THE DEVELOPMENTAL TOXICITY OF BROMOCHLOROACETONITRILE IN PREGNANT LONG-EVANS RATS

EPA Science Inventory

Bromochloroacetonitrile (BCAN) is a by-product of the chlorine disinfection of water containing natural organic material. Adverse effects of BCAN in an in vivo teratology screen (i.e. neonatal survival assay) gave reason for further investigation into the developmental toxicity o...

The red tide toxin, brevetoxin, induces embryo toxicity and developmental abnormalities.

PubMed Central

Kimm-Brinson, K L; Ramsdell, J S

2001-01-01

Brevetoxins are lipophilic polyether toxins produced by the red tide dinoflagellate Gymnodinium breve, and their neurotoxic effects on adult animals have been documented. In this study, we characterized adverse developmental effects of brevetoxin-1 (PbTx-1) using an exposure paradigm that parallels the maternal oocyte transfer of toxin. Medaka fish (Oryzias latipes) embryos were exposed to PbTx-1 via microinjection of toxin reconstituted in a triolein oil droplet. Embryos microinjected with doses of 0.1-8.0 ng/egg (ppm) of brevetoxin-1 exhibited pronounced muscular activity (hyperkinesis) after embryonic day 4. Upon hatching, morphologic abnormalities were commonly found in embryos at the following lowest adverse effect levels: 1.0-3.0 ppm, lateral curvature of the spinal column; 3.1-3.4 ppm, herniation of brain meninges through defects in the skull; and 3.4-4.0 ppm, malpositioned eye. Hatching abnormalities were also commonly observed at brevetoxin doses of 2.0 ppm and higher with head-first, as opposed to the normal tail-first, hatching, and doses > 4.1 ng/egg produced embryos that developed but failed to hatch. Given the similarity of developmental processes found between higher and lower vertebrates, teratogenic effects of brevetoxins have the potential to occur among different phylogenetic classes. The observation of developmental abnormalities after PbTx-1 exposure identifies a new spectrum of adverse effects that may be expected to occur following exposure to G. breve red tide events. PMID:11335186

Practitioner Review: Early Adversity and Developmental Disorders

ERIC Educational Resources Information Center

Taylor, Eric; Rogers, Jody Warner

2005-01-01

Background: Knowledge of genetic influences, on developmental disorders such as autism spectrum, attention deficit/hyperactivity disorder and learning disabilities, has increased the opportunities for understanding the influences of the early environment. Methods: This paper provides a selective, narrative review for clinicians of the effects of…

Developmental Patterns of Adverse Childhood Experiences and Current Symptoms and Impairment in Youth Referred For Trauma-Specific Services.

PubMed

Grasso, Damion J; Dierkhising, Carly B; Branson, Christopher E; Ford, Julian D; Lee, Robert

2016-07-01

By the time children reach adolescence, most have experienced at least one type of severe adversity and many have been exposed to multiple types. However, whether patterns of adverse childhood experiences are consistent or change across developmental epochs in childhood is not known. Retrospective reports of adverse potentially traumatic childhood experiences in 3 distinct developmental epochs (early childhood, 0- to 5-years-old; middle childhood, 6- to 12-years-old; and adolescence, 13- to 18-years-old) were obtained from adolescents (N = 3485) referred to providers in the National Child Traumatic Stress Network (NCTSN) for trauma-focused assessment and treatment. Results from latent class analysis (LCA) revealed increasingly complex patterns of adverse/traumatic experiences in middle childhood and adolescence compared to early childhood. Depending upon the specific developmental epoch assessed, different patterns of adverse/traumatic experiences were associated with gender and with adolescent psychopathology (e.g., internalizing/externalizing behavior problems), and juvenile justice involvement. A multiply exposed subgroup that had severe problems in adolescence was evident in each of the 3 epochs, but their specific types of adverse/traumatic experiences differed depending upon the developmental epoch. Implications for research and clinical practice are identified.

Psychopathology, adversity, and creativity: diversifying experiences in the development of eminent African Americans.

PubMed

Damian, Rodica Ioana; Simonton, Dean Keith

2015-04-01

Symptoms associated with mental illness have been hypothesized to relate to creative achievement because they act as diversifying experiences. However, this theory has only been tested on predominantly majority-culture samples. Do tendencies toward mental illness still predict eminent creativity when they coexist with other diversifying experiences, such as early parental death, minority-status, or poverty? These alternative diversifying experiences can be collectively referred to as examples of developmental adversity. This conjecture was tested on a significant sample of 291 eminent African Americans who, by the nature of their status as long-term minorities, would experience more developmental adversity. Replicating majority-culture patterns, African American artists showed higher mental illness rates than African American scientists. Yet the absolute percentages were significantly lower for the African Americans, regardless of profession. Furthermore, mental illness predicted higher eminence levels only for the African American artists, an effect that diminished when controlling for developmental adversity. Because the latter predicted eminence for both artists and scientists, the "madness-to-genius" link probably represents just 1 of several routes by which diversifying experiences can influence eminence. The same developmental ends can be attained by different means. This inference warrants further research using other eminent creators emerging from minority culture populations. (c) 2015 APA, all rights reserved).

Gene expression profiles in the cerebellum and hippocampus following exposure to a neurotoxicant, Aroclor 1254: Developmental effects.

