apoptotic pathways. Prenatal DES exposure caused thymic atrophy, apoptosis, and up-regulation of Fas and Fas ligand (FasL) expression in thymocytes. To examine the mechanism underlying DES-mediated regulation of Fas and FasL, we performed luciferase assays using T cells transfected with luciferase reporter constructs containing full-length Fas or FasL promoters. There was significant luciferase induction in the presence of Fas or FasL promoters after DES exposure. Further analysis demonstrated the presence of several cis-regulatory motifs on both Fas and FasL promoters. When DES-induced transcription factors were analyzed, estrogen receptor element (ERE), nuclear factor κB (NF-κB), nuclear factor of activated T cells (NF-AT), and activator protein-1 motifs on the Fas promoter, as well as ERE, NF-κB, and NF-AT motifs on the FasL promoter, showed binding affinity with the transcription factors. Electrophoretic mobility-shift assays were performed to verify the binding affinity of cis-regulatory motifs of Fas or FasL promoters with transcription factors. There was shift in mobility of probes (ERE or NF-κB2) of both Fas and FasL in the presence of nuclear proteins from DES-treated cells, and the shift was specific to DES because these probes failed to shift their mobility in the presence of nuclear proteins from vehicle-treated cells. Together, the current study demonstrates that prenatal exposure to DES triggers significant alterations in apoptotic molecules expressed on thymocytes, which may affect T-cell differentiation and cause long-term effects on the immune functions. PMID:22888145

Individual differences in fear extinction and anxiety-like behavior

PubMed Central

King, Gabrielle; Scott, Elliot; Graham, Bronwyn M.; Richardson, Rick

2017-01-01

There is growing appreciation for the substantial individual differences in the acquisition and inhibition of aversive associations, and the insights this might give into identifying individuals particularly vulnerable to stress and psychopathology. We examined whether animals that differed in rate of extinction (i.e., Fast versus Slow) were different in their response to an acute stress in adulthood or following a chronic stress that occurred either early or later in life. We found that Slow Extinguishers had significantly poorer extinction retention than Fast Extinguishers, but an acute stressor did not differentially affect anxiety-like behavior in the two groups. Further, while exposure to chronic stress in adulthood did not impact on the extinction phenotypes or anxiety-like behavior, exposure to chronic stress early in life affected both extinction retention and anxiety-like behavior. These findings have implications for the development of a more nuanced approach to identifying those most at risk of anxiety disorders. PMID:28416629

Detecting and reacting to change: the effect of exposure to narrow categorizations.

PubMed

Chakravarti, Amitav; Fang, Christina; Shapira, Zur

2011-11-01

The ability to detect a change, to accurately assess the magnitude of the change, and to react to that change in a commensurate fashion are of critical importance in many decision domains. Thus, it is important to understand the factors that systematically affect people's reactions to change. In this article we document a novel effect: decision makers' reactions to a change (e.g., a visual change, a technology change) were systematically affected by the type of categorizations they encountered in an unrelated prior task (e.g., the response categories associated with a survey question). We found that prior exposure to narrow, as opposed to broad, categorizations improved decision makers' ability to detect change and led to stronger reactions to a given change. These differential reactions occurred because the prior categorizations, even though unrelated, altered the extent to which the subsequently presented change was perceived as either a relatively large change or a relatively small one.

Biphasic influence of dexamethasone exposure on embryonic vertebrate skeleton development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheng, Xin; Chen, Jian-long; Ma, Zheng-lai

Dexamethasone (Dex) has anti-inflammatory and immunomodulatory properties against many conditions. There is a potential teratogenic risk, however, for pregnant women receiving Dex treatment. It has been claimed that Dex exposure during pregnancy could affect osteogenesis in the developing embryo, which still remains highly controversial. In this study, we employed chick embryos to investigate the effects of Dex exposure on skeletal development using combined in vivo and in vitro approach. First, we demonstrated that Dex (10{sup −8}–10{sup −6} μmol/egg) exposure resulted in a shortening of the developing long bones of chick embryos, and it accelerated the deposition of calcium salts. Secondly,more » histological analysis of chick embryo phalanxes exhibited Dex exposure inhibited the proliferation of chondrocytes, increased apoptosis of chondrocytes and osteocytes, and led to atypical arranged hypertrophic chondrocytes. The expression of genes related to skeletogenesis was also analyzed by semi-quantitative RT-PCR. The expression of ALP, Col1a2 and Col2a1 was decreased in the Dex treated phalanxes. A detectable increase was observed in Runx-2 and Mmp-13 expression. We next examined how Dex affected the different stages of skeletogenesis in vitro. Utilizing limb bud mesenchyme micromass cultures, we determined that Dex exposure exerted no effect on apoptosis but impaired chondrogenic cell proliferation. Interestingly, low dose of Dex moderately prompted nodule formation as revealed by alcian blue staining, but higher doses of Dex significantly inhibited similar chondrogenic differentiation. Dex exposure did not induce apoptosis when the chondrogenic precursors were still at the mesenchymal stage, however, cell viability was suppressed when the mesenchyme differentiated into chondrocytes. Alizarin red staining revealed that the capacity to form mineralized bone nodules was correspondingly enhanced as Dex concentrations increased. The mRNA level of Sox-9 was slightly increased in mesenchymal cell mass treated by low concentration of Dex. Mmp-13 expression was obviously up-regulated by Dex in both mesenchymal cells and primary chondrocyte cultures. And Col10a1 expression was also increased by Dex exposure in chondrocyte. In summary, we have revealed that different concentrations of Dex exposure during early gestation could exert a biphasic effect on vertebrate skeletal development. - Highlights: • Chick embryos occurred shortening of the long bone following Dex exposure. • Dex suppressed chondrocytes proliferation and promoted apoptosis. • Dex exposure decreased ALP production and up-regulated Runx-2 and Mmp-13. • Dex exhibited biphasic effects on chondrogenic proliferation and nodule formation. • The hypertrophy and ossification were accelerated by Dex both in vivo and in vitro.« less

Clearance of ingested neonicotinoid pesticide (imidacloprid) in honey bees (Apis mellifera) and bumblebees (Bombus terrestris).

PubMed

Cresswell, James E; Robert, François-Xavier L; Florance, Hannah; Smirnoff, Nicholas

2014-02-01

Bees in agricultural landscapes are exposed to dietary pesticides such as imidacloprid when they feed from treated mass-flowering crops. Concern about the consequent impact on bees makes it important to understand their resilience. In the laboratory, the authors therefore fed adult worker bees on dosed syrup (125 μg L(-1) of imidacloprid, or 98 μg kg(-1)) either continuously or as a pulsed exposure and measured their behaviour (feeding and locomotory activity) and whole-body residues. On dosed syrup, honey bees maintained much lower bodily levels of imidacloprid than bumblebees (<0.2 ng versus 2.4 ng of imidacloprid per bee). Dietary imidacloprid did not affect the behaviour of honey bees, but it reduced feeding and locomotory activity in bumblebees. After the pulsed exposure, bumblebees cleared bodily imidacloprid after 48 h and recovered behaviourally. The differential behavioural resilience of the two species can be attributed to the observed differential in bodily residues. The ability of bumblebees to recover may be environmentally relevant in wild populations that face transitory exposures from the pulsed blooming of mass-flowering crops. © 2013 Society of Chemical Industry.

Differential sensitivity of osteoblasts and bacterial pathogens to 405-nm light highlighting potential for decontamination applications in orthopedic surgery

NASA Astrophysics Data System (ADS)

Ramakrishnan, Praveen; Maclean, Michelle; MacGregor, Scott J.; Anderson, John G.; Grant, M. Helen

2014-10-01

Healthcare associated infections pose a major threat to patients admitted to hospitals and infection rates following orthopedic arthroplasty surgery are as high as 4%. A 405-nm high-intensity narrow spectrum light has been proven to reduce environmental contamination in hospital isolation rooms, and there is potential to develop this technology for application in arthroplasty surgery. Cultured rat osteoblasts were exposed to varying light intensities and it was found that exposures of up to a dose of 36 J/cm2 had no significant effect on cell viability [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay], function (alkaline phosphatase activity), and proliferation rate (BrdU cell proliferation assay). High irradiance exposures (54 J/cm2) significantly affected the cell viability indicating that the effects of 405-nm light on osteoblasts are dose dependent. Additionally, exposure of a variety of clinically related bacteria to a dose of 36 J/cm2 resulted in up to 100% kill. These results demonstrating the differential sensitivity of osteoblasts and bacteria to 405-nm light are an essential step toward developing the technique for decontamination in orthopedic surgery.

Assessing effects of military aircraft noise on residential property values near airbases

NASA Astrophysics Data System (ADS)

Fidell, Sanford; Tabachnick, Barbara; Silvati, Laura; Cook, Brenda

The question, 'Does military aircraft noise exposure affect residential property values in the vicinity of Air Force bases?', can be asked and answered with varying degrees of generality and tolerable errors of inference. Definitive answers are difficult to develop because the question itself may not be meaningful in some circumstances: property values are affected by many factors other than aircraft noise which can fluctuate greatly in different areas and during different time periods; credible attribution of causality for changes in property values uniquely to aircraft noise requires many costly study design measures; and prior findings suggest that if a relationship exists, it is not a large or especially strong one. Thus, evidence of a simple geographic association between aircraft noise exposure and residential property values does not provide a conclusive answer to the question. In an effort to develop more compelling evidence, the US Air Force is planning to compare historical records of sale prices of properties in areas of differential aircraft noise exposure during specific time periods with predictions of sale prices derived from a validated statistical model of residential property values.

Degree of exposure to domestic violence, psychopathology, and functional impairment in children and adolescents.

PubMed

Bayarri Fernàndez, Eduard; Ezpeleta, Lourdes; Granero, Roser; de la Osa, Núria; Domènech, Josep María

2011-04-01

There are discrepancies about whether children who witness and suffer domestic violence (DV) have similar outcomes in terms of psychopathology. This work examines the relationship between different types of exposure to DV and child psychopathology and functional impairment. One hundred and forty-four Spanish children aged from 4 to 17 years and exposed to DV were evaluated using a diagnostic interview and other instruments of psychopathology and functional impairment. The participants were classified in three groups according to the degree of exposure: witness (n = 72), involved (n = 52), and victim (n = 20). According to mothers' self-reports and mother-child combined information, DV equally affects psychopathology and functional impairment regardless of the degree of the exposure. Children's self-reports showed a linear trend to present greater psychopathology as a victim than as a witness. The differential effect of exposure to DV measured in this study depended on the informant, which underlines the importance of obtaining information from the children exposed to violence at home.

Unpacking Trauma Exposure Risk Factors and Differential Pathways of Influence: Predicting Postwar Mental Distress in Bosnian Adolescents

ERIC Educational Resources Information Center

Layne, Christopher M.; Olsen, Joseph A.; Baker, Aaron; Legerski, John-Paul; Isakson, Brian; Pasalic, Alma; Durakovic-Belko, Elvira; Dapo, Nermin; Campara, Nihada; Arslanagic, Berina; Saltzman, William R.; Pynoos, Robert S.

2010-01-01

Methods are needed for quantifying the potency and differential effects of risk factors to identify at-risk groups for theory building and intervention. Traditional methods for constructing war exposure measures are poorly suited to "unpack" differential relations between specific types of exposure and specific outcomes. This study of…

Molecular cloning of Foxl2 gene and the effects of endocrine-disrupting chemicals on its mRNA level in rare minnow, Gobiocypris rarus.

PubMed

Wang, Houpeng; Wu, Tingting; Qin, Fang; Wang, Lihong; Wang, Zaizhao

2012-06-01

Endocrine-disrupting chemicals (EDCs) can affect normal sexual differentiation in fish. Foxl2, one forkhead transcription factor, plays an important role in ovarian differentiation in the early development of the female gonad in mammals and fish. How EDCs affect Foxl2 expression is little known. In this study, we isolated a Foxl2 cDNA from the ovary of rare minnow Gobiocypris rarus and examined its expression during early development stages and in different adult tissues. Then, we analyzed Foxl2 expression in G. rarus juvenile following 3-day exposure to 17α- ethinylestradiol (EE2), 4-n-nonylphenol (NP), and bisphenol A (BPA). Alignment of known Foxl2 sequences among vertebrates showed high identity in forkhead domain and C-terminal region with other vertebrate proteins. Quantitative RT-PCR analysis showed that Foxl2 expression was linear decrease and cyp19a1a, the downstream target gene of Foxl2, had no correlation with Foxl2 from 18 to 50 days post fertilization (dpf). Among different adult tissues, Foxl2 is mainly expressed in ovary, brain, gill, eye, and male spleen. In the 3-day exposure, the juvenile fish to EDCs, 0.1 nM EE2, and 1 nM BPA significantly up-regulated the expression of Foxl2 gene, while NP had no effect on Foxl2 expression. Altogether, these results provide basic data for further study on how Foxl2 mediates EDCs impact on the sexual differentiation in G. rarus.

Keeping a healthy distance: Self-differentiation and perceived health among ex-prisoners-of-war's wives.

PubMed

Lahav, Yael; Stein, Jacob Y; Solomon, Zahava

2016-10-01

War captivity may affect spouses of former-prisoners-of-war (ex-POWs) in many ways, including posttraumatic stress symptoms (PTSS) and somatic difficulties manifested in negative perceived health. This is generally known as secondary traumatization. Theory suggests that development of secondary traumatization occurs through the relationship with the primary trauma survivor Figley (1986) , thus implying that the ability to keep balanced emotional distance in the relationship may play a pivotal role. Notwithstanding, the contribution of self-differentiation to secondary somatic disturbances remains largely uninvestigated. The current study fills this gap. Ex-POWs' wives (n=143) and control former-combatants' wives (n=102), were assessed prospectively 30 (T1) and 38 (T2) years after the 1973 Yom Kippur War. Self-differentiation and PTSS were assessed at both time-points, while perceived health measures were assessed at T2. Wives of ex-POWs endorsed higher PTSS, lower self-differentiation and negative perceived health, compared to control wives. Indirect exposure to war captivity was related to low self-differentiation and elevated PTSS, which predicted negative perceived health. Furthermore, self-differentiation characterized by fusion-with-others fully mediated the relation between indirect exposure to war captivity and perceived health, beyond the effects of PTSS as a mechanism. Results suggest that tendencies towards fusion-with-others within the marital relationship, act as a risk factor not only for psychological distress but also for somatic distress among secondary trauma survivors. Hence, clinical interventions may seek to improve indirect trauma survivor's self-differentiation capacities, thus potentially facilitating the prevention of secondary somatic distress. Copyright © 2016 Elsevier Inc. All rights reserved.

Cadmium affects the social behaviour of rainbow trout, Oncorhynchus mykiss.

PubMed

Sloman, Katherine A; Scott, Graham R; Diao, Zhongyu; Rouleau, Claude; Wood, Chris M; McDonald, D Gord

2003-10-29

The present study investigated both the effects of cadmium on the social interactions of rainbow trout and the differential accumulation of waterborne cadmium among social ranks of fish. Fish exposed to waterborne cadmium concentrations of 2 microg l(-1) for 24 h, followed by a 1, 2 or 3 day depuration period in clean water, had a decreased ability to compete with non-exposed fish. However, the competitive ability of exposed fish given a 5 day depuration period was not significantly impaired. Cadmium accumulated in the olfactory apparatus of fish exposed to waterborne cadmium for 24 h and decreased significantly only after 5 days depuration in clean water. Among groups of ten fish held in stream tanks, where all fish were exposed to cadmium, there were significant effects on social behaviour and growth rate. Dominance hierarchies formed faster among fish exposed to cadmium than among control fish, and overall growth rates were higher in the cadmium treatment. In groups of ten fish, social status also affected tissue accumulation of cadmium during waterborne exposure, with dominant fish accumulating more cadmium at the gill. In conclusion, exposure to low levels of cadmium, affects the social behaviour of fish, in part due to accumulation in the olfactory apparatus, and dominant fish accumulate more gill cadmium than subordinates during chronic waterborne exposure.

Sleep quality affects cognitive functioning in returning combat veterans beyond combat exposure, PTSD, and mild TBI history.

PubMed

Martindale, Sarah L; Morissette, Sandra B; Rowland, Jared A; Dolan, Sara L

2017-01-01

The purpose of this study was to determine how sleep quality affects cognitive functioning in returning combat veterans after accounting for effects of combat exposure, posttraumatic stress disorder (PTSD), and mild traumatic brain injury (mTBI) history. This was a cross-sectional assessment study evaluating combat exposure, PTSD, mTBI history, sleep quality, and neuropsychological functioning. One hundred and nine eligible male Iraq/Afghanistan combat veterans completed an assessment consisting of a structured clinical interview, neuropsychological battery, and self-report measures. Using partial least squares structural equation modeling, combat experiences and mTBI history were not directly associated with sleep quality. PTSD was directly associated with sleep quality, which contributed to deficits in neuropsychological functioning independently of and in addition to combat experiences, PTSD, and mTBI history. Combat experiences and PTSD were differentially associated with motor speed. Sleep affected cognitive function independently of combat experiences, PTSD, and mTBI history. Sleep quality also contributed to cognitive deficits beyond effects of PTSD. An evaluation of sleep quality may be a useful point of clinical intervention in combat veterans with cognitive complaints. Improving sleep quality could alleviate cognitive complaints, improving veterans' ability to engage in treatment. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Focus on: epigenetics and fetal alcohol spectrum disorders.

PubMed

Kobor, Michael S; Weinberg, Joanne

2011-01-01

Epigenetic changes-stable but potentially reversible alterations in a cell's genetic information that result in changes in gene expression but do not involve changes in the underlying DNA sequence-may mediate some of the detrimental effects of prenatal alcohol exposure and contribute to the deficits and abnormalities associated with fetal alcohol spectrum disorders. These epigenetic processes are linked to the chromatin (i.e., DNA, histone proteins, and other associated proteins) and commonly involve chemical modifications (e.g., methylation) of these molecules, which may result in altered expression of the affected genes. Even alcohol exposure prior to conception appears to be able to induce epigenetic changes in the parental genetic material that can be passed on to the offspring and affect offspring outcome. Similarly, epigenetic processes may occur as a result of maternal alcohol consumption during the period between fertilization of the egg and implantation in the uterus. The period most sensitive to alcohol's adverse effects appears to be gastrulation, which corresponds to prenatal weeks 3 to 8 in the human and prenatal days 7 to 14 in the mouse, when cells are differentiating to form organs. One way in which alcohol exposure may induce epigenetic changes, particularly abnormal DNA methylation, is by affecting a set of biochemical reactions called the methionine-homocysteine cycle.

Focus On: Epigenetics and Fetal Alcohol Spectrum Disorders

PubMed Central

Kobor, Michael S.; Weinberg, Joanne

2011-01-01

Epigenetic changes—stable but potentially reversible alterations in a cell’s genetic information that result in changes in gene expression but do not involve changes in the underlying DNA sequence—may mediate some of the detrimental effects of prenatal alcohol exposure and contribute to the deficits and abnormalities associated with fetal alcohol spectrum disorders. These epigenetic processes are linked to the chromatin (i.e., DNA, histone proteins, and other associated proteins) and commonly involve chemical modifications (e.g., methylation) of these molecules, which may result in altered expression of the affected genes. Even alcohol exposure prior to conception appears to be able to induce epigenetic changes in the parental genetic material that can be passed on to the offspring and affect offspring outcome. Similarly, epigenetic processes may occur as a result of maternal alcohol consumption during the period between fertilization of the egg and implantation in the uterus. The period most sensitive to alcohol’s adverse effects appears to be gastrulation, which corresponds to prenatal weeks 3 to 8 in the human and prenatal days 7 to 14 in the mouse, when cells are differentiating to form organs. One way in which alcohol exposure may induce epigenetic changes, particularly abnormal DNA methylation, is by affecting a set of biochemical reactions called the methionine–homocysteine cycle. PMID:23580038

DOE Office of Scientific and Technical Information (OSTI.GOV)

Polyzos, Aris; Schmid, Thomas Ernst; Pina-Guzman, Belem

Cigarette smoking in men has been associated with increased chromosomal abnormalities in sperm and with increased risks for spontaneous abortions, birth defects and neonatal death. Little is known, however, about the reproductive consequences of paternal exposure to second-hand smoke. We used a mouse model to investigate the effects of paternal exposure to sidestream (SS) smoke, the main constituent of second-hand smoke, on the genetic integrity and function of sperm, and to determine whether male germ cells were equally sensitive to mainstream (MS) and SS smoke. A series of sperm DNA quality and reproductive endpoints were investigated after exposing male micemore » for two weeks to MS or SS smoke. Our results indicated that: (i) only SS smoke significantly affected sperm motility; (ii) only MS smoke induced DNA strand breaks in sperm; (iii) both MS and SS smoke increased sperm chromatin structure abnormalities; and (iv) MS smoke affected both fertilization and the rate of early embryonic development, while SS smoke affected fertilization only. These results show that MS and SS smoke have differential effects on the genetic integrity and function of sperm and provide further evidence that male exposure to second-hand smoke, as well as direct cigarette smoke, may diminish a couple's chance for a successful pregnancy and the birth of a healthy baby.« less

The induction of monocytopoiesis in HL-60 promyelocytic leukemia cells is inhibited by hydroquinone, a toxic metabolite of benzene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oliveira, N.L.

1992-01-01

Chronic exposure of humans to benzene has been shown to have a cytotoxic effect on hematopoietic progenitor cells in intermediate stages of differentiation which can lead to aplastic anemia and acute myelogenous leukemia. This thesis examined the effect of hydroquinone, a toxic metabolite of benzene found in the bone marrow, on the human promyelocytic leukemia cell line (HL-60) which can be induced to differentiate to both monocyte and myeloid cells, and thus has been used as a surrogate for a granulocyte/macrophage progenitor cell. Exposure of HL-60 cells to noncytotoxic concentrations of hydroquinone for three hours prior to induction with 12-O-tetradecanoylmore » phorbol-13-acetate caused a dose-dependent inhibition of the acquisition of characteristics of monocytic differentiation. These included adherence, nonspecific esterase activity and phagocytosis. Hydroquinone had no effect on cell proliferation. Hydroquinone appeared to be affecting maturation beyond the monoblast/promonocyte stages. Hydroquinone also prevented differentiation induced by 1, 25-dihydroxy vitamin D[sub 3], however, the block occurred after the acquisition of adherence. Hydroquinone at concentrations that inhibited monocytic differentiation had no effect on differentiation to granulocytes, suggesting that the block in the differentiation of these bipotential cells is at a step unique to the monocytic pathway. Hydroquinone was unable to prevent differentiation induced by the macrophage-derived cytokine interleukin-1, a differentiation factor for cells of the monocytic lineage. These data demonstrate that treatment of Hl-60 cells with hydroquinone prior to induction of differentiation prevents the acquisition of the monocytic phenotype induced by TPA or 1, 25(OH)[sub 2]D[sub 3] by a mechanism which at present is unknown, but which appears to be specific for the monocytic pathway. These results are of considerable significance for benzene hematotoxicity.« less

Selenium protects reproductive system and foetus development in a rat model of gestational lead exposure.

PubMed

Shen, W; Chen, J; Yin, J; Wang, S-L

2016-01-01

Lead is a common environmental contaminant. Lead accumulation in the body is especially dangerous for pregnant women and newborns. Selenium is a trace element which may rectify the damaging effects of lead. Here we tested potential protective effects of selenium against gestational lead exposure. Pregnant SD rats were exposed to 200 mg/L of lead acetate (given with water), with or without sodium selenite supplementation (2-8 mg/kg/day via intragastric administration). Pregnant rats not exposed to lead or selenium served as control animals. The outcomes in pregnant rats were serum lead and selenium levels, reproductive hormone (follicle-stimulating hormone, luteinizing hormone, prolactin, oestradiol, progesterone) levels, and uterine and ovarian morphological changes. The outcomes in the offspring were sex differentiation, survival rates (day 21 after birth), weight (days 0-35 after birth), weight of reproductive organs, and puberty onset (foreskin separation or vaginal opening). Selenium supplementation dose-dependently decreased serum lead levels, rectified reproductive hormone levels, and attenuated reproductive morphological changes caused by lead exposure. Lead exposure did not affect sex differentiation, but significantly (p < 0.05 vs. control animals) decreased the offspring weight on days 0-28 and the weight of their reproductive organs. Furthermore, lead exposure delayed the onset of puberty. These pathological changes were dose-dependently rectified or attenuated by selenium supplementation. Gestational lead exposure causes damages to the reproductive system of pregnant rats, and negatively modulates growth and reproductive system development of the offspring. These adverse effects are rectified or attenuated by selenium supplementation.

Inhalation of diesel exhaust and allergen alters human bronchial epithelium DNA methylation.

PubMed

Clifford, Rachel L; Jones, Meaghan J; MacIsaac, Julia L; McEwen, Lisa M; Goodman, Sarah J; Mostafavi, Sara; Kobor, Michael S; Carlsten, Chris

2017-01-01

Allergic disease affects 30% to 40% of the world's population, and its development is determined by the interplay between environmental and inherited factors. Air pollution, primarily consisting of diesel exhaust emissions, has increased at a similar rate to allergic disease. Exposure to diesel exhaust may play a role in the development and progression of allergic disease, in particular allergic respiratory disease. One potential mechanism underlying the connection between air pollution and increased allergic disease incidence is DNA methylation, an epigenetic process with the capacity to integrate gene-environment interactions. We sought to investigate the effect of allergen and diesel exhaust exposure on bronchial epithelial DNA methylation. We performed a randomized crossover-controlled exposure study to allergen and diesel exhaust in humans, and measured single-site (CpG) resolution global DNA methylation in bronchial epithelial cells. Exposure to allergen alone, diesel exhaust alone, or allergen and diesel exhaust together (coexposure) led to significant changes in 7 CpG sites at 48 hours. However, when the same lung was exposed to allergen and diesel exhaust but separated by approximately 4 weeks, significant changes in more than 500 sites were observed. Furthermore, sites of differential methylation differed depending on which exposure was experienced first. Functional analysis of differentially methylated CpG sites found genes involved in transcription factor activity, protein metabolism, cell adhesion, and vascular development, among others. These findings suggest that specific exposures can prime the lung for changes in DNA methylation induced by a subsequent insult. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Perfluorooctanoic acid affects endocytosis involving clathrin light chain A and microRNA-133b-3p in mouse testes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu, Yin; Wang, Jianshe

Perfluorooctanoic acid (PFOA) is an abundant perfluoroalkyl substance widely applied in industrial and consumer products. Among its potential health hazards, testicular toxicity is of major concern. To explore the potential effect of miRNA on post-translational regulation after PFOA exposure, changes in miRNAs were detected via miRNA array. Seventeen miRNAs were differentially expressed (eight upregulated, nine downregulated) in male mouse testes after exposure to 5 mg/kg/d of PFOA for 28 d (> 1.5-fold and P < 0.05 compared with the control). Eight of these miRNAs were further selected for TaqMan qPCR analysis. Proteomic profile analysis indicated that many changed proteins aftermore » PFOA treatment, including intersectin 1 (ITSN1), serine protease inhibitor A3K (Serpina3k), and apolipoprotein a1 (APOA1), were involved in endocytosis and blood-testis barrier (BTB) processes. These changes were further verified by immunohistochemical and Western blot analyses. Endocytosis-related genes were selected for qPCR analysis, with many found to be significantly changed after PFOA treatment, including epidermal growth factor receptor pathway substrate 8 (Eps8), Eps15, cortactin, cofilin, espin, vinculin, and zyxin. We further predicted the potential interaction between changed miRNAs and proteins, which indicated that miRNAs might play a role in the post-translational regulation of gene expression after PFOA treatment in mouse testes. Among them, miR-133b-3p/clathrin light chain A (CLTA) was selected and verified in vitro by transfection and luciferase activity assay. Results showed that PFOA exposure affects endocytosis in mouse testes and that CLTA is a potential target of miR-133b-3p. - Highlights: • Endocytosis and blood-testis barrier proteins were changed after PFOA exposure. • Seventeen miRNAs were differentially expressed in testes after PFOA exposure. • MiRNAs might play a role in gene regulation in testes after PFOA exposure.CLTA is a potential target of miR-133b-3p.« less

Social Memory Formation Rapidly and Differentially Affects the Motivation and Performance of Vocal Communication Signals in the Bengalese Finch (Lonchura striata var. domestica)

PubMed Central

Toccalino, Danielle C.; Sun, Herie; Sakata, Jon T.

2016-01-01

Cognitive processes like the formation of social memories can shape the nature of social interactions between conspecifics. Male songbirds use vocal signals during courtship interactions with females, but the degree to which social memory and familiarity influences the likelihood and structure of male courtship song remains largely unknown. Using a habituation-dishabituation paradigm, we found that a single, brief (<30 s) exposure to a female led to the formation of a short-term memory for that female: adult male Bengalese finches were significantly less likely to produce courtship song to an individual female when re-exposed to her 5 min later (i.e., habituation). Familiarity also rapidly decreased the duration of courtship songs but did not affect other measures of song performance (e.g., song tempo and the stereotypy of syllable structure and sequencing). Consistent with a contribution of social memory to the decrease in courtship song with repeated exposures to the same female, the likelihood that male Bengalese finches produced courtship song increased when they were exposed to a different female (i.e., dishabituation). Three consecutive exposures to individual females also led to the formation of a longer-term memory that persisted over days. Specifically, when courtship song production was assessed 2 days after initial exposures to females, males produced fewer and shorter courtship songs to familiar females than to unfamiliar females. Measures of song performance, however, were not different between courtship songs produced to familiar and unfamiliar females. The formation of a longer-term memory for individual females seemed to require at least three exposures because males did not differentially produce courtship song to unfamiliar females and females that they had been exposed to only once or twice. Taken together, these data indicate that brief exposures to individual females led to the rapid formation and persistence of social memories and support the existence of distinct mechanisms underlying the motivation to produce and the performance of courtship song. PMID:27378868

Consequences of ethanol exposure on cued and contextual fear conditioning and extinction in adulthood differ depending on timing of exposure

PubMed Central

Broadwater, Margaret; Spear, Linda P.

2013-01-01

Some evidence suggests that adolescents are more sensitive than adults to ethanol-induced cognitive deficits and that these effects may be long-lasting. The purpose of Exp 1 was to determine if early-mid adolescent [Postnatal day (P) 28-48] intermittent ethanol exposure would affect later learning and memory in a Pavlovian fear conditioning paradigm differently than comparable exposures in adulthood (P70-90). In Exp 2 animals were exposed to ethanol during mid-late adolescence (P35-55) to assess whether age of initiation within the adolescent period would influence learning and memory differentially. Male Sprague-Dawley rats were given 4 g/kg i.g. ethanol (25%) or water every 48 hours for a total of 11 exposures. After a 22 day non-ethanol period, animals were fear conditioned to a context (relatively hippocampal-dependent task) or tone (amygdala-dependent task), followed by retention tests and extinction (mPFC-dependent) of this conditioning. Despite similar acquisition, a deficit in context fear retention was evident in animals exposed to ethanol in early adolescence, an effect not observed after a comparable ethanol exposure in mid-late adolescence or adulthood. In contrast, animals that were exposed to ethanol in mid-late adolescence or adulthood showed enhanced resistance to context extinction. Together these findings suggest that repeated ethanol imparts long-lasting consequences on learning and memory, with outcomes that differ depending on age of exposure. These results may reflect differential influence of ethanol on the brain as it changes throughout ontogeny and may have implications for alcohol use not only throughout the developmental period of adolescence, but also in adulthood. PMID:23938333

Alcohol exposure differentially effects anti-tumor immunity in females by altering dendritic cell function.

PubMed

Thompson, Matthew G; Navarro, Flor; Chitsike, Lennox; Ramirez, Luis; Kovacs, Elizabeth J; Watkins, Stephanie K

2016-12-01

Dendritic cells (DCs) are a critical component of anti-tumor immunity due to their ability to induce a robust immune response to antigen (Ag). Alcohol was previously shown to reduce DC ability to present foreign Ag and promote pro-inflammatory responses in situations of infection and trauma. However the impact of alcohol exposure on generation of an anti-tumor response, especially in the context of generation of an immune vaccine has not been examined. In the clinic, DC vaccines are typically generated from autologous blood, therefore prior exposure to substances such as alcohol may be a critical factor to consider regarding the effectiveness in generating an immune response. In this study, we demonstrate for the first time that ethanol differentially affects DC and tumor Ag-specific T cell responses depending on sex. Signaling pathways were found to be differentially regulated in DC in females compared to males and these differences were exacerbated by ethanol treatment. DC from female mice treated with ethanol were unable to activate Ag-specific cytotoxic T cells (CTL) as shown by reduced expression of CD44, CD69, and decreased production of granzyme B and IFNγ. Furthermore, although FOXO3, an immune suppressive mediator of DC function, was found to be upregulated in DC from female mice, ethanol related suppression was independent of FOXO3. These findings demonstrate for the first time differential impacts of alcohol on the immune system of females compared to males and may be a critical consideration for determining the effectiveness of an immune based therapy for cancer in patients that consume alcohol. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Wage Differentials between Heat-Exposure Risk and No Heat-Exposure Risk Groups

PubMed Central

Kim, Donghyun; Lim, Up

2017-01-01

The goal of this study is to investigate the wage differential between groups of workers who are exposed to heat and those who are not. Workers in the heat-exposure risk group are defined as workers who work in conditions that cause them to spend more than 25% of their work hours at high temperatures. To analyze the wage differential, the Blinder-Oaxaca and Juhn-Murphy-Pierce methods were applied to Korea Working Condition Survey data. The results show that the no heat-exposure risk group received higher wages. In most cases, this can be interpreted as the endowment effect of human capital. As a price effect that lowers the endowment effect, the compensating differential for the heat-exposure risk group was found to be 1%. Moreover, education level, work experience, and employment status counteracted the compensating differentials for heat-exposure risks. A comparison of data sets from 2011 and 2014 shows that the increasing wage gap between the two groups was not caused by systematic social discrimination factors. This study suggests that wage differential factors can be modified for thermal environmental risks that will change working conditions as the impact of climate change increases. PMID:28672804

Wage Differentials between Heat-Exposure Risk and No Heat-Exposure Risk Groups.

PubMed

Kim, Donghyun; Lim, Up

2017-06-24

The goal of this study is to investigate the wage differential between groups of workers who are exposed to heat and those who are not. Workers in the heat-exposure risk group are defined as workers who work in conditions that cause them to spend more than 25% of their work hours at high temperatures. To analyze the wage differential, the Blinder-Oaxaca and Juhn-Murphy-Pierce methods were applied to Korea Working Condition Survey data. The results show that the no heat-exposure risk group received higher wages. In most cases, this can be interpreted as the endowment effect of human capital. As a price effect that lowers the endowment effect, the compensating differential for the heat-exposure risk group was found to be 1%. Moreover, education level, work experience, and employment status counteracted the compensating differentials for heat-exposure risks. A comparison of data sets from 2011 and 2014 shows that the increasing wage gap between the two groups was not caused by systematic social discrimination factors. This study suggests that wage differential factors can be modified for thermal environmental risks that will change working conditions as the impact of climate change increases.

Repeated whole cigarette smoke exposure alters cell differentiation and augments secretion of inflammatory mediators in air-liquid interface three-dimensional co-culture model of human bronchial tissue.

PubMed

Ishikawa, Shinkichi; Ito, Shigeaki

2017-02-01

In vitro models of human bronchial epithelium are useful for toxicological testing because of their resemblance to in vivo tissue. We constructed a model of human bronchial tissue which has a fibroblast layer embedded in a collagen matrix directly below a fully-differentiated epithelial cell layer. The model was applied to whole cigarette smoke (CS) exposure repeatedly from an air-liquid interface culture while bronchial epithelial cells were differentiating. The effects of CS exposure on differentiation were determined by histological and gene expression analyses on culture day 21. We found a decrease in ciliated cells and perturbation of goblet cell differentiation. We also analyzed the effects of CS exposure on the inflammatory response, and observed a significant increase in secretion of IL-8, GRO-α, IL-1β, and GM-CSF. Interestingly, secretion of these mediators was augmented with repetition of whole CS exposure. Our data demonstrate the usefulness of our bronchial tissue model for in vitro testing and the importance of exposure repetition in perturbing the differentiation and inflammation processes. Copyright © 2016 Elsevier B.V. All rights reserved.

ELF-MF exposure affects the robustness of epigenetic programming during granulopoiesis

NASA Astrophysics Data System (ADS)

Manser, Melissa; Sater, Mohamad R. Abdul; Schmid, Christoph D.; Noreen, Faiza; Murbach, Manuel; Kuster, Niels; Schuermann, David; Schär, Primo

2017-03-01

Extremely-low-frequency magnetic fields (ELF-MF) have been classified as “possibly carcinogenic” to humans on the grounds of an epidemiological association of ELF-MF exposure with an increased risk of childhood leukaemia. Yet, underlying mechanisms have remained obscure. Genome instability seems an unlikely reason as the energy transmitted by ELF-MF is too low to damage DNA and induce cancer-promoting mutations. ELF-MF, however, may perturb the epigenetic code of genomes, which is well-known to be sensitive to environmental conditions and generally deranged in cancers, including leukaemia. We examined the potential of ELF-MF to influence key epigenetic modifications in leukaemic Jurkat cells and in human CD34+ haematopoietic stem cells undergoing in vitro differentiation into the neutrophilic lineage. During granulopoiesis, sensitive genome-wide profiling of multiple replicate experiments did not reveal any statistically significant, ELF-MF-dependent alterations in the patterns of active (H3K4me2) and repressive (H3K27me3) histone marks nor in DNA methylation. However, ELF-MF exposure showed consistent effects on the reproducibility of these histone and DNA modification profiles (replicate variability), which appear to be of a stochastic nature but show preferences for the genomic context. The data indicate that ELF-MF exposure stabilizes active chromatin, particularly during the transition from a repressive to an active state during cell differentiation.

Genome-wide gene expression changes associated with exposure of rat liver, heart, and kidney cells to endosulfan.

PubMed

Liu, Ruifeng; Printz, Richard L; Jenkins, Erin C; O'Brien, Tracy P; Te, Jerez A; Shiota, Masakazu; Wallqvist, Anders

2018-04-01

Endosulfan was once the most commonly used pesticide in agriculture and horticulture. It is an environmentally persistent organochlorine compound with the potential to bioaccumulate as it progresses through the food chain. Its acute and chronic toxicity to mammals, including humans, is well known, but the molecular mechanisms of its toxicity are not fully understood. To gain insight to these mechanisms, we examined genome-wide gene expression changes of rat liver, heart, and kidney cells induced by endosulfan exposure. We found that among the cell types examined, kidney and liver cells were the most sensitive and most resilient, respectively, to endosulfan insult. We acquired RNA sequencing information from cells exposed to endosulfan to identify differentially expressed genes, which we further examined to determine the cellular pathways that were affected. In kidney cells, exposure to endosulfan was uniquely associated with altered expression levels of genes constituting the hypoxia-inducible factor-1 (HIF-1) signaling pathway. In heart and liver cells, exposure to endosulfan altered the expression levels of genes for many members of the extracellular matrix (ECM)-receptor interaction pathway. Because both HIF-1 signaling and ECM-receptor interaction pathways directly or indirectly control cell growth, differentiation, proliferation, and apoptosis, our findings suggest that dysregulation of these pathways is responsible for endosulfan-induced cell death. Copyright © 2018 Elsevier Ltd. All rights reserved.

The mediating role of alienation in the development of maladjustment in youth exposed to community violence.

PubMed

O'Donnell, Deborah A; Schwab-Stone, Mary E; Ruchkin, Vladislav

2006-01-01

A study was conducted to determine predictors of high risk/delinquent behavior and psychoemotional maladjustment in 1,478 sixth and eighth graders who took part in a survey of high-risk and adaptive behaviors. The first goal was to determine the extent to which two distinct dimensions of alienation, normlessness, and isolation/self-estrangement mediated the emergence of maladjustment in youth exposed to community violence. The second goal was to distinguish between violence witnessing and violence victimization, and determine whether these subtypes of violence exposure may differentially affect the proposed mediational factors. The results indicated that normlessness partially mediated the relationship between violence exposure and high-risk/delinquent behavior and between violence exposure and psychoemotional maladjustment. Isolation/self-estrangement partially mediated the relation between violence exposure and psychoemotional maladjustment. Although witnessing of, and victimization by, violence were both significant predictors of normlessness, only violent victimization was significantly linked to isolation/self-estrangement. These results elucidate the mechanisms by which community violence exposure may exert negative influences on youth and suggest that there are distinct patterns of risk associated with different forms of exposure.

High environmental ammonia exposure has developmental-stage specific and long-term consequences on the cortisol stress response in zebrafish.

PubMed

Williams, Tegan A; Bonham, Luke A; Bernier, Nicholas J

2017-12-01

The capacity for early life environmental stressors to induce programming effects on the endocrine stress response in fish is largely unknown. In this study we determined the effects of high environmental ammonia (HEA) exposure on the stress response in larval zebrafish, assessed the tolerance of embryonic and larval stages to HEA, and evaluated whether early life HEA exposure has long-term consequences on the cortisol response to a novel stressor. Exposure to 500-2000μM NH 4 Cl for 16h did not affect the gene expression of corticotropin-releasing factor (CRF) system components in 1day post-fertilization (dpf) embryos, but differentially increased crfa, crfb and CRF binding protein (crfbp) expression and stimulated both dose- and time-dependent increases in the whole body cortisol of 5dpf larvae. Pre-acclimation to HEA at 1dpf did not affect the cortisol response to a subsequent NH 4 Cl exposure at 5dpf. In contrast, pre-acclimation to HEA at 5dpf caused a small but significant reduction in the cortisol response to a second NH 4 Cl exposure at 10dpf. While continuous exposure to 500-2000μM NH 4 Cl between 0 and 5dpf had a modest effect on mean survival time, exposure to 400-1000μM NH 4 Cl between 10 and 14dpf decreased mean survival time in a dose-dependent manner. Moreover, pre-acclimation to HEA at 5dpf significantly decreased the risk of mortality to continuous NH 4 Cl exposure between 10 and 14dpf. Finally, while HEA at 1dpf did not affect the cortisol stress response to a novel vortex stressor at 5dpf, the same HEA treatment at 5dpf abolished vortex stressor-induced increases in whole body cortisol at 10 and 60dpf. Together these results show that the impact of HEA on the cortisol stress response during development is life-stage specific and closely linked to ammonia tolerance. Further, we demonstrate that HEA exposure at the larval stage can have persistent effects on the capacity to respond to stressors in later life. Copyright © 2017 Elsevier Inc. All rights reserved.

Human amniotic fluid contaminants alter thyroid hormone signalling and early brain development in Xenopus embryos

NASA Astrophysics Data System (ADS)

Fini, Jean-Baptiste; Mughal, Bilal B.; Le Mével, Sébastien; Leemans, Michelle; Lettmann, Mélodie; Spirhanzlova, Petra; Affaticati, Pierre; Jenett, Arnim; Demeneix, Barbara A.

2017-03-01

Thyroid hormones are essential for normal brain development in vertebrates. In humans, abnormal maternal thyroid hormone levels during early pregnancy are associated with decreased offspring IQ and modified brain structure. As numerous environmental chemicals disrupt thyroid hormone signalling, we questioned whether exposure to ubiquitous chemicals affects thyroid hormone responses during early neurogenesis. We established a mixture of 15 common chemicals at concentrations reported in human amniotic fluid. An in vivo larval reporter (GFP) assay served to determine integrated thyroid hormone transcriptional responses. Dose-dependent effects of short-term (72 h) exposure to single chemicals and the mixture were found. qPCR on dissected brains showed significant changes in thyroid hormone-related genes including receptors, deiodinases and neural differentiation markers. Further, exposure to mixture also modified neural proliferation as well as neuron and oligodendrocyte size. Finally, exposed tadpoles showed behavioural responses with dose-dependent reductions in mobility. In conclusion, exposure to a mixture of ubiquitous chemicals at concentrations found in human amniotic fluid affect thyroid hormone-dependent transcription, gene expression, brain development and behaviour in early embryogenesis. As thyroid hormone signalling is strongly conserved across vertebrates the results suggest that ubiquitous chemical mixtures could be exerting adverse effects on foetal human brain development.

Ethanol deregulates Mecp2/MeCP2 in differentiating neural stem cells via interplay between 5-methylcytosine and 5-hydroxymethylcytosine at the Mecp2 regulatory elements

PubMed Central

Liyanage, Vichithra Rasangi Batuwita; Zachariah, Robby Mathew; Davie, James Ronald; Rastegar, Mojgan

2017-01-01

Methyl CpG Binding Protein 2 (MeCP2) is an important epigenetic factor in the brain. MeCP2 expression is affected by different environmental insults including alcohol exposure. Accumulating evidence supports the role of aberrant MeCP2 expression in ethanol exposure-induced neurological symptoms. However, the underlying molecular mechanisms of ethanol-induced MeCP2 deregulation remain elusive. To study the effect of ethanol on Mecp2/MeCP2 expression during neurodifferentiation, we established an in vitro model of ethanol exposure, using differentiating embryonic brain-derived neural stem cells (NSC). Previously, we demonstrated the impact of DNA methylation at the Mecp2 regulatory elements (REs) on Mecp2/MeCP2 expression in vitro and in vivo. Here, we studied whether altered DNA methylation at these REs is associated with the Mecp2/MeCP2 misexpression induced by ethanol. Binge-like and continuous ethanol exposure upregulated Mecp2/MeCP2, while ethanol withdrawal downregulated its expression. DNA methylation analysis by methylated DNA immunoprecipitation indicated that increased 5-hydroxymethylcytosine (5hmC) and decreased 5-methylcytosine (5mC) enrichment at specific REs were associated with upregulated Mecp2/MeCP2 following continuous ethanol exposure. The reduced Mecp2/MeCP2 expression upon ethanol withdrawal was associated with reduced 5hmC and increased 5mC enrichment at these REs. Moreover, ethanol altered global DNA methylation (5mC and 5hmC). Under the tested conditions, ethanol had minimal effects on NSC cell fate commitment, but caused changes in neuronal morphology and glial cell size. Taken together, our data represent an epigenetic mechanism for ethanol-mediated misexpression of Mecp2/MeCP2 in differentiating embryonic brain cells. We also show the potential role of DNA methylation and MeCP2 in alcohol-related neurological disorders, specifically Fetal Alcohol Spectrum Disorders. PMID:25620416

Peritraumatic Reaction Courses During War in Individuals With Serious Mental Illness: Gender, Mental Health Status, and Exposure.

PubMed

Gelkopf, Marc; Lapid Pickman, Liron; Grinapol, Shulamit; Werbeloff, Nomi; Carlson, Eve B; Greene, Talya

2017-01-01

We assessed in vivo symptom courses of early psychological responses during war and investigated the influence of exposure, gender, and a prior diagnosis of severe mental illness (SMI). Participants were 181 highly exposed individuals from the general population and community psychiatric rehabilitation centers. A 30-day twice-daily Internet-smartphone-based intensive assessment two weeks into the 2014 Israel-Gaza war estimated peritraumatic symptom clusters, sense of threat, negative emotions and cognitions, and siren exposure during two periods that varied in exposure level. Piecewise growth curve modeling procedures were performed. We found different courses for most variables, gender, and SMI status. Women were more reactive two weeks into the war but reduced their reactivity level at a faster pace than males, reaching lower symptom levels one month later. Women's courses were characterized by arousal, negative emotionality, sense of threat, and reactivity to siren exposure. No-SMI men had a stable course followed by a significant reduction in arousal, negative emotions, avoidance, and perceived threat during a "return to routine" lower-level intensity period of the war. Individuals with SMI had higher reactivity levels at study onset; but while women with SMI improved over time, men with SMI worsened. SMI reactivity was characterized by negative cognitions, intrusions, and avoidance. Early reactions during prolonged exposure to war are variable, dynamic, and affected by exposure context. Symptoms, emotions, and cognitions develop differentially over time and are affected by gender and mental health status. The identification of various early stress courses should inform primary intervention strategies.

Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men

PubMed Central

Li, De-kun; Yang, Fen; Pan, Hongjie; Li, Tianqi; Miao, Maohua; Li, Runsheng; Yuan, Wei

2017-01-01

Environmental BPA exposure has been shown to impact human sperm concentration and motility, as well as rodent spermatogenesis. However, it is unclear whether BPA exposure is associated with alteration in DNA hydroxymethylation, a marker for epigenetic modification, in human sperm. A genome-wide DNA hydroxymethylation study was performed using sperm samples of men who were occupationally exposed to BPA. Compared with controls who had no occupational BPA exposure, the total levels of 5-hydroxymethylcytosine (5hmc) increased significantly (19.37% increase) in BPA-exposed men, with 72.69% of genome regions harboring 5hmc. A total of 9,610 differential 5hmc regions (DhMRs) were revealed in BPA-exposed men relative to controls, which were mainly located in intergenic and intron regions. These DhMRs were composed of 8,670 hyper-hMRs and 940 hypo-hMRs, affecting 2,008 genes and the repetitive elements. The hyper-hMRs affected genes were enriched in pathways associated with nervous system, development, cardiovascular diseases and signal transduction. Additionally, enrichment of 5hmc was observed in the promoters of eight maternally expressed imprinted genes in BPA-exposed sperm. Some of the BPA-affected genes, for example, MLH1, CHD2, SPATA12 and SPATA20 might participate in the response to DNA damage in germ cells caused by BPA. Our analysis showed that enrichment of 5hmc both in promoters and gene bodies is higher in the genes whose expression has been detected in human sperm than those whose expression is absent. Importantly, we observed that BPA exposure affected the 5hmc level in 11.4% of these genes expressed in sperm, and in 6.85% of the sperm genome. Finally, we also observed that BPA exposure tends to change the 5hmc enrichment in the genes which was previously reported to be distributed with the trimethylated Histone 3 (H3K27me3, H3K4me2 or H3K4me3) in sperm. Thus, these results suggest that BPA exposure likely interferes with gene expression via affecting DNA hydroxymethylation in a way partially dependent on trimethylation of H3 in human spermatogenesis. Our current study reveals a new mechanism by which BPA exposure reduces human sperm quality. PMID:28582417

Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men.

PubMed

Zheng, Huajun; Zhou, Xiaoyu; Li, De-Kun; Yang, Fen; Pan, Hongjie; Li, Tianqi; Miao, Maohua; Li, Runsheng; Yuan, Wei

2017-01-01

Environmental BPA exposure has been shown to impact human sperm concentration and motility, as well as rodent spermatogenesis. However, it is unclear whether BPA exposure is associated with alteration in DNA hydroxymethylation, a marker for epigenetic modification, in human sperm. A genome-wide DNA hydroxymethylation study was performed using sperm samples of men who were occupationally exposed to BPA. Compared with controls who had no occupational BPA exposure, the total levels of 5-hydroxymethylcytosine (5hmc) increased significantly (19.37% increase) in BPA-exposed men, with 72.69% of genome regions harboring 5hmc. A total of 9,610 differential 5hmc regions (DhMRs) were revealed in BPA-exposed men relative to controls, which were mainly located in intergenic and intron regions. These DhMRs were composed of 8,670 hyper-hMRs and 940 hypo-hMRs, affecting 2,008 genes and the repetitive elements. The hyper-hMRs affected genes were enriched in pathways associated with nervous system, development, cardiovascular diseases and signal transduction. Additionally, enrichment of 5hmc was observed in the promoters of eight maternally expressed imprinted genes in BPA-exposed sperm. Some of the BPA-affected genes, for example, MLH1, CHD2, SPATA12 and SPATA20 might participate in the response to DNA damage in germ cells caused by BPA. Our analysis showed that enrichment of 5hmc both in promoters and gene bodies is higher in the genes whose expression has been detected in human sperm than those whose expression is absent. Importantly, we observed that BPA exposure affected the 5hmc level in 11.4% of these genes expressed in sperm, and in 6.85% of the sperm genome. Finally, we also observed that BPA exposure tends to change the 5hmc enrichment in the genes which was previously reported to be distributed with the trimethylated Histone 3 (H3K27me3, H3K4me2 or H3K4me3) in sperm. Thus, these results suggest that BPA exposure likely interferes with gene expression via affecting DNA hydroxymethylation in a way partially dependent on trimethylation of H3 in human spermatogenesis. Our current study reveals a new mechanism by which BPA exposure reduces human sperm quality.

O-GlcNAcylation Negatively Regulates Cardiomyogenic Fate in Adult Mouse Cardiac Mesenchymal Stromal Cells

PubMed Central

Zafir, Ayesha; Bradley, James A.; Long, Bethany W.; Muthusamy, Senthilkumar; Li, Qianhong; Hill, Bradford G.; Wysoczynski, Marcin; Prabhu, Sumanth D.; Bhatnagar, Aruni; Bolli, Roberto; Jones, Steven P.

2015-01-01

In both preclinical and clinical studies, cell transplantation of several cell types is used to promote repair of damaged organs and tissues. Nevertheless, despite the widespread use of such strategies, there remains little understanding of how the efficacy of cell therapy is regulated. We showed previously that augmentation of a unique, metabolically derived stress signal (i.e., O-GlcNAc) improves survival of cardiac mesenchymal stromal cells; however, it is not known whether enhancing O-GlcNAcylation affects lineage commitment or other aspects of cell competency. In this study, we assessed the role of O-GlcNAc in differentiation of cardiac mesenchymal stromal cells. Exposure of these cells to routine differentiation protocols in culture increased markers of the cardiomyogenic lineage such as Nkx2.5 and connexin 40, and augmented the abundance of transcripts associated with endothelial and fibroblast cell fates. Differentiation significantly decreased the abundance of O-GlcNAcylated proteins. To determine if O-GlcNAc is involved in stromal cell differentiation, O-GlcNAcylation was increased pharmacologically during the differentiation protocol. Although elevated O-GlcNAc levels did not significantly affect fibroblast and endothelial marker expression, acquisition of cardiomyocyte markers was limited. In addition, increasing O-GlcNAcylation further elevated smooth muscle actin expression. In addition to lineage commitment, we also evaluated proliferation and migration, and found that increasing O-GlcNAcylation did not significantly affect either; however, we found that O-GlcNAc transferase—the protein responsible for adding O-GlcNAc to proteins—is at least partially required for maintaining cellular proliferative and migratory capacities. We conclude that O-GlcNAcylation contributes significantly to cardiac mesenchymal stromal cell lineage and function. O-GlcNAcylation and pathological conditions that may affect O-GlcNAc levels (such as diabetes) should be considered carefully in the context of cardiac cell therapy. PMID:26565625

True or false? Memory is differentially affected by stress-induced cortisol elevations and sympathetic activity at consolidation and retrieval.

PubMed

Smeets, Tom; Otgaar, Henry; Candel, Ingrid; Wolf, Oliver T

2008-11-01

Adrenal stress hormones released in response to acute stress may yield memory-enhancing effects when released post-learning and impairing effects at memory retrieval, especially for emotional memory material. However, so far these differential effects of stress hormones on the various memory phases for neutral and emotional memory material have not been demonstrated within one experiment. This study investigated whether, in line with their effects on true memory, stress and stress-induced adrenal stress hormones affect the encoding, consolidation, and retrieval of emotional and neutral false memories. Participants (N=90) were exposed to a stressor before encoding, during consolidation, before retrieval, or were not stressed and then were subjected to neutral and emotional versions of the Deese-Roediger-McDermott word list learning paradigm. Twenty-four hours later, recall of presented words (true recall) and non-presented critical lure words (false recall) was assessed. Results show that stress exposure resulted in superior true memory performance in the consolidation stress group and reduced true memory performance in the retrieval stress group compared to the other groups, predominantly for emotional words. These memory-enhancing and memory-impairing effects were strongly related to stress-induced cortisol and sympathetic activity measured via salivary alpha-amylase levels. Neutral and emotional false recall, on the other hand, was neither affected by stress exposure, nor related to cortisol and sympathetic activity following stress. These results demonstrate the importance of stress-induced hormone-related activity in enhancing memory consolidation and in impairing memory retrieval, in particular for emotional memory material.

Toxicological effects of the different substances in tobacco smoke on human embryonic development by a systems chemo-biology approach.

PubMed

Feltes, Bruno César; de Faria Poloni, Joice; Notari, Daniel Luis; Bonatto, Diego

2013-01-01

The physiological and molecular effects of tobacco smoke in adult humans and the development of cancer have been well described. In contrast, how tobacco smoke affects embryonic development remains poorly understood. Morphological studies of the fetuses of smoking pregnant women have shown various physical deformities induced by constant fetal exposure to tobacco components, especially nicotine. In addition, nicotine exposure decreases fetal body weight and bone/cartilage growth in addition to decreasing cranial diameter and tibia length. Unfortunately, the molecular pathways leading to these morphological anomalies are not completely understood. In this study, we applied interactome data mining tools and small compound interaction networks to elucidate possible molecular pathways associated with the effects of tobacco smoke components during embryonic development in pregnant female smokers. Our analysis showed a relationship between nicotine and 50 additional harmful substances involved in a variety of biological process that can cause abnormal proliferation, impaired cell differentiation, and increased oxidative stress. We also describe how nicotine can negatively affect retinoic acid signaling and cell differentiation through inhibition of retinoic acid receptors. In addition, nicotine causes a stress reaction and/or a pro-inflammatory response that inhibits the agonistic action of retinoic acid. Moreover, we show that the effect of cigarette smoke on the developing fetus could represent systemic and aggressive impacts in the short term, causing malformations during certain stages of development. Our work provides the first approach describing how different tobacco constituents affect a broad range of biological process in human embryonic development.

Toxicological Effects of the Different Substances in Tobacco Smoke on Human Embryonic Development by a Systems Chemo-Biology Approach

PubMed Central

Feltes, Bruno César; Poloni, Joice de Faria; Notari, Daniel Luis; Bonatto, Diego

2013-01-01

The physiological and molecular effects of tobacco smoke in adult humans and the development of cancer have been well described. In contrast, how tobacco smoke affects embryonic development remains poorly understood. Morphological studies of the fetuses of smoking pregnant women have shown various physical deformities induced by constant fetal exposure to tobacco components, especially nicotine. In addition, nicotine exposure decreases fetal body weight and bone/cartilage growth in addition to decreasing cranial diameter and tibia length. Unfortunately, the molecular pathways leading to these morphological anomalies are not completely understood. In this study, we applied interactome data mining tools and small compound interaction networks to elucidate possible molecular pathways associated with the effects of tobacco smoke components during embryonic development in pregnant female smokers. Our analysis showed a relationship between nicotine and 50 additional harmful substances involved in a variety of biological process that can cause abnormal proliferation, impaired cell differentiation, and increased oxidative stress. We also describe how nicotine can negatively affect retinoic acid signaling and cell differentiation through inhibition of retinoic acid receptors. In addition, nicotine causes a stress reaction and/or a pro-inflammatory response that inhibits the agonistic action of retinoic acid. Moreover, we show that the effect of cigarette smoke on the developing fetus could represent systemic and aggressive impacts in the short term, causing malformations during certain stages of development. Our work provides the first approach describing how different tobacco constituents affect a broad range of biological process in human embryonic development. PMID:23637898

The influence of TSA and VPA on the in vitro differentiation of bone marrow mesenchymal stem cells into neuronal lineage cells: Gene expression studies.

PubMed

Fila-Danilow, Anna; Borkowska, Paulina; Paul-Samojedny, Monika; Kowalczyk, Malgorzata; Kowalski, Jan

2017-03-27

Epigenetic mechanisms regulate the transcription of genes, which can affect the differentiation of MSCs. The aim of the current work is to determine how the histone deacetylase inhibitors TSA and VPA affect the expression of neuronal lineage genes in a culture of rat MSCs (rMSCs). We analyzed the expression of early neuron marker gene (Tubb3), mature neuron markers genes (Vacht, Th, Htr2a) and the oligodendrocyte progenitor marker gene (GalC). Moreover, changes in the gene expression after three different periods of exposure to TSA and VPA were investigated for the first time. After six days of exposition to TSA and VPA, the expression of Tubb3 and GalC decreased, while the expression of Th increased. The highest increase of VAChT expression was observed after three days of TSA and VPA treatment. A decrease in Htr2a gene expression was observed after TSA treatment and an increase was observed after VPA treatment. We also observed that TSA and VPA inhibited cell proliferation and the formation of neurospheres in the rMSCs culture. The central findings of our study are that TSA and VPA affect the expression of neuronal lineage genes in an rMSCs culture. After exposure to TSA or VPA, the expression of early neuronal gene decreases but equally the expression of mature neuron genes increases. After TSA and VPA treatment ER of the oligodendrocyte progenitor marker decreased. TSA and VPA inhibit cell proliferation and the formation of neurospheres in rMSCs culture.

DEVELOPMENTAL NEUROTOXICITY OF ORGANOPHOSPHATES TARGETS CELL CYCLE AND APOPTOSIS, REVEALED BY TRANSCRIPTIONAL PROFILES IN VIVO AND IN VITRO

PubMed Central

Slotkin, Theodore A.; Seidler, Frederic J.

2012-01-01

Developmental organophosphate exposure reduces the numbers of neural cells, contributing to neurobehavioral deficits. We administered chlorpyrifos or diazinon to newborn rats on postnatal days 1–4, in doses straddling the threshold for barely-detectable cholinesterase, and evaluated gene expression in the cell cycle and apoptosis pathways on postnatal day 5. Both organophosphates evoked transcriptional changes in 20–25% of the genes in each category; chlorpyrifos and diazinon targeted the same genes, with similar magnitudes of change, as evidenced by high concordance. Furthermore, the same effects were obtained with doses above or below the threshold for cholinesterase inhibition, indicating a mechanism unrelated to anticholinesterase actions. We then evaluated the effects of chlorpyrifos in undifferentiated and differentiating PC12 cells and found even greater targeting of cell cycle and apoptosis genes, affecting up to 40% of all genes in the pathways. Notably, the genes affected in undifferentiated cells were not concordant with those in differentiating cells, pointing to dissimilar outcomes dependent on developmental stage. The in vitro model successfully identified 60–70% of the genes affected by chlorpyrifos in vivo, indicating that the effects are exerted directly on developing neural cells. Our results show that organophosphates target the genes regulating the cell cycle and apoptosis in the developing brain and in neuronotypic cells in culture, with the pattern of vulnerability dependent on the specific stage of development. Equally important, these effects do not reflect actions on cholinesterase and operate at exposures below the threshold for any detectable inhibition of this enzyme. PMID:22222554

Developmental neurotoxicity of organophosphates targets cell cycle and apoptosis, revealed by transcriptional profiles in vivo and in vitro.

PubMed

Slotkin, Theodore A; Seidler, Frederic J

2012-03-01

Developmental organophosphate exposure reduces the numbers of neural cells, contributing to neurobehavioral deficits. We administered chlorpyrifos or diazinon to newborn rats on postnatal days 1-4, in doses straddling the threshold for barely-detectable cholinesterase inhibition, and evaluated gene expression in the cell cycle and apoptosis pathways on postnatal day 5. Both organophosphates evoked transcriptional changes in 20-25% of the genes in each category; chlorpyrifos and diazinon targeted the same genes, with similar magnitudes of change, as evidenced by high concordance. Furthermore, the same effects were obtained with doses above or below the threshold for cholinesterase inhibition, indicating a mechanism unrelated to anticholinesterase actions. We then evaluated the effects of chlorpyrifos in undifferentiated and differentiating PC12 cells and found even greater targeting of cell cycle and apoptosis genes, affecting up to 40% of all genes in the pathways. Notably, the genes affected in undifferentiated cells were not concordant with those in differentiating cells, pointing to dissimilar outcomes dependent on developmental stage. The in vitro model successfully identified 60-70% of the genes affected by chlorpyrifos in vivo, indicating that the effects are exerted directly on developing neural cells. Our results show that organophosphates target the genes regulating the cell cycle and apoptosis in the developing brain and in neuronotypic cells in culture, with the pattern of vulnerability dependent on the specific stage of development. Equally important, these effects do not reflect actions on cholinesterase and operate at exposures below the threshold for any detectable inhibition of this enzyme. Copyright © 2011 Elsevier Inc. All rights reserved.

Hepatic expression of the GH/JAK/STAT/IGF pathway, acute-phase response signalling and complement system are affected in mouse offspring by prenatal and early postnatal exposure to maternal high-protein diet.

PubMed

Vanselow, Jens; Kucia, Marzena; Langhammer, Martina; Koczan, Dirk; Rehfeldt, Charlotte; Metges, Cornelia C

2011-12-01

Effects of pre- and early postnatal exposure to maternal high-protein diets are not well understood. Transcription profiling was performed in male mouse offspring exposed to maternal high-protein diet during pregnancy and/or lactation to identify affected hepatic molecular pathways. Dams were fed isoenergetic diets with control (20% w/w) or high protein levels (40%). The hepatic expression profiles were evaluated by differential microarray analysis 3 days (d3) and 3 weeks (d21) after birth. Offspring from three different high-protein dietary groups, HP (d3, high-protein diet during pregnancy), HPHP (d21, high-protein diet during pregnancy and lactation) and CHP (d21, control diet during pregnancy and high-protein diet during lactation), were compared with age-matched offspring from dams fed control diet. Offspring body and liver mass of all high-protein groups were decreased. Prenatal high-protein diet affected hepatic expression of genes mapping to the acute response/complement system and the GH/JAK/STAT/IGF signalling pathways. Maternal exposure to high-protein diet during lactation affected hepatic gene expression of the same pathways but additionally affected genes mapping to protein, fatty acid, hexose and pyruvate metabolism. (1) Genes of the acute response/complement system and GH/JAK/STAT/IGF pathways were down-regulated in offspring of dams exposed to high-protein diets during pregnancy and/or lactation. (2) Genes related to nutrient and energy metabolism, however, were only affected when high-protein diet was administered during lactation. (3) Modulation of the GH/JAK/STAT/IGF pathway might be responsible for reduced body and liver masses by maternal high-protein diet.

Effects of inorganic lead on the differentiation and growth of cultured hippocampal and neuroblastoma cells.

PubMed

Audesirk, T; Audesirk, G; Ferguson, C; Shugarts, D

1991-01-01

Lead exposure has devastating effects on the developing nervous system, and has been implicated in variety of behavioral and cognitive deficits as well as neural morphological abnormalities. Since lead impacts many calcium-dependent processes, one likely mechanism of lead toxicity is its disruption of calcium dependent processes, among which is neuronal differentiation. We investigated the effects of inorganic lead on survival and several parameters of differentiation of cultured neurons. Three different cell types were used: Rat hippocampal neurons (a primary CNS cell type), B50 rat neuroblastoma cells (a transformed CNS-derived cell line), and N1E-115 mouse neuroblastoma cells (a transformed peripherally-derived cell line). Lead concentrations ranged from low nM to 1 mM. Lead effects differed considerably among the three cell types, with B50 cells least affected. Lead effects were generally multimodal, with fewest effects observed at intermediate concentrations. Lead inhibited neurite initiation in hippocampal neurons, but stimulated initiation in N1E-115 cells. In those cells that differentiated, lead increased dendrite numbers in hippocampal neurons and neurite numbers in N1E-115 cells. Lead exposure increased both the length and the degree of branching of axons in hippocampal neurons and the length of neurites in N1E-115 cells. We hypothesize that lead impacts multiple regulatory processes that influence neuron survival and differentiation, and that its effects show differing dose-dependencies. The differing responses of the different cell types to lead suggests that differentiation may be regulated in different ways by the three types of cells. Alternatively, or additionally, the cell types may differ in their ability to compensate for, sequester, or expel lead.

Estrogens Can Disrupt Amphibian Mating Behavior

PubMed Central

Hoffmann, Frauke; Kloas, Werner

2012-01-01

The main component of classical contraceptives, 17α-ethinylestradiol (EE2), has high estrogenic activity even at environmentally relevant concentrations. Although estrogenic endocrine disrupting compounds are assumed to contribute to the worldwide decline of amphibian populations by adverse effects on sexual differentiation, evidence for EE2 affecting amphibian mating behaviour is lacking. In this study, we demonstrate that EE2 exposure at five different concentrations (0.296 ng/L, 2.96 ng/L, 29.64 ng/L, 2.96 µg/L and 296.4 µg/L) can disrupt the mating behavior of adult male Xenopus laevis. EE2 exposure at all concentrations lowered male sexual arousal, indicated by decreased proportions of advertisement calls and increased proportions of the call type rasping, which characterizes a sexually unaroused state of a male. Additionally, EE2 at all tested concentrations affected temporal and spectral parameters of the advertisement calls, respectively. The classical and highly sensitive biomarker vitellogenin, on the other hand, was only induced at concentrations equal or higher than 2.96 µg/L. If kept under control conditions after a 96 h EE2 exposure (2.96 µg/L), alterations of male advertisement calls vanish gradually within 6 weeks and result in a lower sexual attractiveness of EE2 exposed males toward females as demonstrated by female choice experiments. These findings indicate that exposure to environmentally relevant EE2 concentrations can directly disrupt male mate calling behavior of X. laevis and can indirectly affect the mating behavior of females. The results suggest the possibility that EE2 exposure could reduce the reproductive success of EE2 exposed animals and these effects might contribute to the global problem of amphibian decline. PMID:22355410

Objectification in Virtual Romantic Contexts: Perceived Discrepancies between Self and Partner Ideals Differentially affect Body Consciousness in Women and Men

PubMed Central

Overstreet, Nicole M.; Quinn, Diane M.; Marsh, Kerry L.

2015-01-01

The current study examined whether exposure to sexually objectifying images in a potential romantic partner's virtual apartment affects discrepancies between people's perception of their own appearance (i.e., self-perceptions) and their perception of the body ideal that is considered desirable to a romantic partner (i.e., partner-ideals). Participants were 114 heterosexual undergraduate students (57 women and 57 men) from a northeastern U.S. university. The study used a 2 (Participant Gender) x 2 (Virtual Environment: Sexualized vs. Non-Sexualized) between-subjects design. We predicted that women exposed to sexually objectifying images in a virtual environment would report greater discrepancies between their self-perceptions and partner-ideals than men, which in turn would contribute to women's body consciousness. Findings support this hypothesis and show that perceived discrepancies account for the relationship between exposure to sexually objectifying images and body consciousness for women but not men. We also found gender asymmetries in objectification responses when each component of perceived discrepancies, i.e., self-perceptions versus perceptions of a romantic partner's body ideal, were examined separately. For men, exposure to muscular sexualized images was significantly associated with their self-perceptions but not their perceptions of the body size that is considered desirable to a romantic partner. For women, exposure to thin sexualized images was significantly associated with their perceptions that a romantic partner preferred a woman with a smaller body size. However, exposure to these images did not affect women's self-perceptions. Implications for gender asymmetries in objectification responses and perceived discrepancies that include a romantic partner's perceptions are discussed. PMID:26594085

Differential patterns of injury to the proximal tubule of renal cortical slices following in vitro exposure to mercuric chloride, potassium dichromate, or hypoxic conditions.

PubMed

Ruegg, C E; Gandolfi, A J; Nagle, R B; Brendel, K

1987-09-15

The innate susceptibility of renal cell types to these agents was investigated using precision-cut rabbit renal cortical slices made perpendicular to the cortical-papillary axis. Slices were incubated in DME/F12 medium containing 10 microM, 100 microM, or 1 mM concentrations of either metal for 12 hr or in Krebs-Hepes buffer gassed with nitrogen (100%) for 0.75 to 5 hr of hypoxic exposure. To simulate postischemic reperfusion, some slices were transferred to vessels gassed with oxygen after an initial hypoxic period. Mercuric chloride (100 microM) exposure resulted in damage to the straight regions of proximal tubules by 12 hr leaving convoluted regions unaffected. Hypoxia (2.25 hr) and potassium dichromate (100 microM for 12 hr) both caused injury to the convoluted proximal tubules without affecting straight proximal tubular regions. Mercury concentrations of 10 microM and 1 mM had no effect or injured all cell types within the slice, respectively. Similar results were observed for hypoxic periods less than 1.5 hr or greater than 3 hr of exposure. Potassium dichromate had no measurable affect at 10 microM, but at 1 mM focal lesions were observed after 4 hr of exposure, and by 12 hr all cell types within the slice were affected. Intracellular potassium content normalized to DNA correlated well, but always preceded the pathological lesions observed. These results demonstrate that injury to specific regions of the proximal tubule by these agents relates to an innate susceptibility of the intoxicated cell type independent of physiologic feedback or blood delivery patterns proposed as mechanisms of selective injury from in vivo studies.

Differential sexual survival of Drosophila melanogaster on copper sulfate.

PubMed

Balinski, Michael A; Woodruff, Ronny C

2017-04-01

Based on studies of the influence of X-chromosomes on the viability of Drosophila melanogaster exposed to cadmium, and on the role of X-linked genes on copper homeostasis, we examined the effect of copper sulfate (CuSO 4 ) on offspring viability using three independent, inbred D. melanogaster crosses (ensuring identical autosomes for males and females within each cross). Each cross was performed with attached X-chromosome females and males with a single X-chromosome. As female D. melanogaster have less metallothionein RNA expression than males, we predicted fewer female offspring than male offspring in crosses exposed to CuSO 4 , even though females have two copies of X-chromosome genes, possibly resulting in overdominant heterozygosity. In two of three crosses, CuSO 4 caused significantly higher numbers of male offspring compared to female offspring. We hypothesized that these gender-based viability differences to copper exposure are caused by X-chromosome ploidy and X-linked genetic variation affecting metallothionein expression. Observed differential offspring viability responses among crosses to copper exposure also showed that different genetic backgrounds (autosomal and/or X-chromosome) can result in significant differences in heavy metal and metallothionein regulation. These results suggest that the effect of copper on offspring viability depends on both genetic background and gender, as both factors can affect the regulation of metallothionein proteins as well as homeostasis of biologically necessary heavy metals.

Phosphoproteomics profiling of human skin fibroblast cells reveals pathways and proteins affected by low doses of ionizing radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Feng; Waters, Katrina M.; Miller, John H.

2010-11-30

Background: High doses of ionizing radiation result in biological damage, however the precise relationships between long term health effects, including cancer, and low dose exposures remain poorly understood and are currently extrapolated using high dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose dependent responses to radiation. Principle Findings: We have identified 6845 unique phosphopeptides (2566 phosphoproteins) from control and irradiated (2 and 50 cGy) primary human skin fibroblasts one hour post-exposure. Dual statistical analyses based on spectral counts and peakmore » intensities identified 287 phosphopeptides (from 231 proteins) and 244 phosphopeptides (from 182 proteins) that varied significantly following exposure to 2 and 50 cGy respectively. This screen identified phosphorylation sites on proteins with known roles in radiation responses including TP53BP1 as well as previously unidentified radiation responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatics analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role of MAP kinase and protein kinase A (PKA) signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. Conlcusions: Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provides a basis for the systems level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at different radiation doses and elucidate the impact of low dose radiation exposure on human health.« less

Influence of organophosphate poisoning on human dendritic cells.

PubMed

Schäfer, Marina; Koppe, Franziska; Stenger, Bernhard; Brochhausen, Christoph; Schmidt, Annette; Steinritz, Dirk; Thiermann, Horst; Kirkpatrick, Charles James; Pohl, Christine

2013-12-05

Organophosphourus compounds (OPC, including nerve agents and pesticides) exhibit acute toxicity by inhibition of acetylcholinesterase. Lung affections are frequent complications and a risk factor for death. In addition, epidemiological studies reported immunological alterations after OPC exposure. In our experiments we investigated the effects of organophosphourus pesticides dimethoate and chlorpyrifos on dendritic cells (DC) that are essential for the initial immune response, especially in the pulmonary system. DC, differentiated from the monocyte cell line THP-1 by using various cytokines (IL-4, GM-CSF, TNF-α, Ionomycin), were exposed to organophosphourus compounds at different concentrations for a 24h time period. DC were characterized by flow cytometry and immunofluorescence using typical dendritic cell markers (e.g., CD11c, CD209 and CD83). After OPC exposure we investigated cell death, the secretion profile of inflammatory mediators, changes of DC morphology, and the effect on protein kinase signalling pathways. Our results revealed a successful differentiation of THP-1 into DC. OPC exposure caused a significant concentration-dependent influence on DC: Dendrites of the DC were shortened and damaged, DC-specific cell surface markers (i.e., CD83and CD209) decreased dramatically after chlorpyrifos exposure. Interestingly, the effects caused by dimethoate were in general less pronounced. The organophosphourus compounds affected the release of inflammatory cytokines, such as IL-1ß and IL-8. The anti-inflammatory cytokine IL-10 was significantly down regulated. Protein kinases like the Akt family or ERK, which are essential for cell survival and proliferation, were inhibited by both OPC. These findings indicate that the tested organophosphourus compounds induced significant changes in cell morphology, inhibited anti-inflammatory cytokines and influenced important protein signalling pathways which are involved in regulation of apoptosis. Thus our results highlight novel aspects -apparently independent of AChE inhibition- of OPC poisoning with regard to lung toxicity. Our findings contribute to the basic understanding of pulmonary complications caused by OPC poisoning. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

A differential impact of mycophenolic acid, prednisolone, and tacrolimus exposure on sCD30 levels in adult kidney transplant recipients.

PubMed

Barraclough, Katherine A; Staatz, Christine E; Johnson, David W; Gillis, David; Lee, Katie J; McWhinney, Brett C; Ungerer, Jacobus P J; Campbell, Scott B; Isbel, Nicole M

2013-04-01

Soluble CD30 (sCD30) has been associated with rejection and graft loss in kidney transplantation, leading to the suggestion that sCD30 might be a useful biomarker to adjust immunosuppressant medication dosing. However, there has been minimal study of the influence of individual immunosuppressive drugs on sCD30 levels. To evaluate the influence of mycophenolic acid (MPA), prednisolone, and tacrolimus exposure on sCD30 levels in adult kidney transplant recipients. The sCD30 levels were measured pretransplant and 30 days posttransplant. Area under the concentration-time curve (AUC) for each drug was estimated on day 30 using validated, multiple regression-derived limited sampling strategies. One hundred twenty-five subjects were included. Median (interquartile range) sCD30 levels were lower on day 30 posttransplant compared with pretransplant [10.7 (3.7-20.1) pg/mL versus 66.5 (46.0-95.1) pg/mL; P < 0.0001]. On univariate analyses, day 30 sCD30 levels were negatively correlated with MPA exposure and positively correlated with tacrolimus exposure. Using multivariate logistic regression, higher tacrolimus exposure was independently associated with higher day 30 sCD30 levels (2.2 change in odds for an SD increase in tacrolimus AUC 0-12, P = 0.01; 5.5 change in odds for an SD increase in tacrolimus predose concentration, P < 0.0001). In contrast, MPA and total and free prednisolone exposures were not independently associated with sCD30 levels. The sCD30 levels are significantly reduced in the presence of combination immunosuppression but are differentially affected by different immunosuppressant agents. More research is required before introduction of sCD30 measurement into clinical practice can be considered.

Estrogenic exposure affects metamorphosis and alters sex ratios in the northern leopard frog (Rana pipiens): identifying critically vulnerable periods of development.

PubMed

Hogan, Natacha S; Duarte, Paula; Wade, Michael G; Lean, David R S; Trudeau, Vance L

2008-05-01

During the transformation from larval tadpole to juvenile frog, there are critical periods of metamorphic development and sex differentiation that may be particularly sensitive to endocrine disruption. The aim of the present study was to identify sensitive developmental periods for estrogenic endocrine disruption in the northern leopard frog (Rana pipiens) using short, targeted exposures to the synthetic estrogen, ethinylestradiol (EE2). Post-hatch tadpoles (Gosner stage 27) were exposed over five distinct periods of metamorphosis: early (stage 27-30), mid (stage 30-36), early and mid (stage 27-36), late (stage 36-42), and the entire metamorphic period (chronic; stage 27-42). For each period, animals were sampled immediately following the EE2 exposure and at metamorphic climax (stage 42). The effects of EE2 on metamorphic development and sex differentiation were assessed through measures of length, weight, developmental stage, days to metamorphosis, sex ratios and incidence of gonadal intersex. Our results show that tadpoles exposed to EE2 during mid-metamorphosis were developmentally delayed immediately following exposure and took 2 weeks longer to reach metamorphic climax. In the unexposed groups, there was low proportion (0.15) of intersex tadpoles at stage 30 and gonads appeared to be morphologically distinct (male and female) in all individuals by stage 36. Tadpoles exposed early in development displayed a strong female-biased sex ratio compared to the controls. Moreover, these effects were also seen at metamorphic climax, approximately 2-3 months after the exposure period, demonstrating that transient early life-stage exposure to estrogen can induce effects on the reproductive organs that persist into the beginning of adult life-stages.

Exposure of Monocytes to Lipoarabinomannan Promotes Their Differentiation into Functionally and Phenotypically Immature Macrophages

PubMed Central

Chávez-Galán, Leslie; Ocaña-Guzmán, Ranferi; Torre-Bouscoulet, Luis; García-de-Alba, Carolina; Sada-Ovalle, Isabel

2015-01-01

Lipoarabinomannan (LAM) is a lipid virulence factor secreted by Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis. LAM can be measured in the urine or serum of tuberculosis patients (TB-patients). Circulating monocytes are the precursor cells of alveolar macrophages and might be exposed to LAM in patients with active TB. We speculated that exposing monocytes to LAM could produce phenotypically and functionally immature macrophages. To test our hypothesis, human monocytes were stimulated with LAM (24–120 hours) and various readouts were measured. The study showed that when monocytes were exposed to LAM, the frequency of CD68+, CD33+, and CD86+ macrophages decreased, suggesting that monocyte differentiation into mature macrophages was affected. Regarding functionality markers, TLR2+ and TLR4+ macrophages also decreased, but the percentage of MMR+ expression did not change. LAM-exposed monocytes generated macrophages that were less efficient in producing proinflammatory cytokines such as TNF-α and IFN-γ; however, their phagocytic capacity was not modified. Taken together, these data indicate that LAM exposure influenced monocyte differentiation and produced poorly functional macrophages with a different phenotype. These results may help us understand how mycobacteria can limit the quality of the innate and adaptive immune responses. PMID:26347897

X-ray induced alterations in the differentiation and mineralization potential of murine preosteoblastic cells

NASA Astrophysics Data System (ADS)

Hu, Yueyuan; Lau, Patrick; Baumstark-Khan, Christa; Hellweg, Christine E.; Reitz, Günther

2012-05-01

To evaluate the effects of ionizing radiation (IR) on murine preosteoblastic cell differentiation, we directed OCT-1 cells to the osteoblastic lineage by treatment with a combination of β-glycerophosphate (β-GP), ascorbic acid (AA), and dexamethasone (Dex). In vitro mineralization was evaluated based on histochemical staining and quantification of the hydroxyapatite content of the extracellular bone matrix. Expression of mRNA encoding Runx2, transforming growth factor β1 (TGF-β1), osteocalcin (OCN), and p21CDKN1A was analyzed. Exposure to IR reduced the growth rate and diminished cell survival of OCT-1 cells under standard conditions. Notably, calcium content analysis revealed that deposition of mineralized matrix increased significantly under osteogenic conditions after X-ray exposure in a time-dependent manner. In this study, higher radiation doses exert significant overall effects on TGF-β1, OCN, and p21CDKN1A gene expression, suggesting that gene expression following X-ray treatment is affected in a dose-dependent manner. Additionally, we verified that Runx2 was suppressed within 24 h after irradiation at 2 and 4 Gy. Although further studies are required to verify the molecular mechanism, our observations strongly suggest that treatment with IR markedly alters the differentiation and mineralization process of preosteoblastic cells.

In utero exposure to dioxin causes neocortical dysgenesis through the actions of p27Kip1

PubMed Central

Mitsuhashi, Takayuki; Yonemoto, Junzo; Sone, Hideko; Kosuge, Yasuhiro; Kosaki, Kenjiro; Takahashi, Takao

2010-01-01

Dioxins have been reported to exert various adverse effects, including cell-cycle dysregulation in vitro and impairment of spatial learning and memory after in utero exposure in rodents. Furthermore, children born to mothers who are exposed to dioxin analogs polychlorinated dibenzofurans or polychlorinated biphenyls have developmental impairments in cognitive functions. Here, we show that in utero exposure to dioxins in mice alters differentiation patterns of neural progenitors and leads to decreased numbers of non-GABAergic neurons and thinner deep neocortical layers. This reduction in number of non-GABAergic neurons is assumed to be caused by accumulation of cyclin-dependent kinase inhibitor p27Kip1 in nuclei of neural progenitors. Lending support to this presumption, mice lacking p27Kip1 are not susceptible to in utero dioxin exposure. These results show that environmental pollutants may affect neocortical histogenesis through alterations of functions of specific gene(s)/protein(s) (in our case, dioxins), exerting adverse effects by altering functions of p27Kip1. PMID:20805476

Expression of aromatase in the embryonic brain of the olive ridley sea turtle (Lepidochelys olivacea), and the effect of bisphenol-A in sexually differentiated embryos.

PubMed

Gómez-Picos, Patsy; Sifuentes-Romero, Itzel; Merchant-Larios, Horacio; Hernández-Cornejo, Rubí; Díaz-Hernández, Verónica; García-Gasca, Alejandra

2014-01-01

Brain aromatase participates in several biological processes, such as regulation of the reproductive-endocrine axis, memory, stress, sexual differentiation of the nervous system, male sexual behavior, and brain repair. Here we report the isolation and expression of brain aromatase in olive ridley sea turtle (Lepidochelys olivacea) embryos incubated at male- and female-promoting temperatures (MPT and FPT, respectively), at the thermosensitive period (TSP) and the sex-differentiated period. Also, aromatase expression was assessed in differentiated embryos exposed to bisphenol-A (BPA) during the TSP. BPA is a monomer of polycarbonate plastics and is considered an endocrine-disrupting compound. Normal aromatase expression was measured in both forebrain and hindbrain, showing higher expression levels in the forebrain of differentiated embryos at both incubation temperatures. Although no significant differences were detected in the hindbrain, expression was slightly higher at MPT. BPA did not affect aromatase expression neither in forebrains or hindbrains from embryos incubated at MPT, whereas at FPT an inverted U-shape curve was observed in forebrains with significant differences at lower concentrations, whereas in hindbrains a non-significant increment was observed at higher concentrations. Our data indicate that both incubation temperature and developmental stage are critical factors affecting aromatase expression in the forebrain. Because of the timing and location of aromatase expression in the brain, we suggest that brain aromatase may participate in the imprinting of sexual trends related to reproduction and sexual behavior at the onset of sex differentiation, and BPA exposure may impair aromatase function in the female forebrain.

Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis.

PubMed

Bozec, Aline; Hannemann, Nicole

2016-06-03

Considering that adipose tissue (AT) is an endocrine organ, it can influence whole body metabolism. Excessive energy storage leads to the dysregulation of adipocytes, which in turn induces abnormal secretion of adipokines, triggering metabolic syndromes such as obesity, dyslipidemia, hyperglycemia, hyperinsulinemia, insulin resistance and type 2 diabetes. Therefore, investigating the molecular mechanisms behind adipocyte dysregulation could help to develop novel therapeutic strategies. Our protocol describes methods for evaluating the molecular mechanism affected by hypoxic conditions of the AT, which correlates with adipocyte apoptosis in adult mice. This protocol describes how to analyze AT in vivo through gene expression profiling as well as histological analysis of adipocyte differentiation, proliferation and apoptosis during hypoxia exposure, ascertained through staining of hypoxic cells or HIF-1α protein. Furthermore, in vitro analysis of adipocyte differentiation and its responses to various stimuli completes the characterization of the molecular pathways behind possible adipocyte dysfunction leading to metabolic syndromes.

A Deese-Roediger-McDermott study of trauma memory among employees of New York City companies affected by the September 11, 2001, attacks.

PubMed

Triantafyllou, Dinara; North, Carol S; Zartman, Andrea; Roediger, Henry L

2015-08-01

Posttraumatic stress disorder (PTSD) has been found to be associated with abnormalities in memory function. This relationship has not previously been studied using the Deese-Roediger-McDermott (DRM) false memory paradigm in disaster-exposed populations. Three years after the September 11, 2001 (9/11) attacks, 281 participants from a volunteer sample of 379, recruited from 8 companies directly affected by the attacks, completed an interview about their disaster experience, a structured diagnostic interview, and the DRM paradigm. It was hypothesized that participants with PTSD would demonstrate more associative errors, termed false alarms to critical lures, compared to those without PTSD. This hypothesis was not supported; the only predictor of false alarms to critical lures was direct 9/11 trauma exposure. The finding that 9/11 trauma-exposure was associated with false alarms to critical lures suggests that neural processing of trauma-exposure memory may involve associative elements of overgeneralization coupled with insufficient inhibition of responses to related but harmless stimuli. Future research will be needed to differentiate psychopathology, such as PTSD, from physiological fight-or-flight responses to trauma.

Adolescent exposure to cannabis as a risk factor for psychiatric disorders.

PubMed

Rubino, Tiziana; Zamberletti, Erica; Parolaro, Daniela

2012-01-01

Adolescence represents a critical period for brain development and the endocannabinoid system plays a crucial role in the regulation of neuronal refinement during this period. Cannabis is the most consumed drug among adolescent people and its heavy use may affect maturational refinement by disrupting the regulatory role of the endocannabinoid system. In animals, adolescent cannabinoid exposure has been reported to cause long-term impairment in specific components of learning and memory and to differentially affect emotional reactivity with milder effects on anxiety behaviour and more pronounced effects on depression-like behaviour. Moreover, adolescent exposure to cannabinoids might represent a risk factor for developing psychotic-like symptoms at adulthood. Also epidemiological studies suggest that heavy adolescent cannabis use may increase the risk of cognitive abnormalities, psychotic illness, mood disorders and other illicit substance use later in life. In conclusion, the available data point to the hypothesis that heavy cannabis use in adolescence could increase the risk of developing psychiatric disorders, especially in people who already have a vulnerability to develop a psychiatric syndrome. Only few papers have investigated the neurobiological substrates of this vulnerability, thus further studies are needed to clarify the molecular mechanisms underlying the effect of cannabis on the adolescent brain.

Fluoxetine Induces Proliferation and Inhibits Differentiation of Hypothalamic Neuroprogenitor Cells In Vitro

PubMed Central

Sousa-Ferreira, Lígia; Aveleira, Célia; Botelho, Mariana; Álvaro, Ana Rita; Pereira de Almeida, Luís; Cavadas, Cláudia

2014-01-01

A significant number of children undergo maternal exposure to antidepressants and they often present low birth weight. Therefore, it is important to understand how selective serotonin reuptake inhibitors (SSRIs) affect the development of the hypothalamus, the key center for metabolism regulation. In this study we investigated the proliferative actions of fluoxetine in fetal hypothalamic neuroprogenitor cells and demonstrate that fluoxetine induces the proliferation of these cells, as shown by increased neurospheres size and number of proliferative cells (Ki-67+ cells). Moreover, fluoxetine inhibits the differentiation of hypothalamic neuroprogenitor cells, as demonstrated by decreased number of mature neurons (Neu-N+ cells) and increased number of undifferentiated cells (SOX-2+ cells). Additionally, fluoxetine-induced proliferation and maintenance of hypothalamic neuroprogenitor cells leads to changes in the mRNA levels of appetite regulator neuropeptides, including Neuropeptide Y (NPY) and Cocaine-and-Amphetamine-Regulated-Transcript (CART). This study provides the first evidence that SSRIs affect the development of hypothalamic neuroprogenitor cells in vitro with consequent alterations on appetite neuropeptides. PMID:24598761

The inverse hazard law: blood pressure, sexual harassment, racial discrimination, workplace abuse and occupational exposures in US low-income black, white and Latino workers.

PubMed

Krieger, Nancy; Chen, Jarvis T; Waterman, Pamela D; Hartman, Cathy; Stoddard, Anne M; Quinn, Margaret M; Sorensen, Glorian; Barbeau, Elizabeth M

2008-12-01

Research on societal determinants of health suggests the existence of an "inverse hazard law," which we define as: "The accumulation of health hazards tends to vary inversely with the power and resources of the populations affected." Yet, little empirical research has systematically investigated this topic, including in relation to workplace exposures. We accordingly designed the United for Health study (Greater Boston Area, Massachusetts, 2003-2004) to investigate the joint distribution and health implications of workplace occupational hazards (dust, fumes, chemical, noise, ergonomic strain) and social hazards (racial discrimination, sexual harassment, workplace abuse). Focusing on blood pressure as our health outcome, we found that among the 1202 low-income multi-racial/ethnic working class participants in our cohort - of whom 40% lived below the US poverty line - 79% reported exposure to at least one social hazard and 82% to at least one high-exposure occupational hazard. Only sexual harassment, the least common social hazard, was associated with elevated systolic blood pressure (SBP) among the women workers. By contrast, no statistically significant associations were detectable between the other additional highly prevalent social and occupational hazards and SBP; we did, however, find suggestive evidence of an association between SBP and response to unfair treatment, implying that in a context of high exposure, differential susceptibility to the exposure matters. These results interestingly contrast to our prior findings for this same cohort, in which we found associations between self-reported experiences of racial discrimination and two other health outcomes: psychological distress and cigarette smoking. Likely explanations for these contrasting findings include: (a) the differential etiologic periods and pathways involving somatic health, mental health, and health behaviors, and (b) the high prevalence of adverse exposures, limiting the ability to detect significant associations. As clarified by the "inverse hazard law," to understand health inequities, research is needed that contrasts exposures and health status population-wide, not just among those most inequitably exposed.

Influence of sex and stress exposure across the lifespan on endophenotypes of depression: focus on behavior, glucocorticoids, and hippocampus

PubMed Central

Gobinath, Aarthi R.; Mahmoud, Rand; Galea, Liisa A.M.

2015-01-01

Sex differences exist in vulnerability, symptoms, and treatment of many neuropsychiatric disorders. In this review, we discuss both preclinical and clinical research that investigates how sex influences depression endophenotypes at the behavioral, neuroendocrine, and neural levels across the lifespan. Chronic exposure to stress is a risk factor for depression and we discuss how stress during the prenatal, postnatal, and adolescent periods differentially affects males and females depending on the method of stress and metric examined. Given that the integrity of the hippocampus is compromised in depression, we specifically focus on sex differences in how hippocampal plasticity is affected by stress and depression across the lifespan. In addition, we examine how female physiology predisposes depression in adulthood, specifically in postpartum and perimenopausal periods. Finally, we discuss the underrepresentation of women in both preclinical and clinical research and how this limits our understanding of sex differences in vulnerability, presentation, and treatment of depression. PMID:25610363

Individual differences in fear extinction and anxiety-like behavior.

PubMed

King, Gabrielle; Scott, Elliot; Graham, Bronwyn M; Richardson, Rick

2017-05-01

There is growing appreciation for the substantial individual differences in the acquisition and inhibition of aversive associations, and the insights this might give into identifying individuals particularly vulnerable to stress and psychopathology. We examined whether animals that differed in rate of extinction (i.e., Fast versus Slow) were different in their response to an acute stress in adulthood or following a chronic stress that occurred either early or later in life. We found that Slow Extinguishers had significantly poorer extinction retention than Fast Extinguishers, but an acute stressor did not differentially affect anxiety-like behavior in the two groups. Further, while exposure to chronic stress in adulthood did not impact on the extinction phenotypes or anxiety-like behavior, exposure to chronic stress early in life affected both extinction retention and anxiety-like behavior. These findings have implications for the development of a more nuanced approach to identifying those most at risk of anxiety disorders. © 2017 King et al.; Published by Cold Spring Harbor Laboratory Press.

Estrogenic Environmental Chemicals and Drugs: Mechanisms for Effects on the Developing Male Urogenital System

PubMed Central

Taylor, Julia A.; Richter, Catherine A.; Ruhlen, Rachel L.; vom Saal, Frederick S.

2011-01-01

Development and differentiation of the prostate from the fetal urogenital sinus (UGS) is dependent on androgen action via androgen receptors (AR) in the UGS mesenchyme. Estrogens are not required for prostate differentiation but do act to modulate androgen action. In mice exposure to exogenous estrogen during development results in permanent effects on adult prostate size and function, which is mediated through mesenchymal estrogen receptor (ER) alpha. For many years estrogens were thought to inhibit prostate growth because estrogenic drugs studied were administered at very high concentrations that interfered with normal prostate development. There is now extensive evidence that exposure to estrogen at very low concentrations during the early stages of prostate differentiation can stimulate fetal/neonatal prostate growth and lead to prostate disease in adulthood. Bisphenol A (BPA) is an environmental endocrine disrupting chemical that binds to both ER receptor subtypes as well as to AR. Interest in BPA has increased because of its prevalence in the environment and its detection in over 90% of people in the USA. In tissue culture of fetal mouse UGS mesenchymal cells, BPA and estradiol stimulated changes in the expression of several genes. We discuss here the potential involvement of estrogen in regulating signaling pathways affecting cellular functions relevant to steroid hormone signaling and metabolism and to inter- and intra-cellular communications that promote cell growth. The findings presented here provide additional evidence that BPA and the estrogenic drug ethinylestradiol disrupt prostate development in male mice at administered doses relevant to human exposures. PMID:21827855

Student Award for Outstanding Research Winner in the Ph.D. Category for the 9th World Biomaterials Congress, Chengdu, China, June 1-5, 2012: The interplay of bone-like extracellular matrix and TNF-α signaling on in vitro osteogenic differentiation of mesenchymal stem cells.

PubMed

Mountziaris, Paschalia M; Tzouanas, Stephanie N; Mikos, Antonios G

2012-05-01

As an initial step in the development of a bone tissue engineering strategy to rationally control inflammation, we investigated the interplay of bone-like extracellular matrix (ECM) and varying doses of the inflammatory cytokine tumor necrosis factor alpha (TNF-α) on osteogenically differentiating mesenchymal stem cells (MSCs) cultured in vitro on 3D poly(ε-caprolactone) (PCL) microfiber scaffolds containing pregenerated bone-like ECM. To generate the ECM, PCL scaffolds were seeded with MSCs and cultured in medium containing the typically required osteogenic supplement dexamethasone. However, since dexamethasone antagonizes TNF-α, the interplay of ECM and TNF-α was investigated by culturing naïve MSCs on the decellularized scaffolds in the absence of dexamethasone. MSCs cultured on ECM-coated scaffolds continued to deposit mineralized matrix, a late stage marker of osteogenic differentiation. Mineralized matrix deposition was not adversely affected by exposure to TNF-α for 4-8 days, but was significantly reduced after continuous exposure to TNF-α over 16 days, which simulates the in vivo response, where brief TNF-α signaling stimulates bone regeneration, while prolonged exposure has damaging effects. This underscores the exciting potential of PCL/ECM constructs as a more clinically realistic in vitro culture model to facilitate the design of new bone tissue engineering strategies that rationally control inflammation to promote regeneration. Copyright © 2012 Wiley Periodicals, Inc.

Human Peripheral Blood Mononuclear Cell Function and Dendritic Cell Differentiation Are Affected by Bisphenol-A Exposure

PubMed Central

Ariemma, Fabiana; Cimmino, Ilaria; Bruzzese, Dario; Scerbo, Roberta; Picascia, Stefania; D’Esposito, Vittoria; Beguinot, Francesco; Formisano, Pietro

2016-01-01

Environmental pollutants, including endocrine disruptor chemicals (EDCs), interfere on human health, leading to hormonal, immune and metabolic perturbations. Bisphenol-A (BPA), a main component of polycarbonate plastics, has been receiving increased attention due to its worldwide distribution with a large exposure. In humans, BPA, for its estrogenic activity, may have a role in autoimmunity, inflammatory and allergic diseases. To this aim, we assessed the effect of low BPA doses on functionality of human peripheral blood mononuclear cells (PBMCs), and on in vitro differentiation of dendritic cells from monocytes (mDCs). Fresh peripheral blood samples were obtained from 12 healthy adult volunteers. PBMCs were left unstimulated or were activated with the mitogen phytohemagglutinin (PHA) or the anti-CD3 and anti-CD28 antibodies and incubated in presence or absence of BPA at 0.1 and 1nM concentrations. The immune-modulatory effect of BPA was assessed by evaluating the cell proliferation and the levels of interferon-γ (IFN-γ), interleukin-4 (IL-4), interleukin-10 (IL-10) and interleukin-13 (IL-13) secreted by PBMCs. mDCs were differentiated with IL-4 and GC-CSF with or without BPA and the expression of differentiation/maturation markers (CD11c, CD1a, CD86, HLA-DR) was evaluated by flow cytometry; furthermore, a panel of 27 different cytokines, growth factors and chemokines were assayed in the mDC culture supernatants. PBMCs proliferation significantly increased upon BPA exposure compared to BPA untreated cells. In addition, a significant decrease in IL-10 secretion was observed in PBMCs incubated with BPA, either in unstimulated or mitogen-stimulated cells, and at both 0.1 and 1nM BPA concentrations. Similarly, IL-13 was reduced, mainly in cells activated by antiCD3/CD28. By contrast, no significant changes in IFN-γ and IL-4 production were found in any condition assayed. Finally, BPA at 1nM increased the density of dendritic cells expressing CD1a and concomitantly decreased the expression of HLA-DR and CD86 activation markers. In conclusion, in humans the exposure to BPA causes on PBMCs a significant modulation of proliferative capacity and cytokine production, and on mDCs alteration in differentiation and phenotype. These immune cell alterations suggest that low dose chronic exposure to BPA could be involved in immune deregulation and possibly in the increased susceptibility to develop inflammatory and autoimmune diseases. PMID:27509021

Ionizing Radiation Impacts on Cardiac Differentiation of Mouse Embryonic Stem Cells

PubMed Central

Helm, Alexander; Arrizabalaga, Onetsine; Pignalosa, Diana; Schroeder, Insa S.; Durante, Marco

2016-01-01

Little is known about the effects of ionizing radiation on the earliest stages of embryonic development although it is well recognized that ionizing radiation is a natural part of our environment and further exposure may occur due to medical applications. The current study addresses this issue using D3 mouse embryonic stem cells as a model system. Cells were irradiated with either X-rays or carbon ions representing sparsely and densely ionizing radiation and their effect on the differentiation of D3 cells into spontaneously contracting cardiomyocytes through embryoid body (EB) formation was measured. This study is the first to demonstrate that ionizing radiation impairs the formation of beating cardiomyocytes with carbon ions being more detrimental than X-rays. However, after prolonged culture time, the number of beating EBs derived from carbon ion irradiated cells almost reached control levels indicating that the surviving cells are still capable of developing along the cardiac lineage although with considerable delay. Reduced EB size, failure to downregulate pluripotency markers, and impaired expression of cardiac markers were identified as the cause of compromised cardiomyocyte formation. Dysregulation of cardiac differentiation was accompanied by alterations in the expression of endodermal and ectodermal markers that were more severe after carbon ion irradiation than after exposure to X-rays. In conclusion, our data show that carbon ion irradiation profoundly affects differentiation and thus may pose a higher risk to the early embryo than X-rays. PMID:26506910

Effects of subchronic benzo(a)pyrene exposure on neurotransmitter receptor gene expression in the rat hippocampus related with spatial learning and memory change.

PubMed

Qiu, Chongying; Cheng, Shuqun; Xia, Yinyin; Peng, Bin; Tang, Qian; Tu, Baijie

2011-11-18

Exposure of laboratory rats to Benzo(a)pyrene (BaP), an environmental contaminant with its high lipophilicify which is widely dispersed in the environment and can easily cross the blood brain barrier presenting in the central nervous system, is associated with impaired learning and memory. The purpose of the research was to examine whether subchronic exposure to BaP affects spatial learning and memory, and how it alters normal gene expression in hippocampus, as well as selection of candidate genes involving neurotransmitter receptor attributed to learning and memory. Morris water maze (MWM) was used to evaluate behavioral differences between BaP-treated and vehicle-treated groups. To gain a better insight into the mechanism of BaP-induced neurotoxicity on learning and memory, we used whole genome oligo microarrays as well as Polymerase Chain Reaction (PCR) to assess the global impact of gene expression. Male Sprague-Dawley rats were intraperitoneally injected with 6.25mg/kg of BaP or vehicle for 14 weeks. The results from the Morris water maze (MWM) test showed that rats treated with BaP exhibited significantly higher mean latencies as compared to vehicle controls. BaP exposure significantly decreased the number of crossing the platform and the time spent in the target area. After the hippocampus was collected from each rat, total RNA was isolated. Microarray and PCR revealed that exposure to BaP affected mRNA expression of neurotransmitter receptors. The web tool DAVID was used to analyze the significantly enriched gene ontology (GO) and KEGG pathways in the differentially expressed genes. Analysis showed that the most significantly affected gene ontology category was behavior. Furthermore, the fourth highest significantly affected gene ontology category was learning and memory. KEGG molecular pathway analysis showed that "neuroactive ligand-receptor interaction" was affected by BaP with highest statistical significance, and 9 candidate neurotransmitter receptor genes involving learning and memory were selected out. Our results revealed a close link between behavioral changes and altered neurotransmitter receptor gene expression in BaP-treated rats. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Chronic exposure to a low concentration of bisphenol A during follicle culture affects the epigenetic status of germinal vesicles and metaphase II oocytes.

PubMed

Trapphoff, Tom; Heiligentag, Martyna; El Hajj, Nady; Haaf, Thomas; Eichenlaub-Ritter, Ursula

2013-12-01

To determine whether exposure to low concentrations of the endocrine disrupting chemical bisphenol A (BPA) during follicle culture and oocyte growth alters the methylation status of differentially methylated regions (DMRs) of imprinted genes and histone posttranslational modification patterns in mammalian oocytes. Comparative and control study. Experimental laboratory. C57/Bl6JxCBA/Ca mice. Exposure of oocytes to 3 nM or 300 nM BPA during follicle culture from preantral to antral stage. Methylation status of DMRs of maternally imprinted (Snrpn, Igf2r, and Mest) and paternally imprinted gene(s) (H19) in mouse germinal vesicle oocytes; trimethylation of histone H3K9, acetylation of histone H4K12, and distance between centromeres of sister chromatids in metaphase II oocytes. Exposure to 3 nM BPA was associated with slightly accelerated follicle development, statistically significant increases in allele methylation errors in DMRs of maternally imprinted genes, and statistically significant decreases in histone H3K9 trimethylation and interkinetochore distance. The disturbances in oocyte genomic imprinting and modification of posttranslational histone and centromere architecture provide the first link between low BPA exposures and induction of epigenetic changes that may contribute to chromosome congression failures and meiotic errors, and to altered gene expression that might affect health of the offspring. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Parental verbal affection and verbal aggression in childhood differentially influence psychiatric symptoms and wellbeing in young adulthood.

PubMed

Polcari, Ann; Rabi, Keren; Bolger, Elizabeth; Teicher, Martin H

2014-01-01

Previous research has shown that exposure to parental verbal aggression is common and associated with increased levels of depression, anxiety, dissociation, and drug use. A key question that has not been addressed is whether verbal affection from the same or opposite parent can attenuate the effects of verbal aggression. This cross-sectional study examined the effects of parental verbal aggression and affection during childhood on measures of psychopathology and wellbeing in a community sample of 2,518 individuals (18-25 years). Data were analyzed for moderating influences using mixed effect models and for direct and indirect effects using structural equation models. The moderation analysis suggested that high levels of exposure to verbal affection did not mitigate the effects of verbal aggression from the same parent, and high levels of verbal affection from another parent did not generally result in a significant attenuation of the effects of verbal aggression. Structural equation models showed that verbal aggression was predominantly associated with effects on psychiatric symptoms scores, whereas verbal affection was primarily associated with effects on measures of wellbeing. These findings highlight the relatively independent effects of verbal aggression and verbal affection and suggest that the latter may be particularly important in establishing a foundation for emotional and physical wellbeing. These findings also suggest that ridicule, disdain, and humiliation cannot be easily counteracted by praise and warmth from the same or another parent. Copyright © 2013 Elsevier Ltd. All rights reserved.

Parental Verbal Affection and Verbal Aggression in Childhood Differentially Influence Psychiatric Symptoms and Wellbeing in Young Adulthood

PubMed Central

Polcari, Ann; Rabi, Keren; Bolger, Elizabeth; Teicher, Martin H.

2013-01-01

Previous research has shown that exposure to parental verbal aggression is common and associated with increased levels of depression, anxiety, dissociation, and drug use. A key question that has not been addressed is whether verbal affection from the same or opposite parent can attenuate the effects of verbal aggression. This cross-sectional study examined the effects of parental verbal aggression and affection during childhood on measures of psychopathology and wellbeing in a community sample of 2,518 individuals (18–25 years). Data were analyzed for moderating influences using mixed effect models and for direct and indirect effects using structural equation models. The moderation analysis suggested that high levels of exposure to verbal affection did not mitigate the effects of verbal aggression from the same parent, and high levels of verbal affection from another parent did not generally result in a significant attenuation of the effects of verbal aggression. Structural equation models showed that verbal aggression was predominantly associated with effects on psychiatric symptoms scores, whereas verbal affection was primarily associated with effects on measures of wellbeing. These findings highlight the relatively independent effects of verbal aggression and verbal affection and suggest that the latter may be particularly important in establishing a foundation for emotional and physical wellbeing. These findings also suggest that ridicule, disdain, and humiliation cannot be easily counteracted by praise and warmth from the same or another parent. PMID:24268711

Titanium dioxide nanoparticles activate IL8-related inflammatory pathways in human colonic epithelial Caco-2 cells

NASA Astrophysics Data System (ADS)

Krüger, Kristin; Cossais, François; Neve, Horst; Klempt, Martin

2014-05-01

Nanosized titanium dioxide (TiO2) particles are widely used as food additive or coating material in products of the food and pharmaceutical industry. Studies on various cell lines have shown that TiO2 nanoparticles (NPs) induced the inflammatory response and cytotoxicity. However, the influences of TiO2 NPs' exposure on inflammatory pathways in intestinal epithelial cells and their differentiation have not been investigated so far. This study demonstrates that TiO2 NPs with particle sizes ranging between 5 and 10 nm do not affect enterocyte differentiation but cause an activation of inflammatory pathways in the human colon adenocarcinoma cell line Caco-2. 5 and 10 nm NPs' exposures transiently induce the expression of ICAM1, CCL20, COX2 and IL8, as determined by quantitative PCR, whereas larger particles (490 nm) do not. Further, using nuclear factor (NF)-κB reporter gene assays, we show that NP-induced IL8 mRNA expression occurs, in part, through activation of NF-κB and p38 mitogen-activated protein kinase pathways.

Analysis of differentially regulated proteins in TM4 cells treated with bisphenol A.

PubMed

Lee, Do-Youn; Lee, Sang-Soo; Joo, Won-A; Lee, Eun-Ju; Kim, Chan-Wha

2004-06-01

BPA, bisphenol A, a monomer of epoxy resins and polycarbonate plastic, is used in many consumer products including the plastic linings of cans for food and babies' bottles. BPA has been reported to cause reproductive toxicity and affects cells in rats and mice at high doses. In this study, the effect of BPA on protein expression in TM4 cells (a mouse Sertoli cell line) known to play an essential role in Spermatogenesis was investigated by two-dimensional electrophoresis (2-DE). After 16 h exposure to 50, 100, 150, 200, and 250 microM of BPA, the viability of TM4 cells decreased to about 90, 85, 78, 55, and 30% of control respectively. Approximately 800 protein spots in TM4 cells were analyzed by 2-DE with pH 4-7 linear immobilized pH gradient (IPG) Dry Strip, and 11 proteins which showed significantly different expression levels were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS). Among these, HSP 27 and placental calcium binding protein may be proteins differentially expressed by BPA exposure.

In ovo exposure to o,p -DDE affects sexual development but not sexual differentiation in Japanese medaka (Oryzias latipes).

USGS Publications Warehouse

Papoulias, D.M.; Villalobos, Sergio A.; Meadows, J.; Noltie, Douglas B.; Giesy, J.P.; Tillitt, D.E.

2003-01-01

Despite being banned in many countries, dichlorodiphenyltrichloroethane (DDT) and its metabolites dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD) continue to be found in fish tissues at concentrations of concern. Like o,p -DDT, o,p -DDE is estrogenic and is believed to exert its effects through binding to the estrogen receptor. The limited toxicologic data for o,p -DDE suggest that it decreases fecundity and fertility of fishes. We conducted an egg injection study using the d-rR strain of medaka and environmentally relevant concentrations of o,p -DDE to examine its effects on sexual differentiation and development. The gonads of exposed fish showed no evidence of sex reversal or intersex. However, other gonad abnormalities occurred in exposed individuals. Females exhibited few vitellogenic oocytes and increased atresia. Male testes appeared morphologically normal but were very small. Gonadosomatic index values for both sexes were lower for exposed fish. Our observations of abnormal female and very small male gonads after in ovo o,p -DDE exposure may be indicative of effects on early endocrine processes important for normal ovarian and testicular development.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Galvin, M.J.; MacNichols, G.L.; McRee, D.I.

In this study, the influence of 2450 MHz CW microwave radiation on hematopoiesis in pregnant mice was examined. Dams (mice CD-1 strain) were irradiated during Days 1-6 or 6-15 of pregnancy. The animals were irradiated for a total of 8 hr per day at an average power density of 30 mW/cm/sup 2/. Peripheral blood and bone marrow samples were obtained on Day 18 of pregnancy. The total leukocyte and differential leukocyte counts of peripheral blood samples were not affected by either exposure regimen. In addition, no effects were noted in either the erythroid or myeloid mitotic indices of bone marrowmore » samples. Exposure of pregnant mice to microwave radiation under the conditions of these experiments had no effects on the investigated aspects of hematopoiesis.« less

Acute and chronic cold exposure differentially affects the browning of porcine white adipose tissue.

PubMed

Gao, Y; Qimuge, N R; Qin, J; Cai, R; Li, X; Chu, G Y; Pang, W J; Yang, G S

2018-07-01

Piglets are characteristically cold intolerant and thus susceptible to high mortality. However, browning of white adipose tissue (WAT) can induce non-shivering thermogenesis as a potential strategy to facilitate the animal's response to cold. Whether cold exposure can induce browning of subcutaneous WAT (sWAT) in piglets in a similar manner as it can in humans remains largely unknown. In this study, piglets were exposed to acute cold (4°C, 10 h) or chronic cold exposure (8°C, 15 days), and the genes and proteins of uncoupling protein 1 (UCP1)-dependent and independent thermogenesis, mitochondrial biogenesis, lipogenic and lipolytic processes were analysed. Interestingly, acute cold exposure induced browning of porcine sWAT, smaller adipocytes and the upregulated expression of UCP1, PGC1α, PGC1β, C/EBPβ, Cidea, UCP3, CKMT1 and PM20D1. Conversely, chronic cold exposure impaired the browning process, reduced mitochondrial numbers and the expression of browning markers, including UCP1, PGC1α and PRDM16. The present study demonstrated that acute cold exposure (but not chronic cold exposure) induces porcine sWAT browning. Thus, browning of porcine sWAT could be a novel strategy to balance the body temperature of piglets, and thus could be protective against cold exposure.

Imidacloprid Exposure Suppresses Neural Crest Cells Generation during Early Chick Embryo Development.

PubMed

Wang, Chao-Jie; Wang, Guang; Wang, Xiao-Yu; Liu, Meng; Chuai, Manli; Lee, Kenneth Ka Ho; He, Xiao-Song; Lu, Da-Xiang; Yang, Xuesong

2016-06-15

Imidacloprid is a neonicotinoid pesticide that is widely used in the control pests found on crops and fleas on pets. However, it is still unclear whether imidacloprid exposure could affect early embryo development-despite some studies having been conducted on the gametes. In this study, we demonstrated that imidacloprid exposure could lead to abnormal craniofacial osteogenesis in the developing chick embryo. Cranial neural crest cells (NCCs) are the progenitor cells of the chick cranial skull. We found that the imidacloprid exposure retards the development of gastrulating chick embryos. HNK-1, PAX7, and Ap-2α immunohistological stainings indicated that cranial NCCs generation was inhibited after imidacloprid exposure. Double immunofluorescent staining (Ap-2α and PHIS3 or PAX7 and c-Caspase3) revealed that imidacloprid exposure inhibited both NCC proliferation and apoptosis. In addition, it inhibited NCCs production by repressing Msx1 and BMP4 expression in the developing neural tube and by altering expression of EMT-related adhesion molecules (Cad6B, E-Cadherin, and N-cadherin) in the developing neural crests. We also determined that imidacloprid exposure suppressed cranial NCCs migration and their ability to differentiate. In sum, we have provided experimental evidence that imidacloprid exposure during embryogenesis disrupts NCCs development, which in turn causes defective cranial bone development.

Tributyltin Differentially Promotes Development of a Phenotypically Distinct Adipocyte

PubMed Central

Regnier, Shane M.; El-Hashani, Essam; Kamau, Wakanene; Zhang, Xiaojie; Massad, Nicole L.; Sargis, Robert M.

2015-01-01

Objective Environmental endocrine disrupting chemicals (EDCs) are increasingly implicated in the pathogenesis of obesity. Evidence implicates various EDCs as being pro-adipogenic, including tributyltin (TBT), which activates the peroxisome proliferator activated receptor-γ (PPARγ). However, the conditions required for TBT-induced adipogenesis and its functional consequences are incompletely known. Methods The co-stimulatory conditions necessary for preadipocyte-to-adipocyte differentiation were compared between TBT and the pharmacological PPARγ agonist troglitazone (Trog) in the 3T3-L1 cell line; basal and insulin-stimulated glucose uptake were assessed using radiolabeled 2-deoxyglucose. Results TBT enhanced expression of the adipocyte marker C/EBPα with co-exposure to either isobutylmethylxanthine or insulin in the absence of other adipogenic stimuli. Examination of several adipocyte-specific proteins revealed that TBT and Trog differentially affected protein expression despite comparable PPARγ stimulation. In particular, TBT reduced adiponectin expression upon maximal adipogenic stimulation. Under submaximal stimulation, TBT and Trog differentially promoted adipocyte-specific gene expression despite similar lipid accumulation. Moreover, TBT attenuated Trog-induced adipocyte gene expression under conditions of co-treatment. Finally, TBT-induced adipocytes exhibited altered glucose metabolism, with increased basal glucose uptake. Conclusions TBT-induced adipocytes are functionally distinct from those generated by a pharmacological PPARγ agonist, suggesting that obesogen-induced adipogenesis may generate dysfunctional adipocytes with the capacity to deleteriously affect global energy homeostasis. PMID:26243053

Chronic exposure to bisphenol a impairs progesterone receptor-mediated signaling in the uterus during early pregnancy

PubMed Central

Li, Quanxi; Davila, Juanmahel; Bagchi, Milan K.; Bagchi, Indrani C.

2016-01-01

Environmental and occupational exposure to endocrine disrupting chemicals (EDCs) is a major threat to female reproductive health. Bisphenol A (BPA), an environmental toxicant that is commonly found in polycarbonate plastics and epoxy resins, has received much attention due to its estrogenic activity and high risk of chronic exposure in human. Whereas BPA has been linked to infertility and recurrent miscarriage in women, the impact of its exposure on uterine function during early pregnancy remains unclear. In a recent publication in Endocrinology, we demonstrated that prolonged exposure to an environmental relevant dose of BPA disrupts progesterone receptor-regulated uterine functions, thus affecting uterine receptivity for embryo implantation and decidua morphogenesis, two critical events for establishment and maintenance of early pregnancy. In particular we reported a marked impairment of progesterone receptor (PGR) expression and its downstream effector HAND2 in the uterine stromal cells in response to chronic BPA exposure. In an earlier study we have shown that HAND2 controls embryo implantation by repressing fibroblast growth factor (FGF) expression and the MAP kinase signaling pathway, thus inhibiting epithelial proliferation. Interestingly we observed that downregulation of PGR and HAND2 expression in uterine stroma upon BPA exposure was associated with an enhanced activation of FGFR and MAPK signaling, aberrant proliferation, and lack of uterine receptivity in the epithelium. In addition, the proliferation and differentiation of endometrial stromal cells to decidual cells, an event critical for the maintenance of early pregnancy, was severely compromised in response to BPA. This research highlight will provide an overview of our findings and discuss the potential mechanisms by which chronic BPA impairs PGR-HAND2 pathway and adversely affects implantation and the establishment of pregnancy. PMID:28239613

Prenatal cadmium exposure dysregulates sonic hedgehog and Wnt/beta-catenin signaling in the thymus resulting in altered thymocyte development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hanson, Miranda L.; Brundage, Kathleen M.; Schafer, Rosana

2010-01-15

Cadmium (Cd) is both an environmental pollutant and a component of cigarette smoke. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports in the literature of immunomodulatory effects of prenatal exposure to Cd. The sonic hedgehog (Shh) and Wnt/beta-catenin pathways are required for thymocyte maturation. Several studies have demonstrated that Cd exposure affects these pathways in different organ systems. This study was designed to investigate the effect of prenatal Cd exposure on thymocyte development, and to determine if these effects were linked to dysregulation of Shh and Wnt/beta-catenin pathways. Pregnant C57Bl/6more » mice were exposed to an environmentally relevant dose (10 ppm) of Cd throughout pregnancy and effects on the thymus were assessed on the day of birth. Thymocyte phenotype was determined by flow cytometry. A Gli:luciferase reporter cell line was used to measure Shh signaling. Transcription of target genes and translation of key components of both signaling pathways were assessed using real-time RT-PCR and western blot, respectively. Prenatal Cd exposure increased the number of CD4{sup +} cells and a subpopulation of double-negative cells (DN; CD4{sup -}CD8{sup -}), DN4 (CD44{sup -}CD25{sup -}). Shh and Wnt/beta-catenin signaling were both decreased in the thymus. Target genes of Shh (Patched1 and Gli1) and Wnt/beta-catenin (c-fos, and c-myc) were affected differentially among thymocyte subpopulations. These findings suggest that prenatal exposure to Cd dysregulates two signaling pathways in the thymus, resulting in altered thymocyte development.« less

The effects of perfluorinated chemicals on adipocyte differentiation in vitro.

PubMed

Watkins, Andrew M; Wood, Carmen R; Lin, Mimi T; Abbott, Barbara D

2015-01-15

The 3T3-L1 preadipocyte culture system has been used to examine numerous compounds that influence adipocyte differentiation or function. The perfluoroalkyl acids (PFAAs), used as surfactants in a variety of industrial applications, are of concern as environmental contaminants that are detected worldwide in human serum and animal tissues. This study was designed to evaluate the potential for PFAAs to affect adipocyte differentiation and lipid accumulation using mouse 3T3-L1 cells. Cells were treated with perfluorooctanoic acid (PFOA) (5-100 µM), perfluorononanoic acid (PFNA) (5-100 µM), perfluorooctane sulfonate (PFOS) (50-300 µM), perfluorohexane sulfonate (PFHxS) (40-250 µM), the peroxisome proliferator activated receptor (PPAR) PPARα agonist Wyeth-14,643 (WY-14,643), and the PPARγ agonist rosiglitazone. The PPARγ agonist was included as a positive control as this pathway is critical to adipocyte differentiation. The PPARα agonist was included as the PFAA compounds are known activators of this pathway. Cells were assessed morphometrically and biochemically for number, size, and lipid content. RNA was extracted for qPCR analysis of 13 genes selected for their importance in adipocyte differentiation and lipid metabolism. There was a significant concentration-related increase in cell number and decreased cell size after exposure to PFOA, PFHxS, PFOS, and PFNA. All four PFAA treatments produced a concentration-related decrease in the calculated average area occupied by lipid per cell. However, total triglyceride levels per well increased with a concentration-related trend for all compounds, likely due to the increased cell number. Expression of mRNA for the selected genes was affected by all exposures and the specific impacts depended on the particular compound and concentration. Acox1 and Gapdh were upregulated by all six compounds. The strongest overall effect was a nearly 10-fold induction of Scd1 by PFHxS. The sulfonated PFAAs produced numerous, strong changes in gene expression similar to the effects after treatment with the PPARγ agonist rosiglitazone. By comparison, the effects on gene expression were muted for the carboxylated PFAAs and for the PPARα agonist WY-14,643. In summary, all perfluorinated compounds increased cell number, decreased cell size, increased total triglyceride, and altered expression of genes associated with adipocyte differentiation and lipid metabolism. Published by Elsevier Ireland Ltd.

In Vivo Exposure to Inorganic Arsenic Alters Differentiation-Specific Gene Expression of Adipose-Derived Mesenchymal Stem/Stromal Cells in C57BL/6J Mouse Model

PubMed Central

Shearer, Joseph J.; Figueiredo Neto, Manoel; Umbaugh, C. Samuel; Figueiredo, Marxa L.

2017-01-01

Abstract The number of mesenchymal stem cell (MSC) therapeutic modalities has grown in recent years. Adipose-derived mesenchymal stem/stromal cells (ASCs) can be isolated and expanded relatively easily as compared with their bone-marrow counterparts, making them a particularly promising source of MSCs. And although the biological mechanisms surrounding ASCs are actively being investigated, little is known about the effects that in vivo environmental exposures might have on their ability to properly differentiate. Therefore, we hypothesized that ASCs isolated from mice exposed to inorganic arsenic (iAs) would have an altered response towards adipogenic, osteogenic, and/or chondrogenic differentiation. To test this hypothesis, C57BL/6J male mice were provided drinking water containing 0, 300, or 1000 ppb iAs. ASCs were then isolated and differentiated, which was assessed by immunocytochemistry and real-time quantitative PCR (RT-qPCR). Our results showed that total urinary arsenic equilibrated within 1 week of exposure to iAs and was maintained throughout the study. ASCs isolated from each exposure group maintained differentiation capabilities for each lineage. The magnitude of differentiation-specific gene expression, however, appeared to be concentration dependent. For osteogenesis and chondrogenesis, differentiation-specific gene expression decreased, whereas adipogenesis showed a biphasic response with an initial decrease followed by an increase in adipogenic-related gene expression following iAs exposure. These results suggest that the level in which differentiation-specific genes are induced within these stromal cells might be sensitive to environmental contaminants. These findings highlight the need to take into account potential environmental exposures prior to selecting stromal cell donors, so ASCs can achieve optimal efficiency in regenerative therapy applications. PMID:28206643

Bone morphogenic protein-2 regulates the myogenic differentiation of PMVECs in CBDL rat serum-induced pulmonary microvascular remodeling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Chang; Chen, Lin; Zeng, Jing

Hepatopulmonary syndrome (HPS) is characterized by an arterial oxygenation defect induced by intrapulmonary vasodilation (IPVD) that increases morbidity and mortality. In our previous study, it was determined that both the proliferation and the myogenic differentiation of pulmonary microvascular endothelial cells (PMVECs) play a key role in the development of IPVD. However, the molecular mechanism underlying the relationship between IPVD and the myogenic differentiation of PMVECs remains unknown. Additionally, it has been shown that bone morphogenic protein-2 (BMP2), via the control of protein expression, may regulate cell differentiation including cardiomyocyte differentiation, neuronal differentiation and odontoblastic differentiation. In this study, we observedmore » that common bile duct ligation (CBDL)-rat serum induced the upregulation of the expression of several myogenic proteins (SM-α-actin, calponin, SM-MHC) and enhanced the expression levels of BMP2 mRNA and protein in PMVECs. We also observed that both the expression levels of Smad1/5 and the activation of phosphorylated Smad1/5 were significantly elevated in PMVECs following exposure to CBDL-rat serum, which was accompanied by the down-regulation of Smurf1. The blockage of the BMP2/Smad signaling pathway with Noggin inhibited the myogenic differentiation of PMVECs, a process that was associated with relatively low expression levels of both SM-α-actin and calponin in the setting of CBDL-rat serum exposure, although SM-MHC expression was not affected. These findings suggested that the BMP2/Smad signaling pathway is involved in the myogenic differentiation of the PMVECs. In conclusion, our data highlight the pivotal role of BMP2 in the CBDL-rat serum-induced myogenic differentiation of PMVECs via the activation of both Smad1 and Smad5 and the down-regulation of Smurf1, which may represent a potential therapy for HPS-induced pulmonary vascular remodeling. - Highlights: • CBDL-rat serum promotes the myogenic differentiaton and expression of BMP2 in PMVECs. • CBDL-rat serum activates the BMP2/smad signaling pathway. • The downregulation of Smurf1 stimulates the accumulation of Smad1/5 in PMVECs. • Noggin reverses partially the myogenic differentiaton in PMVECs.« less

Adolescent toluene inhalation in rats affects white matter maturation with the potential for recovery following abstinence.

PubMed

Duncan, Jhodie Rubina; Dick, Alec Lindsay Ward; Egan, Gary; Kolbe, Scott; Gavrilescu, Maria; Wright, David; Lubman, Dan Ian; Lawrence, Andrew John

2012-01-01

Inhalant misuse is common during adolescence, with ongoing chronic misuse associated with neurobiological and cognitive abnormalities. While human imaging studies consistently report white matter abnormalities among long-term inhalant users, longitudinal studies have been lacking with limited data available regarding the progressive nature of such abnormalities, including the potential for recovery following periods of sustained abstinence. We exposed adolescent male Wistar rats (postnatal day 27) to chronic intermittent inhaled toluene (3,000 ppm) for 1 hour/day, 3 times/week for 8 weeks to model abuse patterns observed in adolescent and young adult human users. This dosing regimen resulted in a significant retardation in weight gain during the exposure period (p<0.05). In parallel, we performed longitudinal magnetic resonance imaging (T₂-weighted) and diffusion tensor imaging prior to exposure, and after 4 and 8 weeks, to examine the integrity of white matter tracts, including the anterior commissure and corpus callosum. We also conducted imaging after 8 weeks of abstinence to assess for potential recovery. Chronic intermittent toluene exposure during adolescence and early adulthood resulted in white matter abnormalities, including a decrease in axial (p<0.05) and radial (p<0.05) diffusivity. These abnormalities appeared region-specific, occurring in the anterior commissure but not the corpus callosum and were not present until after at least 4 weeks of exposure. Toluene-induced effects on both body weight and white matter parameters recovered following abstinence. Behaviourally, we observed a progressive decrease in rearing activity following toluene exposure but no difference in motor function, suggesting cognitive function may be more sensitive to the effects of toluene. Furthermore, deficits in rearing were present by 4 weeks suggesting that toluene may affect behaviour prior to detectable white matter abnormalities. Consequently, exposure to inhalants that contain toluene during adolescence and early adulthood appear to differentially affect white matter maturation and behavioural outcomes, although recovery can occur following abstinence.

Adolescent Toluene Inhalation in Rats Affects White Matter Maturation with the Potential for Recovery Following Abstinence

PubMed Central

Egan, Gary; Kolbe, Scott; Gavrilescu, Maria; Wright, David; Lubman, Dan Ian; Lawrence, Andrew John

2012-01-01

Inhalant misuse is common during adolescence, with ongoing chronic misuse associated with neurobiological and cognitive abnormalities. While human imaging studies consistently report white matter abnormalities among long-term inhalant users, longitudinal studies have been lacking with limited data available regarding the progressive nature of such abnormalities, including the potential for recovery following periods of sustained abstinence. We exposed adolescent male Wistar rats (postnatal day 27) to chronic intermittent inhaled toluene (3,000 ppm) for 1 hour/day, 3 times/week for 8 weeks to model abuse patterns observed in adolescent and young adult human users. This dosing regimen resulted in a significant retardation in weight gain during the exposure period (p<0.05). In parallel, we performed longitudinal magnetic resonance imaging (T2-weighted) and diffusion tensor imaging prior to exposure, and after 4 and 8 weeks, to examine the integrity of white matter tracts, including the anterior commissure and corpus callosum. We also conducted imaging after 8 weeks of abstinence to assess for potential recovery. Chronic intermittent toluene exposure during adolescence and early adulthood resulted in white matter abnormalities, including a decrease in axial (p<0.05) and radial (p<0.05) diffusivity. These abnormalities appeared region-specific, occurring in the anterior commissure but not the corpus callosum and were not present until after at least 4 weeks of exposure. Toluene-induced effects on both body weight and white matter parameters recovered following abstinence. Behaviourally, we observed a progressive decrease in rearing activity following toluene exposure but no difference in motor function, suggesting cognitive function may be more sensitive to the effects of toluene. Furthermore, deficits in rearing were present by 4 weeks suggesting that toluene may affect behaviour prior to detectable white matter abnormalities. Consequently, exposure to inhalants that contain toluene during adolescence and early adulthood appear to differentially affect white matter maturation and behavioural outcomes, although recovery can occur following abstinence. PMID:23028622

Effects of ethanol on cellular composition and network excitability of human pluripotent stem cell-derived neurons

PubMed Central

Larsen, Zoe H.; Chander, Praveen; Joyner, Jason A.; Floruta, Crina M.; Demeter, Tess L.; Weick, Jason P.

2016-01-01

Background Prenatal alcohol exposure (PAE) in animal models results in excitatory-inhibitory (E/I) imbalance in neocortex due to alterations in the GABAergic interneuron (IN) differentiation and migration. Thus, E/I imbalance is a potential cause for intellectual disability in individuals with fetal alcohol spectrum disorder (FASD), but whether ethanol (EtOH) changes glutamatergic and GABAergic IN specification during human development remains unknown. Here we created a human cellular model of PAE/FASD and tested the hypothesis that EtOH exposure during differentiation of human pluripotent stem cell-derived neurons (hPSNs) would cause aberrant production of glutamatergic and GABAergic neurons, resulting in E/I imbalance. Methods We applied 50mM EtOH daily to differentiating hPSNs for 50 days to model chronic first trimester exposure. We used quantitative PCR, immunocytochemical, and electrophysiological analysis to examine the effects of EtOH on hPSN specification and functional E/I balance. Results We found that EtOH did not alter neural induction nor general forebrain patterning, and had no effect on the expression of markers of excitatory cortical pyramidal neurons. In contrast, our data revealed highly significant changes to levels of transcripts involved with IN precursor development (e.g. GSX2, DLX1/2/5/6, NR2F2) as well as mature IN specification (e.g. SST, NPY). Interestingly, EtOH did not affect the number of GABAergic neurons generated nor the frequency or amplitude of miniature excitatory and inhibitory postsynaptic currents. Conclusions Similar to in vivo rodent studies, EtOH significantly and specifically altered the expression of genes involved with IN specification from hPSNs but did not cause imbalances of synaptic excitation-inhibition. Thus, our findings corroborate previous studies pointing to aberrant neuronal differentiation as an underlying mechanism of intellectual disability in FASD. However, in contrast to rodent binge models, our chronic exposure model suggests possible compensatory mechanisms that may cause more subtle defects of network processing rather than gross alterations in total E/I balance. PMID:27717039

Human immunotoxicologic markers of chemical exposures: preliminary validation studies.

PubMed

Wartenberg, D; Laskin, D; Kipen, H

1993-01-01

The circulating cells of the immune system are sensitive to environmental contaminants, and effects are often manifested as changes in the cell surface differentiation antigens of affected populations of cells, particularly lymphocytes. In this investigation, we explore the likelihood that variation in the expression of the surface markers of immune cells can be used as an index of exposure to toxic chemicals. We recruited 38 healthy New Jersey men to study pesticides effects: 19 orchard farmers (high exposure); 13 berry farmers (low exposure); and 6 hardware store owners (no exposure). Immunophenotyping was performed assaying the following cell surface antigens: CD2, CD4, CD8, CD14, CD20, CD26, CD29, CD45R, CD56, and PMN. Data were analyzed using univariate and multivariate methods. There were no significant differences among the groups with respect to routine medical histories, physical examinations, or routine laboratory parameters. No striking differences between groups were seen in univariate tests. Multivariate tests suggested some differences among groups and limited ability to correctly classify individuals based on immunophenotyping results. Immunophenotyping represents a fruitful area of research for improved exposure classification. Work is needed both on mechanistic understanding of the patterns observed and on the statistical interpretation of these patterns.

Postnatal chlorpyrifos exposure and apolipoprotein E (APOE) genotype differentially affect cholinergic expression and developmental parameters in transgenic mice.

PubMed

Basaure, Pia; Guardia-Escote, Laia; Cabré, Maria; Peris-Sampedro, Fiona; Sánchez-Santed, Fernando; Domingo, José L; Colomina, Maria Teresa

2018-05-03

Chlorpyrifos (CPF) is one of the most commonly used organophosphate pesticides in the world. Our previous results described that apolipoprotein E (APOE) polymorphisms are a source of individual differences in susceptibility to CPF. The aim of this study was to assess the physical and biochemical effects of postnatal exposure to CPF in the apoE targeted replacement mouse model. Mice were exposed to CPF at 0 or 1 mg/kg/day from postnatal day 10-15. Physical development, plasma and forebrain cholinesterase (ChE) activity and gene expression in liver and forebrain were evaluated. CPF exposure delays physical maturation and decreases the expression of choline acetyltransferase, α4-subunit and the α7 receptor. CPF decreases the expression of vesicular acetylcholine transporter (VAChT) mRNA in the forebrain only in apoE3 mice. The expression of paraoxonase-2 in the forebrain was also influenced by APOE genotype and CPF. Differences between genotypes were observed in litter size, ChE activity, expression of butyrylcholinesterase and paraoxonase-1 in liver and variants of acetylcholinesterase, VAChT and the α7 receptor in the forebrain. These results support that there are different vulnerabilities to postnatal CPF exposure according to the APOE polymorphism, which in turn affects the cholinergic system and defenses to oxidative stress. Copyright © 2018 Elsevier Ltd. All rights reserved.

Densely ionizing radiation affects DNA methylation of selective LINE-1 elements1

PubMed Central

Prior, Sara; Miousse, Isabelle R.; Nzabarushimana, Etienne; Pathak, Rupak; Skinner, Charles; Kutanzi, Kristy R.; Allen, Antiño R.; Raber, Jacob; Tackett, Alan J.; Hauer-Jensen, Martin; Nelson, Gregory A.; Koturbash, Igor

2016-01-01

Long Interspersed Nucleotide Element 1 (LINE-1) retrotransposons are heavily methylated and are the most abundant transposable elements in mammalian genomes. Here, we investigated the differential DNA methylation within the LINE-1 under normal conditions and in response to environmentally relevant doses of sparsely and densely ionizing radiation. We demonstrate that DNA methylation of LINE-1 elements in the lungs of C57BL6 mice is dependent on their evolutionary age, where the elder age of the element is associated with the lower extent of DNA methylation. Exposure to 5-aza-2′-deoxycytidine and methionine-deficient diet affected DNA methylation of selective LINE-1 elements in an age- and promoter type-dependent manner. Exposure to densely IR, but not sparsely IR, resulted in DNA hypermethylation of older LINE-1 elements, while the DNA methylation of evolutionary younger elements remained mostly unchanged. We also demonstrate that exposure to densely IR increased mRNA and protein levels of LINE-1 via the loss of the histone H3K9 dimethylation and an increase in the H3K4 trimethylation at the LINE-1 5′-untranslated region, independently of DNA methylation. Our findings suggest that DNA methylation is important for regulation of LINE-1 expression under normal conditions, but histone modifications may dictate the transcriptional activity of LINE-1 in response to exposure to densely IR. PMID:27419368

Time dependent effects of stress prior to encoding on event-related potentials and 24 h delayed retrieval.

PubMed

Quaedflieg, Conny W E M; Schwabe, Lars; Meyer, Thomas; Smeets, Tom

2013-12-01

Stress can exert profound effects on memory encoding. Here, we investigated whether (sub)cortical information processing during encoding and memory retrieval at a 24 h delayed test are affected by the temporal proximity between stress and memory encoding. Sixty-four participants engaged in the Maastricht Acute Stress Test (MAST) or a no-stress control condition either immediately before (i.e., proximate condition) or 30 min before (i.e., distant condition) a picture encoding task. In general, stress decreased the number of freely recalled and recognized pictures and increased the number of false alarms. However, timing of stress exposure did not differentially affect picture recall, recognition or selective attention processes (i.e., LPP). Nevertheless, stress-induced cortisol responses and correctly recognized neutral pictures were positively associated within the proximate stress condition but negatively associated within the distant stress condition. These findings suggest that the time at which a stressor is applied might differentially impact the association between stress-induced cortisol elevations and memory formation and indicate the need for a finer delineation of the time window during which glucocorticoids affect memory formation processes. Copyright © 2013 Elsevier Ltd. All rights reserved.

Zebrafish retinal defects induced by ethanol exposure are rescued by retinoic acid and folic acid supplement

PubMed Central

Muralidharan, Pooja; Sarmah, Swapnalee; Marrs, James A.

2014-01-01

Fetal Alcohol Spectrum Disorder (FASD) is caused by prenatal alcohol exposure, producing craniofacial, sensory, motor, and cognitive defects. FASD is highly prevalent in low socioeconomic populations, which are frequently accompanied by malnutrition. FASD-associated ocular pathologies include microphthalmia, optic nerve hypoplasia, and cataracts. The present study characterizes specific retinal tissue defects, identifies ethanol-sensitive stages during retinal development, and dissects the effect of nutrient supplements, such as retinoic acid (RA) and folic acid (FA) on ethanol-induced retinal defects. Exposure to pathophysiological concentrations of ethanol (during midblastula transition through somitogenesis; 2–24 hours post fertilization [hpf]) altered critical transcription factor expression involved in retinal cell differentiation, and produced severe retinal ganglion cell, photoreceptor, and Müller glial differentiation defects. Ethanol exposure did not alter retinal cell differentiation induction, but increased retinal cell death and proliferation. RA and FA nutrient co-supplementation rescued retinal photoreceptor and ganglion cell differentiation defects. Ethanol exposure during retinal morphogenesis stages (16–24 hpf) produced retinal defects like those seen with ethanol exposure between 2–24 hpf. Significantly, during an ethanol-sensitive time window (16–24 hpf), RA co-supplementation moderately rescued these defects, whereas FA co-supplementation showed significant rescue of optic nerve and photoreceptor differentiation defects. Interestingly, RA, but not FA, supplementation after ethanol exposure could reverse ethanol-induced optic nerve and photoreceptor differentiation defects. Our results indicate that various ethanol-sensitive events underlie FASD-associated retinal defects. Nutrient supplements like retinoids and folate were effective in alleviating ethanol-induced retinal defects. PMID:25541501

Zebrafish retinal defects induced by ethanol exposure are rescued by retinoic acid and folic acid supplement.

PubMed

Muralidharan, Pooja; Sarmah, Swapnalee; Marrs, James A

2015-03-01

Fetal Alcohol Spectrum Disorder (FASD) is caused by prenatal alcohol exposure, producing craniofacial, sensory, motor, and cognitive defects. FASD is highly prevalent in low socioeconomic populations, which are frequently accompanied by malnutrition. FASD-associated ocular pathologies include microphthalmia, optic nerve hypoplasia, and cataracts. The present study characterizes specific retinal tissue defects, identifies ethanol-sensitive stages during retinal development, and dissects the effect of nutrient supplements, such as retinoic acid (RA) and folic acid (FA) on ethanol-induced retinal defects. Exposure to pathophysiological concentrations of ethanol (during midblastula transition through somitogenesis; 2-24 h post fertilization [hpf]) altered critical transcription factor expression involved in retinal cell differentiation, and produced severe retinal ganglion cell, photoreceptor, and Müller glial differentiation defects. Ethanol exposure did not alter retinal cell differentiation induction, but increased retinal cell death and proliferation. RA and FA nutrient co-supplementation rescued retinal photoreceptor and ganglion cell differentiation defects. Ethanol exposure during retinal morphogenesis stages (16-24 hpf) produced retinal defects like those seen with ethanol exposure between 2 and 24 hpf. Significantly, during an ethanol-sensitive time window (16-24 hpf), RA co-supplementation moderately rescued these defects, whereas FA co-supplementation showed significant rescue of optic nerve and photoreceptor differentiation defects. Interestingly, RA, but not FA, supplementation after ethanol exposure could reverse ethanol-induced optic nerve and photoreceptor differentiation defects. Our results indicate that various ethanol-sensitive events underlie FASD-associated retinal defects. Nutrient supplements like retinoids and folate were effective in alleviating ethanol-induced retinal defects. Copyright © 2015 Elsevier Inc. All rights reserved.

Measurement of seeing and the atmospheric time constant by differential scintillations.

PubMed

Tokovinin, Andrei

2002-02-20

A simple differential analysis of stellar scintillations measured simultaneously with two apertures opens the possibility to estimate seeing. Moreover, some information on the vertical turbulence distribution can be obtained. A general expression for the differential scintillation index for apertures of arbitrary shape and for finite exposure time is derived, and its applications are studied. Correction for exposure time bias by use of the ratio of scintillation indices with and without time binning is studied. A bandpass-filtered scintillation in a small aperture (computed as the differential-exposure index) provides a reasonably good estimate of the atmospheric time constant for adaptive optics.

Long-term alterations to DNA methylation as a biomarker of prenatal alcohol exposure: From mouse models to human children with fetal alcohol spectrum disorders.

PubMed

Laufer, Benjamin I; Chater-Diehl, Eric J; Kapalanga, Joachim; Singh, Shiva M

2017-05-01

Rodent models of Fetal Alcohol Spectrum Disorders (FASD) have revealed that prenatal alcohol exposure (PAE) results in differential DNA cytosine methylation in the developing brain. The resulting genome-wide methylation changes are enriched in genes with neurodevelopmental functions. The profile of differential methylation is dynamic and present in some form for life. The methylation changes are transmitted across subsequent mitotic divisions, where they are maintained and further modified over time. More recent follow up has identified a profile of the differential methylation in the buccal swabs of young children born with FASD. While distinct from the profile observed in brain tissue from rodent models, there are similarities. These include changes in genes belonging to a number of neurodevelopmental and behavioral pathways. Specifically, there is increased methylation at the clustered protocadherin genes and deregulation of genomically imprinted genes, even though no single gene is affected in all patients studied to date. These novel results suggest further development of a methylation based strategy could enable early and accurate diagnostics and therapeutics, which have remained a challenge in FASD research. There are two aspects of this challenge that must be addressed in the immediate future: First, the long-term differential methylomics observed in rodent models must be functionally confirmed. Second, the similarities in differential methylation must be further established in humans at a methylomic level and overcome a number of technical limitations. While a cure for FASD is challenging, there is an opportunity for the development of early diagnostics and attenuations towards a higher quality of life. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Loss and replacement of small particles on the contact surfaces of footwear during successive exposures.