EPA Science Inventory

The developmental consequences of exposure to the polychlorinated biphenyls (PCBs) have been widely studied, making PCBs a unique model to understand issues related to environmental mixture of persistent chemicals. PCB exposure in humans adversely affects neurocognitive developm...

Relationships of maternal and fetal weight changes in developmental toxicology bioassays

EPA Science Inventory

Standard developmental toxicology bioassays are designed to identify agents with the potential to induce adverse effects in the embryo/fetus. Guidelines require the inclusion of a dose level(s) that induces “overt maternal toxicity”. The common occurrence of dose levels at which ...

Moderate Developmental undernutrition: Impact on growth and cognitive function in youth and old age

EPA Science Inventory

Low weight at birth is a common adverse developmental effect reported in human populations and animal toxicity studies. Epidemiological evidence links low birth weight to a syndrome ofmetabolic changes that increase later risk for obesity, type 2 diabetes, hypertension, and cardi...

Adverse Childhood Experiences and Suicide Attempts: The Mediating Influence of Personality Development and Problem Behaviors.

PubMed

Perez, Nicholas M; Jennings, Wesley G; Piquero, Alex R; Baglivio, Michael T

2016-08-01

Adverse childhood experiences, comprised of forms of maltreatment and certain dysfunctional household environments, can affect the development of a child in a variety of different ways. This multitude of developmental changes may subsequently produce compounding harmful effects on the child's life and increase acutely maladaptive outcomes, including adolescent suicidal behavior. This study uses data collected from 2007 to 2012 for 64,329 Florida Department of Juvenile Justice youth (21.67 % female, 42.88 % African American, and 15.37 % Hispanic) to examine the direct and indirect effects of adverse childhood experiences on suicide attempts. Using a generalized structural equation model, the effects of adverse childhood experience scores are estimated on suicidal behavior through pathways of certain aspects of a child's personality development (aggression and impulsivity), as well as adolescent problem behaviors (school difficulties and substance abuse). The results show that a large proportion of the relationship between childhood adversity and suicide is mediated by the aforementioned individual characteristics, specifically through the youth's maladaptive personality development. These results suggest that, if identified early enough, the developmental issues for these youth could potentially be addressed in order to thwart potential suicidal behavior.

The control and prevention of seizures in children, a developmental and environmental approach

NASA Technical Reports Server (NTRS)

Lewinn, E. B.

1978-01-01

The clinical effectiveness of neurophysiological and developmental factors in controlling and preventing seizure mechanisms is detailed. It is shown that as cortical control advances with maturation, it requires increasingly severe environmental adversity to release this residual defensive reflex mechanism. Administration of anticonvulsant drugs is discouraged because of possible undesirable neuronal effects on the very young brain.

Environmental pollutants and lifestyle factors induce oxidative stress and poor prenatal development.

PubMed

Al-Gubory, Kaïs H

2014-07-01

Developmental toxicity caused by exposure to a mixture of environmental pollutants has become a major health concern. Human-made chemicals, including xenoestrogens, pesticides and heavy metals, as well as unhealthy lifestyle behaviours, mainly tobacco smoking, alcohol consumption and medical drug abuse, are major factors that adversely influence prenatal development and increase susceptibility of offspring to diseases. There is evidence to suggest that the developmental toxicological mechanisms of chemicals and lifestyle factors involve the generation of reactive oxygen species (ROS) and cellular oxidative damage. Overproduction of ROS induces oxidative stress, a state where increased ROS generation overwhelms antioxidant protection and subsequently leads to oxidative damage of cellular macromolecules. Data on the involvement of oxidative stress in the mechanism of developmental toxicity following exposure to environmental pollutants are reviewed in an attempt to provide an updated basis for future studies on the toxic effect of such pollutants, particularly the notion of increased risk for developmental toxicity due to combined and cumulative exposure to various environmental pollutants. The aims of such studies are to better understand the mechanisms by which environmental pollutants adversely affect conceptus development and to elucidate the impact of cumulative exposures to multiple pollutants on post-natal development and health outcomes. Developmental toxicity caused by exposure to mixture of environmental pollutants has become a major health concern. Human-made chemicals, including xenoestrogens, pesticides and heavy metals, as well as unhealthy lifestyle behaviors, mainly tobacco smoking, alcohol consumption and medical drug abuse, are major factors that adversely influence prenatal development and increase the susceptibility of offspring to development complications and diseases. There is evidence to suggest that the developmental toxicological mechanisms of human-made chemicals and unhealthy lifestyle factors involve the generation of reactive oxygen species (ROS) and cellular oxidative damage. Overproduction of ROS induces oxidative stress, a state where increased generation of ROS overwhelms antioxidant protection and subsequently leads to oxidative damage of cellular macromolecules. Exposure to various environmental pollutants induces synergic and cumulative dose-additive adverse effects on prenatal development, pregnancy outcomes and neonate health. Data from the literature on the involvement of oxidative stress in the mechanism of developmental toxicity following in vivo exposure to environmental pollutants will be reviewed in an attempt to provide an updated basis for future studies on the toxic effect of such pollutants, particularly the notion of increased risk for developmental toxicity due to combined and cumulative exposure to various environmental pollutants. The aims of such studies are to better understand the mechanisms by which environmental pollutants adversely affect conceptus development and to elucidate the impact of cumulative exposures to multiple pollutants on postnatal development and health outcomes. Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Developmental Programming: Priming Disease Susceptibility for Subsequent Generations.