PubMed

Stoney, David A; Bowen, Andrew M; Stoney, Paul L

2016-12-01

On the contact surfaces of footwear loosely, moderately and strongly held particle fractions were separated and analyzed in an effort to detect different particle signals. Three environmental exposure sites were chosen to have different, characteristic particle types (soil minerals). Shoes of two types (work boots and tennis shoes) were tested, accumulating particles by walking 250m in each environment. Some shoes were exposed to only one environment; others were exposed to all three, in one of six different sequences. Sampling methods were developed to separate particles from the contact surface of the shoe based on how tightly they were held to the sole. Loosely held particles were removed by walking on paper, moderately held particles were removed by electrostatic lifting, and the most tightly held particles were removed by moist swabbing. The resulting numbers and types of particles were determined using forensic microscopy. Particle profiles from the different fractions were compared to test the ability to objectively distinguish the order of exposure to the three environments. Without exception, the samples resulting from differential sampling are dominated by the third site in the sequential footwear exposures. No noticeable differences are seen among the differential samplings of the loosely, moderately and strongly held particles: the same overwhelming presence of the third site is seen. It is clear from these results (1) that the third (final) exposure results in the nearly complete removal of any particles from prior exposures, and (2) that under the experimental conditions loosely, moderately and strongly held particles are affected similarly, without any detectable enrichment of the earlier exposures among the more tightly held particles. These findings have significant implications for casework, demonstrating that particles on the contact surfaces of footwear are rapidly lost and replaced. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Differential effects of inhalation exposure to PM2.5 on hypothalamic monoamines and corticotrophin releasing hormone in lean and obese rats.

PubMed

Balasubramanian, Priya; Sirivelu, Madhu P; Weiss, Kathryn A; Wagner, James G; Harkema, Jack R; Morishita, Masako; Mohankumar, P S; Mohankumar, Sheba M J

2013-05-01

Acute exposure to airborne pollutants, especially particulate matter (PM2.5) is known to increase hospital admissions for cardiovascular conditions, increase cardiovascular related mortality and predispose the elderly and obese individuals to cardiovascular conditions. The mechanisms by which PM2.5 exposure affects the cardiovascular system is not clear. Since the autonomic system plays an important role in cardiovascular regulation, we hypothesized that PM2.5 exposure most likely activates the paraventricular nucleus (PVN) of the hypothalamus to cause an increase in sympathetic nervous system and/or stress axis activity. We also hypothesized that these changes may be sustained in obese rats predisposing them to higher cardiovascular risk. To test this, adult male Brown Norway (BN) rats were subjected to one day or three days of inhalation exposures to filtered air (FA) or concentrated air particulate (CAP) derived from ambient PM2.5. Corpulent JCR-LA rats were exposed to FA or CAP for four days. Animals were sacrificed 24h after the last inhalation exposure. Their brains were removed, frozen and sectioned. The PVN and median eminence (ME) were microdissected. PVN was analyzed for norepinephrine (NE), dopamine (DA) and 5-hydroxy-indole acetic acid (5-HIAA) levels using HPLC-EC. ME was analyzed for corticotrophin releasing hormone (CRH) levels by ELISA. One day exposure to CAP increased NE levels in the PVN and CRH levels in the ME of BN rats. Repeated exposures to CAP did not affect NE levels in the PVN of BN rats, but increased NE levels in JCR/LA rats. A similar pattern was observed with 5-HIAA levels. DA levels on the other hand, were unaffected in both BN and JCR/LA strains. These data suggest that repeated exposures to PM2.5 continue to stimulate the PVN in obese animals but not lean rats. Copyright © 2012 Elsevier Inc. All rights reserved.

Toxicogenomic outcomes predictive of forestomach carcinogenesis following exposure to benzo(a)pyrene: Relevance to human cancer risk

DOE Office of Scientific and Technical Information (OSTI.GOV)

Labib, Sarah, E-mail: Sarah.Labib@hc-sc.gc.ca; Guo, Charles H., E-mail: Charles.Guo@hc-sc.gc.ca; Williams, Andrew, E-mail: Andrew.Williams@hc-sc.gc.ca

2013-12-01

Forestomach tumors are observed in mice exposed to environmental carcinogens. However, the relevance of this data to humans is controversial because humans lack a forestomach. We hypothesize that an understanding of early molecular changes after exposure to a carcinogen in the forestomach will provide mode-of-action information to evaluate the applicability of forestomach cancers to human cancer risk assessment. In the present study we exposed mice to benzo(a)pyrene (BaP), an environmental carcinogen commonly associated with tumors of the rodent forestomach. Toxicogenomic tools were used to profile gene expression response in the forestomach. Adult Muta™Mouse males were orally exposed to 25, 50,more » and 75 mg BaP/kg-body-weight/day for 28 consecutive days. The forestomach was collected three days post-exposure. DNA microarrays, real-time RT-qPCR arrays, and protein analyses were employed to characterize responses in the forestomach. Microarray results showed altered expression of 414 genes across all treatment groups (± 1.5 fold; false discovery rate adjusted P ≤ 0.05). Significant downregulation of genes associated with phase II xenobiotic metabolism and increased expression of genes implicated in antigen processing and presentation, immune response, chemotaxis, and keratinocyte differentiation were observed in treated groups in a dose-dependent manner. A systematic comparison of the differentially expressed genes in the forestomach from the present study to differentially expressed genes identified in human diseases including human gastrointestinal tract cancers using the NextBio Human Disease Atlas showed significant commonalities between the two models. Our results provide molecular evidence supporting the use of the mouse forestomach model to evaluate chemically-induced gastrointestinal carcinogenesis in humans. - Highlights: • Benzo(a)pyrene-mediated transcriptomic response in the forestomach was examined. • The immunoproteosome subunits and MHC class I pathway were the most affected. • Keratinocyte differentiation associated gene expression changes were dose-dependent. • Molecular similarities exist between cancers of the forestomach and human stomach.« less

DNA repair decline during mouse spermiogenesis results in the accumulation of heritable DNA damage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marchetti, Francesco; Marchetti, Francesco; Wryobek, Andrew J

The post-meiotic phase of mouse spermatogenesis (spermiogenesis) is very sensitive to the genomic effects of environmental mutagens because as male germ cells form mature sperm they progressively lose the ability to repair DNA damage. We hypothesized that repeated exposures to mutagens during this repair-deficient phase result in the accumulation of heritable genomic damage in mouse sperm that leads to chromosomal aberrations in zygotes after fertilization. We used a combination of single or fractionated exposures to diepoxybutane (DEB), a component of tobacco smoke, to investigate how differential DNA repair efficiencies during the three weeks of spermiogenesis affected the accumulation of DEB-inducedmore » heritable damage in early spermatids (21-15 days before fertilization, dbf), late spermatids (14-8 dbf) and sperm (7- 1 dbf). Analysis of chromosomalaberrations in zygotic metaphases using PAINT/DAPI showed that late spermatids and sperm are unable to repair DEB-induced DNA damage as demonstrated by significant increases (P<0.001) in the frequencies of zygotes with chromosomal aberrations. Comparisons between single and fractionated exposures suggested that the DNA repair-deficient window during late spermiogenesis may be less than two weeks in the mouse and that during this repair-deficient window there is accumulation of DNA damage in sperm. Finally, the dose-response study in sperm indicated a linear response for both single and repeated exposures. These findings show that the differential DNA repair capacity of post-meioitic male germ cells has a major impact on the risk of paternally transmitted heritable damage and suggest that chronic exposures that may occur in the weeks prior to fertilization because of occupational or lifestyle factors (i.e, smoking) can lead to an accumulation of genetic damage in sperm and result in heritable chromosomal aberrations of paternal origin.« less

DNA Repair Decline During Mouse Spermiogenesis Results in the Accumulation of Heritable DNA Damage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marchetti, Francesco; Marchetti, Francesco; Wyrobek, Andrew J.

The post-meiotic phase of mouse spermatogenesis (spermiogenesis) is very sensitive to the genomic effects of environmental mutagens because as male germ cells form mature sperm they progressively lose the ability to repair DNA damage. We hypothesized that repeated exposures to mutagens during this repair-deficient phase result in the accumulation of heritable genomic damage in mouse sperm that leads to chromosomal aberrations in zygotes after fertilization. We used a combination of single or fractionated exposures to diepoxybutane (DEB), a component of tobacco smoke, to investigate how differential DNA repair efficiencies during the three weeks of spermiogenesis affected the accumulation of DEB-inducedmore » heritable damage in early spermatids (21-15 days before fertilization, dbf), late spermatids (14-8 dbf) and sperm (7-1 dbf). Analysis of chromosomal aberrations in zygotic metaphases using PAINT/DAPI showed that late spermatids and sperm are unable to repair DEB-induced DNA damage as demonstrated by significant increases (P<0.001) in the frequencies of zygotes with chromosomal aberrations. Comparisons between single and fractionated exposures suggested that the DNA repair-deficient window during late spermiogenesis may be less than two weeks in the mouse and that during this repair-deficient window there is accumulation of DNA damage in sperm. Finally, the dose-response study in sperm indicated a linear response for both single and repeated exposures. These findings show that the differential DNA repair capacity of post-meioitic male germ cells has a major impact on the risk of paternally transmitted heritable damage and suggest that chronic exposures that may occur in the weeks prior to fertilization because of occupational or lifestyle factors (i.e, smoking) can lead to an accumulation of genetic damage in sperm and result in heritable chromosomal aberrations of paternal origin.« less

Parent-child aggression, adult-partner violence, and child outcomes: A prospective, population-based study.

PubMed

Maneta, E K; White, M; Mezzacappa, E

2017-06-01

Parent-child physical aggression (PCPA) and adult intimate partner violence (IPV) are common forms of family violence that often co-occur. Their deleterious effects on children and adolescents have been well documented. However, important questions remain regarding whether the type of violence exposure, the experience of one or both forms, the chronicity of violent experiences, and the age, gender, and SES of the child, differentially influence developmental outcomes. Data on 2810 children from the Project on Human Development in Chicago Neighborhoods were analyzed. Children aged 3-9 at the outset were assessed three times, at 3-year intervals. Primary caregivers reported on IPV, PCPA, and children's externalizing and internalizing symptoms. Children's externalizing and internalizing symptoms were examined as a function of time, age, gender, socioeconomic status (SES), and the time-varying effects of cumulative IPV and PCPA exposure. Cumulative experiences of IPV and PCPA each adversely affected the developmental trajectories of both externalizing and internalizing symptoms, but in different ways; and they did so independently of participants' age, gender, or SES, which all functioned as significant, independent predictors of child outcomes. PCPA was by far the more potent of the two forms of violence; and when both forms occurred, they worked additively to affect outcomes. Important questions remain regarding the reasons for the differential potency of these two forms of family violence on childhood symptoms, and related implications for interventions, as well as for later adult behavior. Copyright © 2017 Elsevier Ltd. All rights reserved.

Corticosterone affects the differentiation of a neuronal cerebral cortex-derived cell line through modulation of the nicotinic acetylcholine receptor.

PubMed

Baier, C J; Franco, D L; Gallegos, C E; Mongiat, L A; Dionisio, L; Bouzat, C; Caviedes, P; Barrantes, F J

2014-08-22

Chronic exposure to stress hormones has an impact on brain structures relevant to cognition. Nicotinic acetylcholine receptors (AChRs) are involved in numerous cognitive processes including learning and memory formation. In order to better understand the molecular mechanisms of chronic stress-triggered mental disease, the effect of corticosterone (CORT) on the biology of AChRs was studied in the neuronal cell line CNh. We found that chronic treatment with CORT reduced the expression levels of the α7-type neuronal AChR and, to a lesser extent, of α4-AChR. CORT also delayed the acquisition of the mature cell phenotype in CNh cells. Chronic nicotine treatment affected the differentiation of CNh cells and exerted a synergistic effect with CORT, suggesting that AChR could participate in signaling pathways that control the cell cycle. Overexpression of α7-AChR-GFP abolished the CORT effects on the cell cycle and the specific α7-AChR inhibitor, methyllycaconitine, mimicked the proliferative action exerted by CORT. Whole-cell voltage-clamp recordings showed a significant decrease in nicotine-evoked currents in CORT-treated cells. Taken together, these observations indicate that AChRs, and the α7-AChR in particular, could act as modulators of the differentiation of CNh cells and that CORT could impair the acquisition of a mature phenotype by affecting the function of this AChR subtype. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

[The application of stem together with visible and infrared light in regenerative medicine (Part 2)].

PubMed

Emel'yanov, A N; Kir'yanova, V V

2015-01-01

The objective of the present study was to review the experimental studies concerned with in vitro and in vivo visible and infrared light irradiation of human and animal stem cells (SC) to assess the possibilities of using its photobiomodulatory effects for the purpose of regenerative medicine (RM). Despite the long history of photochromotherapy there is thus far no reliable theoretical basis for the choice of such irradiation parameters as power density, radiation dose and exposure time. Nor is there a generally accepted opinion on the light application for the purpose of regenerative medicine. Therefore, the clinical application of light irradiation remains a matter of controversy, in the first place due to the difficulty of the rational choice of irradiation parameters. In laboratory research, the theoretical basis for the choice of irradiation parameters remains a stumbling block too. A relationship between the increased radiation power density and the cell differentiation rate was documented. SC exposure to light in the absence of the factors causing their differentiation failed to induce it. On the contrary, it increased the features characteristic of undifferentiated cells. The maximum differentiation rate of the same cells was achieved by using irradiation parameters different from those needed to achieve the maxi- mum proliferation rate. The increase of SC differentiation rate upon a rise in radiation power density was induced by increasing ir- radiation energy density. The increase of power density and the reduction of either energy density or exposure time were needed to enhance the SC responsiveness to irradiation in the form of either proliferation or differentiation. The effectiveness of phototherapy at all stages of SC treatment was documented especially when it was applied to stimulate the reservoirs of bone marrow lying far from the site of the pathogenic process together with simultaneous light irradiation of the affected site and pre-treatment of stem cells prior to their administration. Based on the results of this analysis we have proposed "a plot showing the dependence of cell response on the generalized photostimulus" and coined two new terms "photostress" and "photoshock".

Differential exposure and differential vulnerability as counteracting forces linking the psychosocial work environment to socioeconomic health differences.

PubMed

Vanroelen, C; Levecque, K; Louckx, F

2010-10-01

In this article, the link between (1) psychosocial working conditions (job demands, job autonomy, task variation, social support), (2) self-reported health (persistent fatigue, musculoskeletal complaints, emotional well-being) and (3) socioeconomic position (skill levels, occupational status) is explored. The two theoretical pathways linking the psychosocial work environment to socioeconomic differences in health are explored: differential exposure and differential vulnerability. Previously, the focus has often been on social inequalities in exposure to the stressors. The pathway of differential vulnerability in different socioeconomic positions is often neglected. In a representative cross-sectional sample of 11,099 Flemish (Belgian) wage earners, 16-65 years of age (47.5% women), logit modelling is applied. Higher exposure to psychosocial occupational stressors is associated with a higher prevalence of adverse health outcomes. Lower skill levels and subordinate occupational positions show a higher prevalence of musculoskeletal complaints, but not of persistent fatigue or emotional well-being. High demands, job strain and iso-strain are more common in higher-skilled, supervisory and managerial positions, but have the strongest health-damaging effects in lower socioeconomic positions. Low control is more prevalent in lower-skilled and subordinate positions, while having stronger adverse health effects in higher socioeconomic positions-the same holds for social support, although it has no clear socioeconomic distribution. Differential exposure and differential vulnerability constitute two counteracting forces in constituting the association between the psychosocial work environment and socioeconomic differences in self-reported health complaints among wage earners.

Directed Differentiation of Human Embryonic Stem Cells into Prostate Organoids In Vitro and its Perturbation by Low-Dose Bisphenol A Exposure.

PubMed

Calderon-Gierszal, Esther L; Prins, Gail S

2015-01-01

Studies using rodent and adult human prostate stem-progenitor cell models suggest that developmental exposure to the endocrine disruptor Bisphenol-A (BPA) can predispose to prostate carcinogenesis with aging. Unknown at present is whether the embryonic human prostate is equally susceptible to BPA during its natural developmental window. To address this unmet need, we herein report the construction of a pioneer in vitro human prostate developmental model to study the effects of BPA. The directed differentiation of human embryonic stem cells (hESC) into prostatic organoids in a spatial system was accomplished with precise temporal control of growth factors and steroids. Activin-induced definitive endoderm was driven to prostate specification by combined exposure to WNT10B and FGF10. Matrigel culture for 20-30 days in medium containing R-Spondin-1, Noggin, EGF, retinoic acid and testosterone was sufficient for mature prostate organoid development. Immunofluorescence and gene expression analysis confirmed that organoids exhibited cytodifferentiation and functional properties of the human prostate. Exposure to 1 nM or 10 nM BPA throughout differentiation culture disturbed early morphogenesis in a dose-dependent manner with 1 nM BPA increasing and 10 nM BPA reducing the number of branched structures formed. While differentiation of branched structures to mature organoids seemed largely unaffected by BPA exposure, the stem-like cell population increased, appearing as focal stem cell nests that have not properly entered lineage commitment rather than the rare isolated stem cells found in normally differentiated structures. These findings provide the first direct evidence that low-dose BPA exposure targets hESC and perturbs morphogenesis as the embryonic cells differentiate towards human prostate organoids, suggesting that the developing human prostate may be susceptible to disruption by in utero BPA exposures.

FOXP2 drives neuronal differentiation by interacting with retinoic acid signaling pathways.

PubMed

Devanna, Paolo; Middelbeek, Jeroen; Vernes, Sonja C

2014-01-01

FOXP2 was the first gene shown to cause a Mendelian form of speech and language disorder. Although developmentally expressed in many organs, loss of a single copy of FOXP2 leads to a phenotype that is largely restricted to orofacial impairment during articulation and linguistic processing deficits. Why perturbed FOXP2 function affects specific aspects of the developing brain remains elusive. We investigated the role of FOXP2 in neuronal differentiation and found that FOXP2 drives molecular changes consistent with neuronal differentiation in a human model system. We identified a network of FOXP2 regulated genes related to retinoic acid signaling and neuronal differentiation. FOXP2 also produced phenotypic changes associated with neuronal differentiation including increased neurite outgrowth and reduced migration. Crucially, cells expressing FOXP2 displayed increased sensitivity to retinoic acid exposure. This suggests a mechanism by which FOXP2 may be able to increase the cellular differentiation response to environmental retinoic acid cues for specific subsets of neurons in the brain. These data demonstrate that FOXP2 promotes neuronal differentiation by interacting with the retinoic acid signaling pathway and regulates key processes required for normal circuit formation such as neuronal migration and neurite outgrowth. In this way, FOXP2, which is found only in specific subpopulations of neurons in the brain, may drive precise neuronal differentiation patterns and/or control localization and connectivity of these FOXP2 positive cells.

FOXP2 drives neuronal differentiation by interacting with retinoic acid signaling pathways

PubMed Central

Devanna, Paolo; Middelbeek, Jeroen; Vernes, Sonja C.

2014-01-01

FOXP2 was the first gene shown to cause a Mendelian form of speech and language disorder. Although developmentally expressed in many organs, loss of a single copy of FOXP2 leads to a phenotype that is largely restricted to orofacial impairment during articulation and linguistic processing deficits. Why perturbed FOXP2 function affects specific aspects of the developing brain remains elusive. We investigated the role of FOXP2 in neuronal differentiation and found that FOXP2 drives molecular changes consistent with neuronal differentiation in a human model system. We identified a network of FOXP2 regulated genes related to retinoic acid signaling and neuronal differentiation. FOXP2 also produced phenotypic changes associated with neuronal differentiation including increased neurite outgrowth and reduced migration. Crucially, cells expressing FOXP2 displayed increased sensitivity to retinoic acid exposure. This suggests a mechanism by which FOXP2 may be able to increase the cellular differentiation response to environmental retinoic acid cues for specific subsets of neurons in the brain. These data demonstrate that FOXP2 promotes neuronal differentiation by interacting with the retinoic acid signaling pathway and regulates key processes required for normal circuit formation such as neuronal migration and neurite outgrowth. In this way, FOXP2, which is found only in specific subpopulations of neurons in the brain, may drive precise neuronal differentiation patterns and/or control localization and connectivity of these FOXP2 positive cells. PMID:25309332

Monoethylhexyl Phthalate Elicits an Inflammatory Response in Adipocytes Characterized by Alterations in Lipid and Cytokine Pathways

PubMed Central

Manteiga, Sara; Lee, Kyongbum

2016-01-01

Background: A growing body of evidence links endocrine-disrupting chemicals (EDCs) with obesity-related metabolic diseases. While it has been shown that EDCs can predispose individuals toward adiposity by affecting developmental processes, little is known about the chemicals’ effects on adult adipose tissue. Objectives: Our aim was to study the effects of low, physiologically relevant doses of EDCs on differentiated murine adipocytes. Methods: We combined metabolomics, proteomics, and gene expression analysis to characterize the effects of mono-ethylhexyl phthalate (MEHP) in differentiated adipocytes. Results: Repeated exposure to MEHP over several days led to changes in metabolite and enzyme levels indicating elevated lipogenesis and lipid oxidation. The chemical exposure also increased expression of major inflammatory cytokines, including chemotactic factors. Proteomic and gene expression analysis revealed significant alterations in pathways regulated by peroxisome proliferator activated receptor-γ (PPARγ). Inhibiting the nuclear receptor’s activity using a chemical antagonist abrogated not only the alterations in PPARγ-regulated metabolic pathways, but also the increases in cytokine expression. Conclusions: Our results show that MEHP can induce a pro-inflammatory state in differentiated adipocytes. This effect is at least partially mediated PPARγ. Citation: Manteiga S, Lee K. 2017. Monoethylhexyl phthalate elicits an inflammatory response in adipocytes characterized by alterations in lipid and cytokine pathways. Environ Health Perspect 125:615–622; http://dx.doi.org/10.1289/EHP464 PMID:27384973

DNA Methylation Program in Developing Hippocampus and Its Alteration by Alcohol

PubMed Central

Chen, Yuanyuan; Ozturk, Nail Can; Zhou, Feng C.

2013-01-01

During hippocampal development, the Cornus Ammonis (CA) and the dentate gyrus (DG) undergo waves of neurogenesis and neuronal migration and maturation independently. This stage is widely known to be vulnerable to environmental stresses, but its underlying mechanism is unclear. Alcohol exposure has been shown to alter the expression of genes that regulate the fate, survival, migration and differentiation of pyramidal and granule cells. Undermining this process might compromise hippocampal development underlying the learning and memory deficits known in Fetal Alcohol Spectrum Disorders (FASD). We have previously demonstrated that DNA methylation was programmed along with neural tube development. Here, we demonstrated that DNA methylation program (DMP) proceeded along with hippocampal neuronal differentiation and maturation, and how this DMP was affected by fetal alcohol exposure. C57BL/6 mice were treated with 4% v/v ethanol through a liquid diet along with pair-fed and chow-fed controls from gestation day (E) 7 to E16. We found that a characteristic DMP, including 5-methylcytidine (5mC), 5-hydroxylmethylcytidine (5hmC) and their binding proteins, led the hippocampal neuronal differentiation and maturation spatiotemporally as indicated by their phenotypic marks in the CA and DG pre- and post-natally. Alcohol hindered the acquisition and progression of methylation marks, and altered the chromatin translocation of these marks in the nucleus, which was correlated with developmental retardation. PMID:23544149

Pulsed electromagnetic fields promote survival and neuronal differentiation of human BM-MSCs.

PubMed

Urnukhsaikhan, Enerelt; Cho, Hyunjin; Mishig-Ochir, Tsogbadrakh; Seo, Young-Kwon; Park, Jung-Kueg

2016-04-15

Pulsed electromagnetic fields (PEMF) are known to affect biological properties such as differentiation, regulation of transcription factor and cell proliferation. However, the cell-protective effect of PEMF exposure is largely unknown. The aim of this study is to understand the mechanisms underlying PEMF-mediated suppression of apoptosis and promotion of survival, including PEMF-induced neuronal differentiation. Treatment of induced human BM-MSCs with PEMF increased the expression of neural markers such as NF-L, NeuroD1 and Tau. Moreover, treatment of induced human BM-MSCs with PEMF greatly decreased cell death in a dose- and time-dependent manner. There is evidence that Akt and Ras are involved in neuronal survival and protection. Activation of Akt and Ras results in the regulation of survival proteins such as Bad and Bcl-xL. Thus, the Akt/Ras signaling pathway may be a desirable target for enhancing cell survival and treatment of neurological disease. Our analyses indicated that PEMF exposure dramatically increased the activity of Akt, Rsk, Creb, Erk, Bcl-xL and Bad via phosphorylation. PEMF-dependent cell protection was reversed by pretreatment with LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K). Our data suggest that the PI3K/Akt/Bad signaling pathway may be a possible mechanism for the cell-protective effects of PEMF. Copyright © 2016 Elsevier Inc. All rights reserved.

Manganese inhibits the ability of astrocytes to promote neuronal differentiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Giordano, Gennaro; Pizzurro, Daniella; VanDeMark, Kathryn

Manganese (Mn) is a known neurotoxicant and developmental neurotoxicant. As Mn has been shown to accumulate in astrocytes, we sought to investigate whether Mn would alter astrocyte-neuronal interactions, specifically the ability of astrocytes to promote differentiation of neurons. We found that exposure of rat cortical astrocytes to Mn (50-500 {mu}M) impaired their ability to promote axonal and neurite outgrowth in hippocampal neurons. This effect of Mn appeared to be mediated by oxidative stress, as it was reversed by antioxidants (melatonin and PBN) and by increasing glutathione levels, while it was potentiated by glutathione depletion in astrocytes. As the extracellular matrixmore » protein fibronectin plays an important role in astrocyte-mediated neuronal neurite outgrowth, we also investigated the effect of Mn on fibronectin. Mn caused a concentration-dependent decrease of fibronectin protein and mRNA in astrocytes lysate and of fibronectin protein in astrocyte medium; these effects were also antagonized by antioxidants. Exposure of astrocytes to two oxidants, H{sub 2}O{sub 2} and DMNQ, similarly impaired their neuritogenic action, and led to a decreased expression of fibronectin. Mn had no inhibitory effect on neurite outgrowth when applied directly onto hippocampal neurons, where it actually caused a small increase in neuritogenesis. These results indicate that Mn, by targeting astrocytes, affects their ability to promote neuronal differentiation by a mechanism which is likely to involve oxidative stress.« less

Tumour necrosis factor-alpha impairs neuronal differentiation but not proliferation of hippocampal neural precursor cells: Role of Hes1.

PubMed

Keohane, Aoife; Ryan, Sinead; Maloney, Eimer; Sullivan, Aideen M; Nolan, Yvonne M

2010-01-01

Tumour necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine, which influences neuronal survival and function yet there is limited information available on its effects on hippocampal neural precursor cells (NPCs). We show that TNFalpha treatment during proliferation had no effect on the percentage of proliferating cells prepared from embryonic rat hippocampal neurosphere cultures, nor did it affect cell fate towards either an astrocytic or neuronal lineage when cells were then allowed to differentiate. However, when cells were differentiated in the presence of TNFalpha, significantly reduced percentages of newly born and post-mitotic neurons, significantly increased percentages of astrocytes and increased expression of TNFalpha receptors, TNF-R1 and TNF-R2, as well as expression of the anti-neurogenic Hes1 gene, were observed. These data indicate that exposure of hippocampal NPCs to TNFalpha when they are undergoing differentiation but not proliferation has a detrimental effect on their neuronal lineage fate, which may be mediated through increased expression of Hes1. Copyright 2009 Elsevier Inc. All rights reserved.

Chlorpyrifos- and chlorpyrifos oxon-induced neurite retraction in pre-differentiated N2a cells is associated with transient hyperphosphorylation of neurofilament heavy chain and ERK 1/2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sindi, Ramya A., E-mail: ramya.sindi2010@my.ntu.ac

Chlorpyrifos (CPF) and CPF-oxon (CPO) are known to inhibit neurite outgrowth but little is known about their ability to induce neurite retraction in differentiating neuronal cells. The aims of this study were to determine the ability of these compounds to destabilize neurites and to identify the key molecular events involved. N2a cells were induced to differentiate for 20 h before exposure to CPF or CPO for 2–8 h. Fixed cell monolayers labeled with carboxyfluorescein succinimidyl ester or immunofluorescently stained with antibodies to tubulin (B512) or phosphorylated neurofilament heavy chain (Ta51) showed time- and concentration-dependent reductions in numbers and length ofmore » axon-like processes compared to the control, respectively, retraction of neurites being observed within 2 h of exposure by live cell imaging. Neurofilament disruption was also observed in treated cells stained by indirect immunofluorescence with anti-phosphorylated neurofilament heavy chain (NFH) monoclonal antibody SMI34, while the microtubule network was unaffected. Western blotting analysis revealed transiently increased levels of reactivity of Ta51 after 2 h exposure and reduced levels of reactivity of the same antibody following 8 h treatment with both compounds, whereas reactivity with antibodies to anti-total NFH or anti-tubulin was not affected. The alteration in NFH phosphorylation at 2 h exposure was associated with increased activation of extracellular signal-regulated protein kinase ERK 1/2. However, increased levels of phosphatase activity were observed following 8 h exposure. These findings suggest for the first time that organophosphorothionate pesticide-induced neurite retraction in N2a cells is associated with transient increases in NFH phosphorylation and ERK1/2 activation. - Highlights: • Chlorpyrifos and chlorpyrifos oxon induced rapid neurite retraction in N2a cells. • This occurred following transient hyperphosphorylation of ERK 1/2. • It was concomitant with hyperphosphorylation of neurofilament heavy chain (NFH). • Subsequent NFH dephosphorylation was associated with increased phosphatase activity. • Thus, the above changes reflect key events in chlorpyrifos induced neurodegeneration.« less

Protein kinase C activation is required for the lead-induced inhibition of proliferation and differentiation of cultured oligodendroglial progenitor cells.

PubMed

Deng, Wenbin; Poretz, Ronald D

2002-03-01

Lead (Pb) is a common neurotoxicant of major public health concern. Previous studies revealed that cultured oligodendrocyte progenitor cells (OPCs) are highly vulnerable to Pb toxicity. The present study examines the effect of Pb on the survival, proliferation and differentiation of OPCs in vitro. Dose-response studies showed that> or = l5-10 microM Pb is cytotoxic to OPCs within 24 h. However, 1 microM of Pb was found to inhibit the proliferation and differentiation of OPCs without affecting cell viability. Pb markedly decreased the proliferative capability of OPCs and inhibited cell-intrinsic lineage progression of OPCs at a late progenitor stage. The Pb-induced decrease of proliferation and differentiation was abolished by inhibition of protein kinase C (PKC) with bisindolylmaleimide I, while the effect of the PKC-activating agent phorbol-12,13-didecanoate was potentiated by Pb. Furthermore, Pb exposure of OPCs caused the translocation of PKC from the cytoplasm to membrane without an increase in total cellular PKC enzymic activity. These results indicate that Pb inhibits the proliferation and differentiation of oligodendrocyte lineage cells in vitro through a mechanism requiring PKC activation.

Cyclohexane-1,2-dicarboxylic acid diisononyl ester and metabolite effects on rat epididymal stromal vascular fraction differentiation of adipose tissue

DOE Office of Scientific and Technical Information (OSTI.GOV)

Campioli, Enrico; Department of Medicine, McGill University, Montréal, Québec; Duong, Tam B.

Plastics are generally mixed with additives like plasticizers to enhance their flexibility, pliability, and elasticity proprieties. Plasticizers are easily released into the environment and are absorbed mainly through ingestion, dermal contact, and inhalation. One of the main classes of plasticizers, phthalates, has been associated with endocrine and reproductive diseases. In 2002, 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) was introduced in the market for use in plastic materials and articles intended to come into contact with food, and it received final approval from the European Food Safety Authority in 2006. At present, there is limited knowledge about the safety and potentialmore » metabolic and endocrine-disrupting properties of DINCH and its metabolites. The purpose of this study was to evaluate the biological effects of DINCH and its active metabolites, cyclohexane-1,2-dicarboxylic acid (CHDA) and cyclohexane-1,2-dicarboxylic acid mono isononyl ester (MINCH), on rat primary stromal vascular fraction (SVF) of adipose tissue. DINCH and its metabolite, CHDA, were not able to directly affect SVF differentiation. However, exposure of SVF to 50 μM and 100 μM concentrations of MINCH affected the expression of Cebpa and Fabp4, thus inducing SVF preadipocytes to accumulate lipids and fully differentiate into mature adipocytes. The effect of MINCH was blocked by the specific peroxisome proliferator-activated receptor (PPAR)-α antagonist, GW6471. Taken together, these results suggest that MINCH is a potent PPAR-α agonist and a metabolic disruptor, capable of inducing SVF preadipocyte differentiation, that may interfere with the endocrine system in mammals. - Highlights: • DINCH and CHDA did not affect the adipogenesis of the SVF. • MINCH affected the adipogenesis of the SVF. • MINCH effect was blocked by the specific PPAR-α antagonist GW6471. • MINCH exerted a similar effect as MEHP on SVF adipogenesis. • DINCH/MINCH are potential metabolic disruptors.« less

Developmental programming: interaction between prenatal BPA and postnatal overfeeding on cardiac tissue gene expression in female sheep

PubMed Central

Koneva, LA; Vyas, AK; McEachin, RC; Puttabyatappa, M; H-S, Wang; Sartor, MA; Padmanabhan, V

2017-01-01

Epidemiologic studies and studies in rodents point to potential risks from developmental exposure to BPA on cardiometabolic diseases. Furthermore, it is becoming increasingly evident that the manifestation and severity of adverse outcomes is the result of interaction between developmental insults and the prevailing environment. Consistent with this premise, recent studies in sheep found prenatal BPA treatment prevented the adverse effects of postnatal obesity in inducing hypertension. The gene networks underlying these complex interactions are not known. mRNA-seq of myocardium was performed on four groups of four female sheep to assess the effects of prenatal BPA exposure, postnatal overfeeding and their interaction on gene transcription, pathway perturbations and functional effects. The effects of prenatal exposure to BPA, postnatal overfeeding, and prenatal BPA with postnatal overfeeding all resulted in transcriptional changes (85–141 significant differentially expressed genes). Although the effects of prenatal BPA and postnatal overfeeding did not involve dysregulation of many of the same genes, they affected a remarkably similar set of biological pathways. Furthermore, an additive or synergistic effect was not found in the combined treatment group, but rather prenatal BPA treatment led to a partial reversal of the effects of overfeeding alone. Many genes previously known to be affected by BPA and involved in obesity, hypertension, or heart disease were altered following these treatments, and AP-1, EGR1, and EGFR were key hubs affected by BPA and/or overfeeding. PMID:28079927

Differential Growth of and Nanoscale TiO2 Accumulation in Tetrahymena thermophila by Direct Feeding versus Trophic Transfer from Pseudomonas aeruginosa

PubMed Central

Mielke, Randall E.; Priester, John H.; Werlin, Rebecca A.; Gelb, Jeff; Horst, Allison M.; Orias, Eduardo

2013-01-01

Nanoscale titanium dioxide (TiO2) is increasingly used in consumer goods and is entering waste streams, thereby exposing and potentially affecting environmental microbes. Protozoans could either take up TiO2 directly from water and sediments or acquire TiO2 during bactivory (ingestion of bacteria) of TiO2-encrusted bacteria. Here, the route of exposure of the ciliated protozoan Tetrahymena thermophila to TiO2 was varied and the growth of, and uptake and accumulation of TiO2 by, T. thermophila were measured. While TiO2 did not affect T. thermophila swimming or cellular morphology, direct TiO2 exposure in rich growth medium resulted in a lower population yield. When TiO2 exposure was by bactivory of Pseudomonas aeruginosa, the T. thermophila population yield and growth rate were lower than those that occurred during the bactivory of non-TiO2-encrusted bacteria. Regardless of the feeding mode, T. thermophila cells internalized TiO2 into their food vacuoles. Biomagnification of TiO2 was not observed; this was attributed to the observation that TiO2 appeared to be unable to cross the food vacuole membrane and enter the cytoplasm. Nevertheless, our findings imply that TiO2 could be transferred into higher trophic levels within food webs and that the food web could be affected by the decreased growth rate and yield of organisms near the base of the web. PMID:23851096

Effect of alpha-lipoic acid on relieving ammonia stress and hepatic proteomic analyses of broilers.

PubMed

Lu, M; Bai, J; Xu, B; Sun, Q Y; Wei, F X; Tang, X F; Zhang, H F; Li, J; Wang, G L; Yin, Q Q; Li, S Y

2017-01-01

Ammonia in poultry houses not only affects worker health but also induces a variety of poultry diseases. Alpha-lipoic acid (LA) is an effective antioxidant that protects cells against oxidative injury during various toxic and pathological processes. This study was designed to evaluate the mitigating effects of LA supplementation on ammonia stress and hepatic proteome changes in broilers. Male broilers (22 d old) were allocated to 3 groups: (1) a control group without ammonia stress (CTRL); (2) exposure to 70 ppm ammonia (AM); and (3) exposure to 70 ppm ammonia and dietary administration of 300 mg/kg LA (AM+LA). Ammonia exposure significantly decreased broiler growth performance and plasma glutathione peroxidase activity (P < 0.05), and increased plasma malondialdehyde content and glutamic-pyruvic transaminase activity (P < 0.05). These negative effects were eliminated by LA supplementation. Comparative proteomic analyses revealed 291 differentially expressed proteins in the AM group compared to the CTRL and AM+LA groups. A total of 30 proteins were differentially expressed between the AM/CTRL and (AM+LA)/AM groups. The addition of LA restored 24 of these proteins to control levels; these proteins were mainly related to transcription regulation, detoxification, protein translation and degradation, and immune and stress responses. The differentially expressed proteins included the high mobility group box (HMGB) and glutathione S-transferase (GST), which is closely related to immune response and oxidative stress, and collagens, which are implicated in liver injury. The addition of LA to broiler diet may reduce ammonia toxicity by maintaining the antioxidant system, xenobiotic metabolism, and metabolic pathways. © 2016 Poultry Science Association Inc.

DNA methylation signature of human fetal alcohol spectrum disorder.

PubMed

Portales-Casamar, Elodie; Lussier, Alexandre A; Jones, Meaghan J; MacIsaac, Julia L; Edgar, Rachel D; Mah, Sarah M; Barhdadi, Amina; Provost, Sylvie; Lemieux-Perreault, Louis-Philippe; Cynader, Max S; Chudley, Albert E; Dubé, Marie-Pierre; Reynolds, James N; Pavlidis, Paul; Kobor, Michael S

2016-01-01

Prenatal alcohol exposure is the leading preventable cause of behavioral and cognitive deficits, which may affect between 2 and 5 % of children in North America. While the underlying mechanisms of alcohol's effects on development remain relatively unknown, emerging evidence implicates epigenetic mechanisms in mediating the range of symptoms observed in children with fetal alcohol spectrum disorder (FASD). Thus, we investigated the effects of prenatal alcohol exposure on genome-wide DNA methylation in the NeuroDevNet FASD cohort, the largest cohort of human FASD samples to date. Genome-wide DNA methylation patterns of buccal epithelial cells (BECs) were analyzed using the Illumina HumanMethylation450 array in a Canadian cohort of 206 children (110 FASD and 96 controls). Genotyping was performed in parallel using the Infinium HumanOmni2.5-Quad v1.0 BeadChip. After correcting for the effects of genetic background, we found 658 significantly differentially methylated sites between FASD cases and controls, with 41 displaying differences in percent methylation change >5 %. Furthermore, 101 differentially methylated regions containing two or more CpGs were also identified, overlapping with 95 different genes. The majority of differentially methylated genes were highly expressed at the level of mRNA in brain samples from the Allen Brain Atlas, and independent DNA methylation data from cortical brain samples showed high correlations with BEC DNA methylation patterns. Finally, overrepresentation analysis of genes with up-methylated CpGs revealed a significant enrichment for neurodevelopmental processes and diseases, such as anxiety, epilepsy, and autism spectrum disorders. These findings suggested that prenatal alcohol exposure is associated with distinct DNA methylation patterns in children and adolescents, raising the possibility of an epigenetic biomarker of FASD.

The Screening of Genes Sensitive to Long-Term, Low-Level Microwave Exposure and Bioinformatic Analysis of Potential Correlations to Learning and Memory.

PubMed

Zhao, Ya Li; Li, Ying Xian; Ma, Hong Bo; Li, Dong; Li, Hai Liang; Jiang, Rui; Kan, Guang Han; Yang, Zhen Zhong; Huang, Zeng Xin

2015-08-01

To gain a better understanding of gene expression changes in the brain following microwave exposure in mice. This study hopes to reveal mechanisms contributing to microwave-induced learning and memory dysfunction. Mice were exposed to whole body 2100 MHz microwaves with specific absorption rates (SARs) of 0.45 W/kg, 1.8 W/kg, and 3.6 W/kg for 1 hour daily for 8 weeks. Differentially expressing genes in the brains were screened using high-density oligonucleotide arrays, with genes showing more significant differences further confirmed by RT-PCR. The gene chip results demonstrated that 41 genes (0.45 W/kg group), 29 genes (1.8 W/kg group), and 219 genes (3.6 W/kg group) were differentially expressed. GO analysis revealed that these differentially expressed genes were primarily involved in metabolic processes, cellular metabolic processes, regulation of biological processes, macromolecular metabolic processes, biosynthetic processes, cellular protein metabolic processes, transport, developmental processes, cellular component organization, etc. KEGG pathway analysis showed that these genes are mainly involved in pathways related to ribosome, Alzheimer's disease, Parkinson's disease, long-term potentiation, Huntington's disease, and Neurotrophin signaling. Construction of a protein interaction network identified several important regulatory genes including synbindin (sbdn), Crystallin (CryaB), PPP1CA, Ywhaq, Psap, Psmb1, Pcbp2, etc., which play important roles in the processes of learning and memorye. Long-term, low-level microwave exposure may inhibit learning and memory by affecting protein and energy metabolic processes and signaling pathways relating to neurological functions or diseases. Copyright © 2015 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

The role of dopamine D2 receptors in the nucleus accumbens during taste-aversive learning and memory extinction after long-term sugar consumption.

PubMed

Miranda, María Isabel; Rangel-Hernández, José Alejandro; Vera-Rivera, Gabriela; García-Medina, Nadia Edith; Soto-Alonso, Gerardo; Rodríguez-García, Gabriela; Núñez-Jaramillo, Luis

2017-09-17

The nucleus accumbens (NAcc) is a forebrain region that may significantly contribute to the integration of taste and visceral signals during food consumption. Changes in dopamine release in the NAcc have been observed during consumption of a sweet taste and during compulsive consumption of dietary sugars, suggesting that NAcc dopaminergic transmission is strongly correlated with taste familiarity and the hedonic value content. NAcc core and shell nuclei are differentially involved during and after sugar exposure and, particularly, previous evidence suggests that dopamine D2 receptors could be related with the strength of the latent inhibition (LI) of conditioned taste aversion (CTA), which depends on the length of the taste stimulus pre-exposure. Thus, the objective of this work was to evaluate, after long-term exposure to sugar, the function of dopaminergic D2 receptors in the NAcc core during taste memory retrieval preference test, and during CTA. Adult rats were exposed during 14days to 10% sugar solution as a single liquid ad libitum. NAcc core bilateral injections of D2 dopamine receptor antagonist, haloperidol (1μg/μL), were made before third preference test and CTA acquisition. We found that sugar was similarly preferred after 3 acute presentations or 14days of continued sugar consumption and that haloperidol did not disrupt this appetitive memory retrieval. Nevertheless, D2 receptors antagonism differentially affects aversive memory formation after acute or long-term sugar consumption. These results demonstrate that NAcc dopamine D2 receptors have a differential function during CTA depending on the degree of sugar familiarity. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Effects of 17 α-methyltestosterone on transcriptome, gonadal histology and sex steroid hormones in rare minnow Gobiocypris rarus.

PubMed

Gao, Jiancao; Liu, Shaozhen; Zhang, Yingying; Yang, Yanping; Yuan, Cong; Chen, Shu; Wang, Zaizhao

2015-09-01

The 17α-methyltestosterone (MT), a synthetic androgen, is known for its interference effects on the endocrine system. Aiming to investigate the transcriptome profiling of gonads induced by MT and to understand the molecular mechanism by which MT causes adverse effects in fish, transcriptome profiling of gonads, gonadal histology and the sex steroid hormones in response to MT were analyzed in Gobiocypris rarus. Eight libraries, 4 from the ovary and 4 from the testis, were constructed and sequenced and then a total number of clean reads per sample ranging from 7.03 to 9.99 million were obtained. In females, a total of 191 transcripts were differentially regulated by MT, consisting of 102 up-regulated transcripts and 89 down-regulated transcripts. In males, 268 differentially expressed genes with 108 up-regulated and 160 down-regulated were detected upon MT exposure. Testosterone serves as the major sex steroid hormone content in G. rarus of both sexes. The concentrations of 17β-estradiol, testosterone and 11-ketotestosterone were significantly increased in females and decreased in males after MT exposure. Interestingly, MT caused a decreased number of vitellogenic oocytes in the ovary and spermatozoa in the testis. After MT exposure, four differentially expressed genes (ndufa4, slc1a3a, caskin-2 and rpt3) were found in G. rarus of both sexes. Overall, we suggest that MT seemed to affect genes involved in pathways related to physiological processes in the gonads of G. rarus. These processes include the electron transfer of Complex IV, endothelial cell activation, axon growth and guidance, and proteasome assembly and glutamate transport metabolic. Copyright © 2015 Elsevier Inc. All rights reserved.

Smoking cue reactivity across massed extinction trials: negative affect and gender effects.

PubMed

Collins, Bradley N; Nair, Uma S; Komaroff, Eugene

2011-04-01

Designing and implementing cue exposure procedures to treat nicotine dependence remains a challenge. This study tested the hypothesis that gender and negative affect (NA) influence changes in smoking urge over time using data from a pilot project testing the feasibility of massed extinction procedures. Forty-three smokers and ex-smokers completed the behavioral laboratory procedures. All participants were over 17 years old, smoked at least 10 cigarettes daily over the last year (or the year prior to quitting) and had expired CO below 10 ppm at the beginning of the ~4-hour session. After informed consent, participants completed 45 min of baseline assessments, and then completed a series of 12 identical, 5-minute exposure trials with inter-trial breaks. Smoking cues included visual, tactile, and olfactory cues with a lit cigarette, in addition to smoking-related motor behaviors without smoking. After each trial, participants reported urge and negative affect (NA). Logistic growth curve models supported the hypothesis that across trials, participants would demonstrate an initial linear increase followed by a decrease in smoking urge (quadratic effect). Data supported hypothesized gender, NA, and gender×NA effects. Significant linear increases in urge were observed among high and low NA males, but not among females in either NA subgroup. A differential quadratic effect showed a significant decrease in urge for the low NA subgroup, but a non-significant decrease in urge in the high NA group. This is the first study to demonstrate gender differences and the effects of NA on the extinction process using a smoking cue exposure paradigm. Results could guide future cue reactivity research and exposure interventions for nicotine dependence. Copyright © 2010 Elsevier B.V. All rights reserved.

Densely ionizing radiation affects DNA methylation of selective LINE-1 elements

DOE Office of Scientific and Technical Information (OSTI.GOV)

Prior, Sara; Miousse, Isabelle R.

Long Interspersed Nucleotide Element 1 (LINE-1) retrotransposons are heavily methylated and are the most abundant transposable elements in mammalian genomes. Here, we investigated the differential DNA methylation within the LINE-1 under normal conditions and in response to environmentally relevant doses of sparsely and densely ionizing radiation. We demonstrate that DNA methylation of LINE-1 elements in the lungs of C57BL6 mice is dependent on their evolutionary age, where the elder age of the element is associated with the lower extent of DNA methylation. Exposure to 5-aza-2′-deoxycytidine and methionine-deficient diet affected DNA methylation of selective LINE-1 elements in an age- and promotermore » type-dependent manner. Exposure to densely IR, but not sparsely IR, resulted in DNA hypermethylation of older LINE-1 elements, while the DNA methylation of evolutionary younger elements remained mostly unchanged. We also demonstrate that exposure to densely IR increased mRNA and protein levels of LINE-1 via the loss of the histone H3K9 dimethylation and an increase in the H3K4 trimethylation at the LINE-1 5′-untranslated region, independently of DNA methylation. Our findings suggest that DNA methylation is important for regulation of LINE-1 expression under normal conditions, but histone modifications may dictate the transcriptional activity of LINE-1 in response to exposure to densely IR. - Highlights: • DNA methylation of LINE-1 elements is dependent on their evolutionary age. • Densely ionizing radiation affects DNA methylation of selective LINE-1 elements. • Radiation-induced reactivation of LINE-1 is DNA methylation-independent. • Histone modifications dictate the transcriptional activity of LINE-1.« less

Aroclor 1254, a developmental neurotoxicant, alters energy metabolism- and intracellular signaling-associated protein networks in rat cerebellum and hippocampus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kodavanti, Prasada Rao S., E-mail: kodavanti.prasada@epa.gov; Osorio, Cristina; Program on Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill, North Carolina

2011-11-15

The vast literature on the mode of action of polychlorinated biphenyls (PCBs) indicates that PCBs are a unique model for understanding the mechanisms of toxicity of environmental mixtures of persistent chemicals. PCBs have been shown to adversely affect psychomotor function and learning and memory in humans. Although the molecular mechanisms for PCB effects are unclear, several studies indicate that the disruption of Ca{sup 2+}-mediated signal transduction plays significant roles in PCB-induced developmental neurotoxicity. Culminating events in signal transduction pathways include the regulation of gene and protein expression, which affects the growth and function of the nervous system. Our previous studiesmore » showed changes in gene expression related to signal transduction and neuronal growth. In this study, protein expression following developmental exposure to PCB is examined. Pregnant rats (Long Evans) were dosed with 0.0 or 6.0 mg/kg/day of Aroclor-1254 from gestation day 6 through postnatal day (PND) 21, and the cerebellum and hippocampus from PND14 animals were analyzed to determine Aroclor 1254-induced differential protein expression. Two proteins were found to be differentially expressed in the cerebellum following PCB exposure while 18 proteins were differentially expressed in the hippocampus. These proteins are related to energy metabolism in mitochondria (ATP synthase, sub unit {beta} (ATP5B), creatine kinase, and malate dehydrogenase), calcium signaling (voltage-dependent anion-selective channel protein 1 (VDAC1) and ryanodine receptor type II (RyR2)), and growth of the nervous system (dihydropyrimidinase-related protein 4 (DPYSL4), valosin-containing protein (VCP)). Results suggest that Aroclor 1254-like persistent chemicals may alter energy metabolism and intracellular signaling, which might result in developmental neurotoxicity. -- Highlights: Black-Right-Pointing-Pointer We performed brain proteomic analysis of rats exposed to the neurotoxicant, Aroclor 1254. Black-Right-Pointing-Pointer Cerebellum and hippocampus were analyzed by 2D DIGE and Mass spectrometry. Black-Right-Pointing-Pointer Proteins affected participate in Energy metabolism, calcium signaling and nervous system growth.« less

Differential neurotoxic effects of in utero and lactational exposure to hydroxylated polychlorinated biphenyl (OH-PCB 106) on spontaneous locomotor activity and motor coordination in young adult male mice.

PubMed

Haijima, Asahi; Lesmana, Ronny; Shimokawa, Noriaki; Amano, Izuki; Takatsuru, Yusuke; Koibuchi, Noriyuki

2017-01-01

We investigated whether in utero or lactational exposure to 4-hydroxy-2',3,3',4',5'-pentachlorobiphenyl (OH-PCB 106) affects spontaneous locomotor activity and motor coordination in young adult male mice. For in utero exposure, pregnant C57BL/6J mice received 0.05 or 0.5 mg/kg body weight of OH-PCB 106 or corn oil vehicle via gavage every second day from gestational day 10 to 18. For lactational exposure, the different groups of dams received 0.05 or 0.5 mg/kg body weight of OH-PCB 106 or corn oil vehicle via gavage every second day from postpartum day 3 to 13. At 6-7 weeks of age, the spontaneous locomotor activities of male offspring were evaluated for a 24-hr continuous session in a home cage and in an open field for 30-min. Motor coordination function on an accelerating rotarod was also measured. Mice exposed prenatally to OH-PCB 106 showed increased spontaneous locomotor activities during the dark phase in the home cage and during the first 10-min in the open field compared with control mice. Mice exposed lactationally to OH-PCB 106, however, did not show a time-dependent decrease in locomotor activity in the open field. Instead, their locomotor activity increased significantly during the second 10-min block. In addition, mice exposed lactationally to OH-PCB 106 displayed impairments in motor coordination in the rotarod test. These results suggest that perinatal exposure to OH-PCB 106 affects motor behaviors in young adult male mice. Depending on the period of exposure, OH-PCB 106 may have different effects on neurobehavioral development.

Smoking status and occupational exposure affects oxidative DNA injury in boilermakers exposed to metal fume and residual oil fly ash.

PubMed

Mukherjee, Sutapa; Palmer, Lyle J; Kim, Jee Young; Aeschliman, David B; Houk, Robert S; Woodin, Mark A; Christiani, David C

2004-03-01

Epidemiologic studies demonstrate increased cancer incidence among workers exposed to polycyclic aromatic hydrocarbons (PAH) and metals, probably through cumulative oxidative DNA damage in response to carcinogens. Boilermakers are exposed to particulates of residual oil fly ash (ROFA) and metal fume that contain carcinogenic PAH and metals. We conducted a repeated-measures cohort study in boilermakers during the overhaul of an oil-fired boiler to determine a possible association between the level of 8-hydroxy-2'-deoxyguanosine (8-OH-dG; an oxidative injury biomarker) and biomarkers of PAH (1-hydroxypyrene; 1-OHP) and metal exposure. Preshift and postshift urine samples were analyzed for 8-OH-dG, cotinine, 1-OHP, and metals. Generalized estimating equations were used to model the multivariate relationship of 8-OH-dG to the explanatory variables of interest. Biomarker levels were determined for 181 urine samples from 20 male subjects (mean age 45 years, 50% smokers). Metal and 1-OHP levels increased cross-week and were affected by smoking status. Levels of 8-OH-dG were higher in nonsmokers at the start of the workweek yet declined after occupational exposure to similar levels as in smokers. Multivariate analysis indicated that metal x cotinine interaction terms for nickel, vanadium, chromium, and copper were significantly associated with the 8-OH-dG level, but there were differential effects depending on the metal. This study suggests that oxidative DNA damage in boilermakers is influenced by the interaction between occupational exposures and smoking status. In addition, boilermakers may have reduced ability to repair damaged DNA after ROFA and metal fume exposure. This finding has clinical relevance because these exposures may increase the cancer susceptibility of boilermakers.

Long-Term Exposure to Environmental Concentrations of the Pharmaceutical Ethynylestradiol Causes Reproductive Failure in Fish

PubMed Central

Nash, Jon P.; Kime, David E.; Van der Ven, Leo T. M.; Wester, Piet W.; Brion, François; Maack, Gerd; Stahlschmidt-Allner, Petra; Tyler, Charles R.

2004-01-01

Heightened concern over endocrine-disrupting chemicals is driven by the hypothesis that they could reduce reproductive success and affect wildlife populations, but there is little evidence for this expectation. The pharmaceutical ethynylestradiol (EE2) is a potent endocrine modulator and is present in the aquatic environment at biologically active concentrations. To investigate impacts on reproductive success and mechanisms of disruption, we exposed breeding populations (n = 12) of zebrafish (Danio rerio) over multiple generations to environmentally relevant concentrations of EE2. Life-long exposure to 5 ng/L EE2 in the F1 generation caused a 56% reduction in fecundity and complete population failure with no fertilization. Conversely, the same level of exposure for up to 40 days in mature adults in the parental F0 generation had no impact on reproductive success. Infertility in the F1 generation after life-long exposure to 5 ng/L EE2 was due to disturbed sexual differentiation, with males having no functional testes and either undifferentiated or inter-sex gonads. These F1 males also showed a reduced vitellogenic response when compared with F0 males, indicating an acclimation to EE2 exposure. Depuration studies found only a partial recovery in reproductive capacity after 5 months. Significantly, even though the F1 males lacked functional testes, they showed male-pattern reproductive behavior, inducing the spawning act and competing with healthy males to disrupt fertilization. Endocrine disruption is therefore likely to affect breeding dynamics and reproductive success in group-spawning fish. Our findings raise major concerns about the population-level impacts for wildlife of long-term exposure to low concentrations of estrogenic endocrine disruptors. PMID:15579420

Effects of developmental lead exposure on the hippocampal methylome: Influences of sex and timing and level of exposure.

PubMed

Singh, G; Singh, V; Wang, Zi-Xuan; Voisin, G; Lefebvre, F; Navenot, J-M; Evans, B; Verma, M; Anderson, D W; Schneider, J S

2018-06-15

Developmental lead (Pb) exposure results in persistent cognitive/behavioral impairments as well as an elevated risk for developing a variety of diseases in later life. Environmental exposures during development can result in a variety of epigenetic changes, including alterations in DNA methylation, that can influence gene expression patterns and affect the function and development of the nervous system. The present promoter-based methylation microarray profiling study explored the extent to which developmental Pb exposure may modify the methylome of a brain region, hippocampus, known to be sensitive to the effects of Pb exposure. Male and female Long Evans rats were exposed to 0 ppm, 150 ppm, 375 ppm, or 750 ppm Pb through perinatal exposures (gestation through lactation), early postnatal exposures (birth through weaning), or long-term postnatal exposures (birth through postnatal day 55). Results showed a significant contribution of sex to the hippocampal methylome and effects of Pb exposure level, with non-linear dose response effects on methylation. Surprisingly, the developmental period of exposure contributed only a small amount of variance to the overall data and gene ontology (GO) analysis revealed the largest number of overrepresented GO terms in the groups with the lowest level of exposure. The highest number of significant differentially methylated regions was found in females exposed to Pb at the lowest exposure level. Our data reinforce the significant effect that low level Pb exposure may have on gene-specific DNA methylation patterns in brain and that this occurs in a sex-dependent manner. Copyright © 2018 Elsevier B.V. All rights reserved.

Socializing by Day May Affect Performance by Night: Vulnerability to Sleep Deprivation is Differentially Mediated by Social Exposure in Extraverts vs Introverts

PubMed Central

Rupp, Tracy L.; Killgore, William D.S.; Balkin, Thomas J.

2010-01-01

Study Objectives: To examine the effects of socially enriched versus socially impoverished environments on performance and alertness decline during sleep deprivation in extraverts versus introverts. Design: Participants (n = 29 men, n = 19 women) were assigned to socially enriched (n = 24; 13 introverts, 11 extraverts) or socially impoverished (n = 24; 12 introverts, 12 extraverts) conditions (activities matched) for 12 hours (1000–2200) on Day 1 followed by 22 hours of sleep deprivation (2200-2000; 36 h awake total), monitored by actigraphy. The median split of volunteers' Eysenck Extraversion scores was used for extravert/introvert categorization. The Psychomotor Vigilance Task (PVT), modified Maintenance of Wakefulness Test (MWT), and Stanford Sleepiness Scale (SSS) were administered every 2 hours throughout. PVT speed, transformed lapses, modified MWT sleep-onset latency, and SSS were analyzed using mixed-model analyses of variance, with covariates of age and total actigraphic activity during enrichment or impoverishment. Setting: Residential sleep/performance testing facility. Participants: Forty-eight healthy adults (aged 18–39). Interventions: Twelve hours of socially enriched or isolated environments in extraverts and introverts prior to sleep deprivation. Results Social experience interacted with personality type to affect alertness and vigilance. Social enrichment, as compared with social impoverishment, was associated with more PVT lapses at 04:00 overall. Similarly, following social enrichment, PVT speed was significantly slower among extraverts than among introverts during sleep deprivation, but no personality-group differences emerged following social impoverishment. MWT sleep latency and SSS subjective sleepiness did not show significant personality or social-condition effects during sleep deprivation. Conclusions: The effect of social exposure on vulnerability or resiliency to sleep deprivation was modulated by introversion and extraversion. Extraverts exposed to social environments were more vulnerable to subsequent sleep deprivation than were introverts. Citation: Rupp TL; Killgore WDS; Balkin TJ. Socializing by day may affect performance by night: vulnerability to sleep deprivation is differentially mediated by social exposure in extraverts vs introverts. SLEEP 2010;33(11):1475-1485. PMID:21102989

Effect of space relevant radiation exposure on differentiation and mineralization of murine osteoprogenitor cells

NASA Astrophysics Data System (ADS)

Lau, Patrick; Hu, Yueyuan; Hellweg, Christine; Baumstark-Khan, Christa; Reitz, Guenther

Extended exposure to altered gravity conditions like during long-term space flight results in significant bone loss. Exposure to ionizing radiation for cancer therapy causes bone damage and may increase the risk of fractures. Similarly, besides altered gravity conditions, astronauts on exploratory missions beyond low-Earth orbit will be exposed to high-energy heavy ions in addition to proton and photon radiation, although for prolonged periods and at lower doses and dose rates compared with therapy. Space conditions may place astronauts at a greater risk for mission-critical fractures. Until now, little is known about the effects of space radiation on the skeletal system especially on osteoprogenitor cells. Accelerator facilities are used to simulate parts of the radiation environment in space. Heavy ion accelerators therefore could be used to assess radiation risks for astronauts who will be exposed to higher radiation doses e.g. on a Mars mission. The aim of the present study was to determine the biological effects of spaceflight-relevant radiation exposure on the cellular level using murine osteoprogenitor cell lines compared to nonirradiated controls. To gain a deeper understanding of bone cell differenti-ation and mineralization after exposure to heavy ions, we examined gene expression modulation of bone specific transcription factors, osteoblast specific marker genes as well as genes function as coupling factors that link bone resorption to bone formation. We investigated the transcrip-tional modulation of type I collagen (Col I), osteocalcin (Ocn), Transforming growth factor-β1 (TGF-β1), interleukin-6 (IL-6) and the bone specific transcription factor Runx2 (Cbfa1). To gain deeper insight into potential cellular mechanisms involved in cellular response after ex-posure to heavy ions, we investigated gene expression modulations after exposure to energetic carbon ions (35 MeV/u, 73.2 keV/µm), iron ions (1000 MeV/u, 150 keV/µm) and lead ions (29 MeV/u, 9600 keV/µm) versus low LET X-rays. Exposure to X-irradiation dose-dependently increased the mRNA levels of Runx2 (cbfa1) whereas expression values of OCN and TGF-β1 were elevated at later time points. Exposure to heavy ions provoked a more marked effect on bone specific gene expression within the differentiation process. Collectively, our results indi-cate that heavy ions facilitate differentiation more effectively than X-rays as a major response in the progeny of irradiated osteoprogenitor cells. The data presented allow us to suggest that exposure to ionizing radiation interferes with bone formation at the level of cellular differenti-ation. In this regard, further experiments are needed to investigate gene expression patterns in mammalian cells that respond to differentiation after exposure to ionizing radiation.

Antioxidant response of ridgetail white prawn Exopalaemon carinicauda to harmful dinoflagellate Prorocentrum minimum exposure and its histological change

NASA Astrophysics Data System (ADS)

Mu, Cuimin; Ren, Xianyun; Ge, Qianqian; Wang, Jiajia; Li, Jian

2017-04-01

The dinoflagellate Prorocentrum minimum, one of the most widespread red tide causing species, affects marine aquaculture and ecosystems worldwide. In this study, ridgetail white prawn Exopalaemon carinicauda were exposed to P. minimum cells (5 × 104 cells mL-1) to investigate its harmful effects on the shrimp. Antioxidant activities and histological changes were used as indicators of health status of the shrimp. In 72 hours, the mortality of E. carinicauda was not affected, but its antioxidant response and histology were statistically different from those of control. Elevated superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities and depressed catalase (CAT) activity were observed in gill; while increased SOD, glutathione S-transferase (GST), CAT activities and modulated GPX activity were observed in hepatopancreas. Thus, antioxidant activities in gill and hepatopancreas seem to respond differentially to harmful alga exposure. Increased malondialdehyde (MDA) content in early a few hours indicates the damage of the antioxidant defense system. Although MDA content recovered to a low level thereafter, a series of histological abnormalities including accumulation or infiltration of hemocytes, tissue lesions and necrosis were discovered in gill and hepatopancreas. Exposure to P. minimum induced sublethal effects on E. carinicauda, including temporary oxidative damage and histological injury.

From the Cover: Exposing Imidacloprid Interferes With Neurogenesis Through Impacting on Chick Neural Tube Cell Survival.

PubMed

Liu, Meng; Wang, Guang; Zhang, Shi-Yao; Zhong, Shan; Qi, Guo-Long; Wang, Chao-Jie; Chuai, Manli; Lee, Kenneth Ka Ho; Lu, Da-Xiang; Yang, Xuesong

2016-09-01

As a neonicotinoid pesticide, imidacloprid is widely used to control insects in agriculture and fleas on domestic animals. However, it is not known whether imidacloprid exposure negatively affects neurogenesis during embryonic development. In this study, using a chick embryo model, we investigated the effects of imidacloprid exposure on neurogenesis at the earliest stage and during late-stage embryo development. Exposing HH0 chick embryos to imidacloprid in EC culture caused neural tube defects (NTDs) and neuronal differentiation dysplasia as determined by NF/Tuj1 labeling. Furthermore, we found that F-actin accumulation on the apical side of the neural tube was suppressed by exposure to imidacloprid, and the expression of BMP4 and Shh on the dorsal and ventral sides of the neural tubes, respectively, were also reduced, which in turn affects the dorsolateral hinge points during bending of the neural plate. In addition, exposure to imidacloprid reduced cell proliferation and increased cell apoptosis, as determined by pHIS3 labeling and TUNEL staining, respectively, also contributing to the malformation. We obtained similar results in late-stage embryos exposed to imidacloprid. Finally, a bioinformatics analysis was employed to determine which genes identified in this study were involved in NTDs. The experimental evidence and bioinformatics analysis suggested that imidacloprid exposure during chick embryo development could increase the risk of NTDs and neural dysplasia. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Altered Lipid Homeostasis in Sertoli Cells Stressed by Mild Hyperthermia

PubMed Central

Vallés, Ana S.; Aveldaño, Marta I.; Furland, Natalia E.

2014-01-01

Spermatogenesis is known to be vulnerable to temperature. Exposures of rat testis to moderate hyperthermia result in loss of germ cells with survival of Sertoli cells (SC). Because SC provide structural and metabolic support to germ cells, our aim was to test the hypothesis that these exposures affect SC functions, thus contributing to germ cell damage. In vivo, regularly repeated exposures (one of 15 min per day, once a day during 5 days) of rat testes to 43°C led to accumulation of neutral lipids. This SC-specific lipid function took 1–2 weeks after the last of these exposures to be maximal. In cultured SC, similar daily exposures for 15 min to 43°C resulted in significant increase in triacylglycerol levels and accumulation of lipid droplets. After incubations with [3H]arachidonate, the labeling of cardiolipin decreased more than that of other lipid classes. Another specifically mitochondrial lipid metabolic function, fatty acid oxidation, also declined. These lipid changes suggested that temperature affects SC mitochondrial physiology, which was confirmed by significantly increased degrees of membrane depolarization and ROS production. This concurred with reduced expression of two SC-specific proteins, transferrin, and Wilms' Tumor 1 protein, markers of SC secretion and differentiation functions, respectively, and with an intense SC cytoskeletal perturbation, evident by loss of microtubule network (α-tubulin) and microfilament (f-actin) organization. Albeit temporary and potentially reversible, hyperthermia-induced SC structural and metabolic alterations may be long-lasting and/or extensive enough to respond for the decreased survival of the germ cells they normally foster. PMID:24690895

Absence of effects on the rat sperm quality after subacute exposure to low doses of fungicide prochloraz.

PubMed

Sanabria, Marciana; Pessin, Alessandra; Zanutto, Mirella Rossitto; Perobelli, Juliana Elaine; Guerra, Marina Trevizan; Banzato, Thais Petrochelli; Borges, Cibele dos Santos; Kempinas, Wilma De Grava

2015-01-01

Prochloraz (PCZ) is a fungicide and androgen-receptor antagonist used worldwide in horticulture and agriculture. Pre- and perinatal exposure to this pesticide during sexual differentiation is deleterious for male offspring. Since data on the effects of PCZ on epididymal functions are scarce, and because sperm maturation occurs in this organ, the present investigation aimed to determine whether low PCZ doses administered to rats during the phase of sperm transit through the epididymis might affect the morphophysiology of this organ and sperm quality. Adult male Wistar rats were assigned to 4 different groups: 0 (control, vehicle) or 10, 15, or 30 mg/kg bw/d PCZ diluted in corn oil administered orally for 4 consecutive days. Morphofunctional parameters of the male reproductive tract, hormone concentrations, sperm evaluations, and fertility and histopathologic analysis of testis and epididymis were assessed. There were no statistically significant differences between treated and control groups in relation to all evaluated parameters. Data demonstrated show that PCZ exposure for a brief 4-d exposure and low doses did not produce reproductive toxicity or compromise sperm quality in adult rats.

Sexual orientation and gender identity after prenatal exposure to the Dutch famine.

PubMed

de Rooij, Susanne R; Painter, Rebecca C; Swaab, Dick F; Roseboom, Tessa J

2009-06-01

Sexual differentiation of the human brain has been suggested to take place through exposure to sex steroids during intrauterine development. Animal experiments have shown that interference in this process by underfeeding of the mother can result in feminization of the male offspring. We explored the possible effects of prenatal exposure to famine on sexual orientation and gender identity in humans. We used the Klein Sexual Orientation Grid to assess sexual orientation and also assessed gender identity in a group of 380 men and 472 women who were born as term singletons around the time of the 1944-1945 Dutch famine. Prenatal exposure to famine did not affect sexual orientation in men or in women. Three people indicated having some gender identity problems: one woman born before the famine and one man and woman exposed to famine in late gestation. In men, a later birth order was associated with a non-exclusively heterosexual identification. In conclusion, we found no evidence for a significant association between exposure to famine in utero and altered sexual orientation and gender identity. The small sample size of participants with non-exclusively heterosexual identification (possibly due to underreporting of homosexuality) may have reduced our power to detect any differences.

Extremely Low-Frequency Electromagnetic Fields Promote In Vitro Neuronal Differentiation and Neurite Outgrowth of Embryonic Neural Stem Cells via Up-Regulating TRPC1

PubMed Central

Ma, Qinlong; Chen, Chunhai; Deng, Ping; Zhu, Gang; Lin, Min; Zhang, Lei; Xu, Shangcheng; He, Mindi; Lu, Yonghui; Duan, Weixia; Pi, Huifeng; Cao, Zhengwang; Pei, Liping; Li, Min; Liu, Chuan; Zhang, Yanwen; Zhong, Min; Zhou, Zhou; Yu, Zhengping

2016-01-01

Exposure to extremely low-frequency electromagnetic fields (ELF-EMFs) can enhance hippocampal neurogenesis in adult mice. However, little is focused on the effects of ELF-EMFs on embryonic neurogenesis. Here, we studied the potential effects of ELF-EMFs on embryonic neural stem cells (eNSCs). We exposed eNSCs to ELF-EMF (50 Hz, 1 mT) for 1, 2, and 3 days with 4 hours per day. We found that eNSC proliferation and maintenance were significantly enhanced after ELF-EMF exposure in proliferation medium. ELF-EMF exposure increased the ratio of differentiated neurons and promoted the neurite outgrowth of eNSC-derived neurons without influencing astrocyes differentiation and the cell apoptosis. In addition, the expression of the proneural genes, NeuroD and Ngn1, which are crucial for neuronal differentiation and neurite outgrowth, was increased after ELF-EMF exposure. Moreover, the expression of transient receptor potential canonical 1 (TRPC1) was significantly up-regulated accompanied by increased the peak amplitude of intracellular calcium level induced by ELF-EMF. Furthermore, silencing TRPC1 expression eliminated the up-regulation of the proneural genes and the promotion of neuronal differentiation and neurite outgrowth induced by ELF-EMF. These results suggest that ELF-EMF exposure promotes the neuronal differentiation and neurite outgrowth of eNSCs via up-regulation the expression of TRPC1 and proneural genes (NeuroD and Ngn1). These findings also provide new insights in understanding the effects of ELF-EMF exposure on embryonic brain development. PMID:26950212

Chronic ethanol exposure changes dopamine D2 receptor splicing during retinoic acid-induced differentiation of human SH-SY5Y cells.