PubMed

Messer, L C; Boone-Heinonen, J; Mponwane, L; Wallack, L; Thornburg, K L

2015-03-01

Racial and/or ethnic minorities carry the highest burden of many adverse health outcomes intergenerationally We propose a paradigm in which developmental programming exacerbates the effects of racial patterning of adverse environmental conditions, thereby contributing to health disparity persistence. Evidence that developmental programming induces a heightened response to adverse exposures ("second hits") encountered later in life is considered. We evaluated the evidence for the second hit phenomenon reported in animal and human studies from three domains (air, stress, nutrition). Original research including a gestational exposure and a childhood or adulthood second hit exposure was reviewed. Evidence from animal studies suggest that prenatal exposure to air pollutants is associated with an exaggerated reaction to postnatal air pollution exposure, which results in worse health outcomes. It also indicates offspring exposed to prenatal maternal stress produce an exaggerated response to subsequent stressors, including anxiety and hyper-responsiveness of the hypothalamic-pituitary-adrenal axis. Similarly, prenatal and postnatal Western-style diets induce synergistic effects on weight gain, metabolic dysfunction, and atherosclerotic risk. Cross-domain second hits (e.g., gestational air pollution followed by childhood stressor) were also considered. Suboptimal gestational environments induce exaggerated offspring responses to subsequent environmental and social exposures. These developmental programming effects may result in enhanced sensitivity of ongoing, racially patterned, adverse exposures in race/ethnic minorities, thereby exacerbating health disparities from one generation to the next. Empirical assessment of the hypothesized role of priming processes in the propagation of health disparities is needed. Future social epidemiology research must explicitly consider synergistic relationships among social environmental conditions to which gestating females are exposed and offspring exposures when assessing causes for persistent health disparities.

Developmental Programming: Priming Disease Susceptibility for Subsequent Generations

PubMed Central

Boone-Heinonen, J.; Mponwane, L.; Wallack, L.; Thornburg, K. L.

2015-01-01

Racial and/or ethnic minorities carry the highest burden of many adverse health outcomes intergenerationally We propose a paradigm in which developmental programming exacerbates the effects of racial patterning of adverse environmental conditions, thereby contributing to health disparity persistence. Evidence that developmental programming induces a heightened response to adverse exposures (“second hits”) encountered later in life is considered. We evaluated the evidence for the second hit phenomenon reported in animal and human studies from three domains (air, stress, nutrition). Original research including a gestational exposure and a childhood or adulthood second hit exposure was reviewed. Evidence from animal studies suggest that prenatal exposure to air pollutants is associated with an exaggerated reaction to postnatal air pollution exposure, which results in worse health outcomes. It also indicates offspring exposed to prenatal maternal stress produce an exaggerated response to subsequent stressors, including anxiety and hyper-responsiveness of the hypothalamic–pituitary–adrenal axis. Similarly, prenatal and postnatal Western-style diets induce synergistic effects on weight gain, metabolic dysfunction, and atherosclerotic risk. Cross-domain second hits (e.g., gestational air pollution followed by childhood stressor) were also considered. Suboptimal gestational environments induce exaggerated offspring responses to subsequent environmental and social exposures. These developmental programming effects may result in enhanced sensitivity of ongoing, racially patterned, adverse exposures in race/ethnic minorities, thereby exacerbating health disparities from one generation to the next. Empirical assessment of the hypothesized role of priming processes in the propagation of health disparities is needed. Future social epidemiology research must explicitly consider synergistic relationships among social environmental conditions to which gestating females are exposed and offspring exposures when assessing causes for persistent health disparities. PMID:26366336

Assessment of Reproductive and Developmental Toxicity of Mixtures of Regulated Drinking Water Chlorination By-Products in a Multigenerational Rat Bioassay

EPA Science Inventory

Epidemiological and animal toxicity studies have raised concerns regarding possible adverse reproductive and developmental effects of disinfection by-products (DBPs) in drinking water. To address these concerns, we provided mixtures of the regulated trihalomethanes (THMs; chlorof...

Developmental Status and Intimacy in Adult Survivors of Childhood Cancer.

ERIC Educational Resources Information Center

Zevon, Michael A.; Corn, Barbara; Lowrie, Geoffrey; Green, Daniel M.

Whereas aggressive multimodal therapies are responsible for improved survival rates of children and adolescents diagnosed with cancer, concern has grown regarding the potential for adverse and delayed developmental effects resulting from these treatments. In light of this concern, this study assessed 207 adult survivors of childhood cancer in…

Maternal and fetal toxicity in developmental toxicology bioassays: Weight changes and their biological significance

EPA Science Inventory

Standard developmental toxicology bioassays are designed to identify agents with the potential to induce adverse effects in the embryo/fetus. Guidelines call for the inclusion of a dose level(s) that induces “overt maternal toxicity.” The possibility that general maternal toxicit...

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

Johnson, E.M.