PubMed

Wernicke, Catrin; Hellmann, Julian; Finckh, Ulrich; Rommelspacher, Hans

2010-01-01

There is evidence for ethanol-induced impairment of the dopaminergic system in the brain during development. The dopamine D2 receptor (DRD2) and the dopamine transporter (DAT) are decisively involved in dopaminergic signaling. Two splice variants of DRD2 are known, with the short one (DRD2s) representing the autoreceptor and the long one (DRD2l) the postsynaptic receptor. We searched for a model to investigate the impact of chronic ethanol exposure and withdrawal on the expression of these proteins during neuronal differentiation. RA-induced differentiation of human neuroblastoma SH-SY5Y cells seems to represent such a model. Our real-time RT-PCR, Western blot, and immunocytochemistry analyses of undifferentiated and RA-differentiated cells have demonstrated the enhanced expression of both splice variants of DRD2, with the short one being stronger enhanced than the long one under RA-treatment, and the DRD2 distribution on cell bodies and neurites under both conditions. In contrast, DAT was down-regulated by RA. The DAT is functional both in undifferentiated and RA-differentiated cells as demonstrated by [(3)H]dopamine uptake. Chronic ethanol exposure during differentiation for up to 4 weeks resulted in a delayed up-regulation of DRD2s. Ethanol withdrawal caused an increased expression of DRD2l and a normalization of DRD2s. Thus the DRD2s/DRD2l ratio was still disturbed. The dopamine level was increased by RA-differentiation compared to controls and was diminished under RA/ethanol treatment and ethanol withdrawal compared to RA-only treated cells. In conclusion, chronic ethanol exposure impairs differentiation-dependent adaptation of dopaminergic proteins, specifically of DRD2s. RA-differentiating SH-SY5Y cells are suited to study the impact of chronic ethanol exposure and withdrawal on expression of dopaminergic proteins during neuronal differentiation.

Hyperforin inhibits cell proliferation and differentiation in mouse embryonic stem cells.

PubMed

Nakamura, K; Aizawa, K; Yamauchi, J; Tanoue, A

2013-10-01

Hyperforin, a phloroglucinol derivative of St. John's Wort, has been identified as the major molecule responsible for this plant's products anti-depressant effects. It can be expected that exposure to St. John's Wort during pregnancy occurs with some frequency although embryotoxic or teratogenic effects of St. John's Wort and hyperforin have not yet been experimentally examined in detail. In this study, to determine any embryotoxic effects of hyperforin, we have attempted to determine whether hyperforin affects growth and survival processes of employing mouse embryonic stem (mES) cells (representing embryonic tissue) and fibroblasts (representing adult tissues). We used a modified embryonic stem cell test, which has been validated as an in vitro developmental toxicity protocol, mES cells, to assess embryotoxic potential of chemicals under investigation. We have identified that high concentrations of hyperforin inhibited mouse ES cell population growth and induced apoptosis in fibroblasts. Under our cell culture conditions, ES cells mainly differentiated into cardiomyocytes, although various other cell types were also produced. In this condition, hyperforin affected ES cell differentiation into cardiomyocytes in a dose-dependent manner. Analysis of tissue-specific marker expression also revealed that hyperforin at high concentrations partially inhibited ES cell differentiation into mesodermal and endodermal lineages. Hyperforin is currently used in the clinic as a safe and effective antidepressant. Our data indicate that at typical dosages it has only a low risk of embryotoxicity; ingestion of large amounts of hyperforin by pregnant women, however, may pose embryotoxic and teratogenic risks. © 2013 John Wiley & Sons Ltd.

Mode of sexual differentiation and its influence on the relative sensitivity of the fathead minnow and zebrafish in the fish sexual development test.

PubMed

Thorpe, Karen L; Pereira, Maria L a Marca; Schiffer, Heidi; Burkhardt-Holm, Patricia; Weber, Klaus; Wheeler, James R

2011-10-01

Exogenous treatment of fish with natural sex hormones and their mimics has been shown to influence gonadal differentiation resulting in biased phenotypic sex-ratios. This has lead to the development of the Fish Sexual Development Test (FSDT) as a method for the detection of endocrine active chemicals. Proposed test organisms include the medaka, zebrafish (ZF) and stickleback, although the guideline also allows for inclusion of species such as the fathead minnow (FHM), provided the test duration allows for sufficient sexual differentiation. However, although the processes underlying sexual differentiation are known to differ for each of these species, it is not known how, or if, these differences would influence the results of the FSDT. In the experiments reported here, responses of the ZF and FHM to prochloraz, a sterol biosynthesis inhibitor and androgen antagonist, were characterized and compared. Exposure to 320 μg/L of prochloraz, from embryo until 60 (ZF) or 95-125 (FHM) days post hatch inhibited somatic growth of both species, but while a negative impact on ZF larval survival was observed (LOEC 32 μg/L) there was no evidence for an effect on FHM larval survival. Prochloraz influenced sexual differentiation in both species by decreasing the proportion of females (LOEC 100 μg/L (ZF), 320 μg/L (FHM)) and delaying completion of sexual differentiation; manifest as an increased incidence of ovotestis in the ZF (LOEC 100 μg/L) and as an increased number of fish with undifferentiated gonads in the FHM (LOEC 320 μg/L). However, while exposure to 320 μg/L prochloraz delayed maturation of the differentiated FHM testis, there was no such effect in the ZF. These results demonstrate that the different strategy of sexual differentiation in the ZF and FHM influences the profile of responses of their gonads to the masculinising effects of prochloraz, but does not affect their overall sensitivity. Copyright © 2011 Elsevier B.V. All rights reserved.

The Effects of Simulated Microgravity on Gene Expression in Human Bone Marrow MSC's Under Osteogenic Differentiation

NASA Astrophysics Data System (ADS)

Buravkova, L. B.; Gershovich, J. G.; Gershovich, P. M.; Grigoriev, A. I.

2013-02-01

In this work it was found that the expression level of 144 genes significantly changed in human mesenchymal stem cells during their osteogenic differentiation after 20 days of exposure to simulated microgravity: the expression of 30 genes significantly increased (from 1.7 to 11.9 fold), and 114 - decreased (from 0.2 to 0.6 fold). Most of the revealed genes were attributed to the 11 major groups corresponding to its biological role in the cells. Additional group was formed from the genes which did not belong to these categories, or did not have a description in the known databases (such as Pubmed). The greatest number of genes with altered expression was found in the group “Matrix and Adhesion", while the lowest - in the "Apoptosis and the response to external stimuli" group. These findings suggest that cultured hMSCs, placed in non-standard conditions, maintain a high level of viability, but have significantly altered functional properties which could affect their efficiency to differentiate towards osteogenic direction.

Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis

PubMed Central

Bozec, Aline; Hannemann, Nicole

2016-01-01

Considering that adipose tissue (AT) is an endocrine organ, it can influence whole body metabolism. Excessive energy storage leads to the dysregulation of adipocytes, which in turn induces abnormal secretion of adipokines, triggering metabolic syndromes such as obesity, dyslipidemia, hyperglycemia, hyperinsulinemia, insulin resistance and type 2 diabetes. Therefore, investigating the molecular mechanisms behind adipocyte dysregulation could help to develop novel therapeutic strategies. Our protocol describes methods for evaluating the molecular mechanism affected by hypoxic conditions of the AT, which correlates with adipocyte apoptosis in adult mice. This protocol describes how to analyze AT in vivo through gene expression profiling as well as histological analysis of adipocyte differentiation, proliferation and apoptosis during hypoxia exposure, ascertained through staining of hypoxic cells or HIF-1α protein. Furthermore, in vitro analysis of adipocyte differentiation and its responses to various stimuli completes the characterization of the molecular pathways behind possible adipocyte dysfunction leading to metabolic syndromes. PMID:27284940

Urban–rural differentials in the factors associated with exposure to second-hand smoke in India

PubMed Central

Singh, Akansha; Sahoo, Namita

2013-01-01

Objectives This study aims to investigate the role of different factors associated with exposure to second-hand smoke (SHS) in the workplace and home in the urban and rural areas of India. Design Secondary analysis of the data from the Global Adult Tobacco Survey conducted in 2009–2010. Setting and participants Data were analysed from 32 738 rural and 23 202 urban non-smokers at home and 4809 rural and 6227 urban non-smokers in the workplace in India. Outcomes and methods We used two measures of SHS: exposure to SHS at home and exposure to SHS in the workplace. SHS exposure at home is estimated for non-smokers who reported anyone smoking inside his/her home. Exposure to SHS in the workplace is estimated for non-smokers who reported anyone smoking in the workplace in the past 30 days before the survey. Statistical techniques such as χ2 test, logistic regression and discriminant function analysis were used. Results The results showed that SHS exposure in the workplace and home is higher in the rural areas than in the urban areas. As compared with men, women are significantly more likely to be exposed to SHS at home (OR=1.20, 95% CI 1.10 to 1.30) in the rural areas, and less likely at the workplace in the urban areas (OR=0.49, 95% CI 0.40 to 0.59). Education and region are significant predictors of exposure levels to SHS at home and the workplace in the rural and urban areas. The knowledge of number of smoking-related hazards significantly discriminates the SHS exposure in the rural workplace. SHS exposure at home is most affected by region in the rural areas and education in the urban areas. Conclusions The factors which affect SHS exposure differ in the rural and urban areas of India. The study concludes that the risk of getting exposed to SHS at home and the workplace among non-smokers is higher in the rural areas of the country. PMID:24282245

Acute 7,12-dimethylbenz[a]anthracene exposure causes differential concentration-dependent follicle depletion and gene expression in neonatal rat ovaries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Madden, Jill A.; Hoyer, Patricia B.; Devine, Patrick J.

2014-05-01

Chronic exposure to the polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene (DMBA), generated during combustion of organic matter including cigarette smoke, depletes all ovarian follicle types in the mouse and rat, and in vitro models mimic this effect. To investigate the mechanisms involved in follicular depletion during acute DMBA exposure, two concentrations of DMBA at which follicle depletion has (75 nM) and has not (12.5 nM) been observed were investigated. Postnatal day four F344 rat ovaries were maintained in culture for four days before a single exposure to vehicle control (1% DMSO; CT) or DMBA (12 nM; low-concentration or 75 nM; high-concentration). Aftermore » four or eight additional days of culture, DMBA-induced follicle depletion was evaluated via follicle enumeration. Relative to control, DMBA did not affect follicle numbers after 4 days of exposure, but induced large primary follicle loss at both concentrations after 8 days; while, the low-concentration DMBA also caused secondary follicle depletion. Neither concentration affected primordial or small primary follicle number. RNA was isolated and quantitative RT-PCR performed prior to follicle loss to measure mRNA levels of genes involved in xenobiotic metabolism (Cyp2e1, Gstmu, Gstpi, Ephx1), autophagy (Atg7, Becn1), oxidative stress response (Sod1, Sod2) and the phosphatidylinositol 3-kinase (PI3K) pathway (Kitlg, cKit, Akt1) 1, 2 and 4 days after exposure. With the exception of Atg7 and cKit, DMBA increased (P < 0.05) expression of all genes investigated. Also, BECN1 and pAKT{sup Thr308} protein levels were increased while cKIT was decreased by DMBA exposure. Taken together, these results suggest an increase in DMBA bioactivation, add to the mechanistic understanding of DMBA-induced ovotoxicity and raise concern regarding female low concentration DMBA exposures. - Highlights: • Acute DMBA exposures induce large primary and/or secondary follicle loss. • Acute DMBA exposure did not impact primordial and small primary follicle number. • Altered ovarian gene expression was observed due to DMBA exposure.« less

Epigenome-Wide Assessment of DNA Methylation in the Placenta and Arsenic Exposure in the New Hampshire Birth Cohort Study (USA).

PubMed

Green, Benjamin B; Karagas, Margaret R; Punshon, Tracy; Jackson, Brian P; Robbins, David J; Houseman, E Andres; Marsit, Carmen J

2016-08-01

Arsenic is one of the most commonly encountered environmental toxicants, and research from model systems has suggested that one mode of its toxic activity may be through alterations in DNA methylation. In utero exposure to arsenic can affect fetal, newborn, and infant health, resulting in a range of phenotypic outcomes. This study examined variation in placental DNA methylation and its relationship to arsenic exposure in 343 individuals enrolled in the New Hampshire Birth Cohort Study. Linear regression models using a reference-free correction to account for cellular composition were employed to determine CpG loci affected by arsenic levels. Total arsenic measured in maternal urine during the second trimester was not associated with methylation in the placenta, whereas arsenic levels quantified through maternal toenail collected at birth were associated with methylation at a single CpG locus (p = 4.1 × 10-8). Placenta arsenic levels were associated with 163 differentially methylated loci (false discovery rate < 0.05), with 11 probes within the LYRM2 gene reaching genome-wide significance (p < 10-8). Measurement of LYRM2 mRNA levels indicated that methylation was weakly to moderately correlated with expression (r = 0.15, p < 0.06). In addition, we identified pathways suggesting changes in placental cell subpopulation proportions associated with arsenic exposure. These data demonstrate the potential for arsenic, even at levels commonly experienced in a U.S. population, to have effects on the DNA methylation status of specific genes in the placenta and thus supports a potentially novel mechanism for arsenic to affect long-term children's health. Green BB, Karagas MR, Punshon T, Jackson BP, Robbins DJ, Houseman EA, Marsit CJ. 2016. Epigenome-wide assessment of DNA methylation in the placenta and arsenic exposure in the New Hampshire Birth Cohort Study (USA). Environ Health Perspect 124:1253-1260; http://dx.doi.org/10.1289/ehp.1510437.

Gestational Exposure to Bisphenol A Affects the Function and Proteome Profile of F1 Spermatozoa in Adult Mice.

PubMed

Rahman, Md Saidur; Kwon, Woo-Sung; Karmakar, Polash Chandra; Yoon, Sung-Jae; Ryu, Buom-Yong; Pang, Myung-Geol

2017-02-01

Maternal exposure to the endocrine disruptor bisphenol A (BPA) has been linked to offspring reproductive abnormalities. However, exactly how BPA affects offspring fertility remains poorly understood. The aim of the present study was to evaluate the effects of gestational BPA exposure on sperm function, fertility, and proteome profile of F1 spermatozoa in adult mice. Pregnant CD-1 mice (F0) were gavaged with BPA at three different doses (50 μg/kg bw/day, 5 mg/kg bw/day, and 50 mg/kg bw/day) on embryonic days 7 to 14. We investigated the function, fertility, and related processes of F1 spermatozoa at postnatal day 120. We also evaluated protein profiles of F1 spermatozoa to monitor their functional affiliation to disease. BPA inhibited sperm count, motility parameters, and intracellular ATP levels in a dose-dependent manner. These effects appeared to be caused by reduced numbers of stage VIII seminiferous epithelial cells in testis and decreased protein kinase A (PKA) activity and tyrosine phosphorylation in spermatozoa. We also found that BPA compromised average litter size. Proteins differentially expressed in spermatozoa from BPA treatment groups are known to play a critical role in ATP generation, oxidative stress response, fertility, and in the pathogenesis of several diseases. Our study provides mechanistic support for the hypothesis that gestational exposure to BPA alters sperm function and fertility via down-regulation of tyrosine phosphorylation through a PKA-dependent mechanism. In addition, we anticipate that the BPA-induced changes in the sperm proteome might be partly responsible for the observed effects in spermatozoa. Citation: Rahman MS, Kwon WS, Karmakar PC, Yoon SJ, Ryu BY, Pang MG. 2017. Gestational exposure to bisphenol-A affects the function and proteome profile of F1 spermatozoa in adult mice. Environ Health Perspect 125:238-245; http://dx.doi.org/10.1289/EHP378.

Gestational Exposure to Bisphenol A Affects the Function and Proteome Profile of F1 Spermatozoa in Adult Mice

PubMed Central

Rahman, Md Saidur; Kwon, Woo-Sung; Karmakar, Polash Chandra; Yoon, Sung-Jae; Ryu, Buom-Yong; Pang, Myung-Geol

2016-01-01

Background: Maternal exposure to the endocrine disruptor bisphenol A (BPA) has been linked to offspring reproductive abnormalities. However, exactly how BPA affects offspring fertility remains poorly understood. Objectives: The aim of the present study was to evaluate the effects of gestational BPA exposure on sperm function, fertility, and proteome profile of F1 spermatozoa in adult mice. Methods: Pregnant CD-1 mice (F0) were gavaged with BPA at three different doses (50 μg/kg bw/day, 5 mg/kg bw/day, and 50 mg/kg bw/day) on embryonic days 7 to 14. We investigated the function, fertility, and related processes of F1 spermatozoa at postnatal day 120. We also evaluated protein profiles of F1 spermatozoa to monitor their functional affiliation to disease. Results: BPA inhibited sperm count, motility parameters, and intracellular ATP levels in a dose-dependent manner. These effects appeared to be caused by reduced numbers of stage VIII seminiferous epithelial cells in testis and decreased protein kinase A (PKA) activity and tyrosine phosphorylation in spermatozoa. We also found that BPA compromised average litter size. Proteins differentially expressed in spermatozoa from BPA treatment groups are known to play a critical role in ATP generation, oxidative stress response, fertility, and in the pathogenesis of several diseases. Conclusions: Our study provides mechanistic support for the hypothesis that gestational exposure to BPA alters sperm function and fertility via down-regulation of tyrosine phosphorylation through a PKA-dependent mechanism. In addition, we anticipate that the BPA-induced changes in the sperm proteome might be partly responsible for the observed effects in spermatozoa. Citation: Rahman MS, Kwon WS, Karmakar PC, Yoon SJ, Ryu BY, Pang MG. 2017. Gestational exposure to bisphenol-A affects the function and proteome profile of F1 spermatozoa in adult mice. Environ Health Perspect 125:238–245; http://dx.doi.org/10.1289/EHP378 PMID:27384531

Chronic radiation exposure as an ecological factor: Hypermethylation and genetic differentiation in irradiated Scots pine populations.

PubMed

Volkova, P Yu; Geras'kin, S A; Horemans, N; Makarenko, E S; Saenen, E; Duarte, G T; Nauts, R; Bondarenko, V S; Jacobs, G; Voorspoels, S; Kudin, M

2018-01-01

Genetic and epigenetic changes were investigated in chronically irradiated Scots pine (Pinus sylvestris L.) populations from territories that were heavily contaminated by radionuclides as result of the Chernobyl Nuclear Power Plant accident. In comparison to the reference site, the genetic diversity revealed by electrophoretic mobility of AFLPs was found to be significantly higher at the radioactively contaminated areas. In addition, the genome of pine trees was significantly hypermethylated at 4 of the 7 affected sites. Copyright © 2017 Elsevier Ltd. All rights reserved.

Stimulation of neural differentiation in human bone marrow mesenchymal stem cells by extremely low-frequency electromagnetic fields incorporated with MNPs.

PubMed

Choi, Yun-Kyong; Lee, Dong Heon; Seo, Young-Kwon; Jung, Hyun; Park, Jung-Keug; Cho, Hyunjin

2014-10-01

Human bone marrow-derived mesenchymal stem cells (hBM-MSCs) have been investigated as a new cell-therapeutic solution due to their capacity that could differentiate into neural-like cells. Extremely low-frequency electromagnetic fields (ELF-EMFs) therapy has emerged as a novel technique, using mechanical stimulus to differentiate hBM-MSCs and significantly enhance neuronal differentiation to affect cellular and molecular reactions. Magnetic iron oxide (Fe3O4) nanoparticles (MNPs) have recently achieved widespread use for biomedical applications and polyethylene glycol (PEG)-labeled nanoparticles are used to increase their circulation time, aqueous solubility, biocompatibility, and nonspecific cellular uptake as well as to decrease immunogenicity. Many studies have used MNP-labeled cells for differentiation, but there have been no reports of MNP-labeled neural differentiation combined with EMFs. In this study, synthesized PEG-phospholipid encapsulated magnetite (Fe3O4) nanoparticles are used on hBM-MSCs to improve their intracellular uptake. The PEGylated nanoparticles were exposed to the cells under 50 Hz of EMFs to improve neural differentiation. First, we measured cell viability and intracellular iron content in hBM-MSCs after treatment with MNPs. Analysis was conducted by RT-PCR, and immunohistological analysis using neural cell type-specific genes and antibodies after exposure to 50 Hz electromagnetic fields. These results suggest that electromagnetic fields enhance neural differentiation in hBM-MSCs incorporated with MNPs and would be an effective method for differentiating neural cells.

IDENTIFICATION OF NEURAL BIOMARKERS OF ALTERED SEXUAL DIFFERENTIATION FOLLOWING GESTATIONAL EXPOSURE***

EPA Science Inventory

Sexual differentiation of the brain occurs during late gestation through the early postnatal period. The development of the phenotypical male brain is dependent on the aromatization of circulating testosterone to estradiol. Exposure to endocrine disrupting chemicals (EDCs) duri...

Identification of neural biomarkers of altered sexual differentiation following gestational exposure

EPA Science Inventory

Sexual differentiation of the brain occurs during late gestation through the early postnatal period. The development of the phenotypical male brain is dependent on the aromatization of circulating testosterone to estradiol. Exposure to endocrine disrupting chemicals (EDCs) during...

Identification of neural biomarkers of altered sexual differentiation following gestational exposure###

EPA Science Inventory

Sexual differentiation of the brain occurs during late gestation through the early postnatal period. The development of the phenotypical male brain is dependent on the aromatization of circulating testosterone to estradiol. Exposure to endocrine disrupting chemicals (EDCs) duri...

VARIATIONS AT A QUANTITATIVE TRAIT LOCUS (QTL) AFFECT DEVELOPMENT OF BEHAVIOR IN LEAD-EXPOSED DROSOPHILA MELANOGASTER

PubMed Central

Hirsch, Helmut V. B.; Possidente, Debra; Averill, Sarah; Despain, Tamira Palmetto; Buytkins, Joel; Thomas, Valerie; Goebel, W. Paul; Shipp-Hilts, Asante; Wilson, Diane; Hollocher, Kurt; Possidente, Bernard; Lnenicka, Greg; Ruden, Douglas M.

2009-01-01

We developed Drosophila melanogaster as a model to study correlated behavioral, neuronal and genetic effects of the neurotoxin lead, known to affect cognitive and behavioral development in children. We showed that, as in vertebrates, lead affects both synaptic development and complex behaviors (courtship, fecundity, locomotor activity) in Drosophila. By assessing differential behavioral responses to developmental lead exposure among recombinant inbred Drosophila lines (RI), derived from parental lines Oregon R and Russian 2b, we have now identified a genotype by environment interaction (GEI) for a behavioral trait affected by lead. Drosophila Activity Monitors (TriKinetics, Waltham, MA), which measure activity by counting the number of times a single fly in a small glass tube walks through an infrared beam aimed at the middle of the tube, were used to measure activity of flies, reared from eggs to 4 days of adult age on either control or lead-contaminated medium, from each of 75 RI lines. We observed a significant statistical association between the effect of lead on average daytime activity across lines and one marker locus, 30AB, on chromosome 2; we define this as a Quantitative Trait Locus (QTL) associated with behavioral effects of developmental lead exposure. When 30AB was from Russian 2b, lead significantly increased locomotor activity, whereas, when 30AB was from Oregon R, lead decreased it. 30AB contains about 125 genes among which are likely “candidate genes” for the observed lead-dependent behavioral changes. Drosophila are thus a useful, underutilized model for studying behavioral, synaptic and genetic changes following chronic exposure to lead or other neurotoxins during development. PMID:19428504

Regional cholinesterase activity in white-throated sparrow brain is differentially affected by acephate (Orthene®)

USGS Publications Warehouse

Vyas, N.B.; Kuenzel, W.J.; Hill, E.F.; Romo, G.A.; Komaragiri, M.V.S.

1996-01-01

Effects of a 14-day dietary exposure to an organophosphorus pesticide, acephate (acetylphosphoramidothioic acid O,S-dimethyl ester), were determined on cholinesterase activity in three regions (basal ganglia, hippocampus, and hypothalamus) of the white-throated sparrow, Zonotrichia albicollis, brain. All three regions experienced depressed cholinesterase activity between 0.5–2 ppm acephate. The regions exhibited cholinesterase recovery at 2–16 ppm acephate; however, cholinesterase activity dropped and showed no recovery at higher dietary levels (>16 ppm acephate). Evidence indicates that the recovery is initiated by the magnitude of depression, not the duration. In general, as acephate concentration increased, differences in ChE activity among brain regions decreased. Three terms are introduced to describe ChE response to acephate exposure: 1) ChE resistance threshold, 2) ChE compensation threshold, and 3) ChE depression threshold. It is hypothesized that adverse effects to birds in the field may occur at pesticide exposure levels customarily considered negligible.

Evidence of the differential biotransformation and genotoxicity of ZnO and CeO2 nanoparticles on soybean (Glycine max) plants.

PubMed

López-Moreno, Martha L; de la Rosa, Guadalupe; Hernández-Viezcas, José A; Castillo-Michel, Hiram; Botez, Cristian E; Peralta-Videa, José R; Gardea-Torresdey, Jorge L

2010-10-01

Concern and interest related to the effects of nanomaterials on living organisms are growing in both the scientific and public communities. Reports have described the toxicity of nanoparticles (NPs) on micro- and macro-organisms, including some plant species. Nevertheless, to the authors' knowledge there are no reports on the biotransformation of NPs by edible terrestrial plants. Here, shown for the first time, is evidence pertaining to the biotransformation of ZnO and CeO(2) NPs in plant seedlings. Although the NPs did not affect soybean germination, they produced a differential effect on plant growth and element uptake. By using synchrotron X-ray absorption spectroscopy we obtained clear evidence of the presence of CeO(2) NPs in roots, whereas ZnO NPs were not present. Random amplified polymorphic DNA assay was applied to detect DNA damage and mutations caused by NPs. Results obtained from the exposure of soybean plants to CeO(2) NPs show the appearance of four new bands at 2000 mg L(-1) and three new bands at 4000 mg L(-1) treatment. In this study we demonstrated genotoxic effects from the exposure of soybean plants to CeO(2) NPs.

Air Pollution and Epigenetics: Effects on SP-A and Innate Host Defense in the Lung

PubMed Central

Silveyra, Patricia; Floros, Joanna

2013-01-01

Summary An appropriate immune and inflammatory response is key to defend against harmful agents present in the environment such as pathogens, allergens, and inhaled pollutants, including ozone and particulate matter. Air pollution is a serious public health concern worldwide, and cumulative evidence revealed that air pollutants contribute to epigenetic variation in several genes, and this in turn can contribute to disease susceptibility. Several groups of experts have recently reviewed findings on epigenetics and air pollution [1–6]. Surfactant proteins play a central role in pulmonary host defense by mediating pathogen clearance, modulating allergic responses and facilitating the resolution of lung inflammation. Recent evidence indicates that surfactant proteins are subject to epigenetic regulation under hypoxia and other conditions. Oxidative stress caused by ozone, and exposure to particulate matter have been shown to affect the expression of surfactant protein A (SP-A), an important lung host defense molecule, as well as alter its functions. In this review, we discuss recent findings in the fields of epigenetics and air pollution effects on innate immunity, with focus on SP-A, and the human SP-A variants in particular. Their function may be differentially affected by pollutants and specifically by ozone-induced oxidative stress, and this in turn may differentially affect susceptibility to lung disease. PMID:22553125

Differential effects of social isolation in adolescent and adult mice on behavior and cortical gene expression.

PubMed

Lander, Sharon S; Linder-Shacham, Donna; Gaisler-Salomon, Inna

2017-01-01

Intact function of the medial prefrontal cortex (mPFC) function relies on proper development of excitatory and inhibitory neuronal populations and on integral myelination processes. Social isolation (SI) affects behavior and brain circuitry in adulthood, but previous rodent studies typically induced prolonged (post-weaning) exposure and failed to directly compare between the effects of SI in adolescent and adulthood. Here, we assessed the impact of a 3-week SI period, starting in mid-adolescence (around the onset of puberty) or adulthood, on a wide range of behaviors in adult male mice. Additionally, we asked whether adolescent SI would differentially affect the expression of excitatory and inhibitory neuronal markers and myelin-related genes in mPFC. Our findings indicate that mid-adolescent or adult SI increase anxiogenic behavior and locomotor activity. However, SI in adolescence uniquely affects the response to the psychotomimetic drug amphetamine, social and novelty exploration and performance in reversal and attentional set shifting tasks. Furthermore, adolescent but not adult SI increased the expression of glutamate markers in the adult mPFC. Our results imply that adolescent social deprivation is detrimental for normal development and may be particularly relevant to the investigation of developmental psychopathology. Copyright © 2016 Elsevier B.V. All rights reserved.

ROCK inhibitor primes human induced pluripotent stem cells to selectively differentiate towards mesendodermal lineage via epithelial-mesenchymal transition-like modulation.

PubMed

Maldonado, Maricela; Luu, Rebeccah J; Ramos, Michael E P; Nam, Jin

2016-09-01

Robust control of human induced pluripotent stem cell (hIPSC) differentiation is essential to realize its patient-tailored therapeutic potential. Here, we demonstrate a novel application of Y-27632, a small molecule Rho-associated protein kinase (ROCK) inhibitor, to significantly influence the differentiation of hIPSCs in a lineage-specific manner. The application of Y-27632 to hIPSCs resulted in a decrease in actin bundling and disruption of colony formation in a concentration and time-dependent manner. Such changes in cell and colony morphology were associated with decreased expression of E-cadherin, a cell-cell junctional protein, proportional to the increased exposure to Y-27632. Interestingly, gene and protein expression of pluripotency markers such as NANOG and OCT4 were not downregulated by an exposure to Y-27632 up to 36h. Simultaneously, epithelial-to-mesenchymal (EMT) transition markers were upregulated with an exposure to Y-27632. These EMT-like changes in the cells with longer exposure to Y-27632 resulted in a significant increase in the subsequent differentiation efficiency towards mesendodermal lineage. In contrast, an inhibitory effect was observed when cells were subjected to ectodermal differentiation after prolonged exposure to Y-27632. Collectively, these results present a novel method for priming hIPSCs to modulate their differentiation potential with a simple application of Y-27632. Copyright © 2016 Helmholtz Zentrum München. Published by Elsevier B.V. All rights reserved.

Differential Exposure to Hazardous Air Pollution in the United States: A Multilevel Analysis of Urbanization and Neighborhood Socioeconomic Deprivation

PubMed Central

Young, Gary S.; Fox, Mary A.; Trush, Michael; Kanarek, Norma; Glass, Thomas A.; Curriero, Frank C.

2012-01-01

Population exposure to multiple chemicals in air presents significant challenges for environmental public health. Air quality regulations distinguish criteria air pollutants (CAPs) (e.g., ozone, PM2.5) from hazardous air pollutants (HAPs)—187 chemicals which include carcinogens and others that are associated with respiratory, cardiovascular, neurological and numerous other non-cancer health effects. Evidence of the public’s cumulative exposure and the health effects of HAPs are quite limited. A multilevel model is used to assess differential exposure to HAP respiratory, neurological, and cancer hazards (2005) related to the Townsend Index of Socioeconomic Deprivation (TSI), after adjustment for regional population size and economic activity, and local population density. We found significant positive associations between tract TSI and respiratory and cancer HAP exposure hazards, and smaller effects for neurological HAPs. Tracts in the top quintile of TSI have between 38%–60% higher HAP exposure than the bottom quintile; increasing population size from the bottom quintile to the top quintile modifies HAP exposure hazard related to TSI, increasing cancer HAP exposure hazard by 6% to 20% and increasing respiratory HAP exposure hazard by 12% to 27%. This study demonstrates the value of social epidemiological methods for analyzing differential exposure and advancing cumulative risk assessment. PMID:22829799

Differential exposure to hazardous air pollution in the United States: a multilevel analysis of urbanization and neighborhood socioeconomic deprivation.

PubMed

Young, Gary S; Fox, Mary A; Trush, Michael; Kanarek, Norma; Glass, Thomas A; Curriero, Frank C

2012-06-01

Population exposure to multiple chemicals in air presents significant challenges for environmental public health. Air quality regulations distinguish criteria air pollutants (CAPs) (e.g., ozone, PM2.5) from hazardous air pollutants (HAPs)-187 chemicals which include carcinogens and others that are associated with respiratory, cardiovascular, neurological and numerous other non-cancer health effects. Evidence of the public's cumulative exposure and the health effects of HAPs are quite limited. A multilevel model is used to assess differential exposure to HAP respiratory, neurological, and cancer hazards (2005) related to the Townsend Index of Socioeconomic Deprivation (TSI), after adjustment for regional population size and economic activity, and local population density. We found significant positive associations between tract TSI and respiratory and cancer HAP exposure hazards, and smaller effects for neurological HAPs. Tracts in the top quintile of TSI have between 38%-60% higher HAP exposure than the bottom quintile; increasing population size from the bottom quintile to the top quintile modifies HAP exposure hazard related to TSI, increasing cancer HAP exposure hazard by 6% to 20% and increasing respiratory HAP exposure hazard by 12% to 27%. This study demonstrates the value of social epidemiological methods for analyzing differential exposure and advancing cumulative risk assessment.

Differential effects of zinc exposure on male and female oysters (Crassostrea angulata) as revealed by label-free quantitative proteomics.

PubMed

Luo, Lianzhong; Zhang, Qinghong; Kong, Xue; Huang, Heqing; You, Weiwei; Ke, Caihuan

2017-10-01

Oysters accumulate Zn as an adaptation to Zn exposure; however, it is not known whether male and female oysters respond differently to Zn exposure. Proteomic and real-time polymerase chain reaction analyses were used to investigate differential responses of male and female oysters (Crassostrea angulata) to Zn exposure. After exposure to 50 μg L -1 or 500 μg L -1 Zn for 30 d, gonads of female oysters accumulated more Zn than those of males, and gonadal development was accelerated in females but was abnormal in males. Differentially expressed proteins after exposure to Zn were identified and shown to function in Zn transport, Ca transport, phosphate metabolism, energy metabolism, immune regulation, oxidative stress responses, gene expression regulation, and fat metabolism. Proteins with functions in Zn transportation and storage, and multifunctional proteins, such as hemicentin-1 and histidinol dehydrogenase, were expressed at significantly higher levels in the gonads of female than male oysters after Zn exposure. Environ Toxicol Chem 2017;36:2602-2613. © 2017 SETAC. © 2017 SETAC.

Effects of Arsenic on Osteoblast Differentiation in Vitro and on Bone Mineral Density and Microstructure in Rats

PubMed Central

Wu, Cheng-Tien; Lu, Tung-Ying; Chan, Ding-Cheng; Tsai, Keh-Sung; Yang, Rong-Sen

2014-01-01

Background: Arsenic is a ubiquitous toxic element and is known to contaminate drinking water in many countries. Several epidemiological studies have shown that arsenic exposure augments the risk of bone disorders. However, the detailed effect and mechanism of inorganic arsenic on osteoblast differentiation of bone marrow stromal cells and bone loss still remain unclear. Objectives: We investigated the effects and mechanism of arsenic on osteoblast differentiation in vitro and evaluated bone mineral density (BMD) and bone microstructure in rats at doses relevant to human exposure from drinking water. Methods: We used a cell model of rat primary bone marrow stromal cells (BMSCs) and a rat model of long-term exposure with arsenic-contaminated drinking water, and determined bone microstructure and BMD in rats by microcomputed tomography (μCT). Results: We observed significant attenuation of osteoblast differentiation after exposure of BMSCs to arsenic trioxide (0.5 or 1 μM). After arsenic treatment during differentiation, expression of runt-related transcription factor-2 (Runx2), bone morphogenetic protein-2 (BMP-2), and osteocalcin in BMSCs was inhibited and phosphorylation of enhanced extracellular signal-regulated kinase (ERK) was increased. These altered differentiation-related molecules could be reversed by the ERK inhibitor PD98059. Exposure of rats to arsenic trioxide (0.05 or 0.5 ppm) in drinking water for 12 weeks altered BMD and microstructure, decreased Runx2 expression, and increased ERK phosphorylation in bones. In BMSCs isolated from arsenic-treated rats, osteoblast differentiation was inhibited. Conclusions: Our results suggest that arsenic is capable of inhibiting osteoblast differentiation of BMSCs via an ERK-dependent signaling pathway and thus increasing bone loss. Citation: Wu CT, Lu TY, Chan DC, Tsai KS, Yang RS, Liu SH. 2014. Effects of arsenic on osteoblast differentiation in vitro and on bone mineral density and microstructure in rats. Environ Health Perspect 122:559–565; http://dx.doi.org/10.1289/ehp.1307832 PMID:24531206

Exposure to Childhood Abuse and Later Substance Use: Indirect Effects of Emotion Dysregulation and Exposure to Trauma

PubMed Central

Mandavia, Amar; Robinson, Gabriella G. N.; Bradley, Bekh; Ressler, Kerry J.

2016-01-01

Little is known about how emotion dysregulation (ED) and trauma exposure differentially affect the relationship between abuse in childhood and adult substance use. We examined associations between child abuse, trauma exposure, ED, and current substance use in an already existing dataset. Participants (N = 2,014 adults, 90% African American) had been recruited from an urban hospital for a parent study. Analyses showed that drug and alcohol use was significantly positively correlated with child abuse (emotional, physical, and sexual), later trauma exposure, and ED (all ps < .001). Linear regression showed that exposure to abuse when older than a child was significantly associated with drug and alcohol use independent of child abuse and demographic variables (R 2Δ = .08, p < .001; R 2Δ = .04, p < .001). ED was significantly associated with drug and alcohol use independently of child abuse, nonabuse trauma, and demographic variables (R 2Δ = .02, p < .001; R 2Δ = .04, p < .001). Multiple mediation analyses showed that ED and later trauma exposure accounted for variance in the association between emotional abuse and substance use (p < .001). A better understanding of vulnerabilities to additional traumatization and emotion‐regulation deficits in individuals who have been exposed to child abuse and in addition have comorbid substance use problems may inform treatments that lead to improved outcomes. PMID:27622844

Exposure to Childhood Abuse and Later Substance Use: Indirect Effects of Emotion Dysregulation and Exposure to Trauma.

PubMed

Mandavia, Amar; Robinson, Gabriella G N; Bradley, Bekh; Ressler, Kerry J; Powers, Abigail

2016-10-01

Little is known about how emotion dysregulation (ED) and trauma exposure differentially affect the relationship between abuse in childhood and adult substance use. We examined associations between child abuse, trauma exposure, ED, and current substance use in an already existing dataset. Participants (N = 2,014 adults, 90% African American) had been recruited from an urban hospital for a parent study. Analyses showed that drug and alcohol use was significantly positively correlated with child abuse (emotional, physical, and sexual), later trauma exposure, and ED (all ps < .001). Linear regression showed that exposure to abuse when older than a child was significantly associated with drug and alcohol use independent of child abuse and demographic variables (R 2 Δ = .08, p < .001; R 2 Δ = .04, p < .001). ED was significantly associated with drug and alcohol use independently of child abuse, nonabuse trauma, and demographic variables (R 2 Δ = .02, p < .001; R 2 Δ = .04, p < .001). Multiple mediation analyses showed that ED and later trauma exposure accounted for variance in the association between emotional abuse and substance use (p < .001). A better understanding of vulnerabilities to additional traumatization and emotion-regulation deficits in individuals who have been exposed to child abuse and in addition have comorbid substance use problems may inform treatments that lead to improved outcomes. Copyright © 2016 International Society for Traumatic Stress Studies.

Environmental Enrichment Duration Differentially Affects Behavior and Neuroplasticity in Adult Mice.

PubMed

Leger, Marianne; Paizanis, Eleni; Dzahini, Kwamivi; Quiedeville, Anne; Bouet, Valentine; Cassel, Jean-Christophe; Freret, Thomas; Schumann-Bard, Pascale; Boulouard, Michel

2015-11-01

Environmental enrichment is a powerful way to stimulate brain and behavioral plasticity. However the required exposure duration to reach such changes has not been substantially analyzed. We aimed to assess the time-course of appearance of the beneficial effects of enriched environment. Thus, different behavioral tests and neurobiological parameters (such as neurogenesis, brain monoamines levels, and stress-related hormones) were concomitantly realized after different durations of enriched environment (24 h, 1, 3, or 5 weeks). While short enrichment exposure (24 h) was sufficient to improve object recognition memory performances, a 3-week exposure was required to improve aversive stimulus-based memory performances and to reduce anxiety-like behavior; effects that were not observed with longer duration. The onset of behavioral changes after a 3-week exposure might be supported by higher serotonin levels in the frontal cortex, but seems independent of neurogenesis phenomenon. Additionally, the benefit of 3-week exposure on memory was not observed 3 weeks after cessation of enrichment. Thus, the 3-week exposure appears as an optimal duration in order to induce the most significant behavioral effects and to assess the underlying mechanisms. Altogether, these results suggest that the duration of exposure is a keystone of the beneficial behavioral and neurobiological effects of environmental enrichment. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Tumor-based case-control studies of infection and cancer: muddling the when and where of molecular epidemiology.

PubMed

Engels, Eric A; Wacholder, Sholom; Katki, Hormuzd A; Chaturvedi, Anil K

2014-10-01

We describe the "tumor-based case-control" study as a type of epidemiologic study used to evaluate associations between infectious agents and cancer. These studies assess exposure using diseased tissues from affected individuals (i.e., evaluating tumor tissue for cancer cases), but they must utilize nondiseased tissues to assess control subjects, who do not have the disease of interest. This approach can lead to exposure misclassification in two ways. First, concerning the "when" of exposure assessment, retrospective assessment of tissues may not accurately measure exposure at the key earlier time point (i.e., during the etiologic window). Second, concerning the "where" of exposure assessment, use of different tissues in cases and controls can have different accuracy for detecting the exposure (i.e., differential exposure misclassification). We present an example concerning the association of human papillomavirus with various cancers, where tumor-based case-control studies likely overestimate risk associated with infection. In another example, we illustrate how tumor-based case-control studies of Helicobacter pylori and gastric cancer underestimate risk. Tumor-based case-control studies can demonstrate infection within tumor cells, providing qualitative information about disease etiology. However, measures of association calculated in tumor-based case-control studies are prone to over- or underestimating the relationship between infections and subsequent cancer risk. ©2014 American Association for Cancer Research.

In utero undernourishment perturbs the adult sperm methylome and is linked to metabolic disease transmission

PubMed Central

Radford, Elizabeth J.; Corish, Jennifer A.; Seisenberger, Stefanie; Hore, Timothy A.; Reik, Wolf; Erkek, Serap; Peters, Antoine H. F. M.; Patti, Mary-Elizabeth; Ferguson-Smith, Anne C.

2015-01-01

Adverse prenatal environments can promote metabolic disease in offspring and subsequent generations. Animal models and epidemiological data implicate epigenetic inheritance but mechanisms remain unknown. In an intergenerational developmental programming model affecting F2 metabolism, we demonstrate that the in utero nutritional environment of F1 embryos alters the germline DNA methylome of F1 adult males in a locus-specific manner. Differentially methylated regions are hypomethylated and enriched in nucleosome-retaining regions. A substantial fraction is resistant to early embryo methylation reprogramming, potentially impacting F2 development. Importantly, differential methylation is not maintained in F2 tissues, yet locus-specific expression is perturbed. Thus, in utero nutritional exposures during critical windows of germ cell development can impact the male germline methylome, associated with metabolic disease in offspring. PMID:25011554

Deviations from Haber’s Law for Multiple Measures of Acute Lung Injury in Chlorine-Exposed Mice

PubMed Central

Hoyle, Gary W.; Chang, Weiyuan; Chen, Jing; Schlueter, Connie F.; Rando, Roy J.

2010-01-01

Chlorine gas is considered a chemical threat agent that can cause acute lung injury. Studies in the early 20th century on war gases led Haber to postulate that the dose of an inhaled chemical expressed as the product of gas concentration and exposure time leads to a constant toxicological effect (Haber’s Law). In the present work, mice were exposed to a constant dose of chlorine (100 ppm-h) delivered using different combinations of concentration and time (800 ppm/7.5 min, 400 ppm/15 min, 200 ppm/30 min, and 100 ppm/60 min). Significant effects of exposure protocol on survival evaluated 6 h after exposure were observed, ranging from 0% for the 7.5-min exposure to 100% for the 30- and 60-min exposures. Multiple parameters indicative of lung injury were examined to determine if any aspects of lung injury were differentially affected by the exposure protocols. Most parameters (pulmonary edema, neutrophil influx, and levels of protein, immunoglobulin M, and the chemokine KC [Cxcl1] in lavage fluid) indicated that lung injury was most pronounced for the 15-min exposure and least for the 60-min exposure. In contrast, changes in pulmonary function at baseline and in response to inhaled methacholine were similar following the three exposure regimens. The results indicate that the extent of lung injury following chlorine inhalation depends not only on total dose but also on the specifics of exposure concentration and time, and they suggest that evaluation of countermeasures against chlorine-induced lung injury should be performed using multiple types of exposure scenarios. PMID:20819911

Phthalate-induced toxicity: Identifying the vulnerable pathways during sexual differentiation in the male rat

EPA Science Inventory

Human exposures to phthalate ester plasticizer compounds are widespread. Studies in rodents have demonstrated that in utero exposure to various phthalates throughout sexual differentiation (GD14-18) results in decreased fetal testicular androgen production, and ultimately leads t...

Gene expression profiles following exposure to a developmental neurotoxicant, Aroclor 1254: Pathway analysis for possible mode(s) of action

DOE Office of Scientific and Technical Information (OSTI.GOV)

Royland, Joyce E.; Kodavanti, Prasada Rao S.

2008-09-01

Epidemiological studies indicate that low levels of polychlorinated biphenyl (PCB) exposure can adversely affect neurocognitive development. In animal models, perturbations in calcium signaling, neurotransmitters, and thyroid hormones have been postulated as potential mechanisms for PCB-induced developmental neurotoxicity. In order to understand the role of these proposed mechanisms and to identify other mechanisms in PCB-induced neurotoxicity, we have chosen a global approach utilizing oligonucleotide microarrays to examine gene expression profiles in the brain following developmental exposure to Aroclor 1254 (0 or 6 mg/kg/day from gestation day 6 through postnatal day (PND) 21) in Long-Evans rats. Gene expression levels in the cerebellummore » and hippocampus from PNDs 7 and 14 animals were determined on Affymetrix rat 230A{sub 2}.0 chips. In the cerebellum, 87 transcripts were altered at PND7 compared to 27 transcripts at PND14 by Aroclor 1254 exposure, with only one transcript affected at both ages. In hippocampus, 175 transcripts and 50 transcripts were altered at PND7 and PND14, respectively, by Aroclor 1254 exposure with five genes commonly affected. Functional analysis suggests that pathways related to calcium homeostasis (Gng3, Ryr2, Trdn, Cacna1a), intracellular signaling (Camk2d, Stk17b, Pacsin2, Ryr2, Trio, Fert2, Ptk2b), axonal guidance (Lum, Mxd3, Akap11, Gucy1b3), aryl hydrocarbon receptor signaling (Nfia, Col1a2), and transcripts involved in cell proliferation (Gspt2, Cdkn1c, Ptk2b) and differentiation (Ifitm31, Hpca, Zfp260, Igsf4a, Hes5) leading to the development of nervous system were significantly altered by Aroclor 1254 exposure. Of the two brain regions examined, Aroclor 1254-induced genomic changes were greater in the hippocampus than the cerebellum. The genomic data suggests that PCB-induced neurotoxic effects were due to disruption of normal ontogenetic pattern of nervous system growth and development by altering intracellular signaling pathways but not by endocrine disruption.« less

Subchronic exposure to sublethal dose of imidacloprid changes electrophysiological properties and expression pattern of nicotinic acetylcholine receptor subtypes in insect neurosecretory cells.

PubMed

Benzidane, Yassine; Goven, Delphine; Abd-Ella, Aly Ahmed; Deshayes, Caroline; Lapied, Bruno; Raymond, Valérie

2017-09-01

Neonicotinoids are the most important class of insecticides used in agriculture over the last decade. They act as selective agonists of insect nicotinic acetylcholine receptors (nAChRs). The emergence of insect resistance to these insecticides is one of the major problems, which limit the use of neonicotinoids. The aim of our study is to better understand physiological changes appearing after subchronic exposure to sublethal doses of insecticide using complementary approaches that include toxicology, electrophysiology, molecular biology and calcium imaging. We used cockroach neurosecretory cells identified as dorsal unpaired median (DUM) neurons, known to express two α-bungarotoxin-insensitive (α-bgt-insensitive) nAChR subtypes, nAChR1 and nAChR2, which differ in their sensitivity to imidacloprid. Although nAChR1 is sensitive to imidacloprid, nAChR2 is insensitive to this insecticide. In this study, we demonstrate that subchronic exposure to sublethal dose of imidacloprid differentially changes physiological and molecular properties of nAChR1 and nAChR2. Our findings reported that this treatment decreased the sensitivity of nAChR1 to imidacloprid, reduced current density flowing through this nAChR subtype but did not affect its subunit composition (α3, α8 and β1). Subchronic exposure to sublethal dose of imidacloprid also affected nAChR2 functions. However, these effects were different from those reported on nAChR1. We observed changes in nAChR2 conformational state, which could be related to modification of the subunit composition (α1, α2 and β1). Finally, the subchronic exposure affecting both nAChR1 and nAChR2 seemed to be linked to the elevation of the steady-state resting intracellular calcium level. In conclusion, under subchronic exposure to sublethal dose of imidacloprid, cockroaches are capable of triggering adaptive mechanisms by reducing the participation of imidacloprid-sensitive nAChR1 and by optimizing functional properties of nAChR2, which is insensitive to this insecticide. Copyright © 2017 Elsevier B.V. All rights reserved.

Directed Differentiation of Human Embryonic Stem Cells into Prostate Organoids In Vitro and its Perturbation by Low-Dose Bisphenol A Exposure

PubMed Central

Calderon-Gierszal, Esther L.; Prins, Gail S.

2015-01-01

Studies using rodent and adult human prostate stem-progenitor cell models suggest that developmental exposure to the endocrine disruptor Bisphenol-A (BPA) can predispose to prostate carcinogenesis with aging. Unknown at present is whether the embryonic human prostate is equally susceptible to BPA during its natural developmental window. To address this unmet need, we herein report the construction of a pioneer in vitro human prostate developmental model to study the effects of BPA. The directed differentiation of human embryonic stem cells (hESC) into prostatic organoids in a spatial system was accomplished with precise temporal control of growth factors and steroids. Activin-induced definitive endoderm was driven to prostate specification by combined exposure to WNT10B and FGF10. Matrigel culture for 20–30 days in medium containing R-Spondin-1, Noggin, EGF, retinoic acid and testosterone was sufficient for mature prostate organoid development. Immunofluorescence and gene expression analysis confirmed that organoids exhibited cytodifferentiation and functional properties of the human prostate. Exposure to 1 nM or 10 nM BPA throughout differentiation culture disturbed early morphogenesis in a dose-dependent manner with 1 nM BPA increasing and 10 nM BPA reducing the number of branched structures formed. While differentiation of branched structures to mature organoids seemed largely unaffected by BPA exposure, the stem-like cell population increased, appearing as focal stem cell nests that have not properly entered lineage commitment rather than the rare isolated stem cells found in normally differentiated structures. These findings provide the first direct evidence that low-dose BPA exposure targets hESC and perturbs morphogenesis as the embryonic cells differentiate towards human prostate organoids, suggesting that the developing human prostate may be susceptible to disruption by in utero BPA exposures. PMID:26222054

Embryonic mescencephalon derived neurospheres contain progenitors as well as differentiated neurons and glia.

PubMed

Khaing, Zin Z; Roberts, James L

2009-01-01

Stem cells and progenitor cells in the central nervous system may have potential for therapeutic use in patients with degenerative diseases or after injury. Neural precursor cells can be grown in culture in the presence of mitogens as aggregates termed neurospheres (NSs), as a source of proliferating progenitor cells. Withdrawal of mitogen and allowing the NSs to adhere to a substrate is the conventional way to study the differentiation potential of the progenitor cells propagated in NSs form. Here we asked if differentiation occurs within NSs cultured in the normal manner, in the presence of mitogen. We used non-passaged NSs derived from E13.5 mouse ventral mesencephalon. The NSs contained not only progenitor cells but also phenotypically-differentiated neurons and glia, in the presence of mitogen. Extracellular matrix molecules (fibronectin, laminin and collagen type IV) were also detected within these NSs, which may aid in the differentiation of progenitors inside the NSs. The cell types within NSs were also organized in a way that the differentiated cells were found in the inner cell mass while progenitors were found in the outer region. Additionally, the proportion of differentiated cell types within the NSs was also affected by exposure to different mitogens. Moreover, when placed together in to co-culture, dissociated embryonic striatal and mesencephalic cells aggregated spontaneously to form mixed NSs, enhancing the eventual differentiation into dopaminergic neurons from progenitors within these NSs. Therefore, the NSs contained progenitor cells and differentiated neurons and glial cells. In addition, NS culture system can be used to study cellular differentiation in vitro in non-adherent conditions.

Association of direct exposure to terrorism, media exposure to terrorism, and other trauma with emotional and behavioral problems in preschool children.

PubMed

Wang, Yanping; Nomura, Yoko; Pat-Horenczyk, Ruth; Doppelt, Osnat; Abramovitz, Robert; Brom, Daniel; Chemtob, Claude

2006-12-01

This study examined the differential impact of various types of trauma exposure on emotional and behavioral problems in preschool children. Participants were 95 mothers of 1- to 4-year-old children in Israel. Results suggested a differential pattern of associations between the types of trauma exposure (i.e., direct exposure to terrorism, media exposure to terrorism, and other trauma) and children's internalizing and externalizing problems. This line of research is important for the identification of risk factors and the development of effective prevention and intervention strategies to promote resilience in preschool children exposed to specific type(s) of trauma.

Processing deficits and the mediation of positive affect in persuasion.

PubMed

Mackie, D M; Worth, L T

1989-07-01

Motivational and cognitive mediators of the reduced processing of persuasive messages shown by recipients in a positive mood were tested. Ss in positive or neutral moods read strong or weak counterattitudinal advocadies for either a limited time or for as long as they wanted. Under limited exposure conditions, neutral mood Ss showed attitude change indicative of systemic processing, whereas positive mood Ss showed no differentiation of strong and weak versions of the message. When message exposure was unlimited, positive mood Ss viewed the message longer than did neutral mood Ss and systematically processed it rather than relying on persuasion heuristics. These findings replicated with 2 manipulations of mood and 2 different attitude issues. We interpret the results as providing evidence that reduced cognitive capacity to process the message contributes to the decrements shown by positive mood Ss.

Population Ancestry and Genetic Risk for Diabetes and Kidney, Cardiovascular, and Bone Disease: Modifiable Environmental Factors May Produce the Cures

PubMed Central

Freedman, Barry I.; Divers, Jasmin; Palmer, Nicholette D.

2013-01-01

Variable rates of disease observed between members of different continental population groups may be mediated by inherited factors, environmental exposures, or their combination. This manuscript provides evidence in support of differential allele frequency distributions that underlie the higher rates of non-diabetic kidney disease in the focal segmental glomerulosclerosis spectrum of disease and lower rates of coronary artery calcified atherosclerotic plaque and osteoporosis in populations of African ancestry. With recognition that these and other common complex diseases are affected by biologic factors comes the realization that targeted manipulation of environmental exposures and pharmacologic treatments will have different effects based on genotype. The current era of precision medicine will couple one’s genetic make-up with specific therapies to reduce rates of disease based on presence of disease-specific alleles. PMID:23896482

Pre- and postnatal exposure of mice to concentrated urban PM2.5 decreases the number of alveoli and leads to altered lung function at an early stage of life.

PubMed

de Barros Mendes Lopes, Thais; Groth, Espen E; Veras, Mariana; Furuya, Tatiane K; de Souza Xavier Costa, Natalia; Ribeiro Júnior, Gabriel; Lopes, Fernanda Degobbi; de Almeida, Francine M; Cardoso, Wellington V; Saldiva, Paulo Hilario Nascimento; Chammas, Roger; Mauad, Thais

2018-06-04

Gestational exposure to air pollution is associated with negative outcomes in newborns and children. In a previous study, we demonstrated a synergistic negative effect of pre- and postnatal exposure to PM 2.5 on lung development in mice. However, the means by which air pollution affects development of the lung have not yet been identified. In this study, we exposed pregnant BALB/c mice and their offspring to concentrated urban PM 2.5 (from São Paulo, Brazil; target dose 600 μg/m 3 for 1 h daily). Exposure was started on embryonic day 5.5 (E5.5, time of placental implantation). Lung tissue of fetuses and offspring was submitted to stereological and transcriptomic analyses at E14.5 (pseudoglandular stage of lung development), E18.5 (saccular stage) and P40 (postnatal day 40, alveolarized lung). Additionally, lung function and cellularity of bronchoalveolar lavage (BAL) fluid were studied in offspring animals at P40. Compared to control animals that were exposed to filtered air throughout gestation and postnatal life, PM-exposed mice exhibited higher lung elastance and a lower alveolar number at P40 whilst the total lung volume and cellularity of BAL fluid were not affected. Glandular and saccular structures of fetal lungs were not altered upon gestational exposure; transcriptomic signatures, however, showed changes related to DNA damage and its regulation, inflammation and regulation of cell proliferation. A differential expression was validated at E14.5 for the candidates Sox8, Angptl4 and Gas1. Our data substantiate the in utero biomolecular effect of gestational exposure to air pollution and provide first-time stereological evidence that pre- and early life-postnatal exposure compromise lung development, leading to a reduced number of alveoli and an impairment of lung function in the adult mouse. Copyright © 2018 Elsevier Ltd. All rights reserved.

Inhalation exposure of rats to asphalt fumes generated at paving temperatures alters pulmonary xenobiotic metabolism pathways without lung injury.

PubMed Central

Ma, Jane Y C; Rengasamy, Apavoo; Frazer, Dave; Barger, Mark W; Hubbs, Ann F; Battelli, Lori; Tomblyn, Seith; Stone, Samuel; Castranova, Vince

2003-01-01

Asphalt fumes are complex mixtures of various organic compounds, including polycyclic aromatic hydrocarbons (PAHs). PAHs require bioactivation by the cytochrome P-450 monooxygenase system to exert toxic/carcinogenic effects. The present study was carried out to characterize the acute pulmonary inflammatory responses and the alterations of pulmonary xenobiotic pathways in rats exposed to asphalt fumes by inhalation. Rats were exposed at various doses and time periods to air or to asphalt fumes generated at paving temperatures. To assess the acute damage and inflammatory responses, differential cell counts, acellular lactate dehydrogenase (LDH) activity, and protein content of bronchoalveolar lavage fluid were determined. Alveolar macrophage (AM) function was assessed by monitoring generation of chemiluminescence and production of tumor necrosis factor-alpha and interleukin-1. Alteration of pulmonary xenobiotic pathways was determined by monitoring the protein levels and activities of P-450 isozymes (CYP1A1 and CYP2B1), glutathioneS-transferase (GST), and NADPH:quinone oxidoreductase (QR). The results show that acute asphalt fume exposure did not cause neutrophil infiltration, alter LDH activity or protein content, or affect AM function, suggesting that short-term asphalt fume exposure did not induce acute lung damage or inflammation. However, acute asphalt fume exposure significantly increased the activity and protein level of CYP1A1 whereas it markedly reduced the activity and protein level of CYP2B1 in the lung. The induction of CYP1A1 was localized in nonciliated bronchiolar epithelial (Clara) cells, alveolar septa, and endothelial cells by immunofluorescence microscopy. Cytosolic QR activity was significantly elevated after asphalt fume exposure, whereas GST activity was not affected by the exposure. This induction of CYP1A1 and QR with the concomitant down-regulation of CYP2B1 after asphalt fume exposure could alter PAH metabolism and may lead to potential toxic effects in the lung. PMID:12842776

Mechanisms by which pesticides affect insect immunity.

PubMed

James, R R; Xu, J

2012-02-01

The current state of knowledge regarding the effect of pesticides on insect immunity is reviewed here. A basic understanding of these interactions is needed for several reasons, including to improve methods for controlling pest insects in agricultural settings, for controlling insect vectors of human diseases, and for reducing mortality in beneficial insects. Bees are particularly vulnerable to sublethal pesticide exposures because they gather nectar and pollen, concentrating environmental toxins in their nests in the process. Pesticides do have effects on immunity. Organophosphates and some botanicals have been found to impact hemocyte number, differentiation, and thus affect phagocytosis. The phenoloxidase cascade and malanization have also been shown to be affected by several insecticides. Many synthetic insecticides increase oxidative stress, and this could have severe impacts on the production of some antimicrobial peptides in insects, but research is needed to determine the actual effects. Pesticides can also affect grooming behaviors, rendering insects more susceptible to disease. Despite laboratory data documenting pesticide/pathogen interactions, little field data is available at the population level. Published by Elsevier Inc.

Developmental programming: Interaction between prenatal BPA and postnatal overfeeding on cardiac tissue gene expression in female sheep.

PubMed

Koneva, L A; Vyas, A K; McEachin, R C; Puttabyatappa, M; Wang, H-S; Sartor, M A; Padmanabhan, V

2017-01-01

Epidemiologic studies and studies in rodents point to potential risks from developmental exposure to BPA on cardiometabolic diseases. Furthermore, it is becoming increasingly evident that the manifestation and severity of adverse outcomes is the result of interaction between developmental insults and the prevailing environment. Consistent with this premise, recent studies in sheep found prenatal BPA treatment prevented the adverse effects of postnatal obesity in inducing hypertension. The gene networks underlying these complex interactions are not known. mRNA-seq of myocardium was performed on four groups of four female sheep to assess the effects of prenatal BPA exposure, postnatal overfeeding and their interaction on gene transcription, pathway perturbations and functional effects. The effects of prenatal exposure to BPA, postnatal overfeeding, and prenatal BPA with postnatal overfeeding all resulted in transcriptional changes (85-141 significant differentially expressed genes). Although the effects of prenatal BPA and postnatal overfeeding did not involve dysregulation of many of the same genes, they affected a remarkably similar set of biological pathways. Furthermore, an additive or synergistic effect was not found in the combined treatment group, but rather prenatal BPA treatment led to a partial reversal of the effects of overfeeding alone. Many genes previously known to be affected by BPA and involved in obesity, hypertension, or heart disease were altered following these treatments, and AP-1, EGR1, and EGFR were key hubs affected by BPA and/or overfeeding. Environ. Mol. Mutagen. 58:4-18, 2017. © 2016 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

The normative power of food promotions: Australian children's attachments to unhealthy food brands.

PubMed

Kelly, Bridget; Freeman, Becky; King, Lesley; Chapman, Kathy; Baur, Louise A; Gill, Tim

2016-11-01

The formation of food brand associations and attachment is fundamental to brand preferences, which influence purchases and consumption. Food promotions operate through a cascade of links, from brand recognition, to affect, and on to consumption. Frequent exposures to product promotions may establish social norms for products, reinforcing brand affect. These pathways signify potential mechanisms for how children's exposure to unhealthy food promotions can contribute to poor diets. The present study explored children's brand associations and attachments for major food brands. A cross-sectional online survey was conducted. Fourteen study brands were used, with each child viewing a set of seven logos. The questionnaire assessed perceptions of food brands and perceptions of users of brands, using semantic differential scales, and perceived brand 'personalities', using Likert scales. New South Wales, Australia, October-November 2014. Children aged 10-16 years (n 417). Children demonstrated strong positive affect to certain brands, perceiving some unhealthy food brands to have positive attributes, desirable user traits and alignment to their own personality. Brand personality traits of 'smart' and 'sporty' were viewed as indicators of healthiness. Brands with these traits were ranked lower for popularity. Children's brand associations and attachments indicate the potential normative social influences of promotions. While children are aware of brand healthiness as an attribute, this competes with other brand associations, highlighting the challenge of health/nutrition messaging to counter unhealthy food marketing. Restricting children's exposure to unhealthy food marketing and the persuasive nature of marketing is an important part of efforts to improve children's diet-related health.

Salinity-induced inhibition of growth in the aquatic pteridophyte Azolla microphylla primarily involves inhibition of photosynthetic components and signaling molecules as revealed by proteome analysis.

PubMed

Thagela, Preeti; Yadav, Ravindra Kumar; Mishra, Vagish; Dahuja, Anil; Ahmad, Altaf; Singh, Pawan Kumar; Tiwari, Budhi Sagar; Abraham, Gerard

2017-01-01

Salinity stress causes adverse physiological and biochemical changes in the growth and productivity of a plant. Azolla, a symbiotic pteridophyte and potent candidate for biofertilizer due to its nitrogen fixation ability, shows reduced growth and nitrogen fixation during saline stress. To better understand regulatory components involved in salinity-induced physiological changes, in the present study, Azolla microphylla plants were exposed to NaCl (6.74 and 8.61 ds/m) and growth, photochemical reactions of photosynthesis, ion accumulation, and changes in cellular proteome were studied. Maximum dry weight was accumulated in control and untreated plant while a substantial decrease in dry weight was observed in the plants exposed to salinity. Exposure of the organism to different concentrations of salt in hydroponic conditions resulted in differential level of Na + and K + ion accumulation. Comparative analysis of salinity-induced proteome changes in A. microphylla revealed 58 salt responsive proteins which were differentially expressed during the salt exposure. Moreover, 42 % spots among differentially expressed proteins were involved in different signaling events. The identified proteins are involved in photosynthesis, energy metabolism, amino acid biosynthesis, protein synthesis, and defense. Downregulation of these key metabolic proteins appears to inhibit the growth of A. microphylla in response to salinity. Altogether, the study revealed that in Azolla, increased salinity primarily affected signaling and photosynthesis that in turn leads to reduced biomass.

Gene-Specific Differential DNA Methylation and Chronic Arsenic Exposure in an Epigenome-Wide Association Study of Adults in Bangladesh

PubMed Central

Argos, Maria; Chen, Lin; Jasmine, Farzana; Tong, Lin; Pierce, Brandon L.; Roy, Shantanu; Paul-Brutus, Rachelle; Gamble, Mary V.; Harper, Kristin N.; Parvez, Faruque; Rahman, Mahfuzar; Rakibuz-Zaman, Muhammad; Slavkovich, Vesna; Baron, John A.; Graziano, Joseph H.; Kibriya, Muhammad G.

2014-01-01

Background: Inorganic arsenic is one of the most common naturally occurring contaminants found in the environment. Arsenic is associated with a number of health outcomes, with epigenetic modification suggested as a potential mechanism of toxicity. Objective: Among a sample of 400 adult participants, we evaluated the association between arsenic exposure, as measured by blood and urinary total arsenic concentrations, and epigenome-wide white blood cell DNA methylation. Methods: We used linear regression models to examine the associations between arsenic exposure and methylation at each CpG site, adjusted for sex, age, and batch. Differentially methylated loci were subsequently examined in relation to corresponding gene expression for functional evidence of gene regulation. Results: In adjusted analyses, we observed four differentially methylated CpG sites with urinary total arsenic concentration and three differentially methylated CpG sites with blood arsenic concentration, based on the Bonferroni-corrected significance threshold of p < 1 × 10–7. Methylation of PLA2G2C (probe cg04605617) was the most significantly associated locus in relation to both urinary (p = 3.40 × 10–11) and blood arsenic concentrations (p = 1.48 × 10–11). Three additional novel methylation loci—SQSTM1 (cg01225779), SLC4A4 (cg06121226), and IGH (cg13651690)—were also significantly associated with arsenic exposure. Further, there was evidence of methylation-related gene regulation based on gene expression for a subset of differentially methylated loci. Conclusions: We observed significant associations between arsenic exposure and gene-specific differential white blood cell DNA methylation, suggesting that epigenetic modifications may be an important pathway underlying arsenic toxicity. The specific differentially methylated loci identified may inform potential pathways for future interventions. Citation: Argos M, Chen L, Jasmine F, Tong L, Pierce BL, Roy S, Paul-Brutus R, Gamble MV, Harper KN, Parvez F, Rahman M, Rakibuz-Zaman M, Slavkovich V, Baron JA, Graziano JH, Kibriya MG, Ahsan H. 2015. Gene-specific differential DNA methylation and chronic arsenic exposure in an epigenome-wide association study of adults in Bangladesh. Environ Health Perspect 123:64–71; http://dx.doi.org/10.1289/ehp.1307884 PMID:25325195

Effects of radiofrequency exposure emitted from a GSM mobile phone on proliferation, differentiation, and apoptosis of neural stem cells

PubMed Central

Eghlidospour, Mahsa; Ghanbari, Amir

2017-01-01

Due to the importance of neural stem cells (NSCs) in plasticity of the nervous system and treating neurodegenerative diseases, the main goal of this study was to evaluate the effects of radiofrequency radiation emitted from a GSM 900-MHz mobile phone with different exposure duration on proliferation, differentiation and apoptosis of adult murine NSCs in vitro. We used neurosphere assay to evaluate NSCs proliferation, and immunofluorescence assay of neural cell markers to examine NSCs differentiation. We also employed alamarBlue and caspase 3 apoptosis assays to assess harmful effects of mobile phone on NSCs. Our results showed that the number and size of resulting neurospheres and also the percentage of cells differentiated into neurons decreased significantly with increasing exposure duration to GSM 900-MHz radiofrequency (RF)-electromagnetic field (EMF). In contrast, exposure to GSM 900-MHz RF-EMF at different durations did not influence cell viability and apoptosis of NSCs and also their astrocytic differentiation. It is concluded that accumulating dose of GSM 900-MHz RF-EMF might have devastating effects on NSCs proliferation and neurogenesis requiring more causations in terms of using mobile devices. PMID:28713615

Effects of radiofrequency exposure emitted from a GSM mobile phone on proliferation, differentiation, and apoptosis of neural stem cells.

PubMed

Eghlidospour, Mahsa; Ghanbari, Amir; Mortazavi, Seyyed Mohammad Javad; Azari, Hassan

2017-06-01

Due to the importance of neural stem cells (NSCs) in plasticity of the nervous system and treating neurodegenerative diseases, the main goal of this study was to evaluate the effects of radiofrequency radiation emitted from a GSM 900-MHz mobile phone with different exposure duration on proliferation, differentiation and apoptosis of adult murine NSCs in vitro . We used neurosphere assay to evaluate NSCs proliferation, and immunofluorescence assay of neural cell markers to examine NSCs differentiation. We also employed alamarBlue and caspase 3 apoptosis assays to assess harmful effects of mobile phone on NSCs. Our results showed that the number and size of resulting neurospheres and also the percentage of cells differentiated into neurons decreased significantly with increasing exposure duration to GSM 900-MHz radiofrequency (RF)-electromagnetic field (EMF). In contrast, exposure to GSM 900-MHz RF-EMF at different durations did not influence cell viability and apoptosis of NSCs and also their astrocytic differentiation. It is concluded that accumulating dose of GSM 900-MHz RF-EMF might have devastating effects on NSCs proliferation and neurogenesis requiring more causations in terms of using mobile devices.

Environmentally relevant exposure to 17α-ethinylestradiol affects the telencephalic proteome of male fathead minnows

PubMed Central

Martyniuk, Christopher J.; Kroll, Kevin J.; Doperalski, Nicholas J.; Barber, David S.; Denslow, Nancy D.

2010-01-01

Estrogens are key mediators of neuronal processes in vertebrates. As such, xenoestrogens present in the environment have the potential to alter normal central nervous system (CNS) function. The objectives of the present study were 1) to identify proteins with altered expression in the male fathead minnow telencephalon as a result of low level exposure to 17α-ethinylestradiol (EE2), and 2) to better understand the underlying mechanisms of 17β-estradiol (E2) feedback in this important neuroendocrine tissue. Male fathead minnows exposed to a measured concentration of 5.4 ng EE2/L for 48 hours showed decreased plasma E2 levels of approximately 2-fold. Of 77 proteins that were quantified statistically, 14 proteins were down-regulated after EE2 exposure, including four histone proteins, ATP synthase, H+ transporting subunits, and metabolic proteins (lactate dehydrogenase B4, malate dehydrogenase 1b). Twelve proteins were significantly induced by EE2 including microtubule-associated protein tau (MAPT), astrocytic phosphoprotein, ependymin precursor, and calmodulin. MAPT showed an increase in protein abundance but a decrease in mRNA expression after EE2 exposure, suggesting there may be a negative feedback response in the telencephalon to decrease mRNA transcription with increasing MAPT protein abundance. These results demonstrate that a low, environmentally relevant exposure to EE2 can rapidly alter the abundance of proteins involved in cell differentiation and proliferation, neuron network morphology, and long term synaptic potentiation. Together, these findings provide a better understanding of the molecular responses underlying E2 feedback in the brain and demonstrate that quantitative proteomics can be successfully used in ecotoxicology to characterize affected cellular pathways and endocrine physiology. PMID:20381887

Environmentally relevant exposure to 17alpha-ethinylestradiol affects the telencephalic proteome of male fathead minnows.