Human reproduction and development is a cycle of interdependent events. Virtually all of its phases have been shown to be the primary target of one or more non-mutagenic exogenous agents. Such agents interfere with certain of the countless epigenetic or ontogenic events essential for normal completion of the cycle. Mutagens disrupt this cycle at some points, but the overwhelming majority of reproductive and developmental toxins are not mutagenic. As in all aspects of toxicology, the reproductive and developmental effects of chemicals are determined by the intrinsic nature of the chemical, the quantity of the chemical exposure, the duration of exposuremore » and the stage of the cycle at which it occurs. Signs of reproductive toxicity range from reduced fertility to spontaneous abortion. Adverse effects on the conceptus are categorized as functional deficits, developmental retardation, structural abnormality and death. One or more of these is anticipated to occur as a result of excess exposure to most chemicals. Although the degree of hazard and risk potential can be calculated in each instance, chemicals differ markedly in their ability to interfere with reproduction and/or development. Standardized methods for reproductive and developmental toxicity safety evaluation are available for detecting adverse effects upon any aspect of reproduction and development. Data currently available establish that these state-of-the-art tests conducted in laboratory animals are often highly predictive of the type of adverse effect a particular chemical will have in humans, as well as the exposure level at which it will occur. By adding a modest safety factor to the no-observed-effect-level of well-executed animal studies, safe human exposure levels can be established. 40 references.« less

Adverse Associations of both Prenatal and Postnatal Exposure to Organophosphorous Pesticides with Infant Neurodevelopment in an Agricultural Area of Jiangsu Province, China

PubMed Central

Liu, Ping; Wu, Chunhua; Chang, Xiuli; Qi, Xiaojuan; Zheng, Minglan; Zhou, Zhijun

2016-01-01

Background: Prenatal exposure to organophosphorous (OP) pesticides has been found to be associated with adverse effects on child neurodevelopment, but evidence on potential effects induced by both prenatal and postnatal OP exposure in infants is limited. Objectives: Our aim was to investigate the associations of both prenatal and postnatal OP exposure with birth outcomes and infant neurodevelopment. Methods: Exposure to OP in 310 mother–infant pairs was assessed by measuring dimethylphosphate (DM), diethylphosphate (DE), and total dialkylphosphate (DAP) metabolites in urines from pregnant women and their children at 2 years of age. The Gesell Developmental Schedules was administered to examine neurodevelopment of 2-year-old children. Results: Based on the Gesell Developmental Schedules, the proportions of children with developmental delays were < 6%. Adverse associations between head circumference at birth and prenatal OP exposure were demonstrated. Both prenatal and postnatal OP exposure was significantly associated with increased risk of being developmentally delayed. Specifically, odds ratio (OR) value for prenatal DEs was 9.75 (95% CI: 1.28, 73.98, p = 0.028) in the adaptive area, whereas in the social area, OR values for postnatal DEs and DAPs were 9.56 (95% CI: 1.59, 57.57, p = 0.014) and 12.00 (95% CI: 1.23, 117.37, p = 0.033), respectively. Adverse associations were observed only in boys, not in girls. Conclusions: Both prenatal and postnatal OP exposure may adversely affect the neurodevelopment of infants living in the agricultural area. The present study adds to the accumulating evidence on associations of prenatal and postnatal OP exposure with infant neurodevelopment. Citation: Liu P, Wu C, Chang X, Qi X, Zheng M, Zhou Z. 2016. Adverse associations of both prenatal and postnatal exposure to organophosphorous pesticides with infant neurodevelopment in an agricultural area of Jiangsu Province, China. Environ Health Perspect 124:1637–1643; http://dx.doi.org/10.1289/EHP196 PMID:27153333

Quantitative Adverse Outcome Pathway for Neurodevelopmental Effects of Thyroid Peroxidase-Induced Thyroid Hormone Synthesis Inhibition

EPA Science Inventory

Adequate levels of thyroid hormones (TH) are needed for proper brain development and deficiencies lead to adverse neurological outcomes in humans and in animal models. Environmental chemicals have been shown to disrupt TH levels, yet the relationship between developmental exposur...

Identification of developmentally toxic drinking water disinfection byproducts and evaluation of data relevant to mode of action

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

Colman, Joan; Rice, Glenn E., E-mail: rice.glenn@epa.gov; Wright, J. Michael

Reactions between chemicals used to disinfect drinking water and compounds present in source waters produce chemical mixtures containing hundreds of disinfection byproducts (DBPs). Although the results have been somewhat inconsistent, some epidemiological studies suggest associations may exist between DBP exposures and adverse developmental outcomes. The potencies of individual DBPs in rodent and rabbit developmental bioassays suggest that no individual DBP can account for the relative risk estimates reported in the positive epidemiologic studies, leading to the hypothesis that these outcomes could result from the toxicity of DBP mixtures. As a first step in a mixtures risk assessment for DBP developmentalmore » effects, this paper identifies developmentally toxic DBPs and examines data relevant to the mode of action (MOA) for DBP developmental toxicity. We identified 24 developmentally toxic DBPs and four adverse developmental outcomes associated with human DBP exposures: spontaneous abortion, cardiovascular defects, neural tube defects, and low birth weight infancy. A plausible MOA, involving hormonal disruption of pregnancy, is delineated for spontaneous abortion, which some epidemiologic studies associate with total trihalomethane and bromodichloromethane exposures. The DBP data for the other three outcomes were inadequate to define key MOA steps.« less

Child Maltreatment and Children's Developmental Trajectories in Early to Middle Childhood

ERIC Educational Resources Information Center

Font, Sarah A.; Berger, Lawrence M.