PubMed

Martyniuk, Christopher J; Kroll, Kevin J; Doperalski, Nicholas J; Barber, David S; Denslow, Nancy D

2010-07-15

Estrogens are key mediators of neuronal processes in vertebrates. As such, xenoestrogens present in the environment have the potential to alter normal central nervous system (CNS) function. The objectives of the present study were (1) to identify proteins with altered abundance in the male fathead minnow telencephalon as a result of low-level exposure to 17alpha-ethinylestradiol (EE(2)), and (2) to better understand the underlying mechanisms of 17beta-estradiol (E(2)) feedback in this important neuroendocrine tissue. Male fathead minnows exposed to a measured concentration of 5.4 ng EE(2)/L for 48 h showed decreased plasma E(2) levels of approximately 2-fold. Of 77 proteins that were quantified statistically, 14 proteins were down-regulated after EE(2) exposure, including four histone proteins, ATP synthase, H+ transporting subunits, and metabolic proteins (lactate dehydrogenase B4, malate dehydrogenase 1b). Twelve proteins were significantly induced by EE(2) including microtubule-associated protein tau (Mapt), astrocytic phosphoprotein, ependymin precursor, and calmodulin. Mapt showed an increase in protein abundance but a decrease in mRNA expression after EE(2) exposure(,) suggesting there may be a negative feedback response in the telencephalon to decreased mRNA transcription with increasing Mapt protein abundance. These results demonstrate that a low, environmentally relevant exposure to EE(2) can rapidly alter the abundance of proteins involved in cell differentiation and proliferation, neuron network morphology, and long-term synaptic potentiation. Together, these findings provide a better understanding of the molecular responses underlying E(2) feedback in the brain and demonstrate that quantitative proteomics can be successfully used in ecotoxicology to characterize affected cellular pathways and endocrine physiology. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Effects of bisphosphonate treatment on DNA methylation in osteonecrosis of the jaw.

PubMed

Polidoro, Silvia; Broccoletti, Roberto; Campanella, Gianluca; Di Gaetano, Cornelia; Menegatti, Elisa; Scoletta, Matteo; Lerda, Ennio; Matullo, Giuseppe; Vineis, Paolo; Berardi, Daniela; Scully, Crispian; Arduino, Paolo G

2013-10-09

Bisphosphonates are used in the treatment of hypocalcaemia, mainly in cancer and osteoporosis. Some patients experience adverse events, such as BP-related osteonecrosis of the jaw (BRONJ). DNA methylation plays a key role in gene regulation in many tissues, but its involvement in bone homeostasis is not well characterized, and no information is available regarding altered methylation in BRONJ. Using the Illumina Infinium HumanMethylation27 BeadChip assay, we performed an epigenome-wide association study in peripheral blood samples from 68 patients treated with nitrogenous BP, including 35 with BRONJ. Analysis of the estimated cumulative BP exposure distribution indicated that the exposure of the case group to BP was slightly higher than that of the control group; more severely affected cases (i.e., with BRONJ in both mandible and maxilla) were significantly more exposed to BP than were those with BRONJ only in the mandible or maxilla (one-sided Wilcoxon rank sum test, p=0.002). Logistic regression analysis confirmed the positive association between cumulative bisphosphonates exposure and risk of BRONJ (OR 1.015 per mg of cumulative exposure, 95% CI 1.004-1.032, p=0.036). Although no statistically significant differences were observed between case and control groups, methylation levels of probes mapping on three genes, ERCC8, LEPREL1 and SDC2, were strongly associated with cumulative BP exposure levels (p<1.31E-007). Enrichment analysis, combining differentially methylated genes with genes involved in the mevalonate pathway, showed that BP treatment can affect the methylation pattern of genes involved in extracellular matrix organization and inflammatory responses, leading to more frequent adverse effects such as BRONJ. Differences in DNA methylation induced by BP treatment could be involved in the pathogenesis of the bone lesion. Copyright © 2013 Elsevier B.V. All rights reserved.

Environmental estrogens alter early development in Xenopus laevis.

PubMed

Bevan, Cassandra L; Porter, Donna M; Prasad, Anita; Howard, Marthe J; Henderson, Leslie P

2003-04-01

A growing number of environmental toxicants found in pesticides, herbicides, and industrial solvents are believed to have deleterious effects on development by disrupting hormone-sensitive processes. We exposed Xenopus laevis embryos at early gastrula to the commonly encountered environmental estrogens nonylphenol, octylphenol, and methoxychlor, the antiandrogen, p,p-DDE, or the synthetic androgen, 17 alpha-methyltestosterone at concentrations ranging from 10 nM to 10 microM and examined them at tailbud stages (approximately 48 hr of treatment). Exposure to the three environmental estrogens, as well as to the natural estrogen 17 beta-estradiol, increased mortality, induced morphologic deformations, increased apoptosis, and altered the deposition and differentiation of neural crest-derived melanocytes in tailbud stage embryos. Although neural crest-derived melanocytes were markedly altered in embryos treated with estrogenic toxicants, expression of the early neural crest maker Xslug, a factor that regulates both the induction and subsequent migration of neural crest cells, was not affected, suggesting that the disruption induced by these compounds with respect to melanocyte development may occur at later stages of their differentiation. Co-incubation of embryos with the pure antiestrogen ICI 182,780 blocked the ability of nonylphenol to induce abnormalities in body shape and in melanocyte differentiation but did not block the effects of methoxychlor. Our data indicate not only that acute exposure to these environmental estrogens induces deleterious effects on early vertebrate development but also that different environmental estrogens may alter the fate of a specific cell type via different mechanisms. Finally, our data suggest that the differentiation of neural crest-derived melanocytes may be particularly sensitive to the disruptive actions of these ubiquitous chemical contaminants.

Transcription profiling of the chilling requirement for bud break in apples: a putative role for FLC-like genes.

PubMed

Porto, Diogo Denardi; Bruneau, Maryline; Perini, Pâmela; Anzanello, Rafael; Renou, Jean-Pierre; dos Santos, Henrique Pessoa; Fialho, Flávio Bello; Revers, Luís Fernando

2015-05-01

Apple production depends on the fulfilment of a chilling requirement for bud dormancy release. Insufficient winter chilling results in irregular and suboptimal bud break in the spring, with negative impacts on apple yield. Trees from apple cultivars with contrasting chilling requirements for bud break were used to investigate the expression of the entire set of apple genes in response to chilling accumulation in the field and controlled conditions. Total RNA was analysed on the AryANE v.1.0 oligonucleotide microarray chip representing 57,000 apple genes. The data were tested for functional enrichment, and differential expression was confirmed by real-time PCR. The largest number of differentially expressed genes was found in samples treated with cold temperatures. Cold exposure mostly repressed expression of transcripts related to photosynthesis, and long-term cold exposure repressed flavonoid biosynthesis genes. Among the differentially expressed selected candidates, we identified genes whose annotations were related to the circadian clock, hormonal signalling, regulation of growth, and flower development. Two genes, annotated as FLOWERING LOCUS C-like and MADS AFFECTING FLOWERING, showed strong differential expression in several comparisons. One of these two genes was upregulated in most comparisons involving dormancy release, and this gene's chromosomal position co-localized with the confidence interval of a major quantitative trait locus for the timing of bud break. These results indicate that photosynthesis and auxin transport are major regulatory nodes of apple dormancy and unveil strong candidates for the control of bud dormancy. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Municipal wastewater affects adipose deposition in male mice and increases 3T3-L1 cell differentiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Biasiotto, Giorgio; Zanella, Isabella; Department of Molecular and Translational Medicine, University of Brescia, Brescia

Trace concentration of EDs (endocrine disrupting compounds) in water bodies caused by wastewater treatment plant effluents is a recognized problem for the health of aquatic organisms and their potential to affect human health. In this paper we show that continuous exposure of male mice from early development to the adult life (140 days) to unrestricted drinking of wastewater collected from a municipal sewage treatment plant, is associated with an increased adipose deposition and weight gain during adulthood because of altered body homeostasis. In parallel, bisphenol A (BPA) at the administration dose of 5 μg/kg/body weight, shows an increasing effect onmore » total body weight and fat mass. In vitro, a solid phase extract (SPE) of the wastewater (eTW), caused stimulation of 3T3-L1 adipocyte differentiation at dilutions of 0.4 and 1 % in the final culture medium which contained a concentration of BPA of 40 nM and 90 nM respectively. Pure BPA also promoted adipocytes differentiation at the concentration of 50 and 80 μM. BPA effect in 3T3-L1 cells was associated to the specific activation of the estrogen receptor alpha (ERα) in undifferentiated cells and the estrogen receptor beta (ERβ) in differentiated cells. BPA also activated the Peroxisome Proliferator Activated Receptor gamma (PPARγ) upregulating a minimal 3XPPARE luciferase reporter and the PPARγ-target promoter of the aP2 gene in adipose cells, while it was not effective in preadipocytes. The pure estrogen receptor agonist diethylstilbestrol (DES) played an opposite action to that of BPA inhibiting PPARγ activity in adipocytes, preventing cell differentiation, activating ERα in preadipocytes and inhibiting ERα and ERβ regulation in adipocytes. The results of this work show that the drinking of chemically-contaminated wastewater promotes fat deposition in male mice and that EDs present in sewage are likely responsible for this effect through a nuclear receptor-mediated mechanism. - Highlights: • Sewage watewaters (TW) sampled from a Municipal Treatment Sewage Plant are biologically active in mice and in vitro. • In male mice TW promotes an increase in adipose mass deposition following exposure from foetal to adult life. A similar effect is produced by BPA. • The expression of key genes of the adipose metabolism is increased in epidydimal fat both by TW and BPA. • An extract from the TW which concentrated the contained chemicals by a factor of 1000, is able to stimulate 3T3-L1 adipocyte differentiation. • The major chemicals contained in the TW, bisphenol A and nonylphenol, are able to promote adipocyte differentiation at the low environmentally relevant doses as are found in the TW.« less

Decreased expression of the stress protein HSP70 is an early event in murine erythroleukemic cell differentiation.

PubMed Central

Hensold, J O; Housman, D E

1988-01-01

Two-dimensional protein gels were used to systematically assess changes in gene expression in Friend erythroleukemia cells after exposure to inducers of differentiation. A rapid decrease in expression of the stress protein HSP70 was observed after exposure to inducers. The kinetics of this change suggest that it may be related to the cellular events that regulate the onset of differentiation. Images PMID:3164440

Adolescent alcohol exposure: Are there separable vulnerable periods within adolescence?

PubMed

Spear, Linda Patia

2015-09-01

There are two key alcohol use patterns among human adolescents that confer increased vulnerability for later alcohol abuse/dependence, along with neurocognitive alterations: (a) early initiation of use during adolescence, and (b) high rates of binge drinking that are particularly prevalent late in adolescence. The central thesis of this review is that lasting neurobehavioral outcomes of these two adolescent exposure patterns may differ. Although it is difficult to disentangle consequences of early use from later binge drinking in human studies given the substantial overlap between groups, these two types of problematic adolescent use are differentially heritable and hence separable to some extent. Although few studies using animal models have manipulated alcohol exposure age, those studies that have have typically observed timing-specific exposure effects, with more marked (or at least different patterns of) lasting consequences evident after exposures during early-mid adolescence than late-adolescence/emerging adulthood, and effects often restricted to male rats in those few instances where sex differences have been explored. As one example, adult male rats exposed to ethanol during early-mid adolescence (postnatal days [P] 25-45) were found to be socially anxious and to retain adolescent-typical ethanol-induced social facilitation into adulthood, effects that were not evident after exposure during late-adolescence/emerging adulthood (P45-65); exposure at the later interval, however, induced lasting tolerance to ethanol's social inhibitory effects that was not evident after exposure early in adolescence. Females, in contrast, were little influenced by ethanol exposure at either interval. Exposure timing effects have likewise been reported following social isolation as well as after repeated exposure to other drugs such as nicotine (and cannabinoids), with effects often, although not always, more pronounced in males where studied. Consistent with these timing-specific exposure effects, notable maturational changes in brain have been observed from early to late adolescence that could provide differential neural substrates for exposure timing-related consequences, with for instance exposure during early adolescence perhaps more likely to impact later self-administration and social/affective behaviors, whereas exposures later in adolescence may be more likely to influence cognitive tasks whose neural substrates (such as the prefrontal cortex [PFC]) are still undergoing maturation at that time. More work is needed, however to characterize timing-specific effects of adolescent ethanol exposures and their sex dependency, determine their neural substrates, and assess their comparability to and interactions with adolescent exposure to other drugs and stressors. Such information could prove critical for informing intervention/prevention strategies regarding the potential efficacy of efforts directed toward delaying onset of alcohol use versus toward reducing high levels of use and risks associated with that use later in adolescence. Copyright © 2015 Elsevier Inc. All rights reserved.

ADOLESCENT ALCOHOL EXPOSURE: ARE THERE SEPARABLE VULNERABLE PERIODS WITHIN ADOLESCENCE?

PubMed Central

Spear, Linda Patia

2015-01-01

There are two key alcohol use patterns among human adolescents that confer increased vulnerability for later alcohol abuse/dependence, along with neurocognitive alterations: (a) early initiation of use during adolescence, and (b) high rates of binge drinking that are particularly prevalent late in adolescence. The central thesis of this review is that lasting neurobehavioral outcomes of these two adolescent exposure patterns may differ. Although it is difficult to disentangle consequences of early use from later binge drinking in human studies given the substantial overlap between groups, these two types of problematic adolescent use are differentially heritable and hence separable to some extent. Although few studies using animal models have manipulated alcohol exposure age, those studies that have have typically observed timing-specific exposure effects, with more marked (or at least different patterns of) lasting consequences evident after exposures during early-mid adolescence than late-adolescence/emerging adulthood, and effects often restricted to male rats in those few instances where sex differences have been explored. As one example, adult male rats exposed to ethanol during early-mid adolescence (postnatal days [P] 25-45) were found to be socially anxious and to retain adolescent-typical ethanol-induced social facilitation into adulthood, effects that were not evident after exposure during late-adolescence/emerging adulthood (P45-65); exposure at the later interval, however, induced lasting tolerance to ethanol's social inhibitory effects that was not evident after exposure early in adolescence. Females, in contrast, were little influenced by ethanol exposure at either interval. Exposure timing effects have likewise been reported following social isolation as well as after repeated exposure to other drugs such as nicotine (and cannabinoids), with effects often, although not always, more pronounced in males where studied. Consistent with these timing-specific exposure effects, notable maturational changes in brain have been observed from early to late adolescence that could provide differential neural substrates for exposure timing-related consequences, with for instance exposure during early adolescence perhaps more likely to impact later self-administration and social/affective behaviors, whereas exposures later in adolescence may be more likely to influence cognitive tasks whose neural substrates (such as the prefrontal cortex [PFC]) are still undergoing maturation at that time. Substantial more work is needed, however to characterize timing-specific effects of adolescent ethanol exposures and their sex dependency, determine their neural substrates, and assess their comparability to and interactions with adolescent exposure to other drugs and stressors. Such information could prove critical for informing intervention/prevention strategies regarding the potential efficacy of efforts directed toward delaying onset of alcohol use versus toward reducing high levels of use and risks associated with that use later in adolescence. PMID:25624108

Monitoring of Commitment, Blocking, and Continuation of Nutrient Germination of Individual Bacillus subtilis Spores

PubMed Central

Zhang, Pengfei; Liang, Jintao; Yi, Xuan; Setlow, Peter

2014-01-01

Short exposures of Bacillus spores to nutrient germinants can commit spores to germinate when germinants are removed or their binding to the spores' nutrient germinant receptors (GRs) is inhibited. Bacillus subtilis spores were exposed to germinants for various periods, followed by germinant removal to prevent further commitment. Release of spore dipicolinic acid (DPA) was then measured by differential interference contrast microscopy to monitor germination of multiple individual spores, and spores did not release DPA after 1 to 2 min of germinant exposure until ∼7 min after germinant removal. With longer germinant exposures, percentages of committed spores with times for completion of DPA release (Trelease) greater than the time of germinant removal (Tb) increased, while the time Tlag − Tb, where Tlag represents the time when rapid DPA release began, was decreased but rapid DPA release times (ΔTrelease = Trelease − Tlag) were increased; Factors affecting average Trelease values and the percentages of committed spores were germinant exposure time, germinant concentration, sporulation conditions, and spore heat activation, as previously shown for commitment of spore populations. Surprisingly, germination of spores given a 2nd short germinant exposure 30 to 45 min after a 1st exposure of the same duration was significantly higher than after the 1st exposure, but the number of spores that germinated in the 2nd germinant exposure decreased as the interval between germinant exposures increased up to 12 h. The latter results indicate that spores have some memory, albeit transient, of their previous exposure to nutrient germinants. PMID:24769693

Caffeine exposure alters cardiac gene expression in embryonic cardiomyocytes

PubMed Central

Fang, Xiefan; Mei, Wenbin; Barbazuk, William B.; Rivkees, Scott A.

2014-01-01

Previous studies demonstrated that in utero caffeine treatment at embryonic day (E) 8.5 alters DNA methylation patterns, gene expression, and cardiac function in adult mice. To provide insight into the mechanisms, we examined cardiac gene and microRNA (miRNA) expression in cardiomyocytes shortly after exposure to physiologically relevant doses of caffeine. In HL-1 and primary embryonic cardiomyocytes, caffeine treatment for 48 h significantly altered the expression of cardiac structural genes (Myh6, Myh7, Myh7b, Tnni3), hormonal genes (Anp and BnP), cardiac transcription factors (Gata4, Mef2c, Mef2d, Nfatc1), and microRNAs (miRNAs; miR208a, miR208b, miR499). In addition, expressions of these genes were significantly altered in embryonic hearts exposed to in utero caffeine. For in utero experiments, pregnant CD-1 dams were treated with 20–60 mg/kg of caffeine, which resulted in maternal circulation levels of 37.3–65.3 μM 2 h after treatment. RNA sequencing was performed on embryonic ventricles treated with vehicle or 20 mg/kg of caffeine daily from E6.5-9.5. Differential expression (DE) analysis revealed that 124 genes and 849 transcripts were significantly altered, and differential exon usage (DEU) analysis identified 597 exons that were changed in response to prenatal caffeine exposure. Among the DE genes identified by RNA sequencing were several cardiac structural genes and genes that control DNA methylation and histone modification. Pathway analysis revealed that pathways related to cardiovascular development and diseases were significantly affected by caffeine. In addition, global cardiac DNA methylation was reduced in caffeine-treated cardiomyocytes. Collectively, these data demonstrate that caffeine exposure alters gene expression and DNA methylation in embryonic cardiomyocytes. PMID:25354728

Pulmonary function, bronchial reactivity, and epithelial permeability are response phenotypes to ozone and develop differentially in healthy humans.

PubMed

Que, Loretta G; Stiles, Jane V; Sundy, John S; Foster, W Michael

2011-09-01

Effect of laboratory exposure to O₃ (220 ppb) and filtered air (FA) on respiratory physiology were evaluated at two time points (acute and 1 day postexposure) in healthy cohort (n = 138, 18-35 yr, 40% women) comprised mainly of Caucasian (60%) and African American (33.3%) subjects. Randomized exposures had a crossover design and durations of 2.25 h that included rest and treadmill walking. Airway responsiveness (AHR) to methacholine (Mch) and permeability of respiratory epithelium (EI) to hydrophilic radiomarker ((99m)Tc-DTPA, MW = 492), were measured at 1-day postexposure. O₃ significantly affected FEV₁ and FVC indices acutely with mean decrements from pre-exposure values on the order of 7.7 to 8.8% and 1.8 to 2.3% at 1-day post. Acute FEV₁ and FVC decreases were most robust in African American male subjects. At 1-day post, O₃ induced significant changes in AHR (slope of Mch dose response curve) and EI (Tc(99m)-DTPA clearance half-time). Based on conventional thresholds of response and dichotomous classification of subjects as responders and nonresponders, sensitivity to O₃ was shown to be nonuniform. Acute decrements ≥ 15% in FEV₁, a doubling of Mch slope, or ≥ 15% increase in EI developed in 20.3%, 23.1%, and 25.9%, respectively, of subjects evaluated. Results demonstrate a diffuse sensitivity to O₃ and physiological responses, either acutely (decreases in FEV₁) or 1 day post (development of AHR or change in EI) occur differentially in healthy young adults. Random overlap among subjects classified as responsive for respective FEV₁, AHR, and EI endpoints suggests these are separate and independent phenotypes of O₃ exposure.

Pulmonary function, bronchial reactivity, and epithelial permeability are response phenotypes to ozone and develop differentially in healthy humans

PubMed Central

Que, Loretta G.; Stiles, Jane V.; Sundy, John S.

2011-01-01

Effect of laboratory exposure to O3 (220 ppb) and filtered air (FA) on respiratory physiology were evaluated at two time points (acute and 1 day postexposure) in healthy cohort (n = 138, 18–35 yr, 40% women) comprised mainly of Caucasian (60%) and African American (33.3%) subjects. Randomized exposures had a crossover design and durations of 2.25 h that included rest and treadmill walking. Airway responsiveness (AHR) to methacholine (Mch) and permeability of respiratory epithelium (EI) to hydrophilic radiomarker (99mTc-DTPA, MW = 492), were measured at 1-day postexposure. O3 significantly affected FEV1 and FVC indices acutely with mean decrements from pre-exposure values on the order of 7.7 to 8.8% and 1.8 to 2.3% at 1-day post. Acute FEV1 and FVC decreases were most robust in African American male subjects. At 1-day post, O3 induced significant changes in AHR (slope of Mch dose response curve) and EI (Tc99m-DTPA clearance half-time). Based on conventional thresholds of response and dichotomous classification of subjects as responders and nonresponders, sensitivity to O3 was shown to be nonuniform. Acute decrements ≥15% in FEV1, a doubling of Mch slope, or ≥15% increase in EI developed in 20.3%, 23.1%, and 25.9%, respectively, of subjects evaluated. Results demonstrate a diffuse sensitivity to O3 and physiological responses, either acutely (decreases in FEV1) or 1 day post (development of AHR or change in EI) occur differentially in healthy young adults. Random overlap among subjects classified as responsive for respective FEV1, AHR, and EI endpoints suggests these are separate and independent phenotypes of O3 exposure. PMID:21700892

Differential expression of the phthalate syndrome in male Sprague-Dawley and Wistar rats after in utero DEHP exposure

EPA Science Inventory

Exposure to phthalate esters during sexual differentiation disrupts testosterone and insulin-like three hormones resulting in malformations of androgen- and insulin-like three-dependent tissues. The current study was designed to test the hypothesis that gubernacular lesions would...

A NOVEL EFFECT OF DIOXIN: EXPOSURE DURING PREGNANCY SEVERELY IMPAIRS MAMMARY GLAND DIFFERENTIATION

EPA Science Inventory

A novel effect of dioxin: Exposure during pregnancy severely impairs mammary gland differentiation.
Beth A. Vorderstrasse1, Suzanne E. Fenton2, Andrea A. Bohn3, Jennifer A. Cundiff1, and B. Paige Lawrence1,3,4 1Department of Pharmaceutical Sciences, Washington State Universi...

PERINATAL EXPOSURE TO THE PHTHALATES DEHP, BBP AND DINP, BUT NOT DEP, DMP OR DOTP ALTERS SEXUAL DIFFERENTIATION OF THE MALE RAT

EPA Science Inventory

In mammals, exposure to antiandrogenic chemicals during sexual differentiation can produce malformations of the reproductive tract. Perinatal administration of AR antagonists like vinclozolin and procymidone or chemicals like di (2-bis) ethylhexyl phthalate (DEHP), that inhibit ...

Effect of Environmental Chemical Exposures on Adult Human Cardiac Progenitor Cell Viability and Differentiation

EPA Science Inventory

Cell biology has revealed that the adult heart is not a terminally differentiated organ but is capable of generating new cardiomyocytes (CMs) from cardiac stem cells (CSC) and/or progenitor cells (CPC) throughout life. The impact that environmental chemical exposures have on adul...

Biochemical and electrophysiological differentiation profile of a human neuroblastoma (IMR-32) cell line.

PubMed

Rao, Raj R; Kisaalita, William S

2002-09-01

A human neuroblastoma cell line (IMR-32), when differentiated, mimics large projections of the human cerebral cortex and under certain tissue culture conditions, forms intracellular fibrillary material, commonly observed in brains of patients affected with Alzheimer's disease. Our purpose is to use differentiated IMR-32 cells as an in vitro system for magnetic field exposure studies. We have previously studied in vitro differentiation of murine neuroblastoma (N1E-115) cells with respect to resting membrane potential development. The purpose of this study was to extend our investigation to IMR-32 cells. Electrophysiological (resting membrane potential, V(m)) and biochemical (neuron-specific enolase activity [NSE]) measurements were taken every 2 d for a period of 16 d. A voltage-sensitive oxonol dye together with flow cytometry was used to measure relative changes in V(m). To rule out any effect due to mechanical cell detachment, V(m) was indirectly measured by using a slow potentiometric dye (tetramethylrhodamine methyl ester) together with confocal digital imaging microscopy. Neuron-specific enolase activity was measured by following the production of phosphoenolpyruvate from 2-phospho-d-glycerate at 240 nm. Our results indicate that in IMR-32, in vitro differentiation as characterized by an increase in NSE activity is not accompanied by resting membrane potential development. This finding suggests that pathways for morphological-biochemical and electrophysiological differentiations in IMR-32 cells are independent of one another.

Aberrant epithelial differentiation by cigarette smoke dysregulates respiratory host defence.

PubMed

Amatngalim, Gimano D; Schrumpf, Jasmijn A; Dishchekenian, Fernanda; Mertens, Tinne C J; Ninaber, Dennis K; van der Linden, Abraham C; Pilette, Charles; Taube, Christian; Hiemstra, Pieter S; van der Does, Anne M

2018-04-01

It is currently unknown how cigarette smoke-induced airway remodelling affects highly expressed respiratory epithelial defence proteins and thereby mucosal host defence.Localisation of a selected set of highly expressed respiratory epithelial host defence proteins was assessed in well-differentiated primary bronchial epithelial cell (PBEC) cultures. Next, PBEC were cultured at the air-liquid interface, and during differentiation for 2-3 weeks exposed daily to whole cigarette smoke. Gene expression, protein levels and epithelial cell markers were subsequently assessed. In addition, functional activities and persistence of the cigarette smoke-induced effects upon cessation were determined.Expression of the polymeric immunoglobulin receptor, secretory leukocyte protease inhibitor and long and short PLUNC (palate, lung and nasal epithelium clone protein) was restricted to luminal cells and exposure of differentiating PBECs to cigarette smoke resulted in a selective reduction of the expression of these luminal cell-restricted respiratory host defence proteins compared to controls. This reduced expression was a consequence of cigarette smoke-impaired end-stage differentiation of epithelial cells, and accompanied by a significant decreased transepithelial transport of IgA and bacterial killing.These findings shed new light on the importance of airway epithelial cell differentiation in respiratory host defence and could provide an additional explanation for the increased susceptibility of smokers and patients with chronic obstructive pulmonary disease to respiratory infections. Copyright ©ERS 2018.

Windows of susceptibility and consequences of early life exposures to 17β–estradiol on medaka (Oryzias latipes) reproductive success

USGS Publications Warehouse

Lee Pow, Crystal S. D.; Tilahun, Kedamawit; Creech, Kari; Law, J. Mac; Cope, W. Gregory; Kwak, Thomas J.; Rice, James A.; Aday, D. Derek; Kullman, Seth W.

2017-01-01

Estrogens and estrogen mimics are commonly found in surface waters and are associated with deleterious effects in fish populations. Impaired fertility and fecundity in fish following chronic exposures to estrogens and estrogen mimics during critical windows in development are well documented. However, information regarding differential reproductive effects of exposure within defined developmental stages remains sparse. In this study, reproductive capacity was assessed in Japanese medaka (Oryzias latipes) after exposure to two concentrations of 17β–estradiol (E2β; 2 ng/L and 50 ng/L) during four distinct stages of development: gonad development, gonad differentiation, development of secondary sex characteristics (SSC) and gametogenesis. Exposure to E2β did not adversely impact survival, hatch success, growth, or genotypic ratios. In contrast, exposure to 50 ng/L E2β during SSC development altered phenotypic ratios and SSC. Exposure to both E2β treatments reduced reproductive capacity (fertility, fecundity) by 7.3–57.4% in adult medaka breeding pairs, with hindrance of SSC development resulting in the largest disruption in breeding capacity (51.6–57.4% decrease) in the high concentration. This study documents differential effects among four critical stages of development and provides insight into factors (window of exposure, exposure concentration and duration of exposure period) contributing to reproductive disruption in fish.

Direct exposure to mild heat promotes proliferation and neuronal differentiation of neural stem/progenitor cells in vitro

PubMed Central

Hossain, Md Emon; Katakura, Masanori; Sugimoto, Naotoshi; Mamun, Abdullah Al; Islam, Rafiad; Hashimoto, Michio; Shido, Osamu

2017-01-01

Heat acclimation in rats is associated with enhanced neurogenesis in thermoregulatory centers of the hypothalamus. To elucidate the mechanisms for heat acclimation, we investigated the effects of direct mild heat exposure on the proliferation and differentiation of neural stem/progenitor cells (NSCs/NPCs). The NSCs/NPCs isolated from forebrain cortices of 14.5-day-old rat fetuses were propagated as neurospheres at either 37.0°C (control) or 38.5°C (mild heat exposure) for four days, and the effects on proliferation were investigated by MTS cell viability assay, measurement of neurosphere diameter, and counting the total number of cells. The mRNA expressions of heat shock proteins (HSPs) and brain-derived neurotrophic factor (BDNF), cAMP response element-binding (CREB) protein and Akt phosphorylation levels, and intracellular reactive oxygen species (ROS) levels were analyzed using real time PCR, Western blotting and CM-H2DCFDA assay respectively. Heat exposure under proliferation condition increased NSC/NPC viability, neurosphere diameter, and cell count. BDNF mRNA expression, CREB phosphorylation, and ROS level were also increased by heat exposure. Heat exposure increased HSP27 mRNA expression concomitant with enhanced p-Akt level. Moreover, treatment with LY294002 (a PI3K inhibitor) abolished the effects of heat exposure on NSC/NPC proliferation. Furthermore, heat exposure under differentiation conditions increased the proportion of cells positive for Tuj1 (a neuronal marker). These findings suggest that mild heat exposure increases NSC/NPC proliferation, possibly through activation of the Akt pathway, and also enhances neuronal differentiation. Direct effects of temperature on NSCs/NPCs may be one of the mechanisms involved in hypothalamic neurogenesis in heat-acclimated rats. Such heat-induced neurogenesis could also be an effective therapeutic strategy for neurodegenerative diseases. PMID:29287093

Prenatal Exposure to Urban Air Nanoparticles in Mice Causes Altered Neuronal Differentiation and Depression-Like Responses

PubMed Central

Godar, Sean C.; Sander, Thomas K.; Iwata, Nahoko; Pakbin, Payam; Shih, Jean C.; Berhane, Kiros; McConnell, Rob; Sioutas, Constantinos

2013-01-01

Emerging evidence suggests that excessive exposure to traffic-derived air pollution during pregnancy may increase the vulnerability to neurodevelopmental alterations that underlie a broad array of neuropsychiatric disorders. We present a mouse model for prenatal exposure to urban freeway nanoparticulate matter (nPM). In prior studies, we developed a model for adult rodent exposure to re-aerosolized urban nPM which caused inflammatory brain responses with altered neuronal glutamatergic functions. nPMs are collected continuously for one month from a local freeway and stored as an aqueous suspension, prior to re-aerosolization for exposure of mice under controlled dose and duration. This paradigm was used for a pilot study of prenatal nPM impact on neonatal neurons and adult behaviors. Adult C57BL/6J female mice were exposed to re-aerosolized nPM (350 µg/m3) or control filtered ambient air for 10 weeks (3×5 hour exposures per week), encompassing gestation and oocyte maturation prior to mating. Prenatal nPM did not alter litter size, pup weight, or postnatal growth. Neonatal cerebral cortex neurons at 24 hours in vitro showed impaired differentiation, with 50% reduction of stage 3 neurons with long neurites and correspondingly more undifferentiated neurons at Stages 0 and 1. Neuron number after 24 hours of culture was not altered by prenatal nPM exposure. Addition of exogenous nPM (2 µg/ml) to the cultures impaired pyramidal neuron Stage 3 differentiation by 60%. Adult males showed increased depression-like responses in the tail-suspension test, but not anxiety-related behaviors. These pilot data suggest that prenatal exposure to nPM can alter neuronal differentiation with gender-specific behavioral sequelae that may be relevant to human prenatal exposure to urban vehicular aerosols. PMID:23734187

Exposure to violence predicts poor educational outcomes in young children in South Africa and Malawi

PubMed Central

Sherr, L.; Hensels, I. S.; Skeen, S.; Tomlinson, M.; Roberts, K. J.; Macedo, A.

2016-01-01

Background Violence during childhood may affect short and long-term educational factors. There is scant literature on younger children from resource poor settings. Methods This study assessed child violence experiences (harsh punishment and exposure to domestic or community violence) and school enrolment, progress and attendance in children attending community-based organisations in South Africa and Malawi (n=989) at baseline and at 15 months' follow-up, examining differential experience of HIV positive, HIV affected and HIV unaffected children. Results Violence exposure was high: 45.4% experienced some form of psychological violence, 47.8% physical violence, 46.7% domestic violence and 41.8% community violence. Primary school enrolment was 96%. Violence was not associated with school enrolment at baseline but, controlling for baseline, children exposed to psychological violence for discipline were more than ten times less likely to be enrolled at follow-up (OR 0.09; 95% CI 0.01 to 0.57). Harsh discipline was associated with poor school progress. For children HIV positive a detrimental effect of harsh physical discipline was found on school performance (OR 0.10; 95% CI 0.02 to 0.61). Conclusion Violence experiences were associated with a number of educational outcomes, which may have long-term consequences. Community-based organisations may be well placed to address such violence, with a particular emphasis on the challenges faced by children who are HIV positive. PMID:26678567

Brief exposure to methamphetamine (METH) and phencyclidine (PCP) during late development leads to long-term learning deficits in rats.

PubMed

White, Ilsun M; Minamoto, Takehiro; Odell, Joseph R; Mayhorn, Joseph; White, Wesley

2009-04-17

Exposure to methamphetamine (METH) and phencyclidine (PCP) during early development is thought to produce later behavioral deficits. We postulated that exposure to METH and PCP during later development would produce similar behavioral deficits, particularly learning deficits in adulthood. Wistar rats were treated with METH (9 mg/kg), PCP (9 mg/kg), or saline during later development, postnatal days (PD) 50-51, and subsequent behavioral changes were examined including: locomotor activity during the acute drug state (PD 50-51) and the post-drug phase (PD 50-80); social interaction on PD 54-80; and spatial discrimination and reversal in adulthood (after PD 90). METH and PCP differentially affected locomotion during the acute state, but not during the post-drug phase. METH decreased social interaction throughout tests two weeks after drug treatment, whereas PCP decreased social interaction only during the first 8 min of tests. Neither METH nor PCP impaired initial acquisition of spatial discrimination. However, reversal was significantly impaired by PCP, whereas METH produced a mild deficit, compared to controls. Our data provide evidence that exposure to PCP and METH during later development lead to enduring cognitive deficits in adulthood. Selective impairment of reversal may reflect neurological damage in the prefrontal cortex due to early exposure to drugs.

Is There a Critical Period for the Developmental Neurotoxicity of Low-Level Tobacco Smoke Exposure?

PubMed

Slotkin, Theodore A; Stadler, Ashley; Skavicus, Samantha; Card, Jennifer; Ruff, Jonathan; Levin, Edward D; Seidler, Frederic J

2017-01-01

Secondhand tobacco smoke exposure in pregnancy increases the risk of neurodevelopmental disorders. We evaluated in rats whether there is a critical period during which tobacco smoke extract (TSE) affects the development of acetylcholine and serotonin systems, prominent targets for adverse effects of nicotine and tobacco smoke. We simulated secondhand smoke exposure by administering TSE so as to produce nicotine concentrations one-tenth those in active smoking, with 3 distinct, 10-day windows: premating, early gestation or late gestation. We conducted longitudinal evaluations in multiple brain regions, starting in early adolescence (postnatal day 30) and continued to full adulthood (day 150). TSE exposure in any of the 3 windows impaired presynaptic cholinergic activity, exacerbated by a decrement in nicotinic cholinergic receptor concentrations. Although the adverse effects were seen for all 3 treatment windows, there was a distinct progression, with lowest sensitivity for premating exposure and higher sensitivity for gestational exposures. Serotonin receptors were also reduced by TSE exposure with the same profile: little effect with premating exposure, intermediate effect with early gestational exposure and large effect with late gestational exposure. As serotonergic circuits can offset the neurobehavioral impact of cholinergic deficits, these receptor changes were maladaptive. Thus, there is no single 'critical period' for effects of low-level tobacco smoke but there is differential sensitivity dependent upon the developmental stage at the time of exposure. Our findings reinforce the need to avoid secondhand smoke exposure not only during pregnancy, but also in the period prior to conception, or generally for women of childbearing age. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Are newborn rat-derived neural stem cells more sensitive to lead neurotoxicity?★

PubMed Central

Chan, Yan Ho; Gao, Mingyong; Wu, Wutian

2013-01-01

Lead ion (Pb2+) has been proven to be a neurotoxin due to its neurotoxicity on mammalian nervous system, especially for the developing brains of juveniles. However, many reported studies involved the negative effects of Pb2+ on adult neural cells of humans or other mammals, only few of which have examined the effects of Pb2+ on neural stem cells. The purpose of this study was to reveal the biological effects of Pb2+ from lead acetate [Pb (CH3COO)2] on viability, proliferation and differentiation of neural stem cells derived from the hippocampus of newborn rats aged 7 days and adult rats aged 90 days, respectively. This study was carried out in three parts. In the first part, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT viability assay) was used to detect the effects of Pb2+ on the cell viability of passage 2 hippocampal neural stem cells after 48-hour exposure to 0–200 μM Pb2+. In the second part, 10 μM bromodeoxyuridine was added into the culture medium of passage 2 hippocampal neural stem cells after 48-hour exposure to 0–200 μM Pb2+, followed by immunocytochemical staining with anti-bromodeoxyuridine to demonstrate the effects of Pb2+ on cell proliferation. In the last part, passage 2 hippocampal neural stem cells were allowed to grow in the differentiation medium with 0–200 μM Pb2+. Immunocytochemical staining with anti-microtubule-associated protein 2 (a neuron marker), anti-glial fibrillary acidic protein (an astrocyte marker), and anti-RIP (an oligodendrocyte marker) was performed to detect the differentiation commitment of affected neural stem cells after 6 days. The data showed that Pb2+ inhibited not only the viability and proliferation of rat hippocampal neural stem cells, but also their neuronal and oligodendrocyte differentiation in vitro. Moreover, increased activity of astrocyte differentiation of hippocampal neural stem cells from both newborn and adult rats was observed after exposure to high concentration of lead ion in vitro. These findings suggest that hippocampal neural stem cells of newborn rats were more sensitive than those from adult rats to Pb2+ cytotoxicity. PMID:25206702

Xenotransplantation as a model for human testicular development.

PubMed

Hutka, Marsida; Smith, Lee B; Mitchell, Rod T

The developing male reproductive system may be sensitive to disruption by a wide range of exogenous 'endocrine disruptors'. In-utero exposure to environmental chemicals and pharmaceuticals have been hypothesized to have an impact in the increasing incidence of male reproductive disorders. The vulnerability to adverse effects as a consequence of such exposures is elevated during a specific 'window of susceptibility' in fetal life referred to as the masculinisation programing window (MPW). Exposures that occur during prepuberty, such as chemotherapy treatment for cancer during childhood, may also affect future fertility. Much of our current knowledge about fetal and early postnatal human testicular development derives from studies conducted in animal models predictive for humans. Therefore, over recent years, testicular transplantation has been employed as a 'direct' approach to understand the development of human fetal and prepubertal testis in health and disease. In this review we describe the potential use of human testis xenotransplantation to study testicular development and its application for (i) assessing the effects of environmental exposures in humans, and (ii) establishing fertility preservation options for prepubertal boys with cancer. Copyright © 2017 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

Chronic neonicotinoid pesticide exposure and parasite stress differentially affects learning in honeybees and bumblebees

PubMed Central

2016-01-01

Learning and memory are crucial functions which enable insect pollinators to efficiently locate and extract floral rewards. Exposure to pesticides or infection by parasites may cause subtle but ecologically important changes in cognitive functions of pollinators. The potential interactive effects of these stressors on learning and memory have not yet been explored. Furthermore, sensitivity to stressors may differ between species, but few studies have compared responses in different species. Here, we show that chronic exposure to field-realistic levels of the neonicotinoid clothianidin impaired olfactory learning acquisition in honeybees, leading to potential impacts on colony fitness, but not in bumblebees. Infection by the microsporidian parasite Nosema ceranae slightly impaired learning in honeybees, but no interactive effects were observed. Nosema did not infect bumblebees (3% infection success). Nevertheless, Nosema-treated bumblebees had a slightly lower rate of learning than controls, but faster learning in combination with neonicotinoid exposure. This highlights the potential for complex interactive effects of stressors on learning. Our results underline that one cannot readily extrapolate findings from one bee species to others. This has important implications for regulatory risk assessments which generally use honeybees as a model for all bees. PMID:27053744

Memantine, an Antagonist of the NMDA Glutamate Receptor, Affects Cell Proliferation, Differentiation and the Intracellular Cycle and Induces Apoptosis in Trypanosoma cruzi

PubMed Central

Damasceno, Flávia Silva; Barisón, María Julia; Pral, Elisabeth Mieko Furusho; Paes, Lisvane Silva; Silber, Ariel Mariano

2014-01-01

Chagas' disease is caused by the protozoan parasite Trypanosoma cruzi and affects approximately 10 million people in endemic areas of Mexico and Central and South America. Currently available chemotherapies are limited to two compounds: Nifurtimox and Benznidazole. Both drugs reduce the symptoms of the disease and mortality among infected individuals when used during the acute phase, but their efficacy during the chronic phase (during which the majority of cases are diagnosed) remains controversial. Moreover, these drugs have several side effects. The aim of this study was to evaluate the effect of Memantine, an antagonist of the glutamate receptor in the CNS of mammals, on the life cycle of T. cruzi. Memantine exhibited a trypanocidal effect, inhibiting the proliferation of epimastigotes (IC50 172.6 µM). Furthermore, this compound interfered with metacyclogenesis (approximately 30% reduction) and affected the energy metabolism of the parasite. In addition, Memantine triggered mechanisms that led to the apoptosis-like cell death of epimastigotes, with extracellular exposure of phosphatidylserine, increased production of reactive oxygen species, decreased ATP levels, increased intracellular Ca2+ and morphological changes. Moreover, Memantine interfered with the intracellular cycle of the parasite, specifically the amastigote stage (IC50 31 µM). Interestingly, the stages of the parasite life cycle that require more energy (epimastigote and amastigote) were more affected as were the processes of differentiation and cell invasion. PMID:24587468

Low-dose benzo(a)pyrene and its epoxide metabolite inhibit myogenic differentiation in human skeletal muscle-derived progenitor cells.

PubMed

Chiu, Chen-Yuan; Yen, Yuan-Peng; Tsai, Keh-Sung; Yang, Rong-Sen; Liu, Shing-Hwa

2014-04-01

The risk of low birth weights is elevated in prenatal exposure to polycyclic aromatic hydrocarbons (PAHs), which are ubiquitous environmental pollutants generated from combustion of organic compounds, including cigarette smoke. We hypothesized that benzo(a)pyrene (BaP), a member of PAHs existing in cigarette smoke, may affect the myogenesis to cause low birth weights. We investigated the effects of BaP and its main metabolite, benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), on the myogenic differentiation of human skeletal muscle-derived progenitor cells (HSMPCs). HSMPCs were isolated by a modified preplate technique and cultured in myogenic differentiation media with or without BaP and BPDE (0.25 and 0.5 μM) for 4 days. The multinucleated myotube formation was morphologically analyzed by hematoxylin and eosin staining. The expressions of myogenic differentiation markers and related signaling proteins were determined by Western blotting. Both BaP and BPDE at the submicromolar concentrations (0.25 and 0.5 μM) dose-dependently repressed HSMPCs myogenic differentiation without obvious cell toxicity. Both BaP and BPDE inhibited the muscle-specific protein expressions (myogenin and myosin heavy chain) and phosphorylation of Akt (a known modulator in myogenesis), which could be significantly reversed by the inhibitors for aryl hydrocarbon receptor (AhR), estrogen receptor (ER), and nuclear factor (NF)-κB. BaP- and BPDE-activated NF-κB-p65 protein phosphorylation could also be attenuated by both AhR and ER inhibitors. The inhibitory effects of BaP and BPDE on myogenesis were reversed after withdrawing BaP exposure, but not after BPDE withdrawal. These results suggest that both BaP and BPDE are capable of inhibiting myogenesis via an AhR- or/and ER-regulated NF-κB/Akt signaling pathway.

Changes in Ca(2+) channel expression upon differentiation of SN56 cholinergic cells.

PubMed

Kushmerick, C; Romano-Silva, M A; Gomez, M V; Prado, M A

2001-10-19

The SN56 cell line, a fusion of septal neurons and neuroblastoma cells, has been used as a model for central cholinergic neurons. These cells show increased expression of cholinergic neurochemical features upon differentiation, but little is known about how differentiation affects their electrophysiological properties. We examined the changes in Ca(2+) channel expression that occur as these cells undergo morphological differentiation in response to serum withdrawal and exposure to dibutyryl-cAMP. Undifferentiated cells expressed a T-type current with biophysical and pharmacological properties similar, although not identical, to those reported for the current generated by the alpha(1H) (CaV3.2) Ca(2+) channel subunit. Differentiated cells expressed, in addition to this T-type current, high voltage activated currents which were inhibited 38% by the L-type channel antagonist nifedipine (5 microM), 37% by the N-type channel antagonist omega-conotoxin-GVIA (1 microM), and 15% by the P/Q-type channel antagonist omega-agatoxin-IVA (200 nM). Current resistant to these inhibitors accounted for 15% of the high voltage activated current in differentiated SN56 cells. Our data demonstrate that differentiation increases the expression of neuronal type voltage gated Ca(2+) channels in this cell line, and that the channels expressed are comparable to those reported for native basal forebrain cholinergic neurons. This cell line should thus provide a useful model system to study the relationship between calcium currents and cholinergic function and dysfunction.

Differential Effects of 5-HTTLPR Genotypes on Inhibition of Negative Emotional Information Following Acute Stress Exposure and Tryptophan Challenge

PubMed Central

Markus, C Rob; De Raedt, Rudi

2011-01-01

Previous data suggest that a polymorphism at the serotonin (5-HT) transporter gene (5-HTTLPR) may influence stress resilience and stress-related depression symptoms due to interactions between brain 5-HT dysfunction and stress exposure. Although attentional bias for emotional information has been reliably observed in depression, the interaction between 5-HT transporter-linked promoter region (5-HTTLPR), brain 5-HT vulnerability, and acute stress on affective information processing has not yet been investigated. This study examines the effects of tryptophan (TRP) augmentation (indicating 5-HT manipulation) on inhibition of negative emotional information under stress in mainly female S′/S′- vs L′/L′-allele carriers. A total of 15 female homozygotic short-allele 5-HTTLPR (S′/S′=S/S, S/LG, LG/LG) and 13 female homozygotic long-allele 5-HTTLPR (L′/L′=LA/LA) subjects were tested for mood and inhibition of emotional information in a double-blind, placebo-controlled design before and after stress exposure following TRP manipulation. Stress exposure significantly impaired inhibition of negative affective information only in S′/S′ carriers, whereas L′/L′ carriers even showed increased inhibition of negative information. The S′/S′ allele 5-HTTLPR genotype increases cognitive-attentional bias for negative emotional information under acute stress. As this bias is an important component of depression, this may be a mediating mechanism making S′/S′-allele carriers more vulnerability for stress-induced depression symptoms. Moreover, current data suggest that L′/L′-allele genotypes are more resilient, even increasing cognitive emotional (inhibitory) control after stress. PMID:21150915

Differential effects of 5-HTTLPR genotypes on inhibition of negative emotional information following acute stress exposure and tryptophan challenge.

PubMed

Markus, C Rob; De Raedt, Rudi

2011-03-01

Previous data suggest that a polymorphism at the serotonin (5-HT) transporter gene (5-HTTLPR) may influence stress resilience and stress-related depression symptoms due to interactions between brain 5-HT dysfunction and stress exposure. Although attentional bias for emotional information has been reliably observed in depression, the interaction between 5-HT transporter-linked promoter region (5-HTTLPR), brain 5-HT vulnerability, and acute stress on affective information processing has not yet been investigated. This study examines the effects of tryptophan (TRP) augmentation (indicating 5-HT manipulation) on inhibition of negative emotional information under stress in mainly female S'/S'- vs L'/L'-allele carriers. A total of 15 female homozygotic short-allele 5-HTTLPR (S'/S'=S/S, S/L(G), L(G)/L(G)) and 13 female homozygotic long-allele 5-HTTLPR (L'/L'=L(A)/L(A)) subjects were tested for mood and inhibition of emotional information in a double-blind, placebo-controlled design before and after stress exposure following TRP manipulation. Stress exposure significantly impaired inhibition of negative affective information only in S'/S' carriers, whereas L'/L' carriers even showed increased inhibition of negative information. The S'/S' allele 5-HTTLPR genotype increases cognitive-attentional bias for negative emotional information under acute stress. As this bias is an important component of depression, this may be a mediating mechanism making S'/S'-allele carriers more vulnerability for stress-induced depression symptoms. Moreover, current data suggest that L'/L'-allele genotypes are more resilient, even increasing cognitive emotional (inhibitory) control after stress.

Exposure to a Highly Caloric Palatable Diet during the Perinatal Period Affects the Expression of the Endogenous Cannabinoid System in the Brain, Liver and Adipose Tissue of Adult Rat Offspring

PubMed Central

Ramírez-López, María Teresa; Arco, Raquel; Decara, Juan; Vázquez, Mariam; Noemí Blanco, Rosario; Alén, Francisco; Suárez, Juan; Gómez de Heras, Raquel

2016-01-01

Recent studies have linked gestational exposure to highly caloric diets with a disrupted endogenous cannabinoid system (ECS). In the present study, we have extended these studies by analyzing the impact of the exposure to a palatable diet during gestation and lactation on a) the adult expression of endocannabinoid-related behaviors, b) the metabolic profile of adult offspring and c) the mRNA expression of the signaling machinery of the ECS in the hypothalamus, the liver and the adipose tissue of adult offspring of both sexes. Exposure to a palatable diet resulted in a) sex-dimorphic and perinatal diet specific feeding behaviors, including the differential response to the inhibitory effects of the cannabinoid receptor inverse agonist AM251, b) features of metabolic syndrome including increased adiposity, hyperleptinemia, hypertriglyceridemia and hypercholesterolemia and c) tissue and sex-specific changes in the expression of both CB1 and CB2 receptors and in that of the endocannabinoid-degrading enzymes FAAH and MAGL, being the adipose tissue the most affected organ analyzed. Since the effects were observed in adult animals that were weaned while consuming a normal diet, the present results indicate that the ECS is one of the targets of maternal programming of the offspring energy expenditure. These results clearly indicate that the maternal diet has long-term effects on the development of pups through multiple alterations of signaling homeostatic pathways that include the ECS. The potential relevance of these alterations for the current obesity epidemic is discussed. PMID:27806128

Listeria monocytogenes grown at 7° C shows reduced acid survival and an altered transcriptional response to acid shock compared to L. monocytogenes grown at 37° C.

PubMed

Ivy, R A; Wiedmann, M; Boor, K J

2012-06-01

Survival of the food-borne pathogen Listeria monocytogenes in acidic environments (e.g., in the human stomach) is vital to its transmission. Refrigerated, ready-to-eat foods have been sources of listeriosis outbreaks. The purpose of this study was to determine whether growth at a low temperature (i.e., 7°C) affects L. monocytogenes survival or gene transcription after exposure to a simulated gastric environment (i.e., acid shock at 37°C). L. monocytogenes cells grown at 7°C were less resistant to artificial gastric fluid (AGF) or acidified brain heart infusion broth (ABHI) than bacteria grown at higher temperatures (i.e., 30°C or 37°C). For L. monocytogenes grown at 7°C, stationary-phase cells were more resistant to ABHI than log-phase cells, indicating that both temperature and growth phase affect acid survival. Microarray transcriptomic analysis revealed that the number and functional categories of genes differentially expressed after acid shock differed according to both growth temperature and growth phase. The acid response of L. monocytogenes grown to log phase at 37°C involved stress-related transcriptional regulators (i.e., σ(B), σ(H), CtsR, and HrcA), some of which have been implicated in adaptation to the intracellular environment. In contrast, for bacteria grown at 7°C to stationary phase, acid exposure did not result in differential expression of the stress regulons examined. However, two large operons encoding bacteriophage-like proteins were induced, suggesting lysogenic prophage induction. The adaptive transcriptional response observed in 37°C-grown cells was largely absent in 7°C-grown cells, suggesting that temperatures commonly encountered during food storage and distribution affect the ability of L. monocytogenes to survive gastric passage and ultimately cause disease.

Identification of MicroRNAs and Their Targets Associated with Fruit-Bagging and Subsequent Sunlight Re-exposure in the “Granny Smith” Apple Exocarp Using High-Throughput Sequencing

PubMed Central

Qu, Dong; Yan, Fei; Meng, Rui; Jiang, Xiaobing; Yang, Huijuan; Gao, Ziyi; Dong, Yonghui; Yang, Yazhou; Zhao, Zhengyang

2016-01-01

Bagged fruits of green apple cultivar “Granny Smith” have been found to turn cardinal red after debagging during fruit-ripening in the Loess Plateau region of China. To understand this phenomenon at post-transcriptional level, we have investigated the roles of microRNAs (miRNAs) in response to debagging. Three small RNA libraries were primarily constructed from peels of “Granny Smith” apples subjected to bagging followed by sunlight re-exposure treatments (0, 6 h, 1 day) (debagging), and from peels of apples without any bagging treatments (0, 6 h, 1 day). 201 known miRNAs belonging to 43 miRNA families and 220 novel miRNAs were identified via high-throughput sequencing. Some miRNAs were found to be differentially expressed after debagging, which indicated that miRNAs affected anthocyanin accumulation through their target genes in mature apple. To further explore the effect of debagging on miRNAs regulating the expression of anthocyanin regulatory genes, four miRNAs and their target genes regulating anthocyanin accumulation, miR156, miR828, miR858, and miR5072, were compared between green cultivar “Granny Smith” and red cultivar “Starkrimson.” Results showed that mdm-miR828 and mdm-miR858 regulated anthocyanin contents in both apple cultivars, while mdm-miR156 only affected anthocyanin accumulation in “Granny Smith,” and miR5072 affected anthocyanin accumulation in “Starkrimson.” Additional analysis of gene ontology for the differentially expressed miRNAs after debagging treatments and their predicted target genes showed that they were involved in photo-protective response after debagging from 0 h to 1 day; they might play important roles in fruit development and adaptation to high light stress. PMID:26870053

Secondary Traumatization and Differentiation Among the Wives of Former POWs: A Reciprocal Association.

PubMed

Lahav, Yael; Levin, Yafit; Bensimon, Moshe; Kanat-Maymon, Yaniv; Solomon, Zahava

2017-08-01

Repercussions of war captivity may transmit to spouses of former prisoners of war (POW) via posttraumatic stress symptoms (PTSS). Overidentification with their partners underlies the PTSS experienced by former wives of POWs, thus implying impaired self-differentiation. Although wives' indirect exposure to their husbands' captivity and subsequent PTSS has been associated with the wives' PTSS and differentiation, the combined effects remain unclear. Furthermore, previous cross-sectional studies could not illuminate directionality. This prospective study investigates (a) the moderating role of indirect exposure to captivity in the association between husbands' PTSS and wives' PTSS and differentiation; and (b) the directionality of the association between wives' differentiation and PTSS over time. The wives of both former POWs (n = 143) and combatants (n = 102) were assessed 30 (T1) and 38 (T2) years after the 1973 Yom Kippur War. The wives of former POWs endorsed higher PTSS and fusion differentiation, η 2 p = .06 to .14. Indirect exposure to captivity moderated the associations between husbands' PTSS and wives' PTSS, Cohen's f 2 = .01 to .03. The association between the wives' differentiation and PTSS over time was bidirectional, β = -0.18 to 0.68; R 2 = .54 to .73. Results suggest a vicious cycle between PTSS and differentiation, and the need for clinical interventions that further differentiation for spouses of prolonged trauma victims. Copyright © 2017 International Society for Traumatic Stress Studies.

How Does Chronic Cigarette Smoke Exposure Affect Human Skin? A Global Proteomics Study in Primary Human Keratinocytes.

PubMed

Rajagopalan, Pavithra; Nanjappa, Vishalakshi; Raja, Remya; Jain, Ankit P; Mangalaparthi, Kiran K; Sathe, Gajanan J; Babu, Niraj; Patel, Krishna; Cavusoglu, Nükhet; Soeur, Jeremie; Pandey, Akhilesh; Roy, Nita; Breton, Lionel; Chatterjee, Aditi; Misra, Namita; Gowda, Harsha

2016-11-01

Cigarette smoking has been associated with multiple negative effects on human skin. Long-term physiological effects of cigarette smoke are through chronic and not acute exposure. Molecular alterations due to chronic exposure to cigarette smoke remain unclear. Primary human skin keratinocytes chronically exposed to cigarette smoke condensate (CSC) showed a decreased wound-healing capacity with an increased expression of NRF2 and MMP9. Using quantitative proteomics, we identified 4728 proteins, of which 105 proteins were overexpressed (≥2-fold) and 41 proteins were downregulated (≤2-fold) in primary skin keratinocytes chronically exposed to CSC. We observed an alteration in the expression of several proteins involved in maintenance of epithelial barrier integrity, including keratin 80 (5.3 fold, p value 2.5 × 10 -7 ), cystatin A (3.6-fold, p value 3.2 × 10 -3 ), and periplakin (2.4-fold, p value 1.2 × 10 -8 ). Increased expression of proteins associated with skin hydration, including caspase 14 (2.2-fold, p value 4.7 × 10 -2 ) and filaggrin (3.6-fold, p value 5.4 × 10 -7 ), was also observed. In addition, we report differential expression of several proteins, including adipogenesis regulatory factor (2.5-fold, p value 1.3 × 10 -3 ) and histone H1.0 (2.5-fold, p value 6.3 × 10 -3 ) that have not been reported earlier. Bioinformatics analyses demonstrated that proteins differentially expressed in response to CSC are largely related to oxidative stress, maintenance of skin integrity, and anti-inflammatory responses. Importantly, treatment with vitamin E, a widely used antioxidant, could partially rescue adverse effects of CSC exposure in primary skin keratinocytes. The utility of antioxidant-based new dermatological formulations in delaying or preventing skin aging and oxidative damages caused by chronic cigarette smoke exposure warrants further clinical investigations and multi-omics research.

Developmental Toxicity of Zinc Oxide Nanoparticles to Zebrafish (Danio rerio): A Transcriptomic Analysis

PubMed Central

Choi, Jin Soo; Kim, Ryeo-Ok; Yoon, Seokjoo

2016-01-01

Zinc oxide nanoparticles (ZnO NPs) are being utilized in an increasing number of fields and commercial applications. While their general toxicity and associated oxidative stress have been extensively studied, the toxicological pathways that they induce in developmental stages are still largely unknown. In this study, the developmental toxicity of ZnO NPs to embryonic/larval zebrafish was investigated. The transcriptional expression profiles induced by ZnO NPs were also investigated to ascertain novel genomic responses related to their specific toxicity pathway. Zebrafish embryos were exposed to 0.01, 0.1, 1, and 10 mg/L ZnO NPs for 96 h post-fertilization. The toxicity of ZnO NPs, based on their Zn concentration, was quite similar to that in embryonic/larval zebrafish exposed to corresponding ZnSO4 concentrations. Pericardial edema and yolk-sac edema were the principal malformations induced by ZnO NPs. Gene-expression profiling using microarrays demonstrated 689 genes that were differentially regulated (fold change >1.5) following exposure to ZnO NPs (498 upregulated, 191 downregulated). Several genes that were differentially regulated following ZnO NP exposure shared similar biological pathways with those observed with ZnSO4 exposure, but six genes (aicda, cyb5d1, edar, intl2, ogfrl2 and tnfsf13b) associated with inflammation and the immune system responded specifically to ZnO NPs (either in the opposite direction or were unchanged in ZnSO4 exposure). Real-time reverse-transcription quantitative polymerase chain reaction confirmed that the responses of these genes to ZnO NPs were significantly different from their response to ZnSO4 exposure. ZnO NPs may affect genes related to inflammation and the immune system, resulting in yolk-sac edema and pericardia edema in embryonic/larval developmental stages. These results will assist in elucidating the mechanisms of toxicity of ZnO NPs during development of zebrafish. PMID:27504894

Use of electronic tongue for differentiation of tomato taste by cultivar, harvest maturity, and chilling or heating exposure

USDA-ARS?s Scientific Manuscript database

The objective of this research was to evaluate whether an electronic-tongue (etongue) could differentiate “taste” profiles of tomato fruit between different cultivars, harvest maturities, and postharvest chilling or heating exposure. The four cultivars included: two common commercial cultivars, ‘Tyg...

Protective effects of L-selenomethionine on space radiation induced changes in gene expression.

PubMed

Stewart, J; Ko, Y-H; Kennedy, A R

2007-06-01

Ionizing radiation can produce adverse biological effects in astronauts during space travel. Of particular concern are the types of radiation from highly energetic, heavy, charged particles known as HZE particles. The aims of our studies are to characterize HZE particle radiation induced biological effects and evaluate the effects of L-selenomethionine (SeM) on these adverse biological effects. In this study, microarray technology was used to measure HZE radiation induced changes in gene expression, as well as to evaluate modulation of these changes by SeM. Human thyroid epithelial cells (HTori-3) were irradiated (1 GeV/n iron ions) in the presence or in the absence of 5 microM SeM. At 6 h post-irradiation, all cells were harvested for RNA isolation. Gene Chip U133Av2 from Affymetrix was used for the analysis of gene expression, and ANOVA and EASE were used for a determination of the genes and biological processes whose differential expression is statistically significant. Results of this microarray study indicate that exposure to small doses of radiation from HZE particles, 10 and 20 cGy from iron ions, induces statistically significant differential expression of 196 and 610 genes, respectively. In the presence of SeM, differential expression of 77 out of 196 genes (exposure to 10 cGy) and 336 out of 610 genes (exposure to 20 cGy) is abolished. In the presence or in the absence of SeM, radiation from HZE particles induces differential expression of genes whose products have roles in the induction of G1/S arrest during the mitotic cell cycle, as well as heat shock proteins. Some of the genes, whose expressions were affected by radiation from HZE particles and were unchanged in irradiated cells treated with SeM, have been shown to have altered expression levels in cancer cells. The conclusions of this report are that radiation from HZE particles can induce differential expression of many genes, some of which are known to play roles in the same processes that have been shown to be activated in cells exposed to radiation from photons (like cell cycle arrest in G1/S), and that supplementation with SeM abolishes HZE particle-induced differential expression of many genes. Understanding the roles that these genes play in the radiation-induced transformation of cells may help to decipher the origins of radiation-induced cancer.

Effects of Hypogravity on Osteoblast Differentiation

NASA Technical Reports Server (NTRS)

Globus, Ruth; Doty, Steven

1997-01-01

Weightbearing is essential for normal skeletal function. Without weightbearing, the rate of bone formation by osteoblasts decreases in the growing rat. Defective formation may account for the decrease in the maturation, strength and mass of bone that is caused by spaceflight. These skeletal defects may be mediated by a combination of physiologic changes triggered by spaceflight, including skeletal unloading, fluid shifts, and stress-induced endocrine factors. The fundamental question of whether the defects in osteoblast function due to weightlessness are mediated by localized skeletal unloading or by systemic physiologic adaptations such as fluid shifts has not been answered. Furthermore, bone-forming activity of osteoblasts during unloading may be affected by paracrine signals from vascular, monocytic, and neural cells that also reside in skeletal tissue. Therefore we proposed to examine whether exposure of cultured rat osteoblasts to spaceflight inhibits cellular differentiation and impairs mineralization when isolated from the influence of both systemic factors and other skeletal cells.

Violent and nonviolent video games differentially affect physical aggression for individuals high vs. low in dispositional anger.

PubMed

Engelhardt, Christopher R; Bartholow, Bruce D; Saults, J Scott

2011-01-01

Although numerous experiments have shown that exposure to violent video games (VVG) causes increases in aggression, relatively few studies have investigated the extent to which this effect differs as a function of theoretically relevant individual difference factors. This study investigated whether video game content differentially influences aggression as a function of individual differences in trait anger. Participants were randomly assigned to play a violent or nonviolent video game before completing a task in which they could behave aggressively. Results showed that participants high in trait anger were the most aggressive, but only if they first played a VVG. This relationship held while statistically controlling for dimensions other than violent content on which game conditions differed (e.g. frustration, arousal). Implications of these findings for models explaining the effects of video games on behavior are discussed. © 2011 Wiley Periodicals, Inc.

In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism.

PubMed

Radford, Elizabeth J; Ito, Mitsuteru; Shi, Hui; Corish, Jennifer A; Yamazawa, Kazuki; Isganaitis, Elvira; Seisenberger, Stefanie; Hore, Timothy A; Reik, Wolf; Erkek, Serap; Peters, Antoine H F M; Patti, Mary-Elizabeth; Ferguson-Smith, Anne C

2014-08-15

Adverse prenatal environments can promote metabolic disease in offspring and subsequent generations. Animal models and epidemiological data implicate epigenetic inheritance, but the mechanisms remain unknown. In an intergenerational developmental programming model affecting F2 mouse metabolism, we demonstrate that the in utero nutritional environment of F1 embryos alters the germline DNA methylome of F1 adult males in a locus-specific manner. Differentially methylated regions are hypomethylated and enriched in nucleosome-retaining regions. A substantial fraction is resistant to early embryo methylation reprogramming, which may have an impact on F2 development. Differential methylation is not maintained in F2 tissues, yet locus-specific expression is perturbed. Thus, in utero nutritional exposures during critical windows of germ cell development can impact the male germline methylome, associated with metabolic disease in offspring. Copyright © 2014, American Association for the Advancement of Science.

Ultra-fast stem cell labelling using cationised magnetoferritin

NASA Astrophysics Data System (ADS)

Correia Carreira, S.; Armstrong, J. P. K.; Seddon, A. M.; Perriman, A. W.; Hartley-Davies, R.; Schwarzacher, W.

2016-03-01

Magnetic cell labelling with superparamagnetic iron oxide nanoparticles (SPIONs) facilitates many important biotechnological applications, such as cell imaging and remote manipulation. However, to achieve adequate cellular loading of SPIONs, long incubation times (24 hours and more) or laborious surface functionalisation are often employed, which can adversely affect cell function. Here, we demonstrate that chemical cationisation of magnetoferritin produces a highly membrane-active nanoparticle that can magnetise human mesenchymal stem cells (hMSCs) using incubation times as short as one minute. Magnetisation persisted for several weeks in culture and provided significant T2* contrast enhancement during magnetic resonance imaging. Exposure to cationised magnetoferritin did not adversely affect the membrane integrity, proliferation and multi-lineage differentiation capacity of hMSCs, which provides the first detailed evidence for the biocompatibility of magnetoferritin. The combination of synthetic ease and flexibility, the rapidity of labelling and absence of cytotoxicity make this novel nanoparticle system an easily accessible and versatile platform for a range of cell-based therapies in regenerative medicine.Magnetic cell labelling with superparamagnetic iron oxide nanoparticles (SPIONs) facilitates many important biotechnological applications, such as cell imaging and remote manipulation. However, to achieve adequate cellular loading of SPIONs, long incubation times (24 hours and more) or laborious surface functionalisation are often employed, which can adversely affect cell function. Here, we demonstrate that chemical cationisation of magnetoferritin produces a highly membrane-active nanoparticle that can magnetise human mesenchymal stem cells (hMSCs) using incubation times as short as one minute. Magnetisation persisted for several weeks in culture and provided significant T2* contrast enhancement during magnetic resonance imaging. Exposure to cationised magnetoferritin did not adversely affect the membrane integrity, proliferation and multi-lineage differentiation capacity of hMSCs, which provides the first detailed evidence for the biocompatibility of magnetoferritin. The combination of synthetic ease and flexibility, the rapidity of labelling and absence of cytotoxicity make this novel nanoparticle system an easily accessible and versatile platform for a range of cell-based therapies in regenerative medicine. Electronic supplementary information (ESI) available: Detailed characterisation data, and controls of the magnetisation and toxicological profiling studies. See DOI: 10.1039/c5nr07144e

A Review of the Health Benefits of Greenness

PubMed Central

James, Peter; Banay, Rachel F.; Hart, Jaime E.; Laden, Francine

2015-01-01

Researchers are increasingly exploring how neighborhood greenness, or vegetation, may affect health behaviors and outcomes. Greenness may influence health by promoting physical activity and social contact; decreasing stress; and mitigating air pollution, noise, and heat exposure. Greenness is generally measured using satellite-based vegetation indices or land-use databases linked to participants’ addresses. In this review, we found fairly strong evidence for a positive association between greenness and physical activity, and a less consistent negative association between greenness and body weight. Research suggests greenness is protective against adverse mental health outcomes, cardiovascular disease, and mortality, though most studies were limited by cross-sectional or ecological design. There is consistent evidence that greenness exposure during pregnancy is positively associated with birth weight, though findings for other birth outcomes are less conclusive. Future research should follow subjects prospectively, differentiate between greenness quantity and quality, and identify mediators and effect modifiers of greenness-health associations. PMID:26185745

Early social learning triggers neurogenomic expression changes in a swordtail fish.

PubMed

Cui, Rongfeng; Delclos, Pablo J; Schumer, Molly; Rosenthal, Gil G

2017-05-17

Mate choice can play a pivotal role in the nature and extent of reproductive isolation between species. Mating preferences are often dependent on an individual's social experience with adult phenotypes throughout development. We show that olfactory preference in a swordtail fish ( Xiphophorus malinche ) is affected by previous experience with adult olfactory signals. We compare transcriptome-wide gene expression levels of pooled sensory and brain tissues between three treatment groups that differ by social experience: females with no adult exposure, females exposed to conspecifics and females exposed to heterospecifics. We identify potential functionally relevant genes and biological pathways differentially expressed not only between control and exposure groups, but also between groups exposed to conspecifics and heterospecifics. Based on our results, we speculate that vomeronasal receptor type 2 paralogs may detect species-specific pheromone components and thus play an important role in reproductive isolation between species. © 2017 The Author(s).

Increased egg estradiol concentration feminizes digit ratios of male pheasants (Phasianus colchicus)

NASA Astrophysics Data System (ADS)

Saino, N.; Rubolini, D.; Romano, M.; Boncoraglio, G.

2007-03-01

The length ratio between individual digits differs between males and females in humans, other mammals, lizards, and one bird species. Sexual dimorphism in digit ratios and variation among individuals of the same sex may depend on differential exposure to androgens and estrogens during embryonic life. Organizational effects of sex hormones could cause the observed correlations between digit ratios and diverse phenotypic traits in humans. However, no study has investigated experimentally the effect of prenatal estrogens on digit ratios. We analyzed the effect of estradiol injection in ring-necked pheasant (Phasianus colchicus) eggs on digit ratios. Males from control eggs had higher ratios between the second or third and the fourth digit of the right foot compared to females. Estradiol-treated eggs produced males with lower (feminized) right foot second to fourth digit ratio. Thus, we provided the first experimental evidence that prenatal exposure to physiologically high estrogen levels affects bird digit ratios.

[Silicosis: computed tomography findings].

PubMed

González Vázquez, M; Trinidad López, C; Castellón Plaza, D; Calatayud Moscoso Del Prado, J; Tardáguila Montero, F

2013-01-01

Silicosis is an occupational lung disease, which is caused by the inhalation of silica and affects a wide range of jobs. There are many clinical forms of silicosis: acute silicosis, results from exposure to very large amounts of silica dust over a period of less than 2 years. Simple chronic silicosis, the most common type that we see today, results from exposure to low amounts of silica between 2 and 10 years. Chronic silicosis complicated, with silicotic conglomerates. In many cases the diagnosis of silicosis is made according to epidemiological and radiological data, without a histological confirmation. It is important to know the various radiological manifestations of silicosis to differentiate it from other lung diseases and to recognize their complications. The objective of this work is to describe typical and atypical radiological findings of silicosis and their complications in helical and high resolution (HRCT) thorax CT. Copyright © 2011 SERAM. Published by Elsevier Espana. All rights reserved.

Cigarette Smoke Modulates Repair and Innate Immunity following Injury to Airway Epithelial Cells.

PubMed

Amatngalim, Gimano D; Broekman, Winifred; Daniel, Nadia M; van der Vlugt, Luciën E P M; van Schadewijk, Annemarie; Taube, Christian; Hiemstra, Pieter S

2016-01-01

Cigarette smoking is the main risk factor associated with chronic obstructive pulmonary disease (COPD), and contributes to COPD development and progression by causing epithelial injury and inflammation. Whereas it is known that cigarette smoke (CS) may affect the innate immune function of airway epithelial cells and epithelial repair, this has so far not been explored in an integrated design using mucociliary differentiated airway epithelial cells. In this study, we examined the effect of whole CS exposure on wound repair and the innate immune activity of mucociliary differentiated primary bronchial epithelial cells, upon injury induced by disruption of epithelial barrier integrity or by mechanical wounding. Upon mechanical injury CS caused a delayed recovery in the epithelial barrier integrity and wound closure. Furthermore CS enhanced innate immune responses, as demonstrated by increased expression of the antimicrobial protein RNase 7. These differential effects on epithelial repair and innate immunity were both mediated by CS-induced oxidative stress. Overall, our findings demonstrate modulation of wound repair and innate immune responses of injured airway epithelial cells that may contribute to COPD development and progression.

Differential modulatory effects of morphine on acute and chronic stress induced neurobehavioral and cellular markers in rats.

PubMed

Joshi, Jagdish C; Ray, Arunabha; Gulati, Kavita

2014-04-15

The present study evaluated the effects of morphine treatments on elevated plus maze test parameters, oxidative stress markers and Hsp70 expression in normal and stressed rats. Acute and chronic stress caused neurobehavioral suppression, altered prooxidant-antioxidant balance and increased Hsp70 expression in brain homogenates in a differential manner. Morphine (1 and 5mg/kg) attenuated RS induced anxiogenesis, changes in MDA and GSH but further enhanced Hsp70 expression. Similar anxiolytic and Hsp70 enhancing effects were seen after morphine in normal rats (no RS). Exposure to chronic RS did not elicit any appreciable neurobehavioral response in EPM but enhanced MDA, lowered GSH and exaggerated the Hsp70 expression. Pretreatment with morphine did not affect the neurobehavioral response to chronic RS, but reverted the GSH and Hsp70 expression. The results suggest that morphine differentially influences acute and chronic stress induced changes in anxiety behavior and complex interactions between oxidative stress markers and Hsp70 expression which may contribute to these effects. Copyright © 2014 Elsevier B.V. All rights reserved.

Transcriptome and Metabolome Analyses in Exogenous FABP4- and FABP5-Treated Adipose-Derived Stem Cells

PubMed Central

Sugaya, Takeshi; Oikawa, Tsuyoshi; Matsumoto, Megumi; Funahashi, Yasuhito; Matsukawa, Yoshihisa; Gotoh, Momokazu; Miura, Tetsuji

2016-01-01

Adipose-derived stem cells (ADSC), which exist near adipocytes in adipose tissue, have been used as a potential tool of regenerative medicine. Lipid chaperones, fatty acid-binding protein 4 (FABP4) and 5 (FABP5), are abundantly expressed in adipocytes. FABP4 has recently been shown to be secreted from adipocytes during lipolysis in a non-classical pathway and may act as an adipokine. Here, we investigated the role of exogenous FABP4 and FABP5 in transcriptional and metabolic regulation in ADSC. FABP4 and FABP5 were little expressed in ADSC. However, both FABP4 and FABP5 were significantly induced after adipocyte differentiation of ADSC and were secreted from the differentiated adipocytes. Analysis of microarray data, including gene ontology enrichment analysis and cascade analysis of the protein-protein interaction network using a transcription factor binding site search, demonstrated that treatment of ADSC with FABP4 or FABP5 affected several kinds of genes related to inflammatory and metabolic responses and the process of cell differentiation. Notably, myogenic factors, including myocyte enhancer factors, myogenic differentiation 1 and myogenin, were modulated by treatment of ADSC with FABP4, indicating that exogenous FABP4 treatment is partially associated with myogenesis in ADSC. Metabolome analysis showed that treatment of ADSC with FABP4 and with FABP5 similarly, but differently in extent, promoted hydrolysis and/or uptake of lipids, consequentially together with enhancement of β oxidation, inhibition of downstream of the glycolysis pathway, accumulation of amino acids, reduction of nucleic acid components and increase in the ratio of reduced and oxidized nicotinamide adenine dinucleotide phosphates (NADPH/NADP+), an indicator of reducing power, and the ratio of adenosine triphosphate and adenosine monophosphate (ATP/AMP), an indicator of the energy state, in ADSC. In conclusion, secreted FABP4 and FABP5 from adipocytes as adipokines differentially affect transcriptional and metabolic regulation in ADSC near adipocytes. The adiposity condition in the host of regenerative medicine may affect characteristics of ADSC by exposure of the balance of FABP4 and FABP5. PMID:27936164

Transcriptome and Metabolome Analyses in Exogenous FABP4- and FABP5-Treated Adipose-Derived Stem Cells.

PubMed

Yamamoto, Tokunori; Furuhashi, Masato; Sugaya, Takeshi; Oikawa, Tsuyoshi; Matsumoto, Megumi; Funahashi, Yasuhito; Matsukawa, Yoshihisa; Gotoh, Momokazu; Miura, Tetsuji

2016-01-01

Adipose-derived stem cells (ADSC), which exist near adipocytes in adipose tissue, have been used as a potential tool of regenerative medicine. Lipid chaperones, fatty acid-binding protein 4 (FABP4) and 5 (FABP5), are abundantly expressed in adipocytes. FABP4 has recently been shown to be secreted from adipocytes during lipolysis in a non-classical pathway and may act as an adipokine. Here, we investigated the role of exogenous FABP4 and FABP5 in transcriptional and metabolic regulation in ADSC. FABP4 and FABP5 were little expressed in ADSC. However, both FABP4 and FABP5 were significantly induced after adipocyte differentiation of ADSC and were secreted from the differentiated adipocytes. Analysis of microarray data, including gene ontology enrichment analysis and cascade analysis of the protein-protein interaction network using a transcription factor binding site search, demonstrated that treatment of ADSC with FABP4 or FABP5 affected several kinds of genes related to inflammatory and metabolic responses and the process of cell differentiation. Notably, myogenic factors, including myocyte enhancer factors, myogenic differentiation 1 and myogenin, were modulated by treatment of ADSC with FABP4, indicating that exogenous FABP4 treatment is partially associated with myogenesis in ADSC. Metabolome analysis showed that treatment of ADSC with FABP4 and with FABP5 similarly, but differently in extent, promoted hydrolysis and/or uptake of lipids, consequentially together with enhancement of β oxidation, inhibition of downstream of the glycolysis pathway, accumulation of amino acids, reduction of nucleic acid components and increase in the ratio of reduced and oxidized nicotinamide adenine dinucleotide phosphates (NADPH/NADP+), an indicator of reducing power, and the ratio of adenosine triphosphate and adenosine monophosphate (ATP/AMP), an indicator of the energy state, in ADSC. In conclusion, secreted FABP4 and FABP5 from adipocytes as adipokines differentially affect transcriptional and metabolic regulation in ADSC near adipocytes. The adiposity condition in the host of regenerative medicine may affect characteristics of ADSC by exposure of the balance of FABP4 and FABP5.

Genome-wide expression analysis of human in vivo irritated epidermis: differential profiles induced by sodium lauryl sulfate and nonanoic acid.

PubMed

Clemmensen, Anders; Andersen, Klaus E; Clemmensen, Ole; Tan, Qihua; Petersen, Thomas K; Kruse, Torben A; Thomassen, Mads

2010-09-01

The pathogenesis of irritant contact dermatitis (ICD) is poorly understood, and genes participating in the epidermal response to chemical irritants are only partly known. It is commonly accepted that different irritants have different mechanisms of action in the development of ICD. To define the differential molecular events induced in the epidermis by different irritants, we collected sequential biopsies ((1/2), 4, and 24 hours after a single exposure and at day 11 after repeated exposure) from human volunteers exposed to either sodium lauryl sulfate (SLS) or nonanoic acid (NON). Gene expression analysis using high-density oligonucleotide microarrays (representing 47,000 transcripts) revealed essentially different pathway responses (1/2)hours after exposure: NON transiently induced the IL-6 pathway as well as a number of mitogen-activated signaling cascades including extracellular signal-regulated kinase and growth factor receptor signaling, whereas SLS transiently downregulated cellular energy metabolism pathways. Differential expression of the cyclooxygenase-2 and matrix metalloproteinase 3 transcripts was confirmed immunohistochemically. After cumulative exposure, 883 genes were differentially expressed, whereas we identified 23 suggested common biomarkers for ICD. In conclusion, we bring new insights into two hitherto less well-elucidated phases of skin irritancy: the very initial as well as the late phase after single and cumulative mild exposures, respectively.

Chromatin Switches during Neural Cell Differentiation and Their Dysregulation by Prenatal Alcohol Exposure.

PubMed

Gavin, David P; Grayson, Dennis R; Varghese, Sajoy P; Guizzetti, Marina

2017-05-11

Prenatal alcohol exposure causes persistent neuropsychiatric deficits included under the term fetal alcohol spectrum disorders (FASD). Cellular identity emerges from a cascade of intrinsic and extrinsic (involving cell-cell interactions and signaling) processes that are partially initiated and maintained through changes in chromatin structure. Prenatal alcohol exposure influences neuronal and astrocyte development, permanently altering brain connectivity. Prenatal alcohol exposure also alters chromatin structure through histone and DNA modifications. However, the data linking alcohol-induced differentiation changes with developmental alterations in chromatin structure remain to be elucidated. In the first part of this review, we discuss the sequence of chromatin structural changes involved in neural cell differentiation during normal development. We then discuss the effects of prenatal alcohol on developmental histone modifications and DNA methylation in the context of neurogenesis and astrogliogenesis. We attempt to synthesize the developmental literature with the FASD literature, proposing that alcohol-induced changes to chromatin structure account for altered neurogenesis and astrogliogenesis as well as altered neuron and astrocyte differentiation. Together these changes may contribute to the cognitive and behavioral abnormalities in FASD. Future studies using standardized alcohol exposure paradigms at specific developmental stages will advance the understanding of how chromatin structural changes impact neural cell fate and maturation in FASD.

Chromatin Switches during Neural Cell Differentiation and Their Dysregulation by Prenatal Alcohol Exposure

PubMed Central

Gavin, David P.; Grayson, Dennis R.; Varghese, Sajoy P.; Guizzetti, Marina

2017-01-01

Prenatal alcohol exposure causes persistent neuropsychiatric deficits included under the term fetal alcohol spectrum disorders (FASD). Cellular identity emerges from a cascade of intrinsic and extrinsic (involving cell-cell interactions and signaling) processes that are partially initiated and maintained through changes in chromatin structure. Prenatal alcohol exposure influences neuronal and astrocyte development, permanently altering brain connectivity. Prenatal alcohol exposure also alters chromatin structure through histone and DNA modifications. However, the data linking alcohol-induced differentiation changes with developmental alterations in chromatin structure remain to be elucidated. In the first part of this review, we discuss the sequence of chromatin structural changes involved in neural cell differentiation during normal development. We then discuss the effects of prenatal alcohol on developmental histone modifications and DNA methylation in the context of neurogenesis and astrogliogenesis. We attempt to synthesize the developmental literature with the FASD literature, proposing that alcohol-induced changes to chromatin structure account for altered neurogenesis and astrogliogenesis as well as altered neuron and astrocyte differentiation. Together these changes may contribute to the cognitive and behavioral abnormalities in FASD. Future studies using standardized alcohol exposure paradigms at specific developmental stages will advance the understanding of how chromatin structural changes impact neural cell fate and maturation in FASD. PMID:28492482

Prenatal Alcohol Exposure and Cellular Differentiation

PubMed Central

Veazey, Kylee J.; Muller, Daria; Golding, Michael C.

2013-01-01

Exposure to alcohol significantly alters the developmental trajectory of progenitor cells and fundamentally compromises tissue formation (i.e., histogenesis). Emerging research suggests that ethanol can impair mammalian development by interfering with the execution of molecular programs governing differentiation. For example, ethanol exposure disrupts cellular migration, changes cell–cell interactions, and alters growth factor signaling pathways. Additionally, ethanol can alter epigenetic mechanisms controlling gene expression. Normally, lineage-specific regulatory factors (i.e., transcription factors) establish the transcriptional networks of each new cell type; the cell’s identity then is maintained through epigenetic alterations in the way in which the DNA encoding each gene becomes packaged within the chromatin. Ethanol exposure can induce epigenetic changes that do not induce genetic mutations but nonetheless alter the course of fetal development and result in a large array of patterning defects. Two crucial enzyme complexes—the Polycomb and Trithorax proteins—are central to the epigenetic programs controlling the intricate balance between self-renewal and the execution of cellular differentiation, with diametrically opposed functions. Prenatal ethanol exposure may disrupt the functions of these two enzyme complexes, altering a crucial aspect of mammalian differentiation. Characterizing the involvement of Polycomb and Trithorax group complexes in the etiology of fetal alcohol spectrum disorders will undoubtedly enhance understanding of the role that epigenetic programming plays in this complex disorder. PMID:24313167

Genome-wide gene expression effects in B6C3F1 mouse intestinal epithelia following 7 and 90 days of exposure to hexavalent chromium in drinking water

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kopec, Anna K.; Kim, Suntae; Forgacs, Agnes L.

2012-02-15

Chronic administration of high doses of hexavalent chromium [Cr(VI)] as sodium dichromate dihydrate (SDD) elicits alimentary cancers in mice. To further elucidate key events underlying tumor formation, a 90-day drinking water study was conducted in B6C3F1 mice. Differential gene expression was examined in duodenal and jejunal epithelial samples following 7 or 90 days of exposure to 0, 0.3, 4, 14, 60, 170 or 520 mg/L SDD in drinking water. Genome-wide microarray analyses identified 6562 duodenal and 4448 jejunal unique differentially expressed genes at day 8, and 4630 and 4845 unique changes, respectively, in the duodenum and jejunum at day 91.more » Comparative analysis identified significant overlap in duodenal and jejunal differential gene expression. Automated dose–response modeling identified > 80% of the differentially expressed genes exhibited sigmoidal dose–response curves with EC{sub 50} values ranging from 10 to 100 mg/L SDD. Only 16 genes satisfying the dose-dependent differential expression criteria had EC{sub 50} values < 10 mg/L SDD, 3 of which were regulated by Nrf2, suggesting oxidative stress in response to SDD at low concentrations. Analyses of differentially expressed genes identified over-represented functions associated with oxidative stress, cell cycle, lipid metabolism, and immune responses consistent with the reported effects on redox status and histopathology at corresponding SDD drinking water concentrations. Collectively, these data are consistent with a mode of action involving oxidative stress and cytotoxicity as early key events. This suggests that the tumorigenic effects of chronic Cr(VI) oral exposure likely require chronic tissue damage and compensatory epithelial cell proliferation. Highlights: ► Mouse small intestine gene expression is highly responsive to hexavalent chromium [Cr(VI)]. ► Cr(VI) elicits more differential gene expression after 7 days of exposure than 90 days of exposure. ► Oral exposure to Cr(VI) leads to oxidative stress, cell cycle, lipid and immune dysregulation. ► Cr(VI) elicits dose-dependent changes in gene expression with an overall median EC{sub 50} of 47 mg/L SDD.« less

Exposure of differentiated airway epithelial cells to volatile smoke in vitro.

PubMed

Beisswenger, Christoph; Platz, Juliane; Seifart, Carola; Vogelmeier, Claus; Bals, Robert

2004-01-01

Cigarette smoke (CS) is the predominant pathogenetic factor in the development of chronic bronchitis and chronic obstructive pulmonary disease. The knowledge about the cellular and molecular mechanisms underlying the smoke-induced inflammation in epithelial cells is limited. The aim of this study was to develop an in vitro model to monitor the effects of volatile CS on differentiated airway epithelial cells. The airway epithelial cell line MM-39 and primary human bronchial epithelial cells were cultivated as air-liquid interface cultures and exposed directly to volatile CS. We used two types of exposure models, one using ambient air, the other using humidified and warm air. Cytokine levels were measured by quantitative PCR and ELISA. Phosphorylation of p38 MAP kinase was assessed by Western blot analysis. To reduce the smoke-induced inflammation, antisense oligonucleotides directed against the p65 subunit of NF-kappaB were applied. Exposure of epithelia to cold and dry air resulted in a significant inflammatory response. In contrast, exposure to humidified warm air did not elicit a cellular response. Stimulation with CS resulted in upregulation of mRNA for IL-6 and IL-8 and protein release. Exposure to CS combined with heat-inactivated bacteria synergistically increased levels of the cytokines. Reactions of differentiated epithelial cells to smoke are mediated by the MAP kinase p38 and the transcription factor NF-kappaB. We developed an exposure model to examine the consequences of direct exposure of differentiated airway epithelial cells to volatile CS. The model enables to measure the cellular reactions to smoke exposure and to determine the outcome of therapeutic interventions. Copyright 2004 S. Karger AG, Basel

Disconnect between alcohol-induced alterations in chromatin structure and gene transcription in a mouse embryonic stem cell model of exposure.

PubMed

Veazey, Kylee J; Wang, Haiqing; Bedi, Yudhishtar S; Skiles, William M; Chang, Richard Cheng-An; Golding, Michael C

2017-05-01

Alterations to chromatin structure induced by environmental insults have become an attractive explanation for the persistence of exposure effects into subsequent life stages. However, a growing body of work examining the epigenetic impact that alcohol and other drugs of abuse exert consistently notes a disconnection between induced changes in chromatin structure and patterns of gene transcription. Thus, an important question is whether perturbations in the 'histone code' induced by prenatal exposures to alcohol implicitly subvert gene expression, or whether the hierarchy of cellular signaling networks driving development is such that they retain control over the transcriptional program. To address this question, we examined the impact of ethanol exposure in mouse embryonic stem cells cultured under 2i conditions, where the transcriptional program is rigidly enforced through the use of small molecule inhibitors. We find that ethanol-induced changes in post-translational histone modifications are dose-dependent, unique to the chromatin modification under investigation, and that the extent and direction of the change differ between the period of exposure and the recovery phase. Similar to in vivo models, we find post-translational modifications affecting histone 3 lysine 9 are the most profoundly impacted, with the signature of exposure persisting long after alcohol has been removed. These changes in chromatin structure associate with dose-dependent alterations in the levels of transcripts encoding Dnmt1, Uhrf1, Tet1, Tet2, Tet3, and Polycomb complex members Eed and Ezh2. However, in this model, ethanol-induced changes to the chromatin template do not consistently associate with changes in gene transcription, impede the process of differentiation, or affect the acquisition of monoallelic patterns of expression for the imprinted gene Igf2R. These findings question the inferred universal relevance of epigenetic changes induced by drugs of abuse and suggest that changes in chromatin structure cannot unequivocally explain dysgenesis in isolation. Copyright © 2017 Elsevier Inc. All rights reserved.

Impact of ionizing radiation exposure on in vitro differentiation of preosteoblastic cell lines

NASA Astrophysics Data System (ADS)

Hu, Yueyuan; Lau, Patrick; Hellweg, Christine; Baumstark-Khan, Christa; Reitz, Guenther

Bone demineralization of astronauts during residence in microgravity is a well known phe-nomenon during space travel. Besides altered gravity conditions, radiation risk is considered to be one of the major health hazards for astronauts in both orbital and interplanetary space. Un-til know, little is known about the effects of space radiation on the skeletal system especially on the bone forming osteoblasts. Accelerator facilities are used to simulate parts of the radiation environment in space. We examined the effects of heavy ion exposure on osteoblastic differ-entiation of murine preosteoblastic cell lines to gain insight into potential cellular mechanisms involved in bone cellular response after exposure to heavy ions. Therefore, we examined gene expression modulation of bone specific transcription factors, osteoblast specific marker genes as well as genes function as coupling factors that link bone resorption to bone formation. mRNA levels were determined using quantitative real time reverse transcriptase PCR (qRT-PCR). Expression of a target gene was standardized to unregulated reference genes. We investigated the transcriptional regulation of Osteocalcin (OCN) as well as TGF-β1, p21(CDKN1A) and the bone specific transcription factor Runx2 (cbfa1). We investigated gene expression modula-tions after exposure to energetic carbon ions (35 MeV/u, 73 keV/µm), iron ions (1000 MeV/u, 150 keV/µm) and lead ions (29 MeV/u, 9600 keV/µm) versus low LET X-rays. X-irradiation dose-dependently increased the mRNA levels of p21(CDKN1A) and Runx2 (cbfa1) whereas expression of OCN and TGF-β1 were elevated at later time points. Exposure to heavy ions provoked a more pronounced effect on osteoblastic specific gene expression within the dif-ferentiation process. Collectively, our results indicate that heavy ions facilitate osteoblastic differentiation more effectively than X-ray. Using the proposed in vitro model we confirmed that exposure to ionizing radiation significantly modulates gene expression levels of marker genes involved in the differentiation of osteoblasts. The data presented allow us to suggest that exposure to ionizing radiation interferes with bone formation at the level of cell differentiation.

The bone marrow niche, stem cells, and leukemia: impact of drugs, chemicals, and the environment.

PubMed

Snyder, Robert

2014-03-01

Detection, treatment, and prevention of bone marrow diseases have long been the aims of experimental and clinical hematologists and mechanistically oriented toxicologists. Among these diseases is aplastic anemia, which manifests as the cessation of normal blood cell production; the leukemias, in contrast, feature the production of excessive hematologic cancer cells. Both diseases are associated with exposure to either industrial chemicals or cancer chemotherapeutic agents. Studies of hematopoietic bone marrow cells in culture have shown that the generation of circulating blood cells requires the interaction of hematopoietic stem cells (HSCs) with supporting marrow stromal cells; yet, isolation of HSCs from bone destroys the unique morphology of the marrow stroma in which the HSCs reside. Imaging techniques and related studies have made it possible to examine specific niches where HSCs may either initiate differentiation toward mature blood cells or reside in a dormant state awaiting a signal to begin differentiation. HSCs and related cells may be highly vulnerable to the mutagenic or toxic effects of drugs or other chemicals early in these processes. Additional studies are required to determine the mechanisms by which drug or chemical exposure may affect these cells and lead to either depression of bone marrow function or to leukemia. © 2014 New York Academy of Sciences.

Encapsulation of mesenchymal stem cells in chitosan/β-glycerophosphate hydrogel for seeding on a novel calcium phosphate cement scaffold.

PubMed

Liu, Tao; Li, Jian; Shao, Zengwu; Ma, Kaige; Zhang, Zhicai; Wang, Baichuan; Zhang, Yannan

2018-06-01

Due to its moldability, biocompatibility, osteoconductivity and resorbability, calcium phosphate cement (CPC) is a highly promising scaffold material for orthopedic applications. However, pH changes and ionic activity during the CPC setting reaction may adversely affect cells seeded directly on CPC. Moreover, a lack of macropores in CPC limits ingrowth of new bone. The objectives of this study were to prepare macroporous CPC scaffolds via porogen leaching, using mannitol crystals as the porogen and to evaluate the in vitro proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs) encapsulated in chitosan/β-glycerophosphate (C/GP) hydrogel prior to exposure to the novel CPC scaffold. MSCs were found to be adhered to the surfaces of CPC macropores via scanning electron microscopy. The viability and osteogenic differentiation of MSCs in C/GP hydrogel with or without exposure to CPC constructs containing mannitol crystals indicated that coating with C/GP hydrogel protected the cells during cement mixing and setting. In conclusion, novel, macroporous CPC scaffolds were prepared, and our data indicate that a hydrogel encapsulation-based strategy can be used to protect cells during scaffold formation. Thus, the MSC-laden CPC scaffolds show promise for the delivery of stem cells to promote bone regeneration. Copyright © 2018 IPEM. Published by Elsevier Ltd. All rights reserved.

Protein Corona Analysis of Silver Nanoparticles Links to Their Cellular Effects.

PubMed

Juling, Sabine; Niedzwiecka, Alicia; Böhmert, Linda; Lichtenstein, Dajana; Selve, Sören; Braeuning, Albert; Thünemann, Andreas F; Krause, Eberhard; Lampen, Alfonso

2017-11-03

The breadth of applications of nanoparticles and the access to food-associated consumer products containing nanosized materials lead to oral human exposure to such particles. In biological fluids nanoparticles dynamically interact with biomolecules and form a protein corona. Knowledge about the protein corona is of great interest for understanding the molecular effects of particles as well as their fate inside the human body. We used a mass spectrometry-based toxicoproteomics approach to elucidate mechanisms of toxicity of silver nanoparticles and to comprehensively characterize the protein corona formed around silver nanoparticles in Caco-2 human intestinal epithelial cells. Results were compared with respect to the cellular function of proteins either affected by exposure to nanoparticles or present in the protein corona. A transcriptomic data set was included in the analyses in order to obtain a combined multiomics view of nanoparticle-affected cellular processes. A relationship between corona proteins and the proteomic or transcriptomic responses was revealed, showing that differentially regulated proteins or transcripts were engaged in the same cellular signaling pathways. Protein corona analyses of nanoparticles in cells might therefore help in obtaining information about the molecular consequences of nanoparticle treatment.

Acute ethanol does not always affect delay discounting in rats selected to prefer or avoid ethanol.

PubMed

Wilhelm, Clare J; Mitchell, Suzanne H

2012-01-01

The purpose of this study was to determine whether animals predisposed to prefer alcohol possess an altered acute response to alcohol on a delay discounting task relative to animals predisposed to avoid alcohol. We used rats selected to prefer or avoid alcohol to assess whether genotype moderates changes in delay discounting induced by acute ethanol exposure. Selectively bred rat lines of Sardinian alcohol-preferring (sP; n = 8) and non-preferring (sNP; n = 8) rats, and alko alcohol (AA, n = 8) and alko non-alcohol (ANA, n = 8) rats were trained in an adjusting amount task to assess delay discounting. There were no significant effects of line on baseline discounting; however, both lines of alcohol-preferring rats exhibit slowed reaction times. Acute ethanol (0, 0.25, 0.5 g/kg) treatment also had no effect on delay discounting in any of the selectively bred rat lines. Our data indicate that in these lines of animals, alcohol preference or avoidance has no impact on delay discounting following acute ethanol exposure. It is possible that other genetic models or lines may be differentially affected by alcohol and exhibit qualitatively and quantitatively different responses in delay discounting tasks.

Developmental Programming and Endocrine Disruptor Effects on Reproductive Neuroendocrine Systems

PubMed Central

Gore, Andrea C.

2009-01-01

The ability of a species to reproduce successfully requires the careful orchestration of developmental processes during critical time points, particularly the late embryonic and early postnatal periods. This article begins with a brief presentation of the evidence for how gonadal steroid hormones exert these imprinting effects upon the morphology of sexually differentiated hypothalamic brain regions, the mechanisms underlying these effects, and their implications in adulthood. Then, I review the evidence that aberrant exposure to hormonally-active substances such as exogenous endocrine-disrupting chemicals (EDCs), may result in improper hypothalamic programming, thereby decreasing reproductive success in adulthood. The field of endocrine disruption has shed new light on the discipline of basic reproductive neuroendocrinology through studies on how early life exposures to EDCs may alter gene expression via non-genomic, epigenetic mechanisms, including DNA methylation and histone acetylation. Importantly, these effects may be transmitted to future generations if the germline is affected via transgenerational, epigenetic actions. By understanding the mechanisms by which natural hormones and xenobiotics affect reproductive neuroendocrine systems, we will gain a better understanding of normal developmental processes, as well as to develop the potential ability to intervene when development is disrupted. PMID:18394690

Effect of acute ozone exposure on the lung metabolomes of obese and lean mice.

PubMed

Mathews, Joel Andrew; Kasahara, David Itiro; Cho, Youngji; Bell, Lauren Nicole; Gunst, Philip Ross; Karoly, Edward D; Shore, Stephanie Ann

2017-01-01

Pulmonary responses to the air pollutant, ozone, are increased in obesity. Both obesity and ozone cause changes in systemic metabolism. Consequently, we examined the impact of ozone on the lung metabolomes of obese and lean mice. Lean wildtype and obese db/db mice were exposed to acute ozone (2 ppm for 3 h) or air. 24 hours later, the lungs were excised, flushed with PBS to remove blood and analyzed via liquid-chromatography or gas-chromatography coupled to mass spectrometry for metabolites. Both obesity and ozone caused changes in the lung metabolome. Of 321 compounds identified, 101 were significantly impacted by obesity in air-exposed mice. These included biochemicals related to carbohydrate and lipid metabolism, which were each increased in lungs of obese versus lean mice. These metabolite changes may be of functional importance given the signaling capacity of these moieties. Ozone differentially affected the lung metabolome in obese versus lean mice. For example, almost all phosphocholine-containing lysolipids were significantly reduced in lean mice, but this effect was attenuated in obese mice. Glutathione metabolism was also differentially affected by ozone in obese and lean mice. Finally, the lung metabolome indicated a role for the microbiome in the effects of both obesity and ozone: all measured bacterial/mammalian co-metabolites were significantly affected by obesity and/or ozone. Thus, metabolic derangements in obesity appear to impact the response to ozone.

Maternal postpartum corticosterone and fluoxetine differentially affect adult male and female offspring on anxiety-like behavior, stress reactivity, and hippocampal neurogenesis.

PubMed

Gobinath, Aarthi R; Workman, Joanna L; Chow, Carmen; Lieblich, Stephanie E; Galea, Liisa A M

2016-02-01

Postpartum depression (PPD) affects approximately 15% of mothers, disrupts maternal care, and can represent a form of early life adversity for the developing offspring. Intriguingly, male and female offspring are differentially vulnerable to the effects of PPD. Antidepressants, such as fluoxetine, are commonly prescribed for treating PPD. However, fluoxetine can reach offspring via breast milk, raising serious concerns regarding the long-term consequences of infant exposure to fluoxetine. The goal of this study was to examine the long-term effects of maternal postpartum corticosterone (CORT, a model of postpartum stress/depression) and concurrent maternal postpartum fluoxetine on behavioral, endocrine, and neural measures in adult male and female offspring. Female Sprague-Dawley dams were treated daily with either CORT or oil and fluoxetine or saline from postnatal days 2-23, and offspring were weaned and left undisturbed until adulthood. Here we show that maternal postpartum fluoxetine increased anxiety-like behavior and impaired hypothalamic-pituitary-adrenal (HPA) axis negative feedback in adult male, but not female, offspring. Furthermore, maternal postpartum fluoxetine increased the density of immature neurons (doublecortin-expressing) in the hippocampus of adult male offspring but decreased the density of immature neurons in adult female offspring. Maternal postpartum CORT blunted HPA axis negative feedback in males and tended to increase density of immature neurons in males but decreased it in females. These results indicate that maternal postpartum CORT and fluoxetine can have long-lasting effects on anxiety-like behavior, HPA axis negative feedback, and adult hippocampal neurogenesis and that adult male and female offspring are differentially affected by these maternal manipulations. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cigarette smoke condensate induces differential expression and promoter methylation profiles of critical genes involved in lung cancer in NL-20 lung cells in vitro: short-term and chronic exposure.

PubMed

Word, Beverly; Lyn-Cook, Lascelles E; Mwamba, Bibi; Wang, Honggang; Lyn-Cook, Beverly; Hammons, George

2013-01-01

Establishing early diagnostic markers of harm is critical for effective prevention programs and regulation of tobacco products. This study examined effects of cigarette smoke condensate (CSC) on expression and promoter methylation profile of critical genes (DAPK, ECAD, MGMT, and RASSF1A) involved in lung cancer development in different human lung cell lines. NL-20 cells were treated with 0.1-100 μg/ml of CSC for 24 to 72 hrs for short-term exposures. DAPK expression or methylation status was not significantly affected. However, CSC treatment resulted in changes in expression and promoter methylation profile of ECAD, MGMT, and RASSF1A. For chronic studies, cells were exposed to 1 or 10 μg/ml CSC up to 28 days. Cells showed morphological changes associated with transformation and changes in invasion capacities and global methylation status. This study provides critical data suggesting that epigenetic changes could serve as an early biomarker of harm due to exposure to cigarette smoke.

Fetal exposure to teratogens: evidence of genes involved in autism.

PubMed

Dufour-Rainfray, Diane; Vourc'h, Patrick; Tourlet, Sébastien; Guilloteau, Denis; Chalon, Sylvie; Andres, Christian R

2011-04-01

Environmental challenges during the prenatal period can result in behavioral abnormalities and cognitive deficits that appear later in life such as autism. Prenatal exposure to valproic acid, ethanol, thalidomide and misoprostol has been shown to be associated with an increased incidence of autism. In addition, rodents exposed in utero to some of these drugs show autism-like abnormalities, including brain changes and lifelong behavior dysfunction. Our aim is to summarize current understanding of the relationship between in utero exposure to these drugs and autism in humans and in autism-like animal model phenotypes. It also highlights the importance of these models to understanding the neurobiology of autism, particularly in the identification of susceptibility genes. These drugs are able to modulate the expression of many genes involved in processes such as proliferation, apoptosis, neuronal differentiation and migration, synaptogenesis and synaptic activity. It seems essential to focus research on genes expressed during early neurodevelopment which may be the target of mutations or affected by drugs such as those included in this review. Copyright © 2011. Published by Elsevier Ltd.

Feasibility of event-related potential (ERP) biomarker use to study effects of mother's voice exposure on speech sound differentiation of preterm infants.

PubMed

D Chorna, Olena; L Hamm, Ellyn; Shrivastava, Hemang; Maitre, Nathalie L

2018-01-01

Atypical maturation of auditory neural processing contributes to preterm-born infants' language delays. Event-related potential (ERP) measurement of speech-sound differentiation might fill a gap in treatment-response biomarkers to auditory interventions. We evaluated whether these markers could measure treatment effects in a quasi-randomized prospective study. Hospitalized preterm infants in passive or active, suck-contingent mother's voice exposure groups were not different at baseline. Post-intervention, the active group had greater increases in/du/-/gu/differentiation in left frontal and temporal regions. Infants with brain injury had lower baseline/ba/-/ga/and/du/-/gu/differentiation than those without. ERP provides valid discriminative, responsive, and predictive biomarkers of infant speech-sound differentiation.

Intergenerational Transmission of Stress in Humans

PubMed Central

Bowers, Mallory E; Yehuda, Rachel

2016-01-01

The hypothesis that offspring are affected by parental trauma or stress exposure, first noted anecdotally, is now supported empirically by data from Holocaust survivor offspring cohorts and other populations. These findings have been extended to less extreme forms of stress, where differential physical, behavioral, and cognitive outcomes are observed in affected offspring. Parental stress-mediated effects in offspring could be explained by genetics or social learning theory. Alternatively, biological variations stemming from stress exposure in parents could more directly have an impact on offspring, a concept we refer to here as ‘intergenerational transmission', via changes to gametes and the gestational uterine environment. We further extend this definition to include the transmission of stress to offspring via early postnatal care, as animal studies demonstrate the importance of early maternal care of pups in affecting offsprings' long-term behavioral changes. Here, we review clinical observations in offspring, noting that offspring of stress- or trauma-exposed parents may be at greater risk for physical, behavioral, and cognitive problems, as well as psychopathology. Furthermore, we review findings concerning offspring biological correlates of parental stress, in particular, offspring neuroendocrine, epigenetic, and neuroanatomical changes, in an attempt to determine the extent of parental stress effects. Although understanding the etiology of effects in offspring is currently impeded by methodological constraints, and limitations in our knowledge, we summarize current information and conclude by presenting hypotheses that have been prompted by recent studies in the field. PMID:26279078

DIFFERENTIAL TRANSCRIPTION FACTOR ACTIVATION AD GENE EXPRESSION PROFILES IN HUMAN VASCULAR ENDOTHELIAL CELLS ON EXPOSURE TO RESIDUAL OIL FLY ASH (ROFA) AND VANADIUM

EPA Science Inventory

Differential transcription factor activation and gene expression profiles in human vascular endothelial cells on exposure to residual oil fly ash (ROFA) and vanadium.
Srikanth S. Nadadur and Daniel L. Costa, US EPA, ORD, NHEERL (ETD, Pulmonary Toxicology Branch), Research ...

DNA methylation and exposure to ambient air pollution in two prospective cohorts.

PubMed

Plusquin, Michelle; Guida, Florence; Polidoro, Silvia; Vermeulen, Roel; Raaschou-Nielsen, Ole; Campanella, Gianluca; Hoek, Gerard; Kyrtopoulos, Soterios A; Georgiadis, Panagiotis; Naccarati, Alessio; Sacerdote, Carlotta; Krogh, Vittorio; Bas Bueno-de-Mesquita, H; Monique Verschuren, W M; Sayols-Baixeras, Sergi; Panni, Tommaso; Peters, Annette; Hebels, Dennie G A J; Kleinjans, Jos; Vineis, Paolo; Chadeau-Hyam, Marc

2017-11-01

Long-term exposure to air pollution has been associated with several adverse health effects including cardiovascular, respiratory diseases and cancers. However, underlying molecular alterations remain to be further investigated. The aim of this study is to investigate the effects of long-term exposure to air pollutants on (a) average DNA methylation at functional regions and, (b) individual differentially methylated CpG sites. An assumption is that omic measurements, including the methylome, are more sensitive to low doses than hard health outcomes. This study included blood-derived DNA methylation (Illumina-HM450 methylation) for 454 Italian and 159 Dutch participants from the European Prospective Investigation into Cancer and Nutrition (EPIC). Long-term air pollution exposure levels, including NO 2 , NO x , PM 2.5 , PM coarse , PM 10 , PM 2.5 absorbance (soot) were estimated using models developed within the ESCAPE project, and back-extrapolated to the time of sampling when possible. We meta-analysed the associations between the air pollutants and global DNA methylation, methylation in functional regions and epigenome-wide methylation. CpG sites found differentially methylated with air pollution were further investigated for functional interpretation in an independent population (EnviroGenoMarkers project), where (N=613) participants had both methylation and gene expression data available. Exposure to NO 2 was associated with a significant global somatic hypomethylation (p-value=0.014). Hypomethylation of CpG island's shores and shelves and gene bodies was significantly associated with higher exposures to NO 2 and NO x . Meta-analysing the epigenome-wide findings of the 2 cohorts did not show genome-wide significant associations at single CpG site level. However, several significant CpG were found if the analyses were separated by countries. By regressing gene expression levels against methylation levels of the exposure-related CpG sites, we identified several significant CpG-transcript pairs and highlighted 5 enriched pathways for NO 2 and 9 for NO x mainly related to the immune system and its regulation. Our findings support results on global hypomethylation associated with air pollution, and suggest that the shores and shelves of CpG islands and gene bodies are mostly affected by higher exposure to NO 2 and NO x . Functional differences in the immune system were suggested by transcriptome analyses. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Assessment of toxicity and genotoxicity of low doses of 5-fluorouracil in zebrafish (Danio rerio) two-generation study.

PubMed

Kovács, Róbert; Csenki, Zsolt; Bakos, Katalin; Urbányi, Béla; Horváth, Ákos; Garaj-Vrhovac, Vera; Gajski, Goran; Gerić, Marko; Negreira, Noelia; López de Alda, Miren; Barceló, Damià; Heath, Ester; Kosjek, Tina; Žegura, Bojana; Novak, Matjaž; Zajc, Irena; Baebler, Špela; Rotter, Ana; Ramšak, Živa; Filipič, Metka

2015-06-15

Residues of anti-neoplastic drugs represent new and emerging pollutants in aquatic environments. Many of these drugs are genotoxic, and it has been postulated that they can cause adverse effects in aquatic ecosystems. 5-Fluorouracil (5-FU) is one of the most extensively used anti-neoplastic drugs in cancer therapy, and this article describes the results of the first investigation using a two-generation toxicity study design with zebrafish (Danio rerio). Exposure of zebrafish to 5-FU (0.01, 1.0 and 100 μg/L) was initiated with adult zebrafish (F0 generation) and continued through the hatchings and adults of the F1 generation, and the hatchings of the F2 generation, to day 33 post-fertilisation. The exposure did not affect survival, growth and reproduction of the zebrafish; however, histopathological changes were observed in the liver and kidney, along with genotoxic effects, at all 5-FU concentrations. Increases in DNA damage determined using the comet assay were significant in the liver and blood cells, but not in the gills and gonads. In erythrocytes, a significant, dose-dependent increase in frequency of micronuclei was observed at all 5-FU concentrations. Whole genome transcriptomic analysis of liver samples of F1 generation zebrafish exposed to 0.01 μg/L and 1 μg/L 5-FU revealed dose-dependent increases in the number of differentially expressed genes, including up-regulation of several DNA-damage-responsive genes and oncogenes (i.e., jun, myca). Although this chronic exposure to environmentally relevant concentrations of 5-FU did not affect the reproduction of the exposed zebrafish, it cannot be excluded that 5-FU can lead to degenerative changes, including cancers, which over long-term exposure of several generations might affect fish populations. The data from this study contribute to a better understanding of the potential consequences of chronic exposure of fish to low concentrations of anti-neoplastic drugs, and they demonstrate that further studies into multi-generation toxicity are needed. Copyright © 2015. Published by Elsevier Ltd.

Differential transcriptomic responses of Biomphalaria glabrata (Gastropoda, Mollusca) to bacteria and metazoan parasites, Schistosoma mansoni and Echinostoma paraensei (Digenea, Platyhelminthes)

PubMed Central

Adema, Coen M; Hanington, Patrick C.; Lun, Cheng-Man; Rosenberg, George H.; Aragon, Anthony D; Stout, Barbara A; Richard, Mara L. Lennard; Gross, Paul S.; Loker, Eric S

2009-01-01

A 70-mer oligonucleotide-based microarray (1152 features) that emphasizes stress and immune responses factors was constructed to study transcriptomic responses of the snail Biomphalaria glabrata to different immune challenges. In addition to sequences with relevant putative ID and Gene Ontology (GO) annotation, the array features non-immune factors and unknown B. glabrata ESTs for functional gene discovery. The transcription profiles of B. glabrata (3 biological replicates, each a pool of 5 snails) were recorded at 12 hours post wounding, exposure to Gram negative or Gram positive bacteria (Escherichia coli and Micrococcus luteus, respectively), or infection with compatible trematode parasites (S. mansoni or E. paraensei, 20 miracidia/snail), relative to controls, using universal reference RNA. The data were subjected to Significance Analysis for Microarrays (SAM), with a false positive rate (FPR) ≤10%. Wounding yielded a modest differential expression profile (27 up/21 down) with affected features mostly dissimilar from other treatments. Partially overlapping, yet distinct expression profiles were recorded from snails challenged with E. coli (83 up/20 down) or M. luteus (120 up/42 down), mostly showing up-regulation of defense and stress-related features. Significantly altered expression of selected immune features indicates that B. glabrata detects and responds differently to compatible trematodes. Echinostoma paraensei infection was associated mostly with down regulation of many (immune-) transcripts (42 up/68 down), whereas S. mansoni exposure yielded a preponderance of up-regulated features (140 up/23 down), with only few known immune genes affected. These observations may reflect the divergent strategies developed by trematodes during their evolution as specialized pathogens of snails to negate host defense responses. Clearly, the immune defenses of B. glabrata distinguish and respond differently to various immune challenges. PMID:19962194

Gene expression profiling of immune-competent human cells exposed to engineered zinc oxide or titanium dioxide nanoparticles.

PubMed

Tuomela, Soile; Autio, Reija; Buerki-Thurnherr, Tina; Arslan, Osman; Kunzmann, Andrea; Andersson-Willman, Britta; Wick, Peter; Mathur, Sanjay; Scheynius, Annika; Krug, Harald F; Fadeel, Bengt; Lahesmaa, Riitta

2013-01-01

A comprehensive in vitro assessment of two commercial metal oxide nanoparticles, TiO2 and ZnO, was performed using human monocyte-derived macrophages (HMDM), monocyte-derived dendritic cells (MDDC), and Jurkat T cell leukemia-derived cell line. TiO2 nanoparticles were found to be non-toxic whereas ZnO nanoparticles caused dose-dependent cell death. Subsequently, global gene expression profiling was performed to identify transcriptional response underlying the cytotoxicity caused by ZnO nanoparticles. Analysis was done with doses 1 µg/ml and 10 µg/ml after 6 and 24 h of exposure. Interestingly, 2703 genes were significantly differentially expressed in HMDM upon exposure to 10 µg/ml ZnO nanoparticles, while in MDDCs only 12 genes were affected. In Jurkat cells, 980 genes were differentially expressed. It is noteworthy that only the gene expression of metallothioneins was upregulated in all the three cell types and a notable proportion of the genes were regulated in a cell type-specific manner. Gene ontology analysis revealed that the top biological processes disturbed in HMDM and Jurkat cells were regulating cell death and growth. In addition, genes controlling immune system development were affected. Using a panel of modified ZnO nanoparticles, we obtained an additional support that the cellular response to ZnO nanoparticles is largely dependent on particle dissolution and show that the ligand used to modify ZnO nanoparticles modulates Zn(2+) leaching. Overall, the study provides an extensive resource of transcriptional markers for mediating ZnO nanoparticle-induced toxicity for further mechanistic studies, and demonstrates the value of assessing nanoparticle responses through a combined transcriptomics and bioinformatics approach.

Gene Expression Profiling of Immune-Competent Human Cells Exposed to Engineered Zinc Oxide or Titanium Dioxide Nanoparticles

PubMed Central

Tuomela, Soile; Autio, Reija; Buerki-Thurnherr, Tina; Arslan, Osman; Kunzmann, Andrea; Andersson-Willman, Britta; Wick, Peter; Mathur, Sanjay; Scheynius, Annika; Krug, Harald F.; Fadeel, Bengt; Lahesmaa, Riitta

2013-01-01

A comprehensive in vitro assessment of two commercial metal oxide nanoparticles, TiO2 and ZnO, was performed using human monocyte-derived macrophages (HMDM), monocyte-derived dendritic cells (MDDC), and Jurkat T cell leukemia-derived cell line. TiO2 nanoparticles were found to be non-toxic whereas ZnO nanoparticles caused dose-dependent cell death. Subsequently, global gene expression profiling was performed to identify transcriptional response underlying the cytotoxicity caused by ZnO nanoparticles. Analysis was done with doses 1 µg/ml and 10 µg/ml after 6 and 24 h of exposure. Interestingly, 2703 genes were significantly differentially expressed in HMDM upon exposure to 10 µg/ml ZnO nanoparticles, while in MDDCs only 12 genes were affected. In Jurkat cells, 980 genes were differentially expressed. It is noteworthy that only the gene expression of metallothioneins was upregulated in all the three cell types and a notable proportion of the genes were regulated in a cell type-specific manner. Gene ontology analysis revealed that the top biological processes disturbed in HMDM and Jurkat cells were regulating cell death and growth. In addition, genes controlling immune system development were affected. Using a panel of modified ZnO nanoparticles, we obtained an additional support that the cellular response to ZnO nanoparticles is largely dependent on particle dissolution and show that the ligand used to modify ZnO nanoparticles modulates Zn2+ leaching. Overall, the study provides an extensive resource of transcriptional markers for mediating ZnO nanoparticle-induced toxicity for further mechanistic studies, and demonstrates the value of assessing nanoparticle responses through a combined transcriptomics and bioinformatics approach. PMID:23894303

The NRF2-KEAP1 Pathway Is an Early Responsive Gene Network in Arsenic Exposed Lymphoblastoid Cells

PubMed Central

Córdova, Emilio J.; Martínez-Hernández, Angélica; Uribe-Figueroa, Laura; Centeno, Federico; Morales-Marín, Mirna; Koneru, Harsha; Coleman, Matthew A.; Orozco, Lorena

2014-01-01

Inorganic arsenic (iAs), a major environmental contaminant, has risen as an important health problem worldwide. More detailed identification of the molecular mechanisms associated with iAs exposure would help to establish better strategies for prevention and treatment. Although chronic iAs exposures have been previously studied there is little to no information regarding the early events of exposure to iAs. To better characterize the early mechanisms of iAs exposure we conducted gene expression studies using sublethal doses of iAs at two different time-points. The major transcripts differentially regulated at 2 hrs of iAs exposure included antioxidants, detoxificants and chaperones. Moreover, after 12 hrs of exposure many of the down-regulated genes were associated with DNA replication and S phase cell cycle progression. Interestingly, the most affected biological pathway by both 2 or 12 hrs of iAs exposure were the Nrf2-Keap1 pathway, represented by the highly up-regulated HMOX1 transcript, which is transcriptionally regulated by the transcription factor Nrf2. Additional Nrf2 targets included SQSTM1 and ABCB6, which were not previously associated with acute iAs exposure. Signalling pathways such as interferon, B cell receptor and AhR route were also responsive to acute iAs exposure. Since HMOX1 expression increased early (20 min) and was responsive to low iAs concentrations (0.1 µM), this gene could be a suitable early biomarker for iAs exposure. In addition, the novel Nrf2 targets SQSTM1 and ABCB6 could play an important and previously unrecognized role in cellular protection against iAs. PMID:24516582

Assessment of health risks resulting from early-life exposures: Are current chemical toxicity testing protocols and risk assessment methods adequate?

PubMed

Felter, Susan P; Daston, George P; Euling, Susan Y; Piersma, Aldert H; Tassinari, Melissa S

2015-03-01

Abstract Over the last couple of decades, the awareness of the potential health impacts associated with early-life exposures has increased. Global regulatory approaches to chemical risk assessment are intended to be protective for the diverse human population including all life stages. However, questions persist as to whether the current testing approaches and risk assessment methodologies are adequately protective for infants and children. Here, we review physiological and developmental differences that may result in differential sensitivity associated with early-life exposures. It is clear that sensitivity to chemical exposures during early-life can be similar, higher, or lower than that of adults, and can change quickly within a short developmental timeframe. Moreover, age-related exposure differences provide an important consideration for overall susceptibility. Differential sensitivity associated with a life stage can reflect the toxicokinetic handling of a xenobiotic exposure, the toxicodynamic response, or both. Each of these is illustrated with chemical-specific examples. The adequacy of current testing protocols, proposed new tools, and risk assessment methods for systemic noncancer endpoints are reviewed in light of the potential for differential risk to infants and young children.

Time trends and demographic differences in youth exposure to alcohol advertising on television.

PubMed

Ringel, Jeanne S; Collins, Rebecca L; Ellickson, Phyllis L

2006-10-01

To examine trends in youth exposure to alcohol advertising on television across different demographic groups. We used television ratings data on alcohol advertisements to examine trends in exposure between September 1998 and February 2002. Further, we explored the differences in exposure across demographic groups by examining group-level alcohol ad exposure across specific networks, program types, and times of day. We found that boys were more exposed than girls and African-Americans are more exposed than whites. Moreover, the race differential appeared to be increasing over time, whereas the gender differential appeared to increase with age. Differences in viewing patterns across race and gender contributed to the observed differences in exposure to alcohol advertising on television. These results provide guidance in identifying comparative vulnerabilities in exposure to alcohol advertising on television, and can aid in the development of strategies to inoculate youth against those vulnerabilities.

Jet fuel-induced immunotoxicity.

PubMed

Harris, D T; Sakiestewa, D; Titone, D; Robledo, R F; Young, R S; Witten, M

2000-09-01

Chronic exposure to jet fuel has been shown to cause human liver dysfunction, emotional dysfunction, abnormal electroencephalograms, shortened attention spans, and to decrease sensorimotor speed (3-5). Exposure to potential environmental toxicants such as jet fuel may have significant effects on host systems beyond those readily visible (e.g., physiology, cardiology, respiratory, etc.), e.g., the immune system. Significant changes in immune function, even if short-lived, may have serious consequences for the exposed host that may impinge affect susceptibility to infectious agents. Major alterations in immune function that are long lasting may result in an increased likelihood of development and/or progression of cancer, as well as autoimmune diseases. In the current study mice were exposed 1 h/day for 7 days to a 1000-mg/m3 concentration of aerosolized jet fuel obtained from various sources (JP-8, JP-8+100 and Jet A1) and of differing compositions to simulate occupational exposures. Twenty-four hours after the last exposure the mice were analyzed for effects on the immune system. It was observed that exposure to all jet fuel sources examined had detrimental effects on the immune system. Decreases in viable immune cell numbers and immune organ weights were found. Jet fuel exposure resulted in differential losses of immune cell populations in the thymus. Further, jet fuel exposure resulted in significantly decreased immune function, as analyzed by mitogenesis assays. Suppressed immune function could not be overcome by the addition of exogenous growth factors known to stimulate immune function. Thus, short-term, low-concentration exposure of mice to aerosolized jet fuel, regardless of source or composition, caused significant deleterious effects on the immune system.

Arrested neural and advanced mesenchymal differentiation of glioblastoma cells-comparative study with neural progenitors

PubMed Central

2009-01-01

Background Although features of variable differentiation in glioblastoma cell cultures have been reported, a comparative analysis of differentiation properties of normal neural GFAP positive progenitors, and those shown by glioblastoma cells, has not been performed. Methods Following methods were used to compare glioblastoma cells and GFAP+NNP (NHA): exposure to neural differentiation medium, exposure to adipogenic and osteogenic medium, western blot analysis, immunocytochemistry, single cell assay, BrdU incorporation assay. To characterize glioblastoma cells EGFR amplification analysis, LOH/MSI analysis, and P53 nucleotide sequence analysis were performed. Results In vitro differentiation of cancer cells derived from eight glioblastomas was compared with GFAP-positive normal neural progenitors (GFAP+NNP). Prior to exposure to differentiation medium, both types of cells showed similar multilineage phenotype (CD44+/MAP2+/GFAP+/Vimentin+/Beta III-tubulin+/Fibronectin+) and were positive for SOX-2 and Nestin. In contrast to GFAP+NNP, an efficient differentiation arrest was observed in all cell lines isolated from glioblastomas. Nevertheless, a subpopulation of cells isolated from four glioblastomas differentiated after serum-starvation with varying efficiency into derivatives indistinguishable from the neural derivatives of GFAP+NNP. Moreover, the cells derived from a majority of glioblastomas (7 out of 8), as well as GFAP+NNP, showed features of mesenchymal differentiation when exposed to medium with serum. Conclusion Our results showed that stable co-expression of multilineage markers by glioblastoma cells resulted from differentiation arrest. According to our data up to 95% of glioblastoma cells can present in vitro multilineage phenotype. The mesenchymal differentiation of glioblastoma cells is advanced and similar to mesenchymal differentiation of normal neural progenitors GFAP+NNP. PMID:19216795

Long-term programing of psychopathology-like behaviors in male rats by peripubertal stress depends on individual's glucocorticoid responsiveness to stress.

PubMed

Walker, Sophie E; Sandi, Carmen

2018-02-07

Experience of adversity early in life and dysregulation of hypothalamus-pituitary-adrenocortical (HPA) axis activity are risk factors often independently associated with the development of psychopathological disorders, including depression, PTSD and pathological aggression. Additional evidence suggests that in combination these factors may interact to shape the development and expression of psychopathology differentially, though little is known about underlying mechanisms. Here, we studied the long-term consequences of early life stress exposure on individuals with differential constitutive glucocorticoid responsiveness to repeated stressor exposure, assessing both socio-affective behaviors and brain activity in regions sensitive to pathological alterations following stress. Two rat lines, genetically selected for either low or high glucocorticoid responsiveness to repeated stress were exposed to a series of unpredictable, fear-inducing stressors on intermittent days during the peripuberty period. Results obtained at adulthood indicated that having high glucocorticoid responses to repeated stress and having experience of peripuberty stress independently enhanced levels of psychopathology-like behaviors, as well as increasing basal activity in several prefrontal and limbic brain regions in a manner associated with enhanced behavioral inhibition. Interestingly, peripuberty stress had a differential impact on aggression in the two rat lines, enhancing aggression in the low-responsive line but not in the already high-aggressive, high-responsive rats. Taken together, these findings indicate that aberrant HPA axis activity around puberty, a key period in the development of social repertoire in both rats and humans, may alter behavior such that it becomes anti-social in nature.

Thalidomide induces apoptosis in undifferentiated human induced pluripotent stem cells.

PubMed

Tachikawa, Saoko; Nishimura, Toshinobu; Nakauchi, Hiromitsu; Ohnuma, Kiyoshi

2017-10-01

Thalidomide, which was formerly available commercially to control the symptoms of morning sickness, is a strong teratogen that causes fetal abnormalities. However, the mechanism of thalidomide teratogenicity is not fully understood; thalidomide toxicity is not apparent in rodents, and the use of human embryos is ethically and technically untenable. In this study, we designed an experimental system featuring human-induced pluripotent stem cells (hiPSCs) to investigate the effects of thalidomide. These cells exhibit the same characteristics as those of epiblasts originating from implanted fertilized ova, which give rise to the fetus. Therefore, theoretically, thalidomide exposure during hiPSC differentiation is equivalent to that in the human fetus. We examined the effects of thalidomide on undifferentiated hiPSCs and early-differentiated hiPSCs cultured in media containing bone morphogenetic protein-4, which correspond, respectively, to epiblast (future fetus) and trophoblast (future extra-embryonic tissue). We found that only the number of undifferentiated cells was reduced. In undifferentiated cells, application of thalidomide increased the number of apoptotic and dead cells at day 2 but not day 4. Application of thalidomide did not affect the cell cycle. Furthermore, immunostaining and flow cytometric analysis revealed that thalidomide exposure had no effect on the expression of specific markers of undifferentiated and early trophectodermal differentiated cells. These results suggest that the effect of thalidomide was successfully detected in our experimental system and that thalidomide eliminated a subpopulation of undifferentiated hiPSCs. This study may help to elucidate the mechanisms underlying thalidomide teratogenicity and reveal potential strategies for safely prescribing this drug to pregnant women.

The effects of diazinon and cypermethrin on the differentiation of neuronal and glial cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Flaskos, J.; Harris, W.; Sachana, M.

2007-03-15

Diazinon and cypermethrin are pesticides extensively used in sheep dipping. Diazinon is a known anti-cholinesterase, but there is limited information regarding its molecular mechanism of action. This paper describes the effects of diazinon and cypermethrin at a morphological and molecular level on differentiating mouse N2a neuroblastoma and rat C6 glioma cell lines. Concentrations up to 10 {mu}M of both compounds and their mixture had no effect on the viability of either cell line, as determined by methyl blue tetrazolium reduction and total protein assays. Microscopic analysis revealed that 1 {mu}M and 10 {mu}M diazinon but not cypermethrin inhibited the outgrowthmore » of axon-like processes in N2a cells after a 24-h exposure but neither compound affected process outgrowth by differentiating C6 cells at these concentrations. Under these conditions, 10 {mu}M diazinon inhibited AChE slightly compared to the control after a 4-h exposure but not after 24 h. Western blotting analysis showed that morphological changes were associated with reduced cross-reactivity with antibodies that recognize the neurofilament heavy chain (NFH), microtubule associated protein MAP 1B and HSP-70 compared to control cell extracts, whereas reactivity with anti-{alpha}-tubulin antibodies was unchanged. Aggregation of NFH was observed in cell bodies of diazinon-treated N2a cells, as determined by indirect immunofluorescence staining. These data demonstrate that diazinon specifically targets neurite outgrowth in neuronal cells and that this effect is associated with disruption of axonal cytoskeleton proteins, whereas cypermethrin has no effect on the same parameters.« less

Harnessing cellular differentiation to improve ALA-based photodynamic therapy in an artificial skin model

NASA Astrophysics Data System (ADS)

Maytin, Edward; Anand, Sanjay; Sato, Nobuyuki; Mack, Judith; Ortel, Bernhard

2005-04-01

During ALA-based photodynamic therapy (PDT), a pro-drug (aminolevulinic acid; ALA) is taken up by tumor cells and metabolically converted to a photosensitizing intermediate (protoporphyrin IX; PpIX). ALA-based PDT, while an emerging treatment modality, remains suboptimal for most cancers (e.g. squamous cell carcinoma of the skin). Many treatment failures may be largely due to insufficient conversion of ALA to PpIX within cells. We discovered a novel way to increase the conversion of ALA to PpIX, by administering agents that can drive terminal differentiation (i.e., accelerate cellular maturation). Terminally-differentiated epithelial cells show higher levels of intracellular PpIX, apparently via increased levels of a rate-limiting enzyme, coproporphyrinogen oxidase (CPO). To study these mechanisms in a three-dimensional tissue, we developed an organotypic model that mimics true epidermal physiology in a majority of respects. A line of rat epidermal keratinocytes (REKs), when grown in raft cultures, displays all the features of a fully-differentiated epidermis. Addition of ALA to the culture medium results in ALA uptake and PpIX synthesis, with subsequent death of keratinocytes upon exposure to blue light. Using this model, we can manipulate cellular differentiation via three different approaches. (1) Vitamin D, a hormone that enhances keratinocyte differentiation; (2) Hoxb13, a nuclear transcription factor that affects the genetically-controlled differentiation program of stratifying cells (3) Hyaluronan, an abundant extracellular matrix molecule that regulates epidermal differentiation. Because the raft cultures contain only a single cell type (no blood, fibroblasts, etc.) the effects of terminal differentiation upon CPO, PpIX, and keratinocyte cell death can be specifically defined.

miRNA regulation of cytotoxic effects in mouse Sertoli cells exposed to nonylphenol

PubMed Central

2011-01-01

Background It is known that some environmental chemicals affect the human endocrine system. The harmful effects of endocrine disrupting chemical (EDC) nonylphenol (NP) have been studied since the 1980s. It is known that NP adversely affects physiological functions by mimicking the natural hormone 17 beta-estradiol. In the present study, we analyzed the expression of miRNAs and their target genes in mouse Sertoli TM4 cells to better understand the regulatory roles of miRNAs on Sertoli cells after NP exposure. Methods Mouse TM4 Sertoli cells were treated with NP for 3 or 24 h, and global gene and miRNA expression were analyzed using Agilent mouse whole genome and mouse miRNA v13 arrays. Results We identified genes that were > 2-fold differentially expressed in NP-treated cells and control cells (P < 0.05) and analyzed their functions through Gene Ontology analysis. We also identified miRNAs that were differentially expressed in NP-treated and control cells. Of the 186 miRNAs the expression of which differed between NP-treated and control cells, 59 and 147 miRNAs exhibited 1.3-fold increased or decreased expression at 3 and 24 h, respectively. Network analysis of deregulated miRNAs suggested that Ppara may regulate the expression of certain miRNAs, including miR-378, miR-125a-3p miR-20a, miR-203, and miR-101a, after exposure to NP. Additionally, comprehensive analysis of predicted target genes for miRNAs showed that the expression of genes with roles in cell proliferation, the cell cycle, and cell death were regulated by miRNA in NP-treated TM4 cells. Levels of expression of the miRNAs miR-135a* and miR-199a-5p were validated by qRT-PCR. Finally, miR-135a* target gene analysis suggests that the generation of reactive oxygen species (ROS) following exposure to NP exposure may be mediated by miR-135a* through regulation of the Wnt/beta-catenin signaling pathway. Conclusions Collectively, these data help to determine NP's actions on mouse TM4 Sertoli cells and increase our understanding of the molecular mechanisms underlying the adverse effects of xenoestrogens on the reproductive system. PMID:21914226

Conventional and Electronic cigarettes dysregulate the expression of iron transporters and detoxifying enzymes at the brain vascular endothelium: In Vivo Evidence of a Gender-Specific Cellular Response to Chronic Cigarette Smoke Exposure.

PubMed

Kaisar, Mohammad A; Sivandzade, Farzane; Bhalerao, Aditya; Cucullo, Luca

2018-06-04

It is well established that tobacco smoking is associated with vascular endothelial dysfunction in a causative and dose dependent manner primarily related to the tobacco smoke (TS) content of reactive oxygen species (ROS), nicotine, and oxidative stress (OS) -driven inflammation. Preclinical studies have also shown that nicotine (the principal e-liquid's ingredient used in e-cigarettes (e-Cigs) can also cause OS, exacerbation of cerebral ischemia and secondary brain injury. Likewise, chronic e-Cig vaping could be prodromal to vascular endothelial dysfunctions. Herein, we provide direct evidence that similarly to TS, e-Cig promotes mitochondrial depolarization in primary brain vascular endothelial cells as well as the vascular endothelial cell line bEnd3. In addition, both TS and e-Cig exposure upregulated the transmembrane iron exporter Slc40a1 (crucial to maintain cellular iron and redox homeostasis) and that of porphyrin importer Abcb6 (linked to accelerated atherosclerosis). We then investigated in vivo whether gender plays a role in how chronic TS affect vascular endothelial functions. Our results clearly show chronic TS exposure differentially impacts the expression levels of Phase-II enzymes as well as the iron transporters previously investigated in vitro. Although the physiological implications of the gender-specific differential responses to TS are not fully clear, they do demonstrate that gender is a risk factor that needs to be investigated when assessing the potential impact of chronic smoking and perhaps e-Cig vaping. Copyright © 2018. Published by Elsevier B.V.

Sex-specific microRNA expression networks in an acute mouse model of ozone-induced lung inflammation.

PubMed

Fuentes, Nathalie; Roy, Arpan; Mishra, Vikas; Cabello, Noe; Silveyra, Patricia

2018-05-08

Sex differences in the incidence and prognosis of respiratory diseases have been reported. Studies have shown that women are at increased risk of adverse health outcomes from air pollution than men, but sex-specific immune gene expression patterns and regulatory networks have not been well studied in the lung. MicroRNAs (miRNAs) are environmentally sensitive posttranscriptional regulators of gene expression that may mediate the damaging effects of inhaled pollutants in the lung, by altering the expression of innate immunity molecules. Male and female mice of the C57BL/6 background were exposed to 2 ppm of ozone or filtered air (control) for 3 h. Female mice were also exposed at different stages of the estrous cycle. Following exposure, lungs were harvested and total RNA was extracted. We used PCR arrays to study sex differences in the expression of 84 miRNAs predicted to target inflammatory and immune genes. We identified differentially expressed miRNA signatures in the lungs of male vs. female exposed to ozone. In silico pathway analyses identified sex-specific biological networks affected by exposure to ozone that ranged from direct predicted gene targeting to complex interactions with multiple intermediates. We also identified differences in miRNA expression and predicted regulatory networks in females exposed to ozone at different estrous cycle stages. Our results indicate that both sex and hormonal status can influence lung miRNA expression in response to ozone exposure, indicating that sex-specific miRNA regulation of inflammatory gene expression could mediate differential pollution-induced health outcomes in men and women.

Trait anxiety and attenuated negative affect differentiation: a vulnerability factor to consider?

PubMed

Matt, Lindsey M; Fresco, David M; Coifman, Karin G

2016-11-01

Describing emotional experiences using distinct terms, or affect differentiation, has been associated with emotion regulation and adaptive behavior under stress. There is little data, however, examining the association between differentiation and dispositional factors underlying psychopathology. The current study examines the association between differentiation and trait anxiety (TA) given prior evidence of cognitive biases in TA relevant to higher order processing of emotional experiences. We examined cross-sectionally, via lab-based repeated assessment, the association between differentiation of negative and positive experiences and TA. Two hundred twenty-two adults completed an emotion reactivity task including repeated assessments of affect. We hypothesized that individuals higher in trait anxiety (HTA) would have greater difficulty differentiating their experiences. HTA individuals exhibited lower levels of negative affect (NA) differentiation even when controlling for depression. Although negative emotion intensity was consistently associated with lower differentiation, this did not account for the influence of HTA on differentiation. These data suggest that HTA individuals have greater difficulty differentiating negative emotions, regardless of negative emotion intensity and depression. As HTA is common to many emotional disorders; this evidence suggests that poor differentiation may also be an important transdiagnostic consideration in models of risk and of affective disease.

Affect labeling enhances exposure effectiveness for public speaking anxiety.

PubMed

Niles, Andrea N; Craske, Michelle G; Lieberman, Matthew D; Hur, Christopher

2015-05-01

Exposure is an effective treatment for anxiety but many patients do not respond fully. Affect labeling (labeling emotional experience) attenuates emotional responding. The current project examined whether affect labeling enhances exposure effectiveness in participants with public speaking anxiety. Participants were randomized to exposure with or without affect labeling. Physiological arousal and self-reported fear were assessed before and after exposure and compared between groups. Consistent with hypotheses, participants assigned to Affect Labeling, especially those who used more labels during exposure, showed greater reduction in physiological activation than Control participants. No effect was found for self-report measures. Also, greater emotion regulation deficits at baseline predicted more benefit in physiological arousal from exposure combined with affect labeling than exposure alone. The current research provides evidence that behavioral strategies that target prefrontal-amygdala circuitry can improve treatment effectiveness for anxiety and these effects are particularly pronounced for patients with the greatest deficits in emotion regulation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Older and younger adults differently judge the similarity between negative affect terms.

PubMed

Ready, Rebecca E; Santorelli, Gennarina D; Mather, Molly A

2018-01-02

Theoretical models of aging suggest changes across the adult lifespan in the capacity to differentiate emotions. Greater emotion differentiation is associated with advantages in terms of emotion regulation and emotion resiliency. This study utilized a novel method that directly measures judgments of affect differentiation and does not confound affective experience with knowledge about affect terms. Theoretical predictions that older adults would distinguish more between affect terms than younger persons were tested. Older (n = 27; aged 60-92) and younger (n = 56; aged 18-32) adults rated the difference versus similarity of 16 affect terms from the Kessler and Staudinger ( 2009 ) scales; each of the 16 items was paired with every other item for a total of 120 ratings. Participants provided self-reports of trait emotions, alexithymia, and depressive symptoms. Older adults significantly differentiated more between low arousal and high arousal negative affect (NA) items than younger persons. Depressive symptoms were associated with similarity ratings across and within valence and arousal. Findings offer partial support for theoretical predictions that older adults differentiate more between affect terms than younger persons. To the extent that differentiating between negative affects can aid in emotion regulation, older adults may have an advantage over younger persons. Future research should investigate mechanisms that underlie age group differences in emotion differentiation.

Impact of cocaine on adult hippocampal neurogenesis in an animal model of differential propensity to drug abuse.

PubMed

García-Fuster, M J; Perez, J A; Clinton, S M; Watson, S J; Akil, H

2010-01-01

Hippocampal plasticity (e.g. neurogenesis) likely plays an important role in maintaining addictive behavior and/or relapse. This study assessed whether rats with differential propensity to drug-seeking behavior, bred Low-Responders (bLR) and bred High-Responders (bHR) to novelty, show differential neurogenesis regulation after cocaine exposure. Using specific immunological markers, we labeled distinct populations of adult stem cells in the dentate gyrus at different time-points of the cocaine sensitization process; Ki-67 for newly born cells, NeuroD for cells born partway, and 5-bromo-2'-deoxyuridine for older cells born prior to sensitization. Results show that: (i) bHRs exhibited greater psychomotor response to cocaine than bLRs; (ii) acute cocaine did not alter cell proliferation in bLR/bHR rats; (iii) chronic cocaine decreased cell proliferation in bLRs only, which became amplified through the course of abstinence; (iv) neither chronic cocaine nor cocaine abstinence affected the survival of immature neurons in either phenotype; (v) cocaine abstinence decreased survival of mature neurons in bHRs only, an effect that paralleled the greater psychomotor response to cocaine; and (vi) cocaine treatment did not affect the ratio of neurons to glia in bLR/bHR rats as most cells differentiated into neurons in both lines. Thus, cocaine exerts distinct effects on neurogenesis in bLR vs. bHR rats, with a decrease in the birth of new progenitor cells in bLRs and a suppression of the survival of new neurons in bHRs, which likely leads to an earlier decrease in formation of new connections. This latter effect in bHRs could contribute to their enhanced degree of cocaine-induced psychomotor behavioral sensitization.

Pulmonary exposure to carbonaceous nanomaterials and sperm quality.