2015-01-01

Associations between experiencing child maltreatment and adverse developmental outcomes are widely studied, yet conclusions regarding the extent to which effects are bidirectional, and whether they are likely causal, remain elusive. This study uses the Fragile Families and Child Wellbeing Study, a birth cohort of 4,898 children followed from birth…

Effect of socioeconomic status disparity on child language and neural outcome: how early is early?

PubMed

Hurt, Hallam; Betancourt, Laura M

2016-01-01

It is not news that poverty adversely affects child outcome. The literature is replete with reports of deleterious effects on developmental outcome, cognitive function, and school performance in children and youth. Causative factors include poor nutrition, exposure to toxins, inadequate parenting, lack of cognitive stimulation, unstable social support, genetics, and toxic environments. Less is known regarding how early in life adverse effects may be detected. This review proposes to elucidate "how early is early" through discussion of seminal articles related to the effect of socioeconomic status on language outcome and a discussion of the emerging literature on effects of socioeconomic status disparity on brain structure in very young children. Given the young ages at which such outcomes are detected, the critical need for early targeted interventions for our youngest is underscored. Further, the fiscal reasonableness of initiating quality interventions supports these initiatives. As early life adversity produces lasting and deleterious effects on developmental outcome and brain structure, increased focus on programs and policies directed to reducing the impact of socioeconomic disparities is essential.

Developmental Constraints in a Wild Primate

PubMed Central

Lea, Amanda J.; Altmann, Jeanne; Alberts, Susan C.; Tung, Jenny

2015-01-01

Early-life experiences can dramatically affect adult traits. However, the evolutionary origins of such early-life effects are debated. The predictive adaptive response hypothesis argues that adverse early environments prompt adaptive phenotypic adjustments that prepare animals for similar challenges in adulthood. In contrast, the developmental constraints hypothesis argues that early adversity is generally costly. To differentiate between these hypotheses, we studied two sets of wild female baboons: those born during low-rainfall, low-quality years and those born during normal-rainfall, high-quality years. For each female, we measured fertility-related fitness components during years in adulthood that matched and mismatched her early conditions. We found support for the developmental constraints hypothesis: females born in low-quality environments showed greater decreases in fertility during drought years than females born in high-quality environments, even though drought years matched the early conditions of females born in low-quality environments. Additionally, we found that females born in low-quality years to high-status mothers did not experience reduced fertility during drought years. These results indicate that early ecological adversity did not prepare individuals to cope with ecological challenges in later life. Instead, individuals that experienced at least one high-quality early environment—either ecological or social—were more resilient to ecological stress in later life. Together, these data suggest that early adversity carries lifelong costs, which is consistent with the developmental constraints hypothesis. PMID:25996865

The effects of drought and disturbance on the growth and developmental instability of loblolly pine (Pinus taeda L.)

Treesearch

John H. Graham; Jeffrey J. Duda; Michelle L. Brown; Stanley Kitchen; John M. Emlen; Jagadish Malol; Elizabeth Bankstahl; Anthony J. Krzysik; Harold Balbach; D. Carl Freeman

2012-01-01

Ecological indicators provide early warning of adverse environmental change, helping land managers adaptively manage their resources while minimizing costly remediation. In 1999 and 2000, we studied two such indicators, growth and developmental instability, of loblolly pine (Pinus taeda L.) influenced by mechanized infantry training at Fort Benning, Georgia. Disturbed...

Evaluation of submarine atmospheres: effects of carbon monoxide, carbon dioxide and oxygen on general toxicology, neurobehavioral performance, reproduction and development in rats. I. Subacute exposures.

PubMed

Hardt, Daniel J; James, R Arden; Gut, Chester P; McInturf, Shawn M; Sweeney, Lisa M; Erickson, Richard P; Gargas, Michael L

2015-02-01

The inhalation toxicity of submarine contaminants is of concern to ensure the health of men and women aboard submarines during operational deployments. Due to a lack of adequate prior studies, potential general, neurobehavioral, reproductive and developmental toxicity was evaluated in male and female rats exposed to mixtures of three critical submarine atmospheric components: carbon monoxide (CO) and carbon dioxide (CO2; levels elevated above ambient), and oxygen (O2; levels decreased below ambient). In a 14-day, 23 h/day, whole-body inhalation study of exposure to clean air (0.4 ppm CO, 0.1% CO2 and 20.6% O2), low-dose, mid-dose and high-dose gas mixtures (high dose of 88.4 ppm CO, 2.5% CO2 and 15.0% O2), no adverse effects on survival, body weight or histopathology were observed. Reproductive, developmental and neurobehavioral performance were evaluated after a 28-day exposure in similar atmospheres. No adverse effects on estrus phase, mating, gestation or parturition were observed. No developmental or functional deficits were observed in either exposed parents or offspring related to motor activity, exploratory behavior or higher-level cognitive functions (learning and memory). Only minimal effects were discovered in parent-offspring emotionality tests. While statistically significant increases in hematological parameters were observed in the offspring of exposed parents compared to controls, these parameters remained within normal clinical ranges for blood cells and components and were not considered adverse. In summary, subacute exposures to elevated concentrations of the submarine atmosphere gases did not affect the ability of rats to reproduce and did not appear to have any significant adverse health effects.