PubMed

Skovmand, Astrid; Jacobsen Lauvås, Anna; Christensen, Preben; Vogel, Ulla; Sørig Hougaard, Karin; Goericke-Pesch, Sandra

2018-01-31

Semen quality parameters are potentially affected by nanomaterials in several ways: Inhaled nanosized particles are potent inducers of pulmonary inflammation, leading to the release of inflammatory mediators. Small amounts of particles may translocate from the lungs into the lung capillaries, enter the systemic circulation and ultimately reach the testes. Both the inflammatory response and the particles may induce oxidative stress which can directly affect spermatogenesis. Furthermore, spermatogenesis may be indirectly affected by changes in the hormonal milieu as systemic inflammation is a potential modulator of endocrine function. The aim of this study was to investigate the effects of pulmonary exposure to carbonaceous nanomaterials on sperm quality parameters in an experimental mouse model. Effects on sperm quality after pulmonary inflammation induced by carbonaceous nanomaterials were investigated by intratracheally instilling sexually mature male NMRI mice with four different carbonaceous nanomaterials dispersed in nanopure water: graphene oxide (18 μg/mouse/i.t.), Flammruss 101, Printex 90 and SRM1650b (0.1 mg/mouse/i.t. each) weekly for seven consecutive weeks. Pulmonary inflammation was determined by differential cell count in bronchoalveolar lavage fluid. Epididymal sperm concentration and motility were measured by computer-assisted sperm analysis. Epididymal sperm viability and morphological abnormalities were assessed manually using Hoechst 33,342/PI flourescent and Spermac staining, respectively. Epididymal sperm were assessed with regard to sperm DNA integrity (damage). Daily sperm production was measured in the testis, and testosterone levels were measured in blood plasma by ELISA. Neutrophil numbers in the bronchoalveolar fluid showed sustained inflammatory response in the nanoparticle-exposed groups one week after the last instillation. No significant changes in epididymal sperm parameters, daily sperm production or plasma testosterone levels were found. Despite the sustained pulmonary inflammatory response, an eight week exposure to graphene oxide, Flammruss 101, Printex 90 and the diesel particle SRM1650b in the present study did not appear to affect semen parameters, daily sperm production or testosterone concentration in male NMRI mice.

Differential impact of a complex environment on positive affect in an animal model of individual differences in emotionality.

PubMed

Perez-Sepulveda, J A; Flagel, S B; Garcia-Fuster, M J; Slusky, R J; Aldridge, J W; Watson, S; Akil, H

2013-09-17

Anhedonia, or the inability to experience positive feelings is a hallmark of depression. However, few animal models have relied on decreased positive affect as an index of susceptibility to depression. Rats emit frequency-modulated ultrasonic vocalizations (USVs), designated as "positive" calls in the 50-kHz range. USVs have been associated with pharmacological activation of motivational reward circuits. Here we utilized selectively-bred rats differing in "emotionality" to ask whether there are associated differences in USVs. Rats bred based on locomotor response to novelty and classified as bred High Responders (bHRs) or bred Low Responders (bLRs) exhibit inborn differences in response to environmental cues, stress responsiveness, and depression-like behavior. These animals also exhibit differences in anxiety-like behavior, which are reversed by exposure to environmental complexity (EC). Finally, these animals exhibit unique profiles of responsiveness to rewarding stimuli accompanied with distinct patterns of dopamine regulation. We investigated whether acute and chronic environmental manipulations impacted USVs in bHRs and bLRs. We found that, relative to bLRs, bHRs emitted significantly more 50-kHz USVs. However, if a bLR is accompanied by another bLR, there is a significant increase in 50-kHZ USVs emitted by this phenotype. bHRs emitted increases in 50-kHZ UVSs upon first exposure to EC, whereas bLRs showed a similar increase only after repeated exposure. bLRs' increase in positive affect after chronic EC was coupled with significant positive correlations between corticosterone levels and c-fos mRNA in the accumbens. Conversely, a decline in the rate of positive calls in bHRs after chronic EC was associated with a negative correlation between corticosterone and accumbens c-fos mRNA. These studies demonstrate that inborn differences in emotionality interact with the environment to influence positive affect and underscore the potential interaction between glucocorticoids and the mesolimbic reward circuitry in modulating 50-kHz calls. Published by Elsevier Ltd.

Relative sensitivity of developmental and immune parameters in juvenile versus adult male rats after exposure to di(2-ethylhexyl) phthalate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tonk, Elisa C.M., E-mail: ilse.tonk@rivm.nl; Laboratory for Health Protection Research, National Institute for Public Health and the Environment; Verhoef, Aart

The developing immune system displays a relatively high sensitivity as compared to both general toxicity parameters and to the adult immune system. In this study we have performed such comparisons using di(2-ethylhexyl) phthalate (DEHP) as a model compound. DEHP is the most abundant phthalate in the environment and perinatal exposure to DEHP has been shown to disrupt male sexual differentiation. In addition, phthalate exposure has been associated with immune dysfunction as evidenced by effects on the expression of allergy. Male wistar rats were dosed with corn oil or DEHP by gavage from postnatal day (PND) 10–50 or PND 50–90 atmore » doses between 1 and 1000 mg/kg/day. Androgen-dependent organ weights showed effects at lower dose levels in juvenile versus adult animals. Immune parameters affected included TDAR parameters in both age groups, NK activity in juvenile animals and TNF-α production by adherent splenocytes in adult animals. Immune parameters were affected at lower dose levels compared to developmental parameters. Overall, more immune parameters were affected in juvenile animals compared to adult animals and effects were observed at lower dose levels. The results of this study show a relatively higher sensitivity of juvenile versus adult rats. Furthermore, they illustrate the relative sensitivity of the developing immune system in juvenile animals as compared to general toxicity and developmental parameters. This study therefore provides further argumentation for performing dedicated developmental immune toxicity testing as a default in regulatory toxicology. -- Highlights: ► In this study we evaluate the relative sensitivities for DEHP induced effects. ► Results of this study demonstrate the age-dependency of DEHP toxicity. ► Functional immune parameters were more sensitive than structural immune parameters. ► Immune parameters were affected at lower dose levels than developmental parameters. ► Findings demonstrate the susceptibility of the developing immune system for DEHP.« less

Publicizing female athletes' weights: implications for female psychology undergraduates acting as spectators.

PubMed

Holm-Denoma, Jill; Smith, April; Waesche, Matthew

2014-09-01

The purpose of this study was to examine the effects of including female athletes' weights in athletic event programs on female spectators' body image, eating disorder symptoms, self-esteem, and affective state and to investigate whether the magnitude of the athletes' reported weights had differential effects on female spectators (i.e., do female spectators who view heavier athletes respond differently than those who view less heavy athletes?). We used an experimental design to examine hypotheses derived from competing theories to determine whether exposure to female athletes of varying weight would adversely or beneficially impact female undergraduates (N = 152) who served as athletic event spectators. Analyses indicated that in this simulated study, female spectators' body image, eating disorder symptoms, self-esteem, and affective states were not impacted by the presence or by the magnitude of female athletes' weights in athletic event programs. The results imply that including athletes' weights in game-day programs at women's athletic events does not affect female spectators on an individual level.

PRENATAL EXPOSURE TO THE FUNGICIDE PROCHLORAZ ALTERS THE ONSET OF PARTURITION IN THE DAM AND SEXUAL DIFFERENTIATION IN MALE RAT OFFSPRING

EPA Science Inventory

Prenatal Exposure to the Fungicide Prochloraz alters the onset of Parturition in
the Dam and Sexual Differentiation in Male Rat Offspring.
N. Noriega1; E. Gray1; J. Ostby1; C. Lambright1; V. Wilson1
1. RTD, NHEERL, ORD, USEPA, RTP, NC, USA;

Prochloraz...

Genetic and epigenetic variation in Spartina alterniflora following the Deepwater Horizon oil spill.

PubMed

Robertson, Marta; Schrey, Aaron; Shayter, Ashley; Moss, Christina J; Richards, Christina

2017-09-01

Catastrophic events offer unique opportunities to study rapid population response to stress in natural settings. In concert with genetic variation, epigenetic mechanisms may allow populations to persist through severe environmental challenges. In 2010, the Deepwater Horizon oil spill devastated large portions of the coastline along the Gulf of Mexico. However, the foundational salt marsh grass, Spartina alterniflora , showed high resilience to this strong environmental disturbance. Following the spill, we simultaneously examined the genetic and epigenetic structure of recovering populations of S. alterniflora to oil exposure. We quantified genetic and DNA methylation variation using amplified fragment length polymorphism and methylation sensitive fragment length polymorphism (MS-AFLP) to test the hypothesis that response to oil exposure in S. alterniflora resulted in genetically and epigenetically based population differentiation. We found high genetic and epigenetic variation within and among sites and found significant genetic differentiation between contaminated and uncontaminated sites, which may reflect nonrandom mortality in response to oil exposure. Additionally, despite a lack of genomewide patterns in DNA methylation between contaminated and uncontaminated sites, we found five MS-AFLP loci (12% of polymorphic MS-AFLP loci) that were correlated with oil exposure. Overall, our findings support genetically based differentiation correlated with exposure to the oil spill in this system, but also suggest a potential role for epigenetic mechanisms in population differentiation.

Prenatal alcohol exposure and cellular differentiation: a role for Polycomb and Trithorax group proteins in FAS phenotypes?

PubMed

Veazey, Kylee J; Muller, Daria; Golding, Michael C

2013-01-01

Exposure to alcohol significantly alters the developmental trajectory of progenitor cells and fundamentally compromises tissue formation (i.e., histogenesis). Emerging research suggests that ethanol can impair mammalian development by interfering with the execution of molecular programs governing differentiation. For example, ethanol exposure disrupts cellular migration, changes cell-cell interactions, and alters growth factor signaling pathways. Additionally, ethanol can alter epigenetic mechanisms controlling gene expression. Normally, lineage-specific regulatory factors (i.e., transcription factors) establish the transcriptional networks of each new cell type; the cell's identity then is maintained through epigenetic alterations in the way in which the DNA encoding each gene becomes packaged within the chromatin. Ethanol exposure can induce epigenetic changes that do not induce genetic mutations but nonetheless alter the course of fetal development and result in a large array of patterning defects. Two crucial enzyme complexes--the Polycomb and Trithorax proteins--are central to the epigenetic programs controlling the intricate balance between self-renewal and the execution of cellular differentiation, with diametrically opposed functions. Prenatal ethanol exposure may disrupt the functions of these two enzyme complexes, altering a crucial aspect of mammalian differentiation. Characterizing the involvement of Polycomb and Trithorax group complexes in the etiology of fetal alcohol spectrum disorders will undoubtedly enhance understanding of the role that epigenetic programming plays in this complex disorder.

Effects of Ionizing Radiation on Human Adipose Derived Mesenchymal Stem Cells and their Differentiation towards the Osteoblastic Lineage

NASA Astrophysics Data System (ADS)

Konda, Bikash; Baumstark-Khan, Christa; Hellweg, Christine; Reitz, Guenther; Lau, Patrick

Radiation exposure and musculoskeletal disuse are among the major challenges during space missions. Astronauts face the problem to lose bone calcium due to uncoupling of bone formation and resorption. Bone forming osteoblasts can be derived from the undifferentiated mesenchymal stem cell compartment (MSC). In this study, the ability of human adipose tissue derived stem cells (ATSC) to differentiate into the osteoblastic lineage was examined after radiation exposure in presence of medium supplementation with osteogenic additives (ß-glycerophosphate, ascorbic acid and dexamethasone). The SAOS-2 cell line (human osteosarcoma cell line) was used as control for osteoblastic differentiation. Changes in cellular morphology, cell cycle progression, as well as cellular radiation sensitivity were characterized after ionizing radiation exposure with X-rays and heavy ions (Ti). Rapidly proliferating SAOS-2 cells are less radiation-sensitive than slowly proliferating ATSC cells after X-ray (CFA: dose effect curves show D0 values of 1 Gy and 0.75 Gy for SAOS-2 and ATSC, respectively) exposure. Heavy ion (Ti) exposure resulted in a greater extent of cells accumulating in the G2/M phase of the cell cycle in a dose-dependent manner when compared to X-ray exposure. Differentiation of cells towards the osteoblastic lineage was quantified by hydroxyapatite (HA) deposition using Lonza OsteoImageTM mineralization assay. The deposition of HA after X- and Ti-irradiation for highly proliferating SAOS-2 cells showed a dose-dependent time delay while slowly proliferating ATSC showed no effect from radiation exposure. More detailed investigation is required to reveal the radiation dependent mechanism of bone loss in astronauts.

Grandmaternal stress during pregnancy and DNA methylation of the third generation: an epigenome-wide association study

PubMed Central

Serpeloni, F; Radtke, K; de Assis, S G; Henning, F; Nätt, D; Elbert, T

2017-01-01

Stress during pregnancy may impact subsequent generations, which is demonstrated by an increased susceptibility to childhood and adulthood health problems in the children and grandchildren. Although the importance of the prenatal environment is well reported with regards to future physical and emotional outcomes, little is known about the molecular mechanisms that mediate the long-term consequences of early stress across generations. Recent studies have identified DNA methylation as a possible mediator of the impact of prenatal stress in the offspring. Whether psychosocial stress during pregnancy also affects DNA methylation of the grandchildren is still not known. In the present study we examined the multigenerational hypothesis, that is, grandmaternal exposure to psychosocial stress during pregnancy affecting DNA methylation of the grandchildren. We determined the genome-wide DNA methylation profile in 121 children (65 females and 56 males) and tested for associations with exposure to grandmaternal interpersonal violence during pregnancy. We observed methylation variations of five CpG sites significantly (FDR<0.05) associated with the grandmother’s report of exposure to violence while pregnant with the mothers of the children. The results revealed differential methylation of genes previously shown to be involved in circulatory system processes (FDR<0.05). This study provides support for DNA methylation as a biological mechanism involved in the transmission of stress across generations and motivates further investigations to examine prenatal-dependent DNA methylation as a potential biomarker for health problems. PMID:28809857

Exposure to violence predicts poor educational outcomes in young children in South Africa and Malawi.

PubMed

Sherr, L; Hensels, I S; Skeen, S; Tomlinson, M; Roberts, K J; Macedo, A

2016-01-01

Violence during childhood may affect short and long-term educational factors. There is scant literature on younger children from resource poor settings. This study assessed child violence experiences (harsh punishment and exposure to domestic or community violence) and school enrolment, progress and attendance in children attending community-based organisations in South Africa and Malawi (n=989) at baseline and at 15 months' follow-up, examining differential experience of HIV positive, HIV affected and HIV unaffected children. Violence exposure was high: 45.4% experienced some form of psychological violence, 47.8% physical violence, 46.7% domestic violence and 41.8% community violence. Primary school enrolment was 96%. Violence was not associated with school enrolment at baseline but, controlling for baseline, children exposed to psychological violence for discipline were more than ten times less likely to be enrolled at follow-up (OR 0.09; 95% CI 0.01 to 0.57). Harsh discipline was associated with poor school progress. For children HIV positive a detrimental effect of harsh physical discipline was found on school performance (OR 0.10; 95% CI 0.02 to 0.61). Violence experiences were associated with a number of educational outcomes, which may have long-term consequences. Community-based organisations may be well placed to address such violence, with a particular emphasis on the challenges faced by children who are HIV positive. © The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.

Differential effects of tri-allelic 5-HTTLPR polymorphisms in healthy subjects on mood and stress performance after tryptophan challenge.

PubMed

Markus, C Rob; Firk, Christine

2009-12-01

Earlier data suggest that a polymorphism at the serotonin (5-HT) transporter gene (5-HTTLPR) may affect depression particularly in the face of stress due to interactions between 5-HT vulnerability and stress exposure. However, this interaction between 5-HT transporter-linked transcriptional promoter region (5-HTTLPR), 5-HT vulnerability and the affective effects of stress exposure has not yet been investigated. As participants with short-allele 5-HTTLPR genotypes may exhibit enhanced 5-HT vulnerability, this study examines the effects of tryptophan challenge on stress reactivity and performance in healthy participants with S'/S' vs L'/L' genotypes. Sixteen healthy subjects with homozygotic short alleles (S'/S'=S/L(G,) L(G)/L(G)) and 14 subjects with homozygotic long alleles (L'/L'=L(A)/L(A)) of the 5-HTTLPR were tested in a double-blind placebo-controlled design under acute stress exposure following tryptophan challenge or placebo. Although there were no 5-HTTLPR-related differences in stress responses, significant beneficial effects of tryptophan challenge on mood and stress performance were exclusively found in participants with S'/S' genotypes. These findings suggest greater brain 5-HT vulnerability to tryptophan manipulations in participants with S'/S' as compared with L'/L' 5-HTTLPR genotypes. This apparent genetic 5-HT vulnerability may become a meaningful risk factor for depression when brain 5-HT falls below functional need in the face of real severe stressful life events.

Lethal and sub-lethal responses of native freshwater mussels exposed to granular Bayluscide®, a sea lamprey larvicide

USGS Publications Warehouse

Newton, Teresa; Boogaard, Michael A.; Gray, Brian R.; Hubert, Terrance D.; Schloesser, Nicholas

2017-01-01

The invasive sea lamprey (Petromyzon marinus) poses a substantial threat to fish communities in the Great Lakes. Efforts to control sea lamprey populations typically involve treating tributary streams with lampricides on a recurring cycle. The presence of a substantial population of larval sea lampreys in the aquatic corridor between Lakes Huron and Erie prompted managers to propose a treatment using the granular formulation of Bayluscide® that targets larval sea lampreys that reside in sediments. However, these treatments could cause adverse effects on native freshwater mussels—imperiled animals that also reside in sediments. We estimated the risk of mortality and sub-lethal effects among eight species of adult and sub-adult mussels exposed to Bayluscide® for durations up to 8 h to mimic field applications. Mortality was appreciable in some species, especially in sub-adults (range, 23–51%). The lethal and sub-lethal effects were positively associated with the duration of exposure in most species and life stage combinations. Estimates of the median time of exposure that resulted in lethal and sub-lethal effects suggest that sub-adults were often affected by Bayluscide® earlier than adults. Siphoning activity and burrowing position of mussels during exposure may have moderated the uptake of Bayluscide® and may have influenced lethal and sub-lethal responses. Given that the various species and life stages were differentially affected, it will be difficult to predict the effects of Bayluscide® treatments on mussels.

Grandmaternal stress during pregnancy and DNA methylation of the third generation: an epigenome-wide association study.

PubMed

Serpeloni, F; Radtke, K; de Assis, S G; Henning, F; Nätt, D; Elbert, T

2017-08-15

Stress during pregnancy may impact subsequent generations, which is demonstrated by an increased susceptibility to childhood and adulthood health problems in the children and grandchildren. Although the importance of the prenatal environment is well reported with regards to future physical and emotional outcomes, little is known about the molecular mechanisms that mediate the long-term consequences of early stress across generations. Recent studies have identified DNA methylation as a possible mediator of the impact of prenatal stress in the offspring. Whether psychosocial stress during pregnancy also affects DNA methylation of the grandchildren is still not known. In the present study we examined the multigenerational hypothesis, that is, grandmaternal exposure to psychosocial stress during pregnancy affecting DNA methylation of the grandchildren. We determined the genome-wide DNA methylation profile in 121 children (65 females and 56 males) and tested for associations with exposure to grandmaternal interpersonal violence during pregnancy. We observed methylation variations of five CpG sites significantly (FDR<0.05) associated with the grandmother's report of exposure to violence while pregnant with the mothers of the children. The results revealed differential methylation of genes previously shown to be involved in circulatory system processes (FDR<0.05). This study provides support for DNA methylation as a biological mechanism involved in the transmission of stress across generations and motivates further investigations to examine prenatal-dependent DNA methylation as a potential biomarker for health problems.

Prenatal and lactational exposure to low-doses of bisphenol A alters adult mice behavior.

PubMed

Nakamura, Keiko; Itoh, Kyoko; Dai, Hongmei; Han, Longzhe; Wang, Xiaohang; Kato, Shingo; Sugimoto, Tohru; Fushiki, Shinji

2012-01-01

Bisphenol A (BPA) is an endocrine-disrupting chemical, widely used in dentistry and various industries. We previously reported that BPA affected murine neocortical development by accelerating neuronal differentiation/migration, resulting in abnormal neocortical architecture as well as aberrant thalamocortical connections in the brains of adult mice. The aim of this study was to investigate whether prenatal and lactational BPA exposure affected behavior in adult mice. Pregnant mice were injected subcutaneously with 20μg/kg of BPA daily from embryonic day 0 (E0) until postnatal day 21 (P21). Control animals received a vehicle alone. Behavioral tests (n=15-20) were conducted at postnatal 3weeks (P3W) and P10-15W. After an open-field test, an elevated plus maze and Morris water maze tests were performed. The total distance in the elevated plus maze test at P3W and in the open-field test at P10W was significantly decreased in the BPA-exposed group, compared with the control group. Significant sex differences were observed in the time spent in the central area in the open-field test at P3W and in the total distance in the elevated plus maze test at P11W. These results indicated that prenatal and lactational BPA exposure disturbed the murine behavior in the postnatal development period and the adult mice. Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Obesity-Induced Metabolic Stress Leads to Biased Effector Memory CD4+ T Cell Differentiation via PI3K p110δ-Akt-Mediated Signals.

PubMed

Mauro, Claudio; Smith, Joanne; Cucchi, Danilo; Coe, David; Fu, Hongmei; Bonacina, Fabrizia; Baragetti, Andrea; Cermenati, Gaia; Caruso, Donatella; Mitro, Nico; Catapano, Alberico L; Ammirati, Enrico; Longhi, Maria P; Okkenhaug, Klaus; Norata, Giuseppe D; Marelli-Berg, Federica M

2017-03-07

Low-grade systemic inflammation associated to obesity leads to cardiovascular complications, caused partly by infiltration of adipose and vascular tissue by effector T cells. The signals leading to T cell differentiation and tissue infiltration during obesity are poorly understood. We tested whether saturated fatty acid-induced metabolic stress affects differentiation and trafficking patterns of CD4 + T cells. Memory CD4 + T cells primed in high-fat diet-fed donors preferentially migrated to non-lymphoid, inflammatory sites, independent of the metabolic status of the hosts. This was due to biased CD4 + T cell differentiation into CD44 hi -CCR7 lo -CD62L lo -CXCR3 + -LFA1 + effector memory-like T cells upon priming in high-fat diet-fed animals. Similar phenotype was observed in obese subjects in a cohort of free-living people. This developmental bias was independent of any crosstalk between CD4 + T cells and dendritic cells and was mediated via direct exposure of CD4 + T cells to palmitate, leading to increased activation of a PI3K p110δ-Akt-dependent pathway upon priming. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Airway and serum adipokines after allergen and diesel exposure in a controlled human crossover study of atopic adults.

PubMed

Kramer, Marabeth M; Hirota, Jeremy A; Sood, Akshay; Teschke, Kay; Carlsten, Christopher

2017-04-01

Adipokines are mediators released from adipose tissue. These proteins are regarded as active elements of systemic and pulmonary inflammation, whose dysregulation can alter an individual's risk of developing allergic lung diseases. Despite this knowledge, adipokine responses to inhaled stimuli are poorly understood. We sought to measure serum and lung adiponectin, leptin, and resistin in an atopic adult study population following exposure to allergen and diesel exhaust (DE). Two types of lung samples including bronchoalveolar lavage (BAL) and bronchial wash (BW), and a time course of serum samples, were collected from the 18 subjects who participated in the randomized, double-blinded controlled human study. The two crossover exposure triads in this study were inhaled DE and filtered air each followed by instilled allergen or saline. Serum and lung adipokine responses to these exposures were quantified using enzyme-linked immunosorbent assay. Allergen significantly increased adiponectin and leptin in BAL, and adiponectin in the BW 48 hours after exposure. Serum leptin and resistin responses were not differentially affected by exposure, but varied over time. Coexposure with DE and allergen revealed significant correlations between the adiponectin/leptin ratio and FEV 1 changes and airway responsiveness measures. Changes in lung and serum adipokines in response to allergen exposure were identified in the context of a controlled exposure study. Coexposure identified a potentially protective role of adiponectin in the lung. This response was not observed in those with baseline airway hyper-responsiveness, or after allergen exposure alone. The clinical relevance of this potentially adaptive adipokine pattern warrants further study. Copyright © 2016 Elsevier Inc. All rights reserved.

[Effects of occupational exposure to pesticides on semen quality of workers in an agricultural community of Merida state, Venezuela].

PubMed

Miranda-Contreras, Leticia; Cruz, Ibis; Osuna, Jesús A; Gómez-Pérez, Roald; Berrueta, Lisbeth; Salmen, Siham; Colmenares, Melisa; Barreto, Silvio; Balza, Alirio; Morales, Yasmin; Zavala, Leisalba; Labarca, Emilitza; García, Nelly; Sanchez, Beluardi; Contreras, Carlos A; Andrade, Henry

2015-06-01

Numerous studies report adverse effects of pesticides on male reproductive health. The objectives of this study were to investigate whether there is a relationship between occupational exposure to pesticides and semen quality, and to determine whether chronic exposure to pesticides differentially affects semen quality in men of different ages. A comparative study of 64 farmers and 64 control men was performed. The farmers were interviewed to determine their occupational history and particularly, activities that may involve exposure to pesticides. Semen parameters were evaluated and a comparative analysis of semen variables between exposed and control groups, as well as between age groups: 18-29, 30-37 and 38-60 years was done. Significant alterations of some semen parameters in the exposed group were found, such as: decreases in sperm concentration, slow progressive motility and sperm membrane integrity; at the same time, increases in eosin Y positive and sperm DNA fragmentation index. The results obtained by age groups showed significant differences between exposed and control groups for the parameters of membrane integrity, eosin Y positive and sperm DNA fragmentation index, being the exposed group between 18-29 years that showed the highest altered cases of these parameters. Our results prove that occupational pesticide exposure is associated with alterations in sperm quality, creating a risk to farm workers in their reproductive capacity.

Treatment hurts: Lay theories of graded exposure in the treatment of four anxiety disorders

PubMed Central

Furnham, Adrian; Wilson, Emma; Chapman, Amy; Persuad, Raj

2013-01-01

Objective This paper concerned the perceived suffering/side effects caused by various well-known treatments for personal problems. It looked at whether people understood whether potentially painful treatments that confront negative aversive affect were effective or not. Method In total, 106 participants completed a long questionnaire assessing the ‘psychological pain’ ratings of 30 psychotherapy treatments, varying in fear exposure, for four relatively common anxiety disorders: social phobia, agoraphobia, post-traumatic stress disorder, and obsessive compulsive disorder. Results Factor analytic results revealed four clear factors underlying lay efficacy beliefs of psychotherapy interventions, varying in fear exposure: talking therapies, fear confrontation, fear avoidance, and alternative therapies. Talking therapies were rated the most effective across all disorders, but also the most painful. Fear avoidance therapies were rated the least effective and, along with alternative medicine, the least painful. Treatments involving fear exposure were rated the most painful. Regression analysis revealed talking therapies to be rated more efficacious by younger subjects than older subjects. Conclusion Most people seem able to differentiate between the efficacies of interventions for different anxiety disorders and hold consensually held optimistic conceptions about the usefulness of psychotherapy treatments and counseling that involve fear exposure, despite knowledge of the psychophysical side effects that these therapies often entail. They favored talking cures over others, but that may have been due to misleading items in the questionnaire. PMID:26405431

Inhalation of Hydrocarbon Jet Fuel Suppress Central Auditory Nervous System Function.

PubMed

Guthrie, O'neil W; Wong, Brian A; McInturf, Shawn M; Reboulet, James E; Ortiz, Pedro A; Mattie, David R

2015-01-01

More than 800 million L/d of hydrocarbon fuels is used to power cars, boats, and jet airplanes. The weekly consumption of these fuels necessarily puts the public at risk for repeated inhalation exposure. Recent studies showed that exposure to hydrocarbon jet fuel produces lethality in presynaptic sensory cells, leading to hearing loss, especially in the presence of noise. However, the effects of hydrocarbon jet fuel on the central auditory nervous system (CANS) have not received much attention. It is important to investigate the effects of hydrocarbons on the CANS in order to complete current knowledge regarding the ototoxic profile of such exposures. The objective of the current study was to determine whether inhalation exposure to hydrocarbon jet fuel might affect the functions of the CANS. Male Fischer 344 rats were randomly divided into four groups (control, noise, fuel, and fuel + noise). The structural and functional integrity of presynaptic sensory cells was determined in each group. Neurotransmission in both peripheral and central auditory pathways was simultaneously evaluated in order to identify and differentiate between peripheral and central dysfunctions. There were no detectable effects on pre- and postsynaptic peripheral functions. However, the responsiveness of the brain was significantly depressed and neural transmission time was markedly delayed. The development of CANS dysfunctions in the general public and the military due to cumulative exposure to hydrocarbon fuels may represent a significant but currently unrecognized public health issue.

Developmental ethanol exposure alters the morphology of mouse prefrontal neurons in a layer-specific manner.

PubMed

Louth, Emma L; Luctkar, Hanna D; Heney, Kayla A; Bailey, Craig D C

2018-01-01

Chronic developmental exposure to ethanol can lead to a wide variety of teratogenic effects, which in humans are known as fetal alcohol spectrum disorders (FASD). Individuals affected by FASD may exhibit persistent impairments to cognitive functions such as learning, memory, and attention, which are highly dependent on medial prefrontal cortex (mPFC) circuitry. The objective of this study was to determine long-term effects of chronic developmental ethanol exposure on mPFC neuron morphology, in order to better-understand potential neuronal mechanisms underlying cognitive impairments associated with FASD. C57BL/6-strain mice were exposed to ethanol or an isocaloric/isovolumetric amount of sucrose (control) via oral gavage, administered both to the dam from gestational day 10-18 and directly to pups from postnatal day 4-14. Brains from male mice were collected at postnatal day 90 and neurons were stained using a modified Golgi-Cox method. Pyramidal neurons within layers II/III, V and VI of the mPFC were imaged, traced in three dimensions, and assessed using Sholl and branch structure analyses. Developmental ethanol exposure differentially impacted adult pyramidal neuron morphology depending on mPFC cortical layer. Neurons in layer II/III exhibited increased size and diameter of dendrite trees, whereas neurons in layer V were not affected. Layer VI neurons with long apical dendrites had trees with decreased diameter that extended farther from the soma, and layer VI neurons with short apical dendrite trees exhibited decreased tree size overall. These layer-specific alterations to mPFC neuron morphology may form a novel morphological mechanism underlying long-term mPFC dysfunction and resulting cognitive impairments in FASD. Copyright © 2017 Elsevier B.V. All rights reserved.

Relationship between ketamine-induced developmental neurotoxicity and NMDA receptor-mediated calcium influx in neural stem cell-derived neurons.

PubMed

Wang, Cheng; Liu, Fang; Patterson, Tucker A; Paule, Merle G; Slikker, William

2017-05-01

Ketamine, a noncompetitive NMDA receptor antagonist, is used as a general anesthetic and recent data suggest that general anesthetics can cause neuronal damage when exposure occurs during early brain development. To elucidate the underlying mechanisms associated with ketamine-induced neurotoxicity, stem cell-derived models, such as rodent neural stem cells harvested from rat fetuses and/or neural stem cells derived from human induced pluripotent stem cells (iPSC) can be utilized. Prolonged exposure of rodent neural stem cells to clinically-relevant concentrations of ketamine resulted in elevated NMDA receptor levels as indicated by NR1subunit over-expression in neurons. This was associated with enhanced damage in neurons. In contrast, the viability and proliferation rate of undifferentiated neural stem cells were not significantly affected after ketamine exposure. Calcium imaging data indicated that 50μM NMDA did not cause a significant influx of calcium in typical undifferentiated neural stem cells; however, it did produce an immediate elevation of intracellular free Ca 2+ [Ca 2+ ] i in differentiated neurons derived from the same neural stem cells. This paper reviews the literature on this subject and previous findings suggest that prolonged exposure of developing neurons to ketamine produces an increase in NMDA receptor expression (compensatory up-regulation) which allows for a higher/toxic influx of calcium into neurons once ketamine is removed from the system, leading to neuronal cell death likely due to elevated reactive oxygen species generation. The absence of functional NMDA receptors in cultured neural stem cells likely explains why clinically-relevant concentrations of ketamine did not affect undifferentiated neural stem cell viability. Published by Elsevier B.V.

Exposure to multiple cholinergic pesticides impairs olfactory learning and memory in honeybees.

PubMed

Williamson, Sally M; Wright, Geraldine A

2013-05-15

Pesticides are important agricultural tools often used in combination to avoid resistance in target pest species, but there is growing concern that their widespread use contributes to the decline of pollinator populations. Pollinators perform sophisticated behaviours while foraging that require them to learn and remember floral traits associated with food, but we know relatively little about the way that combined exposure to multiple pesticides affects neural function and behaviour. The experiments reported here show that prolonged exposure to field-realistic concentrations of the neonicotinoid imidacloprid and the organophosphate acetylcholinesterase inhibitor coumaphos and their combination impairs olfactory learning and memory formation in the honeybee. Using a method for classical conditioning of proboscis extension, honeybees were trained in either a massed or spaced conditioning protocol to examine how these pesticides affected performance during learning and short- and long-term memory tasks. We found that bees exposed to imidacloprid, coumaphos, or a combination of these compounds, were less likely to express conditioned proboscis extension towards an odor associated with reward. Bees exposed to imidacloprid were less likely to form a long-term memory, whereas bees exposed to coumaphos were only less likely to respond during the short-term memory test after massed conditioning. Imidacloprid, coumaphos and a combination of the two compounds impaired the bees' ability to differentiate the conditioned odour from a novel odour during the memory test. Our results demonstrate that exposure to sublethal doses of combined cholinergic pesticides significantly impairs important behaviours involved in foraging, implying that pollinator population decline could be the result of a failure of neural function of bees exposed to pesticides in agricultural landscapes.

Prenatal Exposure to Progesterone Affects Sexual Orientation in Humans.

PubMed

Reinisch, June M; Mortensen, Erik Lykke; Sanders, Stephanie A

2017-07-01

Prenatal sex hormone levels affect physical and behavioral sexual differentiation in animals and humans. Although prenatal hormones are theorized to influence sexual orientation in humans, evidence is sparse. Sexual orientation variables for 34 prenatally progesterone-exposed subjects (17 males and 17 females) were compared to matched controls (M age = 23.2 years). A case-control double-blind design was used drawing on existing data from the US/Denmark Prenatal Development Project. Index cases were exposed to lutocyclin (bioidentical progesterone = C 21 H 30 O 2 ; M W : 314.46) and no other hormonal preparation. Controls were matched on 14 physical, medical, and socioeconomic variables. A structured interview conducted by a psychologist and self-administered questionnaires were used to collect data on sexual orientation, self-identification, attraction to the same and other sex, and history of sexual behavior with each sex. Compared to the unexposed, fewer exposed males and females identified as heterosexual and more of them reported histories of same-sex sexual behavior, attraction to the same or both sexes, and scored higher on attraction to males. Measures of heterosexual behavior and scores on attraction to females did not differ significantly by exposure. We conclude that, regardless of sex, exposure appeared to be associated with higher rates of bisexuality. Prenatal progesterone may be an underappreciated epigenetic factor in human sexual and psychosexual development and, in light of the current prevalence of progesterone treatment during pregnancy for a variety of pregnancy complications, warrants further investigation. These data on the effects of prenatal exposure to exogenous progesterone also suggest a potential role for natural early perturbations in progesterone levels in the development of sexual orientation.

Hypoxia-Related Hormonal Appetite Modulation in Humans during Rest and Exercise: Mini Review

PubMed Central

Debevec, Tadej

2017-01-01

Obesity is associated with numerous chronic ailments and represents one of the major health and economic issues in the modernized societies. Accordingly, there is an obvious need for novel treatment approaches. Recently, based on the reports of reduced appetite and subsequent weight loss following high-altitude sojourns, exposure to hypoxia has been proposed as a viable weight-reduction strategy. While altitude-related appetite modulation is complex and not entirely clear, hypoxia-induced alterations in hormonal appetite modulation might be among the key underlying mechanisms. The present paper summarizes the up-to-date research on hypoxia/altitude-induced changes in the gut and adipose tissue derived peptides related to appetite regulation. Orexigenic hormone ghrelin and anorexigenic peptides leptin, glucagon-like peptide-1, peptide YY, and cholecystokinin have to-date been investigated as potential modulators of hypoxia-driven appetite alterations. Current evidence suggests that hypoxia can, especially acutely, lead to decreased appetite, most probably via reduction of acylated ghrelin concentration. Hypoxia-related short and long-term changes in other hormonal markers are more unclear although hypoxia seems to importantly modulate leptin levels, especially following prolonged hypoxic exposures. Limited evidence also suggests that different activity levels during exposures to hypoxia do not additively affect hormonal appetite markers. Although very few studies have been performed in obese/overweight individuals, the available data indicate that hypoxia/altitude exposures do not seem to differentially affect appetite regulation via hormonal pathways in this cohort. Given the lack of experimental data, future well-controlled acute and prolonged studies are warranted to expand our understanding of hypoxia-induced hormonal appetite modulation and its kinetics in health and disease. PMID:28611686

Acute Ethanol Withdrawal Impairs Contextual Learning and Enhances Cued Learning

PubMed Central

Tipps, Megan E.; Raybuck, Jonathan D.; Buck, Kari J.; Lattal, K. Matthew

2014-01-01

Background Alcohol affects many of the brain regions and neural processes that support learning and memory, and these effects are thought to underlie, at least in part, the development of addiction. Although much work has been done regarding the effects of alcohol intoxication on learning and memory, little is known about the effects of acute withdrawal from a single alcohol exposure. Methods We assess the effects of acute ethanol withdrawal (6 h post-injection with 4 g/kg ethanol) on two forms of fear conditioning (delay and trace fear conditioning) in C57BL/6J and DBA/2J mice. The influence of a number of experimental parameters (pre- and post-training withdrawal exposure; foreground/background processing; training strength; non-associative effects) is also investigated. Results Acute ethanol withdrawal during training had a bidirectional effect on fear conditioned responses, decreasing contextual responses and increasing cued responses. These effects were apparent for both trace and delay conditioning in DBA/2J mice and for trace conditioning in C57BL/6J mice; however, C57BL/6J mice were selectively resistant to the effects of acute withdrawal on delay cued responses. Conclusions Our results show that acute withdrawal from a single, initial ethanol exposure is sufficient to alter long-term learning in mice. In addition, the differences between the strains and conditioning paradigms used suggest that specific learning processes can be differentially affected by acute withdrawal in a manner that is distinct from the reported effects of both alcohol intoxication and withdrawal following chronic alcohol exposure. Thus, our results suggest a unique effect of acute alcohol withdrawal on learning and memory processes. PMID:25684050

Exposure to multiple cholinergic pesticides impairs olfactory learning and memory in honeybees

PubMed Central

Williamson, Sally M.; Wright, Geraldine A.

2013-01-01

SUMMARY Pesticides are important agricultural tools often used in combination to avoid resistance in target pest species, but there is growing concern that their widespread use contributes to the decline of pollinator populations. Pollinators perform sophisticated behaviours while foraging that require them to learn and remember floral traits associated with food, but we know relatively little about the way that combined exposure to multiple pesticides affects neural function and behaviour. The experiments reported here show that prolonged exposure to field-realistic concentrations of the neonicotinoid imidacloprid and the organophosphate acetylcholinesterase inhibitor coumaphos and their combination impairs olfactory learning and memory formation in the honeybee. Using a method for classical conditioning of proboscis extension, honeybees were trained in either a massed or spaced conditioning protocol to examine how these pesticides affected performance during learning and short- and long-term memory tasks. We found that bees exposed to imidacloprid, coumaphos, or a combination of these compounds, were less likely to express conditioned proboscis extension towards an odor associated with reward. Bees exposed to imidacloprid were less likely to form a long-term memory, whereas bees exposed to coumaphos were only less likely to respond during the short-term memory test after massed conditioning. Imidacloprid, coumaphos and a combination of the two compounds impaired the bees' ability to differentiate the conditioned odour from a novel odour during the memory test. Our results demonstrate that exposure to sublethal doses of combined cholinergic pesticides significantly impairs important behaviours involved in foraging, implying that pollinator population decline could be the result of a failure of neural function of bees exposed to pesticides in agricultural landscapes. PMID:23393272

Additive effect between IL-13 polymorphism and cesarean section delivery/prenatal antibiotics use on atopic dermatitis: a birth cohort study (COCOA).

PubMed

Lee, So-Yeon; Yu, Jinho; Ahn, Kang-Mo; Kim, Kyung Won; Shin, Youn Ho; Lee, Kyung-Shin; Hong, Seo Ah; Jung, Young-Ho; Lee, Eun; Yang, Song-I; Seo, Ju-Hee; Kwon, Ji-Won; Kim, Byoung-Ju; Kim, Hyo-Bin; Kim, Woo-Kyung; Song, Dae Jin; Jang, Gwang Cheon; Shim, Jung Yeon; Lee, Soo-Young; Kwon, Ja-Young; Choi, Suk-Joo; Lee, Kyung-Ju; Park, Hee Jin; Won, Hye-Sung; Yoo, Ho-Sung; Kang, Mi-Jin; Kim, Hyung-Young; Hong, Soo-Jong

2014-01-01

Although cesarean delivery and prenatal exposure to antibiotics are likely to affect the gut microbiome in infancy, their effect on the development of atopic dermatitis (AD) in infancy is unclear. The influence of individual genotypes on these relationships is also unclear. To evaluate with a prospective birth cohort study whether cesarean section, prenatal exposure to antibiotics, and susceptible genotypes act additively to promote the development of AD in infancy. The Cohort for Childhood of Asthma and Allergic Diseases (COCOA) was selected from the general Korean population. A pediatric allergist assessed 412 infants for the presence of AD at 1 year of age. Their cord blood DNA was subjected to interleukin (IL)-13 (rs20541) and cluster-of-differentiation (CD)14 (rs2569190) genotype analysis. The combination of cesarean delivery and prenatal exposure to antibiotics associated significantly and positively with AD (adjusted odds ratio, 5.70; 95% CI, 1.19-27.3). The association between cesarean delivery and AD was significantly modified by parental history of allergic diseases or risk-associated IL-13 (rs20541) and CD14 (rs2569190) genotypes. There was a trend of interaction between IL-13 (rs20541) and delivery mode with respect to the subsequent risk of AD. (P for interaction = 0.039) Infants who were exposed prenatally to antibiotics and were born by cesarean delivery had a lower total microbiota diversity in stool samples at 6 months of age than the control group. As the number of these risk factors increased, the AD risk rose (trend p<0.05). Cesarean delivery and prenatal antibiotic exposure may affect the gut microbiota, which may in turn influence the risk of AD in infants. These relationships may be shaped by the genetic predisposition.

Preterm birth disrupts cerebellar development by affecting granule cell proliferation program and Bergmann glia.

PubMed

Iskusnykh, Igor Y; Buddington, Randal K; Chizhikov, Victor V

2018-08-01

Preterm birth is a leading cause of long-term motor and cognitive deficits. Clinical studies suggest that some of these deficits result from disruption of cerebellar development, but the mechanisms that mediate cerebellar abnormalities in preterm infants are largely unknown. Furthermore, it remains unclear whether preterm birth and precocious exposure to the ex-utero environment directly disrupt cerebellar development or indirectly by increasing the probability of cerebellar injury, including that resulting from clinical interventions and protocols associated with the care of preterm infants. In this study, we analyzed the cerebellum of preterm pigs delivered via c-section at 91% term and raised for 10 days, until term-equivalent age. The pigs did not receive any treatments known or suspected to affect cerebellar development and had no evidence of brain damage. Term pigs sacrificed at birth were used as controls. Immunohistochemical analysis revealed that preterm birth did not affect either size or numbers of Purkinje cells or molecular layer interneurons at term-equivalent age. The number of granule cell precursors and Bergmann glial fibers, however, were reduced in preterm pigs. Preterm pigs had reduced proliferation but not differentiation of granule cells. qRT-PCR analysis of laser capture microdissected external granule cell layer showed that preterm pigs had a reduced expression of Ccnd1 (Cyclin D1), Ccnb1 (Cyclin B1), granule cell master regulatory transcription factor Atoh1, and signaling molecule Jag1. In vitro rescue experiments identified Jag1 as a central granule cell gene affected by preterm birth. Thus, preterm birth and precocious exposure to the ex-utero environment disrupt cerebellum by modulating expression of key cerebellar developmental genes, predominantly affecting development of granule precursors and Bergmann glia. Copyright © 2018 Elsevier Inc. All rights reserved.

[Relationship between phthalates and testicular dysgenesis syndrome].

PubMed

Chen, Guo-Rong; Dong, Lei; Ge, Ren-Shan; Hardy, Matthew P

2007-03-01

Recent epidemiological evidence demonstrates that boys born to women exposed to phthalates during pregnancy have an increased incidence of cryptorchidism, hypospadias, testicular cancer and spermatogenic dysfunction, which are collectively referred to as testicular dysgenesis syndrome (TDS). TDS may be attributed to the dysfunction of Leydig cells and Sertoli cells during their differentiation after exposure to phthalates in utero. Fox example, Leydig cell functions are significantly affected by phthalates, leading to the decrease of two Leydig cell products--insulin-like growth factor 3 (INSL3) and testosterone, which are critical factors for testis descent. The disorientation of Leydig cells and Sertoli cells in the adult testis may be the cause of spermatogenic dysfunction.

MR signal-fat-fraction analysis and T2* weighted imaging measure BAT reliably on humans without cold exposure.

PubMed

Holstila, Milja; Pesola, Marko; Saari, Teemu; Koskensalo, Kalle; Raiko, Juho; Borra, Ronald J H; Nuutila, Pirjo; Parkkola, Riitta; Virtanen, Kirsi A

2017-05-01

Brown adipose tissue (BAT) is compositionally distinct from white adipose tissue (WAT) in terms of triglyceride and water content. In adult humans, the most significant BAT depot is localized in the supraclavicular area. Our aim is to differentiate brown adipose tissue from white adipose tissue using fat T2* relaxation time mapping and signal-fat-fraction (SFF) analysis based on a commercially available modified 2-point-Dixon (mDixon) water-fat separation method. We hypothesize that magnetic resonance (MR) imaging can reliably measure BAT regardless of the cold-induced metabolic activation, with BAT having a significantly higher water and iron content compared to WAT. The supraclavicular area of 13 volunteers was studied on 3T PET-MRI scanner using T2* relaxation time and SFF mapping both during cold exposure and at ambient temperature; and 18 F-FDG PET during cold exposure. Volumes of interest (VOIs) were defined semiautomatically in the supraclavicular fat depot, subcutaneous WAT and muscle. The supraclavicular fat depot (assumed to contain BAT) had a significantly lower SFF and fat T2* relaxation time compared to subcutaneous WAT. Cold exposure did not significantly affect MR-based measurements. SFF and T2* values measured during cold exposure and at ambient temperature correlated inversely with the glucose uptake measured by 18 F-FDG PET. Human BAT can be reliably and safely assessed using MRI without cold activation and PET-related radiation exposure. Copyright © 2017 Elsevier Inc. All rights reserved.

Unequal Exposure or Unequal Vulnerability? Contributions of Neighborhood Conditions and Cardiovascular Risk Factors to Socioeconomic Inequality in Incident Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis.

PubMed

Hussein, Mustafa; Diez Roux, Ana V; Mujahid, Mahasin S; Hastert, Theresa A; Kershaw, Kiarri N; Bertoni, Alain G; Baylin, Ana

2017-11-23

Risk factors can drive socioeconomic inequalities in cardiovascular disease (CVD) through differential exposure and differential vulnerability. We show how econometric decomposition directly enables simultaneous, policy-oriented assessment of these two mechanisms. We specifically estimated contributions via these mechanisms of neighborhood environment and proximal risk factors to socioeconomic inequality in CVD incidence. We followed 5,608 participants in the Multi-Ethnic Study of Atherosclerosis (2000-2012) until the first CVD event (median follow-up 12.2 years). We used a summary measure of baseline socioeconomic position (SEP). Covariates included baseline demographics, neighborhood, psychosocial, behavioral, and biomedical risk factors. Using Poisson models, we decomposed the difference (inequality) in incidence rates between low- and high-SEP groups into contributions of 1) differences in covariate means (differential exposure), and 2) differences in CVD risk associated with covariates (differential vulnerability). Notwithstanding large uncertainty in neighborhood estimates, our analysis suggests that differential exposure to poorer neighborhood socioeconomic conditions, adverse social environment, diabetes, and hypertension accounts for most of inequality. Psychosocial and behavioral contributions were negligible. Further, neighborhood SEP, female gender, and White race were more strongly associated with CVD among low-SEP (vs. high-SEP) participants. These differentials in vulnerability also accounted for nontrivial portions of the inequality, and could have important implications for intervention. © The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Neonatal diethylstilbestrol exposure alters the metabolic profile of uterine epithelial cells

PubMed Central

Yin, Yan; Lin, Congxing; Veith, G. Michael; Chen, Hong; Dhandha, Maulik; Ma, Liang

2012-01-01

SUMMARY Developmental exposure to diethylstilbestrol (DES) causes reproductive tract malformations, affects fertility and increases the risk of clear cell carcinoma of the vagina and cervix in humans. Previous studies on a well-established mouse DES model demonstrated that it recapitulates many features of the human syndrome, yet the underlying molecular mechanism is far from clear. Using the neonatal DES mouse model, the present study uses global transcript profiling to systematically explore early gene expression changes in individual epithelial and mesenchymal compartments of the neonatal uterus. Over 900 genes show differential expression upon DES treatment in either one or both tissue layers. Interestingly, multiple components of peroxisome proliferator-activated receptor-γ (PPARγ)-mediated adipogenesis and lipid metabolism, including PPARγ itself, are targets of DES in the neonatal uterus. Transmission electron microscopy and Oil-Red O staining further demonstrate a dramatic increase in lipid deposition in uterine epithelial cells upon DES exposure. Neonatal DES exposure also perturbs glucose homeostasis in the uterine epithelium. Some of these neonatal DES-induced metabolic changes appear to last into adulthood, suggesting a permanent effect of DES on energy metabolism in uterine epithelial cells. This study extends the list of biological processes that can be regulated by estrogen or DES, and provides a novel perspective for endocrine disruptor-induced reproductive abnormalities. PMID:22679223

Non-Thermal Atmospheric Pressure Plasma Efficiently Promotes the Proliferation of Adipose Tissue-Derived Stem Cells by Activating NO-Response Pathways

PubMed Central

Park, Jeongyeon; Lee, Hyunyoung; Lee, Hae June; Kim, Gyoo Cheon; Kim, Do Young; Han, Sungbum; Song, Kiwon

2016-01-01

Non-thermal atmospheric pressure plasma (NTAPP) is defined as a partially ionized gas with electrically charged particles at atmospheric pressure. Our study showed that exposure to NTAPP generated in a helium-based dielectric barrier discharge (DBD) device increased the proliferation of adipose tissue-derived stem cells (ASCs) by 1.57-fold on an average, compared with untreated cells at 72 h after initial NTAPP exposure. NTAPP-exposed ASCs maintained their stemness, capability to differentiate into adipocytes but did not show cellular senescence. Therefore, we suggested that NTAPP can be used to increase the proliferation of ASCs without affecting their stem cell properties. When ASCs were exposed to NTAPP in the presence of a nitric oxide (NO) scavenger, the proliferation-enhancing effect of NTAPP was not obvious. Meanwhile, the proliferation of NTAPP-exposed ASCs was not much changed in the presence of scavengers for reactive oxygen species (ROS). Also, Akt, ERK1/2, and NF-κB were activated in ASCs after NTAPP exposure. These results demonstrated that NO rather than ROS is responsible for the enhanced proliferation of ASCs following NTAPP exposure. Taken together, this study suggests that NTAPP would be an efficient tool for use in the medical application of ASCs both in vitro and in vivo. PMID:27991548

Genetic Diversity Influences the Response of the Brain to Developmental Lead Exposure

PubMed Central

Schneider, Jay S.; Talsania, Keyur; Mettil, William; Anderson, David W.

2014-01-01

Although extrinsic factors, such as nutritional status, and some intrinsic genetic factors may modify susceptibility to developmental lead (Pb) poisoning, no studies have specifically examined the influence of genetic background on outcomes from Pb exposure. In this study, we used gene microarray profiling to identify Pb-responsive genes in rats of different genetic backgrounds, including inbred (Fischer 344 (F344)) and outbred (Long Evans (LE), Sprague Dawley (SD)) strains, to investigate the role that genetic variation may play in influencing outcomes from developmental Pb exposure. Male and female animals received either perinatal (gestation through lactation) or postnatal (birth through weaning) exposure to Pb in food (0, 250, or 750 ppm). RNA was extracted from the hippocampus at day 55 and hybridized to Affymetrix Rat Gene 1.0 ST Arrays. There were significant strain-specific effects of Pb on the hippocampal transcriptome with 978 transcripts differentially expressed in LE rats across all experimental groups, 269 transcripts differentially expressed in F344 rats, and only 179 transcripts differentially expressed in SD rats. These results were not due to strain-related differences in brain accumulation of Pb. Further, no genes were consistently differentially regulated in all experimental conditions. There was no set of “Pb toxicity” genes that are a molecular signature for Pb neurotoxicity that transcended sex, exposure condition, and strain. These results demonstrate the influence that strain and genetic background play in modifying the brain's response to developmental Pb exposure and may have relevance for better understanding the molecular underpinnings of the lack of a neurobehavioral signature in childhood Pb poisoning. PMID:24913800

Differential Pro-Inflammatory Responses of Astrocytes and Microglia Involve STAT3 Activation in Response to 1800 MHz Radiofrequency Fields

PubMed Central

Lu, Yonghui; He, Mindi; Zhang, Yang; Xu, Shangcheng; Zhang, Lei; He, Yue; Chen, Chunhai; Liu, Chuan; Pi, Huifeng; Yu, Zhengping; Zhou, Zhou

2014-01-01

Microglia and astrocytes play important role in maintaining the homeostasis of central nervous system (CNS). Several CNS impacts have been postulated to be associated with radiofrequency (RF) electromagnetic fields exposure. Given the important role of inflammation in neural physiopathologic processes, we investigated the pro-inflammatory responses of microglia and astrocytes and the involved mechanism in response to RF fields. Microglial N9 and astroglial C8-D1A cells were exposed to 1800 MHz RF for different time with or without pretreatment with STAT3 inhibitor. Microglia and astrocytes were activated by RF exposure indicated by up-regulated CD11b and glial fibrillary acidic protein (GFAP). However, RF exposure induced differential pro-inflammatory responses in astrocytes and microglia, characterized by different expression and release profiles of IL-1β, TNF-α, IL-6, PGE2, nitric oxide (NO), inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2). Moreover, the RF exposure activated STAT3 in microglia but not in astrocytes. Furthermore, the STAT3 inhibitor Stattic ameliorated the RF-induced release of pro-inflammatory cytokines in microglia but not in astrocytes. Our results demonstrated that RF exposure differentially induced pro-inflammatory responses in microglia and astrocytes, which involved differential activation of STAT3 in microglia and astrocytes. Our data provide novel insights into the potential mechanisms of the reported CNS impacts associated with mobile phone use and present STAT3 as a promising target to protect humans against increasing RF exposure. PMID:25275372

Mediators and Treatment Factors in Intervention for Children Exposed to Interparental Violence.

PubMed

Overbeek, Mathilde M; De Schipper, J Clasien; Willemen, Agnes M; Lamers-Winkelman, Francien; Schuengel, Carlo

2017-01-01

Changes in children's emotion differentiation, coping skills, parenting stress, parental psychopathology, and parent-child interaction were explored as mediators of treatment factors in two selective preventive group interventions for children exposed to interparental violence (IPV) and their parents. One hundred thirty-four IPV-exposed children (ages 6-12 years, 52% boys) and their parents were randomized to an IPV-focused or common factors community-based group intervention and completed baseline, posttest, and follow-up assessments for posttraumatic stress (PTS). A multilevel model tested mediators that included children's ability to differentiate emotions and coping skills, parenting stress, parental psychopathology, and parent-child interactions. In both conditions, exposure to nonspecific factors, specific factors unrelated to IPV and trauma-specific intervention factors was coded from videotaped child and parent sessions. Improved parental mental health mediated the link between greater exposure to nonspecific treatment factors and decreases in PTS symptoms. In addition, an increase in emotion differentiation and a decrease in parenting stress were associated with a decrease in PTS symptoms. Greater exposure to trauma-specific factors in child sessions was associated with a small decrease in emotion differentiation, an increase in coping skills, and a decrease in PTS symptoms over time. Greater exposure to nonspecific treatment factors in child and parent sessions was associated with more positive parent-child interaction. Parental mental health appears to be an important mechanism of change that can be promoted through exposure to nonspecific factors in parent intervention. For children, the effect of greater exposure to trauma-specific factors in intervention is less clear and may not have clear benefits.

Differential pro-inflammatory responses of astrocytes and microglia involve STAT3 activation in response to 1800 MHz radiofrequency fields.

PubMed

Lu, Yonghui; He, Mindi; Zhang, Yang; Xu, Shangcheng; Zhang, Lei; He, Yue; Chen, Chunhai; Liu, Chuan; Pi, Huifeng; Yu, Zhengping; Zhou, Zhou

2014-01-01

Microglia and astrocytes play important role in maintaining the homeostasis of central nervous system (CNS). Several CNS impacts have been postulated to be associated with radiofrequency (RF) electromagnetic fields exposure. Given the important role of inflammation in neural physiopathologic processes, we investigated the pro-inflammatory responses of microglia and astrocytes and the involved mechanism in response to RF fields. Microglial N9 and astroglial C8-D1A cells were exposed to 1800 MHz RF for different time with or without pretreatment with STAT3 inhibitor. Microglia and astrocytes were activated by RF exposure indicated by up-regulated CD11b and glial fibrillary acidic protein (GFAP). However, RF exposure induced differential pro-inflammatory responses in astrocytes and microglia, characterized by different expression and release profiles of IL-1β, TNF-α, IL-6, PGE2, nitric oxide (NO), inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2). Moreover, the RF exposure activated STAT3 in microglia but not in astrocytes. Furthermore, the STAT3 inhibitor Stattic ameliorated the RF-induced release of pro-inflammatory cytokines in microglia but not in astrocytes. Our results demonstrated that RF exposure differentially induced pro-inflammatory responses in microglia and astrocytes, which involved differential activation of STAT3 in microglia and astrocytes. Our data provide novel insights into the potential mechanisms of the reported CNS impacts associated with mobile phone use and present STAT3 as a promising target to protect humans against increasing RF exposure.

Early exposure to interleukin-21 limits rapidly generated anti-Epstein-Barr virus T-cell line differentiation.

PubMed

Orio, Julie; Carli, Cédric; Janelle, Valérie; Giroux, Martin; Taillefer, Julie; Goupil, Mathieu; Richaud, Manon; Roy, Denis-Claude; Delisle, Jean-Sébastien

2015-04-01

The adoptive transfer of ex vivo-expanded Epstein-Barr virus (EBV)-specific T-cell lines is an attractive strategy to treat EBV-related neoplasms. Current evidence suggests that for adoptive immunotherapy in general, clinical responses are superior if the transferred cells have not reached a late or terminal effector differentiation phenotype before infusion. The cytokine interleukin (IL)-21 has shown great promise at limiting late T-cell differentiation in vitro, but this remains to be demonstrated in anti-viral T-cell lines. We adapted a clinically validated protocol to rapidly generate EBV-specific T-cell lines in 12 to 14 days and tested whether the addition of IL-21 at the initiation of the culture would affect T-cell expansion and differentiation. We generated clinical-scale EBV-restricted T-cell line expansion with balanced T-cell subset ratios. The addition of IL-21 at the beginning of the culture decreased both T-cell expansion and effector memory T-cell accumulation, with a relative increase in less-differentiated T cells. Within CD4 T-cell subsets, exogenous IL-21 was notably associated with the cell surface expression of CD27 and high KLF2 transcript levels, further arguing for a role of IL-21 in the control of late T-cell differentiation. Our results show that IL-21 has profound effects on T-cell differentiation in a rapid T-cell line generation protocol and as such should be further explored as a novel approach to program anti-viral T cells with features associated with early differentiation and optimal therapeutic efficacy. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Effects of Chronic Ethanol Consumption on Rat GABAA and Strychnine-sensitive Glycine Receptors Expressed by Lateral/Basolateral Amygdala Neurons

PubMed Central

McCool, Brian A.; Frye, Gerald D.; Pulido, Marisa D.; Botting, Shaleen K.

2010-01-01

It is well known that the anxiolytic potential of ethanol is maintained during chronic exposure. We have confirmed this using a light-dark box paradigm following chronic ethanol ingestion via a liquid diet. However, cessation from chronic ethanol exposure is known to cause severe withdrawal anxiety. These opposing effects on anxiety likely result from neuro-adaptations of neurotransmitter systems within the brain regions regulating anxiety. Recent work highlights the importance of amygdala ligand-gated chloride channels in the expression of anxiety. We have therefore examined the effects of chronic ethanol exposure on GABAA and strychnine-sensitive glycine receptors expressed by acutely isolated adult rat lateral/basolateral amygdala neurons. Chronic ethanol exposure increased the functional expression of GABAA receptors in acutely isolated basolateral amygdala neurons without altering strychnine-sensitive glycine receptors. Neither the acute ethanol nor benzodiazepine sensitivity of either receptor system was affected. We explored the likelihood that subunit composition might influence each receptor’s response to chronic ethanol. Importantly, when expressed in a mammalian heterologous system, GABAA receptors composed of unique α subunits were differentially sensitive to acute ethanol. Likewise, the presence of the β subunit appeared to influence the acute ethanol sensitivity of glycine receptors containing the α2 subunit. Our results suggest that the facilitation of GABAA receptors during chronic ethanol exposure may help explain the maintenance of ethanol’s anti-anxiety effects during chronic ethanol exposure. Furthermore, the subunit composition of GABAA and strychnine-sensitive glycine receptors may ultimately influence the response of each system to chronic ethanol exposure. PMID:12560122

Effects of chronic ethanol consumption on rat GABA(A) and strychnine-sensitive glycine receptors expressed by lateral/basolateral amygdala neurons.

PubMed

McCool, Brian A; Frye, Gerald D; Pulido, Marisa D; Botting, Shaleen K

2003-02-14

It is well known that the anxiolytic potential of ethanol is maintained during chronic exposure. We have confirmed this using a light-dark box paradigm following chronic ethanol ingestion via a liquid diet. However, cessation from chronic ethanol exposure is known to cause severe withdrawal anxiety. These opposing effects on anxiety likely result from neuro-adaptations of neurotransmitter systems within the brain regions regulating anxiety. Recent work highlights the importance of amygdala ligand-gated chloride channels in the expression of anxiety. We have therefore examined the effects of chronic ethanol exposure on GABA(A) and strychnine-sensitive glycine receptors expressed by acutely isolated adult rat lateral/basolateral amygdala neurons. Chronic ethanol exposure increased the functional expression of GABA(A) receptors in acutely isolated basolateral amygdala neurons without altering strychnine-sensitive glycine receptors. Neither the acute ethanol nor benzodiazepine sensitivity of either receptor system was affected. We explored the likelihood that subunit composition might influence each receptor's response to chronic ethanol. Importantly, when expressed in a mammalian heterologous system, GABA(A) receptors composed of unique alpha subunits were differentially sensitive to acute ethanol. Likewise, the presence of the beta subunit appeared to influence the acute ethanol sensitivity of glycine receptors containing the alpha(2) subunit. Our results suggest that the facilitation of GABA(A) receptors during chronic ethanol exposure may help explain the maintenance of ethanol's anti-anxiety effects during chronic ethanol exposure. Furthermore, the subunit composition of GABA(A) and strychnine-sensitive glycine receptors may ultimately influence the response of each system to chronic ethanol exposure.

An overview of confounding. Part 2: how to identify it and special situations.

PubMed

Howards, Penelope P

2018-04-01

Confounding biases study results when the effect of the exposure on the outcome mixes with the effects of other risk and protective factors for the outcome that are present differentially by exposure status. However, not all differences between the exposed and unexposed group cause confounding. Thus, sources of confounding must be identified before they can be addressed. Confounding is absent in an ideal study where all of the population of interest is exposed in one universe and is unexposed in a parallel universe. In an actual study, an observed unexposed population represents the unobserved parallel universe. Thinking about differences between this substitute population and the unexposed parallel universe helps identify sources of confounding. These differences can then be represented in a diagram that shows how risk and protective factors for the outcome are related to the exposure. Sources of confounding identified in the diagram should be addressed analytically and through study design. However, treating all factors that differ by exposure status as confounders without considering the structure of their relation to the exposure can introduce bias. For example, conditions affected by the exposure are not confounders. There are also special types of confounding, such as time-varying confounding and unfixable confounding. It is important to evaluate carefully whether factors of interest contribute to confounding because bias can be introduced both by ignoring potential confounders and by adjusting for factors that are not confounders. The resulting bias can result in misleading conclusions about the effect of the exposure of interest on the outcome. © 2018 Nordic Federation of Societies of Obstetrics and Gynecology.

[Effects of acute exposure to high altitude on hepatic function and CYP1A2 and CYP3A4 activities in rats].

PubMed

Li, Wenbin; Jia, Zhengping; Xie, Hua; Zhang, Juanhong; Wang, Yanling; Hao, Ying; Wang, Rong

2014-07-01

To investigate the changes in hepatic functions and activities of CYP1A2 and CYP3A4 in rats after acute exposure to high altitude. Twelve healthy male Wistar rats were randomly divided into control group and exposure group for acute exposure to normal and high altitude (4010 m) environment. Blood samples were collected from the vena orbitalis posterior for detection of the hepatic function. Hepatic pathologies of the rats were examined microscopically with HE staining. Liver microsomes were extracted by differential centrifugation to assess the activities of CYP1A2 and 3A4 using P450-GloTM kit. In rats with acute exposure to high altitude, AST, ALT, and ALP all increased significantly by 48.50%, 47.90%, and 103.02%, respectively, and TP decreased significantly by 17.80% as compared with those in rats maintained in normal altitude environment (P<0.05). Pathological examination of the liver revealed edema of the central vein of the liver and hepatocyte karyopyknosis in rats after acute exposure to high altitude, which also resulted in significantly lowered activities of CYP1A2 and 3A4 in the liver (by 96.56% and 43.53%, respectively). Acute exposure to high altitude can cause obvious liver injuries and lowered activities of CYP1A2 and 3A4 in rats to severely affect drug metabolism in the liver and result in increased concentration, prolonged half-life and reduced clearance of drugs.

Trait and state anxiety reduce the mere exposure effect

PubMed Central

Ladd, Sandra L.; Gabrieli, John D. E.

2015-01-01

The mere exposure effect refers to an affective preference elicited by exposure to previously unfamiliar items. Although it is a well-established finding, its mechanism remains uncertain, with some positing that it reflects affective processes and others positing that it reflects perceptual or motor fluency with repeated items. Here we examined whether individual differences in trait and state anxiety, which have been associated with the experience of emotion, influence the mere exposure effect. Participants’ trait (Study 1) and state (Study 2) anxiety were characterized with the State-Trait Anxiety Inventory. Greater trait and state anxiety correlated with greater negative affect and lesser positive affect. In both experiments, greater anxiety was associated with a reduced mere exposure effect. Measures of fluency (response times at study and test) were unrelated to the mere exposure effect. These findings support the role of affective processes in the mere exposure effect, and offer a new insight into the nature of anxiety such that anxiety is associated with a reduced experience of positive affect typically associated with familiarity. PMID:26074851

Trait and state anxiety reduce the mere exposure effect.

PubMed

Ladd, Sandra L; Gabrieli, John D E

2015-01-01

The mere exposure effect refers to an affective preference elicited by exposure to previously unfamiliar items. Although it is a well-established finding, its mechanism remains uncertain, with some positing that it reflects affective processes and others positing that it reflects perceptual or motor fluency with repeated items. Here we examined whether individual differences in trait and state anxiety, which have been associated with the experience of emotion, influence the mere exposure effect. Participants' trait (Study 1) and state (Study 2) anxiety were characterized with the State-Trait Anxiety Inventory. Greater trait and state anxiety correlated with greater negative affect and lesser positive affect. In both experiments, greater anxiety was associated with a reduced mere exposure effect. Measures of fluency (response times at study and test) were unrelated to the mere exposure effect. These findings support the role of affective processes in the mere exposure effect, and offer a new insight into the nature of anxiety such that anxiety is associated with a reduced experience of positive affect typically associated with familiarity.

Disruption of canonical TGFβ-signaling in murine coronary progenitor cells by low level arsenic

DOE Office of Scientific and Technical Information (OSTI.GOV)

Allison, Patrick; Huang, Tianfang; Broka, Derrick

2013-10-01

Exposure to arsenic results in several types of cancers as well as heart disease. A major contributor to ischemic heart pathologies is coronary artery disease, however the influences by environmental arsenic in this disease process are not known. Similarly, the impact of toxicants on blood vessel formation and function during development has not been studied. During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types including smooth muscle cells which contribute to the coronary vessels. The TGFβ family of ligands and receptors is essential for developmental cardiac epithelial to mesenchymal transition (EMT) and differentiation into coronarymore » smooth muscle cells. In this in vitro study, 18 hour exposure to 1.34 μM arsenite disrupted developmental EMT programming in murine epicardial cells causing a deficit in cardiac mesenchyme. The expression of EMT genes including TGFβ2, TGFβ receptor-3, Snail, and Has-2 are decreased in a dose-dependent manner following exposure to arsenite. TGFβ2 cell signaling is abrogated as detected by decreases in phosphorylated Smad2/3 when cells are exposed to 1.34 μM arsenite. There is also loss of nuclear accumulation pSmad due to arsenite exposure. These observations coincide with a decrease in vimentin positive mesenchymal cells invading three-dimensional collagen gels. However, arsenite does not block TGFβ2 mediated smooth muscle cell differentiation by epicardial cells. Overall these results show that arsenic exposure blocks developmental EMT gene programming in murine coronary progenitor cells by disrupting TGFβ2 signals and Smad activation, and that smooth muscle cell differentiation is refractory to this arsenic toxicity. - Highlights: • Arsenic blocks TGFβ2 induced expression of EMT genes. • Arsenic blocks TGFβ2 triggered Smad2/3 phosphorylation and nuclear translocation. • Arsenic blocks epicardial cell differentiation into cardiac mesenchyme. • Arsenic does not block TGFβ2 induced smooth muscle cell differentiation.« less

Subcellular proteomic analysis of host-pathogen interactions using human monocytes exposed to Yersinia pestis and Yersinia pseudotuberculosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, C G; Gonzales, A D; Choi, M W

2004-05-20

Yersinia pestis, the etiological agent of plague, is of concern to human health both from an infectious disease and a civilian biodefense perspective. While Y. pestis and Y. pseudotuberculosis share more than 90% DNA homology, they have significantly different clinical manifestations. Plague is often fatal if untreated, yet Y. pseudotuberculosis causes severe intestinal distress and is rarely fatal. A better understanding of host response to these closely related pathogens may help explain the different mechanisms of virulence and pathogenesis that result in such different clinical outcomes. The aim of this study was to characterize host protein expression changes in humanmore » monocyte-like U937 cells after exposure to Y. pestis and Y. pseudotuberculosis. In order to gain global proteomic coverage of host response, proteins from cytoplasmic, nuclear and membrane fractions of host cells were studied by 2-dimensional differential gel electrophoresis (2-D DIGE) and relative protein expression differences were quantitated. Differentially expressed proteins, with at least 1.5 fold expression changes and p values of 0.01 or less, were identified by MALDI-MS or LC/MS/MS. With these criteria, differential expression was detected in 16 human proteins after Y. pestis exposure and 13 human proteins after Y. pseudotuberculosis exposure, of which only two of the differentially expressed proteins identified were shared between the two exposures. Proteins identified in this study are reported to be involved in a wide spectrum of cellular functions and host defense mechanisms including apoptosis, cytoskeletal rearrangement, protein synthesis and degradation, DNA replication and transcription, metabolism, protein folding, and cell signaling. Notably, the differential expression patterns observed can distinguish the two pathogen exposures from each other and from unexposed host cells. The functions of the differentially expressed proteins identified provide insight on the different virulence and pathogenic mechanisms of Y. pestis and Y. pseudotuberculosis.« less

Effects of exposure to BPF on development and sexual differentiation during early life stages of zebrafish (Danio rerio).

PubMed

Yang, Qian; Yang, Xianhai; Liu, Jining; Chen, Yingwen; Shen, Shubao

2018-05-16

Bisphenol F (BPF) has become a predominant bisphenol contaminant in recent years. It has significant estrogenic properties in both in vivo and in vitro studies. We have previously studied the disrupting mechanisms of BPF on the hypothalamic-pituitary-gonadal axis of adult zebrafish. However, the effects of BPF exposure on development and sexual differentiation of zebrafish embryos/larvae remain unclear. To determine the effects of BPF on the critical stage of sex differentiation in zebrafish, zebrafish embryos/larvae were exposed to 1, 10, 100, and 1000 μg/L BPF from fertilization to 60 days post-fertilization (dpf). Developmental malformations were induced by exposure to BPF from 2 h post-fertilization (hpf), with a LC 50 of 10,030 μg/L at 96 hpf and 9391 μg/L at 120 hpf. Long-term exposure during sex differentiation tended to result in a female sex ratio bias. Histological analyses at 60 dpf indicated that the development of ovo-testes and immature ovaries was induced by 100 and 1000 μg/L BPF. Homogenate testosterone levels decreased and 17β-estradiol levels increased in zebrafish in a concentration-dependent manner. BPF exposure suppressed gene expression of double sex, Mab3-related transcription factor 1(dmrt1), fushi tarazu factor 1d (ff1d), sry-box containing gene 9a (sox9a) and anti-Mullerian hormone (amh); induced expression of the forkhead box L2 transcription factor (foxl2), leading to increased expression of aromatase (cyp19a1a), which promoted production of estrogens, and further caused phenotypic feminization of zebrafish. These results suggest that developmental exposure to BPF has adverse effects on sexual differentiation, and the results were useful for a BPF risk assessment. Copyright © 2018. Published by Elsevier Inc.