Using developing cortical cultures on microelectrode arrays to identify and prioritize compounds based on changes in network formation

EPA Science Inventory

Characterization of the potential adverse effects is lacking for tens of thousands of chemicals that are present in the environment, and characterization of developmental neurotoxicity (DNT) hazard lags behind that of other adverse outcomes (e.g. hepatotoxicity). This is due in p...

Longitudinal and Integrative Tests of Family Stress Model Effects on Mexican-Origin Adolescents

PubMed Central

White, Rebecca M. B.; Liu, Yu; Nair, Rajni L.; Tein, Jenn-Yun

2015-01-01

The family stress model represents a common framework through which to examine the effects of environmental stressors on adolescent adjustment. The model suggests that economic and neighborhood stressors influence youth adjustment via disruptions to parenting. Incorporating integrative developmental theory, we examined the degree to which parents’ cultural value orientations mitigated the effects of stressors on parenting disruptions and the degree to which environmental adversity qualified the effect of parenting on adolescent adjustment. We tested the hypothesized Integrative Family Stress Model longitudinally in a sample of mother-youth dyads (N = 749) and father-youth dyads (N = 467) from Mexican origin families, across three times points spanning early to middle adolescence. Providing the first longitudinal evidence of family stress mediated effects, mothers’ perceptions of economic pressure were associated with increases in adolescent externalizing symptoms five years later via intermediate increases in harsh parenting. The remaining findings supported the notion that integrative developmental theory can inform family stress model hypothesis testing that is culturally and contextually relevant for wide range of diverse families and youth. For example, fathers’ perceptions of economic pressure and neighborhood danger had important implications for adolescent internalizing, via reductions in paternal warmth, but only at certain levels of neighborhood adversity. Mothers’ familism value orientations mitigated the effects of economic pressure on maternal warmth, protecting their adolescents from experiencing developmental costs associated with environmental stressors. Results are discussed in terms of identifying how integrative developmental theory intersects with the family stress model to set diverse youth on different developmental pathways. PMID:25751100

Longitudinal and integrative tests of family stress model effects on Mexican origin adolescents.

PubMed

White, Rebecca M B; Liu, Yu; Nair, Rajni L; Tein, Jenn-Yun

2015-05-01

The family stress model represents a common framework through which to examine the effects of environmental stressors on adolescent adjustment. The model suggests that economic and neighborhood stressors influence youth adjustment via disruptions to parenting. Incorporating integrative developmental theory, we examined the degree to which parents' cultural value orientations mitigated the effects of stressors on parenting disruptions and the degree to which environmental adversity qualified the effect of parenting on adolescent adjustment. We tested the hypothesized integrative family stress model longitudinally in a sample of mother-youth dyads (N = 749) and father-youth dyads (N = 467) from Mexican origin families, across 3 times points spanning early to middle adolescence. Providing the first longitudinal evidence of family stress mediated effects, mothers' perceptions of economic pressure were associated with increases in adolescent externalizing symptoms 5 years later via intermediate increases in harsh parenting. The remaining findings supported the notion that integrative developmental theory can inform family stress model hypothesis testing that is culturally and contextually relevant for a wide range of diverse families and youth. For example, fathers' perceptions of economic pressure and neighborhood danger had important implications for adolescent internalizing, via reductions in paternal warmth, but only at certain levels of neighborhood adversity. Mothers' familism value orientations mitigated the effects of economic pressure on maternal warmth, protecting their adolescents from experiencing developmental costs associated with environmental stressors. Results are discussed in terms of identifying how integrative developmental theory intersects with the family stress model to set diverse youth on different developmental pathways. (c) 2015 APA, all rights reserved).

Child Maltreatment and Children's Developmental Trajectories in Early- to Middle-Childhood

PubMed Central

Font, Sarah A.; Berger, Lawrence M.

2014-01-01

Associations between experiencing child maltreatment and adverse developmental outcomes are widely studied, yet conclusions regarding the extent to which effects are bidirectional, and whether they are likely causal, remain elusive. This study uses the Fragile Families and Child Well-Being study, a birth cohort of 4,898 children followed from birth through age 9. Hierarchical linear modeling and structural equation modeling are employed to estimate associations of maltreatment with cognitive and social-emotional well-being. Results suggest that effects of early childhood maltreatment emerge immediately, though developmental outcomes are also affected by newly occurring maltreatment over time. Additionally, findings indicate that children's early developmental scores predict their subsequent probability of experiencing maltreatment, though to a lesser extent than early maltreatment predicts subsequent developmental outcomes. PMID:25521556

Adverse morphological development in embryonic zebrafish exposed to environmental concentrations of contaminants individually and in mixture.

PubMed

Kinch, Cassandra D; Kurrasch, Deborah M; Habibi, Hamid R

2016-06-01

Exposure to environmental contaminants has been linked to developmental and reproductive abnormalities leading to infertility, spontaneous abortion, reduced number of offspring, and metabolic disorders. In addition, there is evidence linking environmental contaminants and endocrine disruption to abnormal developmental rate, defects in heart and eye morphology, and alterations in behavior. Notably, these effects could not be explained by interaction with a single hormone receptor. Here, using a whole-organism approach, we investigated morphological changes to developing zebrafish caused by exposure to a number of environmental contaminants, including bisphenol A (BPA), di(2-ethylhexyl)phthalate (DEHP), nonylphenol, and fucosterol at concentrations measured in a local water body (Oldman River, AB), individually and in mixture. Exposure to nanomolar contaminant concentrations resulted in abnormal morphological development, including changes to body length, pericardia (heart), and the head. We also characterize the spatiotemporal expression profiles of estrogen, androgen, and thyroid hormone receptors to demonstrate that localization of these receptors might be mediating contaminant effects on development. Finally, we examined the effects of contaminants singly and in mixture. Combined, our results support the hypothesis that adverse effects of contaminants are not mediated by single hormone receptor signaling, and adversity of contaminants in mixture could not be predicted by simple additive effect of contaminants. The findings provide a framework for better understanding of developmental toxicity of environmental contaminants in zebrafish and other vertebrate species. Copyright © 2016 Elsevier B.V. All rights reserved.