Chromatin remodeling agent trichostatin A: a key-factor in the hepatic differentiation of human mesenchymal stem cells derived of adult bone marrow

PubMed Central

Snykers, Sarah; Vanhaecke, Tamara; De Becker, Ann; Papeleu, Peggy; Vinken, Mathieu; Van Riet, Ivan; Rogiers, Vera

2007-01-01

Background The capability of human mesenchymal stem cells (hMSC) derived of adult bone marrow to undergo in vitro hepatic differentiation was investigated. Results Exposure of hMSC to a cocktail of hepatogenic factors [(fibroblast growth factor-4 (FGF-4), hepatocyte growth factor (HGF), insulin-transferrin-sodium-selenite (ITS) and dexamethasone)] failed to induce hepatic differentiation. Sequential exposure to these factors (FGF-4, followed by HGF, followed by HGF+ITS+dexamethasone), however, resembling the order of secretion during liver embryogenesis, induced both glycogen-storage and cytokeratin (CK)18 expression. Additional exposure of the cells to trichostatin A (TSA) considerably improved endodermal differentiation, as evidenced by acquisition of an epithelial morphology, chronological expression of hepatic proteins, including hepatocyte-nuclear factor (HNF)-3β, alpha-fetoprotein (AFP), CK18, albumin (ALB), HNF1α, multidrug resistance-associated protein (MRP)2 and CCAAT-enhancer binding protein (C/EBP)α, and functional maturation, i.e. upregulated ALB secretion, urea production and inducible cytochrome P450 (CYP)-dependent activity. Conclusion hMSC are able to undergo mesenchymal-to-epithelial transition. TSA is hereby essential to promote differentiation of hMSC towards functional hepatocyte-like cells. PMID:17407549

Prior irradiation and the development of coexistent differentiated thyroid cancer and hyperparathyroidism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Prinz, R.A.; Barbato, A.L.; Braithwaite, S.S.

1982-03-01

Twelve patients with coexistent well-differentiated thyroid carcinoma and primary hyperparathyoidism were studied to determine the frequency of previous radiation exposure. Eight were found to have received prior irradiation. External radiation was administered to the head and neck region for benign conditions such as tonsillar enlargement, acne, scrofula, and thyroid enlargement. One patient received 131I therapy for carcinoma of the thyroid. The observation that 67% of the patients in this series had previous radiation to the head and neck strongly implicates radiation exposure in the development of coexistent well-differentiated thyroid carcinoma and hyperparathyroidism.

Differential effects of herbicides atrazine and fenoxaprop-ethyl, and insecticides diazinon and malathion, on viability and maturation of porcine oocytes in vitro.

PubMed

Casas, Eduardo; Bonilla, Edmundo; Ducolomb, Yvonne; Betancourt, Miguel

2010-02-01

Exposure to pesticides may be a major cause of reproductive dysfunction in humans and animals. Atrazine and fenoxaprop-ethyl, widely used herbicides, and malathion and diazinon, organophosphate insecticides, are considered only slightly toxic to vertebrates; however, there is evidence of greater effects on reproductive function. The aim of this study was to evaluate the effect of these pesticides on oocyte viability and in vitro maturation. Gametes were matured in increasing concentrations of the pesticides and then stained with MTT to evaluate viability and bisbenzimide to assess the maturation stage, in the same oocyte. Atrazine had no effect on viability but maturation was significantly reduced, while fenoxaprop-ethyl affected both parameters. The insecticides affected viability and maturation but to a different degree. The four pesticides showed a more pronounced effect on maturation than on viability, due to a blockage at germinal vesicle stage.

Combined metabolome and proteome analysis of the mantle tissue from Pacific oyster Crassostrea gigas exposed to elevated pCO2.

PubMed

Wei, Lei; Wang, Qing; Ning, Xuanxuan; Mu, Changkao; Wang, Chunlin; Cao, Ruiwen; Wu, Huifeng; Cong, Ming; Li, Fei; Ji, Chenglong; Zhao, Jianmin

2015-03-01

Ocean acidification (OA) has been found to affect an array of normal physiological processes in mollusks, especially posing a significant threat to the fabrication process of mollusk shell. In the current study, the impact of exposure to elevated pCO2 condition was investigated in mantle tissue of Crassostrea gigas by an integrated metabolomic and proteomic approach. Analysis of metabolome and proteome revealed that elevated pCO2 could affect energy metabolism in oyster C. gigas, marked by differentially altered ATP, succinate, MDH, PEPCK and ALDH levels. Moreover, the up-regulated calponin-2, tropomyosins and myosin light chains indicated that elevated pCO2 probably caused disturbances in cytoskeleton structure in mantle tissue of oyster C. gigas. This work demonstrated that a combination of proteomics and metabolomics could provide important insights into the effects of OA at molecular levels. Copyright © 2014 Elsevier Inc. All rights reserved.

How Explicit and Implicit Test Instructions in an Implicit Learning Task Affect Performance

PubMed Central

Witt, Arnaud; Puspitawati, Ira; Vinter, Annie

2013-01-01

Typically developing children aged 5 to 8 years were exposed to artificial grammar learning. Following an implicit exposure phase, half of the participants received neutral instructions at test while the other half received instructions making a direct, explicit reference to the training phase. We first aimed to assess whether implicit learning operated in the two test conditions. We then evaluated the differential impact of age on learning performances as a function of test instructions. The results showed that performance did not vary as a function of age in the implicit instructions condition, while age effects emerged when explicit instructions were employed at test. However, performance was affected differently by age and the instructions given at test, depending on whether the implicit learning of short or long units was assessed. These results suggest that the claim that the implicit learning process is independent of age needs to be revised. PMID:23326409

Dual exposure interferometry. [gas dynamics and flow visualization

NASA Technical Reports Server (NTRS)

Smeets, G.; George, A.

1982-01-01

The application of dual exposure differential interferometry to gas dynamics and flow visualization is discussed. A differential interferometer with Wallaston prisms can produce two complementary interference fringe systems, depending on the polarization of the incident light. If these two systems are superimposed on a film, with one exposure during a phenomenon, the other before or after, the phenomenon will appear on a uniform background. By regulating the interferometer to infinite fringe distance, a resolution limit of approximately lambda/500 can be obtained in the quantitative analysis of weak phase objects. This method was successfully applied to gas dynamic investigations.

Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice.

PubMed

Schraut, K G; Jakob, S B; Weidner, M T; Schmitt, A G; Scholz, C J; Strekalova, T; El Hajj, N; Eijssen, L M T; Domschke, K; Reif, A; Haaf, T; Ortega, G; Steinbusch, H W M; Lesch, K P; Van den Hove, D L

2014-10-21

The serotonin transporter gene (5-HTT/SLC6A4)-linked polymorphic region has been suggested to have a modulatory role in mediating effects of early-life stress exposure on psychopathology rendering carriers of the low-expression short (s)-variant more vulnerable to environmental adversity in later life. The underlying molecular mechanisms of this gene-by-environment interaction are not well understood, but epigenetic regulation including differential DNA methylation has been postulated to have a critical role. Recently, we used a maternal restraint stress paradigm of prenatal stress (PS) in 5-HTT-deficient mice and showed that the effects on behavior and gene expression were particularly marked in the hippocampus of female 5-Htt+/- offspring. Here, we examined to which extent these effects are mediated by differential methylation of DNA. For this purpose, we performed a genome-wide hippocampal DNA methylation screening using methylated-DNA immunoprecipitation (MeDIP) on Affymetrix GeneChip Mouse Promoter 1.0 R arrays. Using hippocampal DNA from the same mice as assessed before enabled us to correlate gene-specific DNA methylation, mRNA expression and behavior. We found that 5-Htt genotype, PS and their interaction differentially affected the DNA methylation signature of numerous genes, a subset of which showed overlap with the expression profiles of the corresponding transcripts. For example, a differentially methylated region in the gene encoding myelin basic protein (Mbp) was associated with its expression in a 5-Htt-, PS- and 5-Htt × PS-dependent manner. Subsequent fine-mapping of this Mbp locus linked the methylation status of two specific CpG sites to Mbp expression and anxiety-related behavior. In conclusion, hippocampal DNA methylation patterns and expression profiles of female prenatally stressed 5-Htt+/- mice suggest that distinct molecular mechanisms, some of which are promoter methylation-dependent, contribute to the behavioral effects of the 5-Htt genotype, PS exposure and their interaction.

Embryotoxic and pharmacologic potency ranking of six azoles in the rat whole embryo culture by morphological and transcriptomic analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dimopoulou, Myrto, E-mail: myrto.dimopoulou@wur.nl

Differential gene expression analysis in the rat whole embryo culture (WEC) assay provides mechanistic insight into the embryotoxicity of test compounds. In our study, we hypothesized that comparative analysis of the transcriptomes of rat embryos exposed to six azoles (flusilazole, triadimefon, ketoconazole, miconazole, difenoconazole and prothioconazole) could lead to a better mechanism-based understanding of their embryotoxicity and pharmacological action. For evaluating embryotoxicity, we applied the total morphological scoring system (TMS) in embryos exposed for 48 h. The compounds tested showed embryotoxicity in a dose-response fashion. Functional analysis of differential gene expression after 4 h exposure at the ID{sub 10} (effectivemore » dose for 10% decreased TMS), revealed the sterol biosynthesis pathway and embryonic development genes, dominated by genes in the retinoic acid (RA) pathway, albeit in a differential way. Flusilazole, ketoconazole and triadimefon were the most potent compounds affecting the RA pathway, while in terms of regulation of sterol function, difenoconazole and ketoconazole showed the most pronounced effects. Dose-dependent analysis of the effects of flusilazole revealed that the RA pathway related genes were already differentially expressed at low dose levels while the sterol pathway showed strong regulation at higher embryotoxic doses, suggesting that this pathway is less predictive for the observed embryotoxicity. A similar analysis at the 24-hour time point indicated an additional time-dependent difference in the aforementioned pathways regulated by flusilazole. In summary, the rat WEC assay in combination with transcriptomics could add a mechanistic insight into the embryotoxic potency ranking and pharmacological mode of action of the tested compounds. - Highlights: • Embryonic exposure to azoles revealed concentration-dependent malformations. • Transcriptomics could enhance the mechanistic knowledge of embryotoxicants. • Retinoic acid gene set identifies early embryotoxic responses to azoles. • Toxic versus pharmacologic potency determines functional efficacy.« less

Prenatal arsenic exposure alters REST/NRSF and microRNA regulators of embryonic neural stem cell fate in a sex-dependent manner

PubMed Central

Tyler, Christina R.; Labrecque, Matthew T.; Solomon, Elizabeth R.; Guo, Xun; Allan, Andrea M.

2016-01-01

Exposure to arsenic, a common environmental toxin found in drinking water, leads to a host of neurological pathologies. We have previously demonstrated that developmental exposure to a low level of arsenic (50 ppb) alters epigenetic processes that underlie deficits in adult hippocampal neurogenesis leading to aberrant behavior. It is unclear if arsenic impacts the programming and regulation of embryonic neurogenesis during development when exposure occurs. The master negative regulator of neural-lineage, REST/NRSF, controls the precise timing of fate specification and differentiation of neural stem cells (NSCs). Early in development (embryonic day 14), we observed increased expression of Rest, its co-repressor, CoREST, and the inhibitory RNA binding/splicing protein, Ptbp1, and altered expression of mRNA spliced isoforms of Pbx1 that are directly regulated by these factors in the male brain in response to prenatal 50 ppb arsenic exposure. These increases were concurrent with decreased expression of microRNA-9 (miR-9), miR-9*, and miR-124, all of which are REST/NRSF targets and inversely regulate Rest expression to allow for maturation of NSCs. Exposure to arsenic decreased the formation of neuroblasts in vitro from NSCs derived from male pup brains. The female response to arsenic was limited to increased expression of CoREST and Ptbp2, an RNA binding protein that allows for appropriate splicing of genes involved in the progression of neurogenesis. These changes were accompanied by increased neuroblast formation in vitro from NSCs derived from female pups. Unexposed male mice express transcriptomic factors to induce differentiation earlier in development compared to unexposed females. Thus, arsenic exposure likely delays differentiation of NSCs in males while potentially inducing precocious differentiation in females early in development. These effects are mitigated by embryonic day 18 of development. Arsenic-induced dysregulation of the regulatory loop formed by REST/NRSF, its target microRNAs, miR-9 and miR-124, and RNA splicing proteins, PTBP1 and 2, leads to aberrant programming of NSC function that is perhaps perpetuated into adulthood inducing deficits in differentiation we have previously observed. PMID:27751817

Binge Toluene Exposure Alters Glutamate, Glutamine and GABA in the Adolescent Rat Brain as Measured by Proton Magnetic Resonance Spectroscopy*

PubMed Central

Perrine, Shane A.; O'Leary-Moore, Shonagh K.; Galloway, Matthew P.; Hannigan, John H.; Bowen, Scott E.

2010-01-01

Despite the high incidence of toluene abuse in adolescents, little is known regarding the effect of binge exposure on neurochemical profiles during this developmental stage. In the current study, the effects of binge toluene exposure during adolescence on neurotransmitter levels were determined using high-resolution proton magnetic resonance spectroscopy ex vivo at 11.7 T. Adolescent male Sprague-Dawley rats were exposed to toluene (0, 8,000 , or 12,000 ppm) for 15 min twice daily from postnatal day 28 (P28) through P34 and then euthanized either one or seven days later (on P35 or P42) to assess glutamate, glutamine, and GABA levels in intact tissue punches from the medial prefrontal cortex (mPFC), anterior striatum and hippocampus. In the mPFC, toluene reduced glutamate one day after exposure, with no effect on GABA, while after seven days, glutamate was no longer affected but there was an increase in GABA levels. In the hippocampus, neither GABA nor glutamate was altered one day after exposure, whereas seven days after exposure, increases were observed in GABA and glutamate. Striatal glutamate and GABA levels measured after either one or seven days were not altered after toluene exposure. These findings show that one week of binge toluene inhalation selectively alters these neurotransmitters in the mPFC and hippocampus in adolescent rats, and that some of these effects endure at least one week after the exposure. The results suggest that age-dependent, differential neurochemical responses to toluene may contribute to the unique behavioral patterns associated with drug abuse among older children and young teens. PMID:21126832

Microarray-based analysis of the lung recovery process after stainless-steel welding fume exposure in Sprague-Dawley rats.

PubMed

Oh, Jung-Hwa; Yang, Mi-jin; Yang, Young-Su; Park, Han-Jin; Heo, Sun Hee; Lee, Eun-Hee; Song, Chang-Woo; Yoon, Seokjoo

2009-02-01

Repeated exposure to welding fumes promotes a reversible increase in pulmonary disease risk, but the molecular mechanisms by which welding fumes induce lung injury and how the lung recovers from such insults are unclear. In the present study, pulmonary function and gene-expression profiles in the lung were analyzed by Affymetrix GeneChip microarray after 30 days of consecutive exposure to manual metal arc welding combined with stainless-steel (MMA-SS) welding fumes, and again after 30 days of recovery from MMA-SS fume exposure. In total, 577 genes were identified as being either up-regulated or down-regulated (over twofold changes, p < 0.05) in the lungs of low-dose or high-dose groups. Differentially expressed genes were classified based on a k-means clustering algorithm and biological functions and molecular networks were further analyzed using Ingenuity Pathways Analysis. Among the genes affected by exposure to or recovery from MMA-SS fumes, the transcriptional changes of 13 genes that were highly altered by treatment were confirmed by quantitative real-time PCR. Notably, Mmp12, Cd5l, Ccl7, Cxcl5, and Spp1 related to the immune response were up-regulated only in the exposure group, whereas Trem2, IgG-2a, Igh-1a, and Igh were persistently up-regulated in both the exposure and recovery groups. In addition, several genes that might play a role in the repair process of the lung were up-regulated exclusively in the recovery group. Collectively, these data may help elucidate the molecular mechanism of the recovery process of the lung after welding fume exposure.

Repeated exposure to immobilization or two different footshock intensities reveals differential adaptation of the hypothalamic-pituitary-adrenal axis.

PubMed

Rabasa, Cristina; Muñoz-Abellán, Cristina; Daviu, Núria; Nadal, Roser; Armario, Antonio

2011-05-03

Factors involved in adaptation to repeated stress are not well-characterized. For instance, acute footshock (FS) of high intensity appears to be less severe than immobilization (IMO) in light of the speed of post-stress recovery of the hypothalamic-pituitary-adrenal (HPA) axis and other physiological variables. However, repeated exposure to IMO consistently resulted in reduction of the HPA response to the same stressor (adaptation), whereas failure to adapt has been usually reported after FS. Thus, in the present work we directly compared the activation of HPA axis and other physiological changes in response to both acute and repeated exposure to IMO and two intensities of FS (medium and high) in adult male rats. Control rats were exposed to the FS boxes but they did not receive shocks. Daily repeated exposure to IMO resulted in significant adaptation of the overall ACTH and corticosterone responses to the stressor. Such a reduction was also observed with repeated exposure to FS boxes and FS-medium, whereas repeated exposure to FS-high only resulted in a small reduction of the corticosterone response during the post-stress period. This suggests that some properties of FS-high make adaptation to it difficult. Interestingly, overall changes in food intake and body weight gain throughout the week of exposure to the stressors reveal a greater impact of IMO than FS-high, indicating that factors other than the intensity of a stressor, at least when evaluated in function of the above physiological variables, can influence HPA adaptation. Since FS exposure is likely to cause more pain than IMO, activation of nociceptive signals above a certain level may negatively affect HPA adaptation to repeated stressors. Copyright © 2011 Elsevier Inc. All rights reserved.

Maternal Interpersonal Trauma and Child Social-Emotional Development: An Intergenerational Effect.

PubMed

Folger, Alonzo T; Putnam, Karen T; Putnam, Frank W; Peugh, James L; Eismann, Emily A; Sa, Ting; Shapiro, Robert A; Van Ginkel, Judith B; Ammerman, Robert T

2017-03-01

Evidence suggests that maternal interpersonal trauma can adversely affect offspring health, but little is known about potential transmission pathways. We investigated whether interpersonal trauma exposure had direct and indirect associations with offspring social-emotional development at 12-months of age in an at-risk, home visited population. A retrospective cohort study was conducted of 1172 mother-child dyads who participated in a multi-site, early childhood home visiting program. Children were born January 2007 to June 2010 and data were collected at enrolment (prenatal/birth) through 12-months of age. Multivariable path analyses were used to examine the relationship between maternal interpersonal trauma, subsequent psychosocial mediators (maternal depressive symptoms, social support, and home environment), and the outcome of child social-emotional development measured with the Ages and Stages Questionnaire: Social-Emotional (ASQ:SE). Maternal interpersonal trauma was characterized as any previous exposure, the level of exposure, and type (e.g. abuse) of exposure. The prevalence of maternal interpersonal trauma exposure was 69.1%, and exposures ranged from 1 type (19.3%) to 7 types (2.3%). Interpersonal trauma was associated with a 3.6 point (95% confidence interval 1.8, 5.4) higher ASQ:SE score among offspring and indicated greater developmental risk. An estimated 23.4% of the total effect was mediated by increased maternal depressive symptoms and lower social support. Differential effects were observed by the level and type of interpersonal trauma exposure. Maternal interpersonal trauma exposures can negatively impact child social-emotional development, acting in part through maternal psychosocial factors. Future research is needed to further elucidate the mechanisms of intergenerational risk. © 2017 John Wiley & Sons Ltd.

Testing the use of juvenile Salmo trutta L. as biomonitors of heavy metal pollution in freshwater.

PubMed

Lamas, S; Fernández, J A; Aboal, J R; Carballeira, A

2007-02-01

Individual specimens of Salmo trutta were captured, from four sampling sites in Galician rivers (NW Spain) affected by different types of contamination: diffuse urban waste, run-off from an unrestored dump at a copper mine and waste from a fish farm. The ages of the captured trouts were established and only those belonging to the 1+ age class were selected for study. The liver and kidney were removed from each fish and analysed to determine the tissue concentrations of Cu, Fe and Zn. The results obtained showed that: (i) the use of 1+ individuals allowed differentiation of contamination scenarios on the basis of the tissue concentrations of metal; (ii) the use of 1+ individuals allowed standardization of the time of exposure, which was sufficiently long for differential uptake to have taken place; (iii) liver tissue provided the best results as, less effort was required than for processing kidney tissue, and significant differences between sampling sites were detected because the intrapopulational variability in metal levels was lower than for kidney, and (iv) the levels of elements detected were not affected by basal tissue concentrations or residual concentrations due to past contamination, which older trouts may have been exposed to. In addition, the use of 1+ trout may provide better results in annual environmental sampling surveys.

Arsenic-induced alteration in the expression of genes related to type 2 diabetes mellitus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Diaz-Villasenor, Andrea; Burns, Anna L.; Facultad de Medicina, Universidad Nacional Autonoma de Mexico

2007-12-01

Chronic exposure to high concentrations of arsenic in drinking water is associated with an increased risk for developing type 2 diabetes. The present revision focuses on the effect of arsenic on tissues that participate directly in glucose homeostasis, integrating the most important published information about the impairment of the expression of genes related to type 2 diabetes by arsenic as one of the possible mechanisms by which it leads to the disease. Many factors are involved in the manner in which arsenic contributes to the occurrence of diabetes. The reviewed studies suggest that arsenic might increase the risk for typemore » 2 diabetes via multiple mechanisms, affecting a cluster of regulated events, which in conjunction trigger the disease. Arsenic affects insulin sensitivity in peripheral tissue by modifying the expression of genes involved in insulin resistance and shifting away cells from differentiation to the proliferation pathway. In the liver arsenic disturbs glucose production, whereas in pancreatic beta-cells arsenic decreases insulin synthesis and secretion and reduces the expression of antioxidant enzymes. The consequences of these changes in gene expression include the reduction of insulin secretion, induction of oxidative stress in the pancreas, alteration of gluconeogenesis, abnormal proliferation and differentiation pattern of muscle and adipocytes as well as peripheral insulin resistance.« less

Skin barrier disruption by sodium lauryl sulfate-exposure alters the expressions of involucrin, transglutaminase 1, profilaggrin, and kallikreins during the repair phase in human skin in vivo.

PubMed

Törmä, Hans; Lindberg, Magnus; Berne, Berit

2008-05-01

Detergents are skin irritants affecting keratinocytes. In this study, healthy volunteers were exposed to water (vehicle) and 1% sodium lauryl sulfate (SLS) under occlusive patch tests for 24 hours. The messenger RNA (mRNA) expression of keratinocyte differentiation markers and of enzymes involved in corneodesmosome degradation was examined in skin biopsies (n=8) during the repair phase (6 hours to 7 days postexposure) using real-time reverse-transcription PCR. It was found that the expression of involucrin was increased at 6 hours, but then rapidly normalized. The expression of transglutaminase 1 exhibited a twofold increase after 24 hours in the SLS-exposed skin. Profilaggrin was decreased after 6 hours. Later (4-7 days), the expression in SLS-exposed areas was >50% above than in control areas. An increased and altered immunofluorescence pattern of involucrin, transglutaminase 1, and filaggrin was also found (n=4). At 6 hours post-SLS exposure, the mRNA expression of kallikrein-7 (KLK-7) and kallikrein-5 (KLK-5) was decreased by 50 and 75%, respectively, as compared with control and water-exposed areas. Thereafter, the expression pattern of KLK-7 and KLK-5 was normalized. Changes in protein expression of KLK-5 were also found. In conclusion, SLS-induced skin barrier defects induce altered mRNA expression of keratinocyte differentiation markers and enzymes degrading corneodesmosomes.

Changes in Gene Expression of Arabidopsis Thaliana Cell Cultures Upon Exposure to Real and Simulated Partial- g Forces

NASA Astrophysics Data System (ADS)

Fengler, Svenja; Spirer, Ina; Neef, Maren; Ecke, Margret; Hauslage, Jens; Hampp, Rüdiger

2016-06-01

Cell cultures of the plant model organism Arabidopsis thaliana were exposed to partial- g forces during parabolic flight and clinostat experiments (0.16 g, 0.38 g and 0.5 g were tested). In order to investigate gravity-dependent alterations in gene expression, samples were metabolically quenched by the fixative RNA later Ⓡ to stabilize nucleic acids and used for whole-genome microarray analysis. An attempt to identify the potential threshold acceleration for the gravity-dependent response showed that the smaller the experienced g-force, the greater was the susceptibility of the cell cultures. Compared to short-term μ g during a parabolic flight, the number of differentially expressed genes under partial- g was lower. In addition, the effect on the alteration of amounts of transcripts decreased during partial- g parabolic flight due to the sequence of the different parabolas (0.38 g, 0.16 g and μ g). A time-dependent analysis under simulated 0.5 g indicates that adaptation occurs within minutes. Differentially expressed genes (at least 2-fold up- or down-regulated in expression) under real flight conditions were to some extent identical with those affected by clinorotation. The highest number of homologuous genes was detected within seconds of exposure to 0.38 g (both flight and clinorotation). To a considerable part, these genes deal with cell wall properties. Additionally, responses specific for clinorotation were observed.

Receptor for advanced glycation endproducts (RAGE) maintains pulmonary structure and regulates the response to cigarette smoke.

PubMed

Wolf, Lisa; Herr, Christian; Niederstraßer, Julia; Beisswenger, Christoph; Bals, Robert

2017-01-01

The receptor for advanced glycation endproducts (RAGE) is highly expressed in the lung but its physiological functions in this organ is still not completely understood. To determine the contribution of RAGE to physiological functions of the lung, we analyzed pulmonary mechanics and structure of wildtype and RAGE deficient (RAGE-/-) mice. RAGE deficiency spontaneously resulted in a loss of lung structure shown by an increased mean chord length, increased respiratory system compliance, decreased respiratory system elastance and increased concentrations of serum protein albumin in bronchoalveolar lavage fluids. Pulmonary expression of RAGE was mainly localized on alveolar epithelial cells and alveolar macrophages. Primary murine alveolar epithelial cells isolated from RAGE-/- mice revealed an altered differentiation and defective barrier formation under in vitro conditions. Stimulation of interferone-y (IFNy)-activated alveolar macrophages deficient for RAGE with Toll-like receptor (TLR) ligands resulted in significantly decreased release of proinflammatory cytokines and chemokines. Exposure to chronic cigarette smoke did not affect emphysema-like changes in lung parenchyma in RAGE-/- mice. Acute cigarette smoke exposure revealed a modified inflammatory response in RAGE-/- mice that was characterized by an influx of macrophages and a decreased keratinocyte-derived chemokine (KC) release. Our data suggest that RAGE regulates the differentiation of alveolar epithelial cells and impacts on the development and maintenance of pulmonary structure. In cigarette smoke-induced lung pathology, RAGE mediates inflammation that contributes to lung damage.

Morphological and transcriptomic effects of endocrine modulators on the gonadal differentiation of chicken embryos: The case of tributyltin (TBT).

PubMed

Scheider, Jessica; Afonso-Grunz, Fabian; Jessl, Luzie; Hoffmeier, Klaus; Winter, Peter; Oehlmann, Jörg

2018-03-01

Morphological malformations induced by tributyltin (TBT) exposure during embryonic development have already been characterized in various taxonomic groups, but, nonetheless, the molecular processes underlying these changes remain obscure. The present study provides the first genome-wide screening for differentially expressed genes that are linked to morphological alterations of gonadal tissue from chicken embryos after exposure to TBT. We applied a single injection of TBT (between 0.5 and 30 pg as Sn/g egg) into incubated fertile eggs to simulate maternal transfer of the endocrine disruptive compound. Methyltestosterone (MT) served as a positive control (30 pg/g egg). After 19 days of incubation, structural features of the gonads as well as genome-wide gene expression profiles were assessed simultaneously. TBT induced significant morphological and histological malformations of gonadal tissue from female embryos that show a virilization of the ovaries. This phenotypical virilization was mirrored by altered expression profiles of sex-dependent genes. Among these are several transcription and growth factors (e.g. FGF12, CTCF, NFIB), whose altered expression might serve as a set of markers for early identification of endocrine active chemicals that affect embryonic development by transcriptome profiling without the need of elaborate histological analyses. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

Formaldehyde exposure impairs the function and differentiation of NK cells.

PubMed

Kim, Eun-Mi; Lee, Hwa-Youn; Lee, Eun-Hee; Lee, Ki-Mo; Park, Min; Ji, Kon-Young; Jang, Ji-Hun; Jeong, Yun-Hwa; Lee, Kwang-Ho; Yoon, Il-Joo; Kim, Su-Man; Jeong, Moon-Jin; Kim, Kwang Dong; Kang, Hyung-Sik

2013-11-25

We investigated the cytotoxic effects of formaldehyde (FA) on lymphocytes. FA-exposed mice showed a profound reduction not only in the number of natural killer (NK) cells but also in the expression of NK cell-specific receptors, but these mice did not exhibit decreases in the numbers of T or B lymphocytes. FA exposure also induced decreases in NK cytolytic activity and in the expression of NK cell-associated genes, such as IFN-γ, perforin and CD122. To determine the effect of FA on tumorigenicity, C57BL/6 mice were subcutaneously injected with B16F10 melanoma cells after FA exposure. The mass of the B16F10 tumor and the concentration of extravascular polymorphonuclear leukocytes were greater than those in unexposed tumor-bearing control mice. The number and cytolytic activity of NK cells were also reduced in B16F10 tumor-bearing mice exposed to FA. To determine how FA reduces the NK cell number, NK precursor (pNK) cells were treated with FA, and the differentiation status of the NK cells was analyzed. NK cell differentiation was impaired by FA treatment in a concentration-dependent manner. These findings indicate that FA exposure may promote tumor progression by impairing NK cell function and differentiation. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Differential pulmonary and cardiac effects of pulmonary exposure to a panel of PM-associated metals

EPA Science Inventory

Biological mechanisms underlying the epidemiological association between exposure to particulate matter (PM) and increased risk of cardiovascular health effects are under investigation. Water soluble metals reaching systemic circulation following pulmonary exposure are likely exe...

ZINC-DEFICIENCY ENHANCES PRO-INFLAMMATORY RESPONSES AFTER OZONE EXPOSURE

EPA Science Inventory

Epidemiological and controlled exposure studies have demonstrated that humans are differentially susceptible to adverse health effects induced by exposure to ozone. Serum analysis of vitamins and trace elements have shown that the elderly (people >65 years) are deficient in sever...

DEVELOPMENT OF MICROARRAYS AS A TOOL FOR DISCOVERING ENVIRONMENTAL EXPOSURE INDICATORS

EPA Science Inventory

Toxicogenomics includes research to identify differential gene expression in laboratory and field animals exposed to toxicants, and ultimately, to link the earliest indicators of exposure to adverse effects in organisms and populations. The USEPA National Exposure Research Labor...

Genetic modification of human mesenchymal stem cells helps to reduce adiposity and improve glucose tolerance in an obese diabetic mouse model.

PubMed

Sen, Sabyasachi; Domingues, Cleyton C; Rouphael, Carol; Chou, Cyril; Kim, Chul; Yadava, Nagendra

2015-12-09

Human mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into fat, muscle, bone and cartilage cells. Exposure of subcutaneous abdominal adipose tissue derived AD-MSCs to high glucose (HG) leads to superoxide accumulation and up-regulation of inflammatory molecules. Our aim was to inquire how HG exposure affects MSCs differentiation and whether the mechanism is reversible. We exposed human adipose tissue derived MSCs to HG (25 mM) and compared it to normal glucose (NG, 5.5 mM) exposed cells at 7, 10 and 14 days. We examined mitochondrial superoxide accumulation (Mitosox-Red), cellular oxygen consumption rate (OCR, Seahorse) and gene expression. HG increased reactive superoxide (ROS) accumulation noted by day 7 both in cytosol and mitochondria. The OCR between the NG and HG exposed groups however did not change until 10 days at which point OCR of HG exposed cells were reduced significantly. We noted that HG exposure upregulated mRNA expression of adipogenic (PPARG, FABP-4, CREBP alpha and beta), inflammatory (IL-6 and TNF alpha) and antioxidant (SOD2 and Catalase) genes. Next, we used AdSOD2 to upregulate SOD2 prior to HG exposure and thereby noted reduction in superoxide generation. SOD2 upregulation helped reduce mRNA over-expression of PPARG, FABP-4, IL-6 and TNFα. In a series of separate experiments, we delivered the eGFP and SOD2 upregulated MSCs (5 days post ex-vivo transduction) and saline intra-peritoneally (IP) to obese diabetic (db/db) mice. We confirmed homing-in of eGFP labeled MSCs, delivered IP, to different inflamed fat pockets, particularly omental fat. Mice receiving SOD2-MSCs showed progressive reduction in body weight and improved glucose tolerance (GTT) at 4 weeks, post MSCs transplantation compared to the GFP-MSC group (control). High glucose evokes superoxide generation, OCR reduction and adipogenic differentiation. Mitochondrial superoxide dismutase upregulation quenches excess superoxide and reduces adipocyte inflammation. Delivery of superoxide dismutase (SOD2) using MSCs as a gene delivery vehicle reduces inflammation and improves glucose tolerance in vivo. Suppression of superoxide production and adipocyte inflammation using mitochondrial superoxide dismutase may be a novel and safe therapeutic tool to combat hyperglycemia mediated effects.

Soy Formula and Epigenetic Modifications: Analysis of Vaginal Epithelial Cells from Infant Girls in the IFED Study

PubMed Central

Harlid, Sophia; Adgent, Margaret; Jefferson, Wendy N.; Panduri, Vijayalakshmi; Umbach, David M.; Xu, Zongli; Stallings, Virginia A.; Williams, Carmen J.; Rogan, Walter J.; Taylor, Jack A.

2016-01-01

Background: Early-life exposure to estrogenic compounds affects the development of the reproductive system in rodent models and humans. Soy products, which contain phytoestrogens such as genistein, are one source of exposure in infants fed soy formula, and they result in high serum concentrations. Objectives: Our goal was to determine whether soy exposure is associated with differential DNA methylation in vaginal cells from soy-fed infant girls. Methods: Using the Illumina HumanMethylation450 BeadChip, we evaluated epigenome-wide DNA methylation in vaginal cells from four soy formula–fed and six cow formula–fed girls from the Infant Feeding and Early Development (IFED) study. Using pyrosequencing we followed up the two most differentially methylated sites in 214 vaginal cell samples serially collected between birth and 9 months of age from 50 girls (28 soy formula–fed and 22 cow formula–fed). With a mouse model, we examined the effect of neonatal exposure to genistein on gene specific mRNA levels in vaginal tissue. Results: The epigenome-wide scan suggested differences in methylation between soy formula–fed and cow formula–fed infants at three CpGs in the gene proline rich 5 like (PRR5L) (p < 104). Pyrosequencing of the two feeding groups found that methylation levels progressively diverged with age, with pointwise differences becoming statistically significant after 126 days. Genistein-exposed mice showed a 50% decrease in vaginal Prr5l mRNA levels compared to controls. Conclusions: Girls fed soy formula have altered DNA methylation in vaginal cell DNA which may be associated with decreased expression of an estrogen-responsive gene. Citation: Harlid S, Adgent M, Jefferson WN, Panduri V, Umbach DM, Xu Z, Stallings VA, Williams CJ, Rogan WJ, Taylor JA. 2017. Soy formula and epigenetic modifications: analysis of vaginal epithelial cells from infant girls in the IFED study. Environ Health Perspect 125:447–452; http://dx.doi.org/10.1289/EHP428 PMID:27539829

Experimental model for ELF-EMF exposure: Concern for human health

PubMed Central

D’Angelo, C.; Costantini, E.; Kamal, M.A.; Reale, M.

2014-01-01

Low frequency (LF) electromagnetic fields (EMFs) are abundantly present in modern society and in the last 20 years the interest about the possible effect of extremely low frequency (ELF) EMFs on human health has increased progressively. Epidemiological studies, designed to verify whether EMF exposure may be a potential risk factor for health, have led to controversial results. The possible association between EMFs and an increased incidence of childhood leukemia, brain tumors or neurodegenerative diseases was not fully elucidated. On the other hand, EMFs are widely used, in neurology, psychiatry, rheumatology, orthopedics and dermatology, both in diagnosis and in therapy. In vitro studies may help to evaluate the mechanism by which LF-EMFs affect biological systems. Invitro model of wound healing used keratinocytes (HaCaT), neuroblastoma cell line (SH-SY5Y) as a model for analysis of differentiation, metabolism and functions related to neurodegenerative processes, and monocytic cell line (THP-1) was used as a model for inflammation and cytokines production, while leukemic cell line (K562) was used as a model for hematopoietic differentiation. MCP-1, a chemokine that regulates the migration and infiltration of memory T cells, natural killer (NK), monocytes and epithelial cells, has been demonstrated to be induced and involved in various diseases. Since, varying the parameters of EMFs different effects may be observed, we have studied MCP-1 expression in HaCaT, SH-SY5Y, THP-1 and K562 exposed to a sinusoidal EMF at 50 Hz frequency with a flux density of 1 mT (rms). Our preliminary results showed that EMF-exposure differently modifies the expression of MCP-1 in different cell types. Thus, the MCP-1 expression needs to be better determined, with additional studies, with different parameters and times of exposure to ELF-EMF. PMID:25561888

Antenatal steroid exposure in the late preterm period is associated with reduced cord blood neurotrophin-3.

PubMed

Hodyl, Nicolette A; Crawford, Tara M; McKerracher, Lorna; Lawrence, Andrew; Pitcher, Julia B; Stark, Michael J

2016-10-01

Neurotrophins are proteins critically involved in neural growth, survival and differentiation, and therefore important for fetal brain development. Reduced cord blood neurotrophins have been observed in very preterm infants (<32weeks gestation) who subsequently develop brain injury. Antenatal steroid exposure can alter neurotrophin concentrations, yet studies to date have not examined whether this occurs in the late preterm infant (33-36weeks gestation), despite increasing recognition of subtle neurodevelopmental deficits in this population. To assess the impact of antenatal steroids on cord blood neurotrophins in late preterm infants following antenatal steroid exposure. Retrospective analysis. Late preterm infants (33-36weeks; n=119) and term infants (37-41weeks; n=129) born at the Women's and Children's Hospital, Adelaide. Cord blood neurotrophin-3 (NT-3), NT-4, nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) concentrations measured by ELISA. Cord blood NT-4 and NGF were increased at term compared to the late preterm period (p<0.001), while BDNF and NT-3 were not different. In the late preterm period, cord blood NT-3 was reduced when antenatal steroids were administered >24h prior to delivery (p<0.01). This study identified an association between reduced cord blood NT-3 and antenatal steroid exposure in the late preterm period. The reduced NT-3 may be a consequence of steroids inducing neuronal apoptosis, thereby reducing endogenous neuronal NT3 production, or be an action of steroids on other maternal or fetal NT-3 producing cells, which may then affect neuronal growth, differentiation and survival. Regardless of the specific mechanism, a reduction in NT-3 may have long term implications for child neurodevelopment, and emphasizes the ongoing vulnerability of the fetal brain across the full preterm period. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Soy Formula and Epigenetic Modifications: Analysis of Vaginal Epithelial Cells from Infant Girls in the IFED Study.

PubMed

Harlid, Sophia; Adgent, Margaret; Jefferson, Wendy N; Panduri, Vijayalakshmi; Umbach, David M; Xu, Zongli; Stallings, Virginia A; Williams, Carmen J; Rogan, Walter J; Taylor, Jack A

2017-03-01

Early-life exposure to estrogenic compounds affects the development of the reproductive system in rodent models and humans. Soy products, which contain phytoestrogens such as genistein, are one source of exposure in infants fed soy formula, and they result in high serum concentrations. Our goal was to determine whether soy exposure is associated with differential DNA methylation in vaginal cells from soy-fed infant girls. Using the Illumina HumanMethylation450 BeadChip, we evaluated epigenome-wide DNA methylation in vaginal cells from four soy formula-fed and six cow formula-fed girls from the Infant Feeding and Early Development (IFED) study. Using pyrosequencing we followed up the two most differentially methylated sites in 214 vaginal cell samples serially collected between birth and 9 months of age from 50 girls (28 soy formula-fed and 22 cow formula-fed). With a mouse model, we examined the effect of neonatal exposure to genistein on gene specific mRNA levels in vaginal tissue. The epigenome-wide scan suggested differences in methylation between soy formula-fed and cow formula-fed infants at three CpGs in the gene proline rich 5 like ( PRR5L ) ( p < 10 4 ). Pyrosequencing of the two feeding groups found that methylation levels progressively diverged with age, with pointwise differences becoming statistically significant after 126 days. Genistein-exposed mice showed a 50% decrease in vaginal Prr5l mRNA levels compared to controls. Girls fed soy formula have altered DNA methylation in vaginal cell DNA which may be associated with decreased expression of an estrogen-responsive gene. Citation: Harlid S, Adgent M, Jefferson WN, Panduri V, Umbach DM, Xu Z, Stallings VA, Williams CJ, Rogan WJ, Taylor JA. 2017. Soy formula and epigenetic modifications: analysis of vaginal epithelial cells from infant girls in the IFED study. Environ Health Perspect 125:447-452; http://dx.doi.org/10.1289/EHP428.

Cadmium (Cd(2+)) exposure differentially elicits both cell proliferation and cell death related responses in SK-RC-45.

PubMed

Sinha, Krishnendu; Pal, Pabitra Bikash; Sil, Parames C

2014-03-01

Cadmium (Cd(2+)) is a major nephrotoxic environmental pollutant, affecting mostly proximal convoluted tubule (PCT) cells of the mammalian kidney, while conditionally Cd(2+) could also elicit protective responses with great variety and variability in different systems. The present study was designed to evaluate the molecular mechanism of Cd(2+) toxicity on human PCT derived Renal Cell Carcinoma (RCC), SK-RC-45 and compare its responses with normal human PCT derived cell line, NKE. Exposure of SK-RC-45 cells with different concentrations of CdCl2 (e.g. 0, 10 and 20μM) in serum free medium for 24h generate considerable amount of ROS, accompanied with decreased cell viability and alternations in the cellular and nuclear morphologies, heat shock responses and GCLC mediated protective responses. Also phosphatidylserine externalization, augmentation in the level of caspase-3, PARP, BAD, Apaf1 and cleaved caspase-9 along with decreased expression of Bcl2 and release of cytochrome c confirmed that, Cd(2+) dose dependently induces solely intrinsic pathway of apoptosis in SK-RC-45, independent of JNK. Furthermore, the non-toxic concentration (10μM) of Cd(2+) induced nuclear translocation of Nrf2 and increased expression in the level of HO-1 enzyme suggesting that at the milder concentration, Cd(2+) induces protective signaling pathways. On the other hand, exposure of NKE to different concentrations of CdCl2 (e.g. 0, 10, 20, 30 and 50μM) under the same conditions elevate stronger heat shock and SOD2 mediated protective responses. In contrary to the RCC PCT, the normal PCT derived cell follows JNK dependent and extrinsic pathways of apoptosis. Cumulatively, these results suggest that Cd(2+) exposure dose dependently elicit both cell proliferative and cell death related responses in SK-RC-45 cells and is differentially regulated with respect to normal kidney epithelia derived NKE cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

Cbl-phosphatidylinositol 3 kinase interaction differentially regulates macrophage colony-stimulating factor-mediated osteoclast survival and cytoskeletal reorganization.

PubMed

Adapala, Naga Suresh; Barbe, Mary F; Langdon, Wallace Y; Tsygankov, Alexander Y; Sanjay, Archana

2010-03-01

The Cbl protein is a key player in macrophage colony-stimulating factor (M-CSF)-induced signaling. To examine the role of Cbl in M-CSF-mediated cellular events, we used Cbl(YF/YF) knockin mice in which the regulatory tyrosine 737, which when phosphorylated binds to the p85 subunit of phosphatidylinositol 3 kinase (PI3K), is substituted to phenylalanine. In ex vivo cultures, M-CSF and receptor activator of nuclear factor-kappaB ligand-mediated differentiation of bone marrow precursors from Cbl(YF/YF) mice generated increased number of osteoclasts; however, osteoclast numbers in Cbl(YF/YF) cultures were unchanged with increasing doses of M-CSF. We found that Cbl(YF/YF) osteoclasts have enhanced intrinsic ability to survive, and this response was further augmented upon exposure to M-CSF. Treatment of osteoclasts with M-CSF-induced actin reorganization and lamellipodia formation in wild-type osteoclasts; however, in Cbl(YF/YF) osteoclasts lamellipodia formation was compromised. Collectively, these results indicate that abrogation of the Cbl-PI3K interaction, although not affecting M-CSF-induced proliferation and differentiation of precursors, is required for regulation of survival and actin cytoskeletal reorganization of mature osteoclasts.

Developmental exposure to methimazole increases anxiety behavior in zebrafish.

PubMed

Reider, Masha; Connaughton, Victoria P

2015-10-01

The role of thyroid hormones in vertebrate development has been well documented for several decades. As hypothyroidism during critical periods of development can cause defects to the development of every major organ system, including brain, eye, and general morphology, we hypothesized that hypothyroidism would affect specific behaviors. To assess this, we treated zebrafish with the hypothyroid drug methimazole (MMI) and examined changes in anxiety, shoaling, vision, and locomotion. Following low-dose MMI exposure for the first 10 days of life, a time of rapid and significant development, larvae were removed from treatment and allowed to develop until 1 month of age. Comparisons between treated and controls took place between 10 and 30 days postfertilization to examine times both during and after treatment. Using the novel tank and startle response tests, we found that anxiety behaviors are significantly increased following MMI treatment. These effects persisted for several days following removal from treatment and indicate a prolonged effect of early hypothyroidism. However, permanent MMI effects on anxiety were not observed, as anxiety behaviors of early treated zebrafish recovered to control levels following 10 days out of treatment. In contrast to the strong link between MMI treatment and anxiety, shoaling and visual behaviors were not significantly affected within our experimental parameters. This indicates that disruption of thyroid system functioning early in life can differentially affect behavior by specifically altering anxiety responses without producing indiscriminate changes to overall behavioral development. (c) 2015 APA, all rights reserved).

Organic Cation Transporter-Mediated Ergothioneine Uptake in Mouse Neural Progenitor Cells Suppresses Proliferation and Promotes Differentiation into Neurons

PubMed Central

Ishimoto, Takahiro; Nakamichi, Noritaka; Hosotani, Hiroshi; Masuo, Yusuke; Sugiura, Tomoko; Kato, Yukio

2014-01-01

The aim of the present study is to clarify the functional expression and physiological role in neural progenitor cells (NPCs) of carnitine/organic cation transporter OCTN1/SLC22A4, which accepts the naturally occurring food-derived antioxidant ergothioneine (ERGO) as a substrate in vivo. Real-time PCR analysis revealed that mRNA expression of OCTN1 was much higher than that of other organic cation transporters in mouse cultured cortical NPCs. Immunocytochemical analysis showed colocalization of OCTN1 with the NPC marker nestin in cultured NPCs and mouse embryonic carcinoma P19 cells differentiated into neural progenitor-like cells (P19-NPCs). These cells exhibited time-dependent [3H]ERGO uptake. These results demonstrate that OCTN1 is functionally expressed in murine NPCs. Cultured NPCs and P19-NPCs formed neurospheres from clusters of proliferating cells in a culture time-dependent manner. Exposure of cultured NPCs to ERGO or other antioxidants (edaravone and ascorbic acid) led to a significant decrease in the area of neurospheres with concomitant elimination of intracellular reactive oxygen species. Transfection of P19-NPCs with small interfering RNA for OCTN1 markedly promoted formation of neurospheres with a concomitant decrease of [3H]ERGO uptake. On the other hand, exposure of cultured NPCs to ERGO markedly increased the number of cells immunoreactive for the neuronal marker βIII-tubulin, but decreased the number immunoreactive for the astroglial marker glial fibrillary acidic protein (GFAP), with concomitant up-regulation of neuronal differentiation activator gene Math1. Interestingly, edaravone and ascorbic acid did not affect such differentiation of NPCs, in contrast to the case of proliferation. Knockdown of OCTN1 increased the number of cells immunoreactive for GFAP, but decreased the number immunoreactive for βIII-tubulin, with concomitant down-regulation of Math1 in P19-NPCs. Thus, OCTN1-mediated uptake of ERGO in NPCs inhibits cellular proliferation via regulation of oxidative stress, and also promotes cellular differentiation by modulating the expression of basic helix-loop-helix transcription factors via an unidentified mechanism different from antioxidant action. PMID:24586778

Is the PentaBDE replacement, tris (1,3-dichloro-2-propyl) phosphate (TDCPP), a developmental neurotoxicant? Studies in PC12 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dishaw, Laura V.; Powers, Christina M.; Ryde, Ian T.

Organophosphate flame retardants (OPFRs) are used as replacements for the commercial PentaBDE mixture that was phased out in 2004. OPFRs are ubiquitous in the environment and detected at high concentrations in residential dust, suggesting widespread human exposure. OPFRs are structurally similar to neurotoxic organophosphate pesticides, raising concerns about exposure and toxicity to humans. This study evaluated the neurotoxicity of tris (1,3-dichloro-2-propyl) phosphate (TDCPP) compared to the organophosphate pesticide, chlorpyrifos (CPF), a known developmental neurotoxicant. We also tested the neurotoxicity of three structurally similar OPFRs, tris (2-chloroethyl) phosphate (TCEP), tris (1-chloropropyl) phosphate (TCPP), and tris (2,3-dibromopropyl) phosphate (TDBPP), and 2,2 Primemore » ,4,4 Prime -tetrabromodiphenyl ether (BDE-47), a major component of PentaBDE. Using undifferentiated and differentiating PC12 cells, changes in DNA synthesis, oxidative stress, differentiation into dopaminergic or cholinergic neurophenotypes, cell number, cell growth and neurite growth were assessed. TDCPP displayed concentration-dependent neurotoxicity, often with effects equivalent to or greater than equimolar concentrations of CPF. TDCPP inhibited DNA synthesis, and all OPFRs decreased cell number and altered neurodifferentiation. Although TDCPP elevated oxidative stress, there was no adverse effect on cell viability or growth. TDCPP and TDBPP promoted differentiation into both neuronal phenotypes, while TCEP and TCPP promoted only the cholinergic phenotype. BDE-47 had no effect on cell number, cell growth or neurite growth. Our results demonstrate that different OPFRs show divergent effects on neurodifferentiation, suggesting the participation of multiple mechanisms of toxicity. Additionally, these data suggest that OPFRs may affect neurodevelopment with similar or greater potency compared to known and suspected neurotoxicants.« less

The Phosphoproteomic Response of Rice Seedlings to Cadmium Stress.

PubMed

Zhong, Min; Li, Sanfeng; Huang, Fenglin; Qiu, Jiehua; Zhang, Jian; Sheng, Zhonghua; Tang, Shaoqing; Wei, Xiangjin; Hu, Peisong

2017-09-27

The environmental damage caused by cadmium (Cd) pollution is of increasing concern in China. While the overall plant response to Cd has been investigated in some depth, the contribution (if any) of protein phosphorylation to the detoxification of Cd and the expression of tolerance is uncertain. Here, the molecular basis of the plant response has been explored in hydroponically raised rice seedlings exposed to 10 μΜ and 100 μΜ Cd 2+ stress. An analysis of the seedlings' quantitative phosphoproteome identified 2454 phosphosites, associated with 1244 proteins. A total of 482 of these proteins became differentially phosphorylated as a result of exposure to Cd stress; the number of proteins affected in this way was six times greater in the 100 μΜ Cd 2+ treatment than in the 10 μΜ treatment. A functional analysis of the differentially phosphorylated proteins implied that a significant number was involved in signaling, in stress tolerance and in the neutralization of reactive oxygen species, while there was also a marked representation of transcription factors.

The Phosphoproteomic Response of Rice Seedlings to Cadmium Stress

PubMed Central

Zhong, Min; Li, Sanfeng; Huang, Fenglin; Qiu, Jiehua; Sheng, Zhonghua; Tang, Shaoqing; Wei, Xiangjin; Hu, Peisong

2017-01-01

The environmental damage caused by cadmium (Cd) pollution is of increasing concern in China. While the overall plant response to Cd has been investigated in some depth, the contribution (if any) of protein phosphorylation to the detoxification of Cd and the expression of tolerance is uncertain. Here, the molecular basis of the plant response has been explored in hydroponically raised rice seedlings exposed to 10 μΜ and 100 μΜ Cd2+ stress. An analysis of the seedlings’ quantitative phosphoproteome identified 2454 phosphosites, associated with 1244 proteins. A total of 482 of these proteins became differentially phosphorylated as a result of exposure to Cd stress; the number of proteins affected in this way was six times greater in the 100 μΜ Cd2+ treatment than in the 10 μΜ treatment. A functional analysis of the differentially phosphorylated proteins implied that a significant number was involved in signaling, in stress tolerance and in the neutralization of reactive oxygen species, while there was also a marked representation of transcription factors. PMID:28953215

Momentary smoking context as a mediator of the relationship between SES and smoking.

PubMed

Jahnel, Tina; Ferguson, Stuart G; Shiffman, Saul; Thrul, Johannes; Schüz, Benjamin

2018-08-01

There is a well-established socioeconomic gradient in smoking behavior: those with lower socioeconomic status smoke more. However, much less is known about the mechanisms explaining how SES is linked to smoking. This study takes a social-ecological perspective by examining whether socioeconomic status affects smoking behavior by differential exposure to places where smoking is allowed. Exposure to smoking restrictions was assessed in real-time using Ecological Momentary Assessment methods. A sample of 194 daily smokers, who were not attempting to quit, recorded their smoking and information about situational and contextual factors for three weeks using an electronic diary. We tested whether a smoker's momentary context mediated the relationship between socioeconomic status (educational attainment) and cigarettes smoked per day (CPD). Momentary context was operationalized as the proportion of random assessments answered in locations where smoking was allowed versus where smoking was not allowed. Data were analysed using multilevel regression (measurements nested within participants) with a lower level mediation model (2-1-1 mediation). Although no significant direct effect of SES on CPD were observed, there was a significant indirect effect of SES on CPD via the momentary context. Compared to participants with higher education, lower educated participants were more likely to encounter places where smoking was allowed, and this in turn, was associated with a higher number of CPD. These findings suggest that SES is associated with smoking at least partially via differential exposure to smoking-friendly environments, with smokers from lower SES backgrounds accessing more places where smoking is allowed. Implications for current smoke-free legislation are discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Potent antiandrogen and androgen receptor activities of an Angelica gigas-containing herbal formulation: identification of decursin as a novel and active compound with implications for prevention and treatment of prostate cancer.

PubMed

Jiang, Cheng; Lee, Hyo-Jeong; Li, Guang-xun; Guo, Junming; Malewicz, Barbara; Zhao, Yan; Lee, Eun-Ok; Lee, Hyo-Jung; Lee, Jae-Ho; Kim, Min-Seok; Kim, Sung-Hoon; Lu, Junxuan

2006-01-01

Androgen and androgen receptor (AR)-mediated signaling are crucial for the development of prostate cancer. Identification of novel and naturally occurring phytochemicals that target androgen and AR signaling from Oriental medicinal herbs holds exciting promises for the chemoprevention of this disease. In this article, we report the discovery of strong and long-lasting antiandrogen and AR activities of the ethanol extract of a herbal formula (termed KMKKT) containing Korean Angelica gigas Nakai (AGN) root and nine other Oriental herbs in the androgen-dependent LNCaP human prostate cancer cell model. The functional biomarkers evaluated included a suppression of the expression of prostate-specific antigen (PSA) mRNA and protein (IC50, approximately 7 microg/mL, 48-hour exposure) and an inhibition of androgen-induced cell proliferation through G1 arrest and of the ability of androgen to suppress neuroendocrine differentiation at exposure concentrations that did not cause apoptosis. Through activity-guided fractionation, we identified decursin from AGN as a novel antiandrogen and AR compound with an IC50 of approximately 0.4 microg/mL (1.3 micromol/L, 48-hour exposure) for suppressing PSA expression. Decursin also recapitulated the neuroendocrine differentiation induction and G1 arrest actions of the AGN and KMKKT extracts. Mechanistically, decursin in its neat form or as a component of AGN or KMKKT extracts inhibited androgen-stimulated AR translocation to the nucleus and down-regulated AR protein abundance without affecting the AR mRNA level. The novel antiandrogen and AR activities of decursin and decursin-containing herbal extracts have significant implications for the chemoprevention and treatment of prostate cancer and other androgen-dependent diseases.

Using cyclodextrin complexation to enhance secondary photoprotection of topically applied ibuprofen.

PubMed

Godwin, Donald A; Wiley, Cody J; Felton, Linda A

2006-01-01

Each year millions of people are overexposed to the sun resulting in photodamage of the skin. Secondary photoprotection is the application of medicinal agents to the body after sun exposure to reduce this damage. The objective of this study was to determine the affects of hydroxypropyl-beta-cyclodextrin (HPCD) complexation on the secondary photoprotective properties of topically applied ibuprofen. Complexation of ibuprofen by HPCD was demonstrated by differential scanning calorimetry, while solubilities were determined using HPLC. A linear (r2>0.999) relationship was found between ibuprofen solubility and HPCD concentration. For subsequent experiments, the concentration of ibuprofen was held constant at the solubility in 10% HPCD (10.6 mg/ml), while the HPCD concentration varied from 0 to 20% (w/w). In vitro transdermal permeation experiments demonstrated a parabolic relationship between transdermal kinetic parameters and HPCD concentration, with maximum values for both flux and skin accumulation occurring with the 10% HPCD formulation. In vivo experiments were performed by exposing hairless mice to UV radiation and applying ibuprofen-HPCD formulations topically at various times following UV exposure. Edema and epidermal lipid damage data demonstrated that application of ibuprofen-HPCD formulations within 1h of UV exposure provided significant photoprotection.

Effect of a long-term fire retardant (Fire Trol 934) on the germination of nine Mediterranean-type shrub species.

PubMed

Cruz, Alberto; Serrano, Marián; Navarro, Esther; Luna, Belén; Moreno, José M

2005-12-01

Fire Trol 934 is a long-term fire retardant commonly used in fire prevention and extinction. Our objective was to determine the effect of this chemical on seed germination of nine plant species from Mediterranean-type shrublands, where these chemicals are potentially used. Seeds were exposed to five different Fire Trol concentrations, (0 (control) to 10%, on a log scale) and monitored in a germination chamber for nine weeks. Seeds from four Cistus species were subjected to an additional heat treatment that simulated thermal scarification caused by fire. Retardant exposure caused a significant decrease in total germination in all species, and exposure to the highest Fire Trol concentration (10%) resulted in complete inhibition of germination. However, the sensitivity to Fire Trol varied across species and this differential species sensitivity may potentially lead to different impacts in the soil seed banks depending on whether sites are burned or unburned. Exposure to Fire Trol 934 may affect recruitment of shrubland species particularly during dry autumns, due to limited leaching of these chemicals from the soil surface. Consequently, its use should be avoided in sites where particularly sensitive plant species are present. Copyright (c) 2005 Wiley Periodicals, Inc.

Effects of tributyltin (TBT) on in vitro hormonal and biotransformation responses in Atlantic salmon (Salmo salar).

PubMed

Mortensen, Anne S; Arukwe, Augustine

2009-01-01

The mechanisms by which the biocide tributyltin (TBT) and its metabolites affect the hormonal and xenobiotic biotransformation pathways in aquatic species are not well understood. In this study hepatocytes isolated from salmon were used to evaluate the mechanistical effects of TBT on fish hormonal and xenobiotic biotransformation pathways. Cells were exposed to 0.01, 0.1, 1, or 5 microM TBT and samples were collected at 0, 12, 24, or 48 h following exposure. Gene expression patterns were evaluated using quantitative polymerase chain reaction (PCR), and cytochrome P-450 (CYP)-mediated enzyme activities were evaluated by ethoxyresorufin, benzyloxyresorufin, and pentoxyresorufin O-deethylase (EROD, BROD, and PROD, respectively) activity assays. Generally, exposure of hepatocytes to 1 microM (at 48 h) and 5 microM TBT (at 12, 24, and 48 h) consistently produced reductions in all mRNA species investigated. TBT produced significant decreases of vitellogen (Vtg) expression at 48 h and modified the expression patterns of estrogen receptors (ERalpha and ERbeta) and androgen receptor-beta (ARbeta) that were dependent on time and TBT concentration. In the xenobiotic biotransformation pathway, TBT produced differential expression patterns that were dependent on exposure time and concentration for all salmonid AhR2 isoforms (AhR2alpha, AhR2beta, AhR2delta, and AhR2gamma). For CYP1A1, CYP3A, AhRR, and Arnt mRNA, TBT produced exposure- and time-specific modulations. Catalytic CYP activities showed that BROD activity increased in an apparent concentration-specific manner in cells exposed to TBT for 12 h. Interestingly, EROD activity showed a TBT concentration-dependent increase at 24 h and PROD at 12 and 48 h of exposure. In general our data show that TBT differentially modulated hormonal and biotransformation responses in the salmon in vitro system. The apparent and consistent decrease of the studied responses with time in 1 and 5 microM exposed hepatocytes suggest a possible transcription inhibitory effect of TBT.

NEW APPROACHES AND TOOLS FOR THE CONDUCT OF COMMUNITY-BASED CUMULATIVE RISK ASSESSMENTS

EPA Science Inventory

Individuals have differential exposures and potential risk of adverse health effects, regardless of whether chemical exposure occurs singly or as mixtures of several chemicals. Elevated exposures can result from frequent contact with environmental contaminants and depends on the...

Reserve stem cells: Reprogramming of differentiated cells fuels repair, metaplasia, and neoplasia in the adult gastrointestinal tract

PubMed Central

Mills, Jason C.; Sansom, Owen J.

2016-01-01

It has long been known that differentiated cells can switch fates, especially in vitro, but only recently has there been a critical mass of publications describing the mechanisms adult, post-mitotic cells use in vivo to reverse their differentiation state. We propose that this sort of cellular reprogramming is a fundamental cellular process akin to apoptosis or mitosis. Because reprogramming can invoke regenerative cells from mature cells, it is critical to the longterm maintenance of tissues like the pancreas, which encounter large insults during adulthood but lack constitutively active adult stem cells to repair the damage. However, even in tissues with adult stem cells, like stomach and intestine, reprogramming may allow mature cells to serve as reserve (“quiescent”) stem cells when normal stem cells are compromised. We propose that the potential downside to reprogramming is that it increases risk for cancers that occur late in adulthood. Mature, long-lived cells may have years of exposure to mutagens. Mutations that affect the physiological function of differentiated, post-mitotic cells may lead to apoptosis, but mutations in genes that govern proliferation might not be selected against. Hence, reprogramming with reentry into the cell cycle might unmask those mutations, causing an irreversible progenitor-like, proliferative state. We review recent evidence showing that reprogramming fuels irreversible metaplastic and precancerous proliferations in stomach and pancreas. Finally, we illustrate how we think reprogrammed differentiated cells are likely candidates as cells of origin for cancers of the intestine. PMID:26175494

Antimicrobial peptide hLF1-11 directs granulocyte-macrophage colony-stimulating factor-driven monocyte differentiation toward macrophages with enhanced recognition and clearance of pathogens.

PubMed

van der Does, Anne M; Bogaards, Sylvia J P; Ravensbergen, Bep; Beekhuizen, Henry; van Dissel, Jaap T; Nibbering, Peter H

2010-02-01

The human lactoferrin-derived peptide hLF1-11 displays antimicrobial activities in vitro and is effective against infections with antibiotic-resistant bacteria and fluconazole-resistant Candida albicans in animals. However, the mechanisms underlying these activities remain largely unclear. Since hLF1-11 is ineffective in vitro at physiological salt concentrations, we suggested modulation of the immune system as an additional mechanism of action of the peptide. We investigated whether hLF1-11 affects human monocyte-macrophage differentiation and determined the antimicrobial activities of the resulting macrophages. Monocytes were cultured for 7 days with GM-CSF in the presence of hLF1-11, control peptide, or saline for various intervals. At day 6, the cells were stimulated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), or heat-killed C. albicans for 24 h. Thereafter, the levels of cytokines in the culture supernatants, the expression of pathogen recognition receptors, and the antimicrobial activities of these macrophages were determined. The results showed that a short exposure of monocytes to hLF1-11 during GM-CSF-driven differentiation is sufficient to direct differentiation of monocytes toward a macrophage subset characterized by both pro- and anti-inflammatory cytokine production and increased responsiveness to microbial structures. Moreover, these macrophages are highly effective against C. albicans and Staphylococcus aureus. In conclusion, hLF1-11 directs GM-CSF-driven differentiation of monocytes toward macrophages with enhanced effector functions.

Breast cancer risk accumulation starts early – Prevention must also

PubMed Central

Colditz, Graham A; Bohlke, Kari; Berkey, Catherine S.

2014-01-01

Purpose Nearly 1 in 4 breast cancers is diagnosed before the age of 50, and many early-stage premalignant lesions are present but not yet diagnosed. Therefore, we review evidence to support the strategy that breast cancer prevention efforts must begin early in life. Methods Literature review Results Exposures during childhood and adolescence affect a woman’s long-term risk of breast cancer, but have received far less research attention than exposures that occur later in life. Breast tissue undergoes rapid cellular proliferation between menarche and first full-term pregnancy, and risk accumulates rapidly until the terminal differentiation that accompanies first pregnancy. Evidence on childhood diet and growth in height, and adolescent alcohol intake, among other adolescent factors are related to breast cancer risk and risk of premalignant proliferative benign lesions. Conclusion Breast cancer prevention efforts will have the greatest effect when initiated at an early age and continued over a lifetime. Gaps in knowledge are identified and deserve increase attention to inform prevention. PMID:24820413

Chronic ethanol exposure and folic acid supplementation: fetal growth and folate status in the maternal and fetal guinea pig.

PubMed

Hewitt, Amy J; Knuff, Amber L; Jefkins, Matthew J; Collier, Christine P; Reynolds, James N; Brien, James F

2011-05-01

Chronic ethanol exposure (CEE) can produce developmental abnormalities in the CNS of the embryo and developing fetus. Folic acid (FA) is an important nutrient during pregnancy and low folate status exacerbates ethanol-induced teratogenicity. This study tested the hypotheses that (1) CEE depletes folate stores in the mother and fetus; and (2) maternal FA supplementation maintains folate stores. CEE decreased fetal body, brain, hippocampus weights, and brain to body weight ratio but not hippocampus to body weight ratio. These effects of CEE were not mitigated by maternal FA administration. The FA regimen prevented the CEE-induced decrease of term fetal liver folate. However, it did not affect maternal liver folate or fetal RBC folate at term, and did not mitigate the nutritional deficit-induced decrease of term fetal hippocampus folate. This study suggests that maternal FA supplementation may have differential effects on folate status in the mother and the fetus. Copyright © 2011 Elsevier Inc. All rights reserved.

Preferences of newborn mice for odours indicating closer genetic relatedness: is experience necessary?

PubMed

Todrank, Josephine; Busquet, Nicolas; Baudoin, Claude; Heth, Giora

2005-10-07

Evidence from studies with adult rodents indicates that individual recognition enables distinctions between familiar individuals irrespective of relatedness (but including close kin) and a separate mechanism enables discriminations based on genetic relatedness without prior familiarity. For example, adult mice could assess the extent of their genetic relatedness to unfamiliar individuals using perceptual similarities between their individual odours. The ontogeny of this genetic relatedness assessment mechanism, however, had not been investigated. Here, in two-choice tests, newborn mice differentially preferred odours of more genetically similar lactating females (paternal aunts to unrelated conspecific and conspecific to heterospecific) even without prior direct exposure to adults with the tested genotypes. The results provide a direct demonstration of genetic relatedness assessment abilities in newborns and show that experience with parental odours is not necessary for genetic relatedness distinctions. Future studies will be necessary to determine whether exposure to odours of other foetuses in the womb or littermates shortly after birth affects this genetic relatedness assessment process.

Preferences of newborn mice for odours indicating closer genetic relatedness: is experience necessary?

PubMed Central

Todrank, Josephine; Busquet, Nicolas; Baudoin, Claude; Heth, Giora

2005-01-01

Evidence from studies with adult rodents indicates that individual recognition enables distinctions between familiar individuals irrespective of relatedness (but including close kin) and a separate mechanism enables discriminations based on genetic relatedness without prior familiarity. For example, adult mice could assess the extent of their genetic relatedness to unfamiliar individuals using perceptual similarities between their individual odours. The ontogeny of this genetic relatedness assessment mechanism, however, had not been investigated. Here, in two-choice tests, newborn mice differentially preferred odours of more genetically similar lactating females (paternal aunts to unrelated conspecific and conspecific to heterospecific) even without prior direct exposure to adults with the tested genotypes. The results provide a direct demonstration of genetic relatedness assessment abilities in newborns and show that experience with parental odours is not necessary for genetic relatedness distinctions. Future studies will be necessary to determine whether exposure to odours of other foetuses in the womb or littermates shortly after birth affects this genetic relatedness assessment process. PMID:16191620

Fluoride’s Effects on the Formation of Teeth and Bones, and the Influence of Genetics

PubMed Central

Everett, E.T.

2011-01-01

Fluorides are present in the environment. Excessive systemic exposure to fluorides can lead to disturbances of bone homeostasis (skeletal fluorosis) and enamel development (dental/enamel fluorosis). The severity of dental fluorosis is also dependent upon fluoride dose and the timing and duration of fluoride exposure. Fluoride’s actions on bone cells predominate as anabolic effects both in vitro and in vivo. More recently, fluoride has been shown to induce osteoclastogenesis in mice. Fluorides appear to mediate their actions through the MAPK signaling pathway and can lead to changes in gene expression, cell stress, and cell death. Different strains of inbred mice demonstrate differential physiological responses to ingested fluoride. Genetic studies in mice are capable of identifying and characterizing fluoride-responsive genetic variations. Ultimately, this can lead to the identification of at-risk human populations who are susceptible to the unwanted or potentially adverse effects of fluoride action and to the elucidation of fundamental mechanisms by which fluoride affects biomineralization. PMID:20929720

Breast cancer risk accumulation starts early: prevention must also.

PubMed

Colditz, Graham A; Bohlke, Kari; Berkey, Catherine S

2014-06-01

Nearly one in four breast cancers is diagnosed before the age of 50, and many early-stage premalignant lesions are present but not yet diagnosed. Therefore, we review evidence to support the strategy that breast cancer prevention efforts must begin early in life. This study follows the literature review methods and format. Exposures during childhood and adolescence affect a woman's long-term risk of breast cancer, but have received far less research attention than exposures that occur later in life. Breast tissue undergoes rapid cellular proliferation between menarche and first full-term pregnancy, and risk accumulates rapidly until the terminal differentiation that accompanies first pregnancy. Evidence on childhood diet and growth in height, and adolescent alcohol intake, among other adolescent factors is related to breast cancer risk and risk of premalignant proliferative benign lesions. Breast cancer prevention efforts will have the greatest effect when initiated at an early age and continued over a lifetime. Gaps in knowledge are identified and deserve increase attention to inform prevention.

Effects of long-term endocrine disrupting compound exposure on Macaca mulatta embryonic stem cells

PubMed Central

Midic, Uros; Vincent, Kailey A.; VandeVoort, Catherine A; Latham, Keith E.

2016-01-01

Endocrine disrupting chemicals (EDCs) exert significant effects on health and physiology, many traceable to effects on stem cell programming underlying development. Understanding risk of low-level, chronic EDC exposure will be enhanced by knowledge of effects on stem cells. We exposed rhesus monkey embryonic stem cells to low levels of five EDCs [bisphenol A (BPA), atrazine (ATR), tributyltin (TBT), perfluorooctanoic acid (PFOA), and di-(2-ethylhexyl) phthalate (DEHP)] for 28 days, and evaluated effects on gene expression by RNAseq transcriptome profiling. We observed little effect of BPA, and small numbers of affected genes (≤119) with other EDCs. There was substantial overlap in effects across two, three, or four treatments. Ingenuity Pathway analysis indicated suppression of cell survival genes and genes downstream of several stress response mediators, activation of cell death genes, and modulations in several genes regulating pluripotency, differentiation, and germ layer development. Potential adverse effects of these changes on development are discussed. PMID:27614199