Cumulative adversity in childhood and emergent risk factors for long-term health.

PubMed

Slopen, Natalie; Koenen, Karestan C; Kubzansky, Laura D

2014-03-01

To examine whether and when effects of cumulative adversity in the first 7 years of life are evident in relation to 3 childhood markers of risk for poor adult physical health. The study data are from an English birth cohort. Parental reports of 8 social risk factors were obtained during the child's first 7 years, and scores were created to reflect cumulative adversity at 4 developmental periods. At age 7 and 11 years, weight, height, and blood pressure (BP) were measured by clinic staff, and caregivers reported behavior problems. Linear regression was used to estimate associations of cumulative adversity with each outcome (n = 4361) and changes in these outcomes between 7 and 11 years (n = 3348). At age 7 years, mean adversity and chronic exposure to high adversity were associated with elevated body mass index (BMI) and internalizing and externalizing symptoms (P < .05), but not elevated BP. Adversity in all developmental periods was associated with elevated numbers of internalizing and externalizing symptoms (P < .0001), but associations were less robust for BMI. Adversity did not predict change in BMI or BP between age 7 and 11 years, however, it predicted increases in internalizing and externalizing symptoms (P < .0001). Cumulative adversity was associated with BMI and behavior problems at age 7 years, and our data indicate that timing and chronicity of exposure to adversity differentially influence diverse indicators of long-term health risk commonly measured in childhood. This research suggests the hypothesis that interventions to address adversity could reduce the development of multiple chronic disease risk factors and limit their effects on health. Copyright © 2014 Mosby, Inc. All rights reserved.

Neurobehavioral assessment of children and adolescents attending a developmental disabilities clinic.

PubMed

Brasić, James Robert; Barnett, Jacqueline Y; Kowalik, S; Tsaltas, Margaret Owen; Ahmad, Raheela

2004-12-01

Although the risk of the eventual development of tardive dyskinesia and other persistent adverse effects of neuroleptics is high, among adults with mental retardation and other developmental disabilities, neuroleptics may ameliorate dyskinesias, aggression, and inattention. The effects of traditional neuroleptics on a comparable population of children and adolescents with mental retardation and other developmental disabilities are unknown. The objective of this study was to develop an assessment battery to describe the effects of traditional neuroleptics on the behavior and movements of a small sample of children and adolescents with mental retardation and other developmental disabilities. 13 children and adolescents aged 6 to 16 years attending a developmental disabilities clinic were evaluated utilizing a Movement Assessment Battery to measure behavior and motions. Five subjects took traditional neuroleptic medications. Trained raters can reliably assess the movements and behaviors of children and adolescents with multiple handicaps. Children and adolescents with developmental disabilities may be vulnerable to experience functional impairment and akathisia, tics, and other dyskinesias when administered traditional neuroleptic medications.

A Review of Nitrates in Drinking Water: Maternal Exposure and Adverse Reproductive and Developmental Outcomes

PubMed Central

Manassaram, Deana M.; Backer, Lorraine C.; Moll, Deborah M.

2006-01-01

In this review we present an update on maternal exposure to nitrates in drinking water in relation to possible adverse reproductive and developmental effects, and also discuss nitrates in drinking water in the United States. The current standard for nitrates in drinking water is based on retrospective studies and approximates a level that protects infants from methemoglobinemia, but no safety factor is built into the standard. The current standard applies only to public water systems. Drinking water source was related to nitrate exposure (i.e., private systems water was more likely than community system water to have nitrate levels above the maximum contaminant limit). Animal studies have found adverse reproductive effects resulting from higher doses of nitrate or nitrite. The epidemiologic evidence of a direct exposure–response relationship between drinking water nitrate level and adverse reproductive effect is still not clear. However, some reports have suggested an association between exposure to nitrates in drinking water and spontaneous abortions, intrauterine growth restriction, and various birth defects. Uncertainties in epidemiologic studies include the lack of individual exposure assessment that would rule out confounding of the exposure with some other cause. Nitrates may be just one of the contaminants in drinking water contributing to adverse outcomes. We conclude that the current literature does not provide sufficient evidence of a causal relationship between exposure to nitrates in drinking water and adverse reproductive effects. Future studies incorporating individual exposure assessment about users of private wells—the population most at risk—should be considered. PMID:16507452

Trace elements as paradigms of developmental neurotoxicants: lead, methylmercury and arsenic

PubMed Central

Grandjean, Philippe; Herz, Katherine T.

2014-01-01

Trace elements have contributed unique insights into developmental neurotoxicity and serve as paradigms for such adverse effects. Many trace elements are retained in the body for long periods and can be easily measured to assess exposure by inexpensive analytical methods that became available several decades ago so that past and cumulated exposures could be easily characterized through analysis of biological samples, e.g. blood and urine. The first compelling evidence resulted from unfortunate poisoning events that allowed scrutiny of long-term outcomes of acute exposures that occurred during early development. Pursuant to this documentation, prospective studies of children's cohorts that applied sensitive neurobehavioral methods supported the notion that the brain is uniquely vulnerable to toxic damage during early development. Lead, methylmercury, and arsenic thereby serve as paradigm neurotoxicants that provide a reference for other substances that may have similar adverse effects. Less evidence is available on manganese, fluoride, and cadmium, but experience from the former trace elements suggest that, with time, adverse effects are likely to be documented at exposures previously thought to be low and safe. PMID:25175507

Trace elements as paradigms of developmental neurotoxicants: Lead, methylmercury and arsenic.

PubMed

Grandjean, Philippe; Herz, Katherine T

2015-01-01

Trace elements have contributed unique insights into developmental neurotoxicity and serve as paradigms for such adverse effects. Many trace elements are retained in the body for long periods and can be easily measured to assess exposure by inexpensive analytical methods that became available several decades ago so that past and cumulated exposures could be easily characterized through analysis of biological samples, e.g. blood and urine. The first compelling evidence resulted from unfortunate poisoning events that allowed scrutiny of long-term outcomes of acute exposures that occurred during early development. Pursuant to this documentation, prospective studies of children's cohorts that applied sensitive neurobehavioral methods supported the notion that the brain is uniquely vulnerable to toxic damage during early development. Lead, methylmercury, and arsenic thereby serve as paradigm neurotoxicants that provide a reference for other substances that may have similar adverse effects. Less evidence is available on manganese, fluoride, and cadmium, but experience from the former trace elements suggest that, with time, adverse effects are likely to be documented at exposures previously thought to be low and safe. Copyright © 2014 Elsevier GmbH. All rights reserved.

Child maltreatment and children's developmental trajectories in early to middle childhood.

PubMed

Font, Sarah A; Berger, Lawrence M

2015-01-01

Associations between experiencing child maltreatment and adverse developmental outcomes are widely studied, yet conclusions regarding the extent to which effects are bidirectional, and whether they are likely causal, remain elusive. This study uses the Fragile Families and Child Wellbeing Study, a birth cohort of 4,898 children followed from birth through age 9. Hierarchical linear modeling and structural equation modeling are employed to estimate associations of maltreatment with cognitive and social-emotional well-being. Results suggest that effects of early childhood maltreatment emerge immediately, though developmental outcomes are also affected by newly occurring maltreatment over time. Additionally, findings indicate that children's early developmental scores predict their subsequent probability of experiencing maltreatment, though to a lesser extent than early maltreatment predicts subsequent developmental outcomes. © 2014 The Authors. Child Development © 2014 Society for Research in Child Development, Inc.

Emerging Environmental Contaminants: What’s New

EPA Science Inventory

Much has been achieved in the way of environmental protection over the last 30 years. However, as we learn more, new concerns arise; for example, potential adverse health effects (e.g., cancer, reproductive and developmental effects, and endocrine disruption), bioaccumulation, an...

Modeling Steroidogenesis Disruption Using High-Throughput In Vitro Screening Data (SOT)

EPA Science Inventory

Environmental chemicals can elicit endocrine disruption by altering steroid hormone biosynthesis and metabolism (steroidogenesis) causing adverse reproductive and developmental effects. Historically, a lack of assays resulted in few chemicals having been evaluated for effects on ...

Tobacco as a Reproductive and Developmental Toxicant

EPA Science Inventory

Maternal cigarette smoking has long been known to result in effects on offspring including lower birthweight and neurobehavioral effects. Continuing studies have expanded the list of adverse outcomes in offspring to include Sudden Infant Death Syndrome, impaired lung function, an...

EPA’s Nonmonotonic Dose Response Curve Workplan

EPA Pesticide Factsheets

EPA’s standard guidelines for reproductive and developmental toxicity testing and risk assessment are needed in order to detect and characterize low-dose adverse effects of endocrine disrupting chemicals (EDCs).

Developmental origins of inflammatory and immune diseases

PubMed Central

Chen, Ting; Liu, Han-xiao; Yan, Hui-yi; Wu, Dong-mei; Ping, Jie

2016-01-01

Epidemiological and experimental animal studies show that suboptimal environments in fetal and neonatal life exert a profound influence on physiological function and risk of diseases in adult life. The concepts of the ‘developmental programming’ and Developmental Origins of Health and Diseases (DOHaD) have become well accepted and have been applied across almost all fields of medicine. Adverse intrauterine environments may have programming effects on the crucial functions of the immune system during critical periods of fetal development, which can permanently alter the immune function of offspring. Immune dysfunction may in turn lead offspring to be susceptible to inflammatory and immune diseases in adulthood. These facts suggest that inflammatory and immune disorders might have developmental origins. In recent years, inflammatory and immune disorders have become a growing health problem worldwide. However, there is no systematic report in the literature on the developmental origins of inflammatory and immune diseases and the potential mechanisms involved. Here, we review the impacts of adverse intrauterine environments on the immune function in offspring. This review shows the results from human and different animal species and highlights the underlying mechanisms, including damaged development of cells in the thymus, helper T cell 1/helper T cell 2 balance disturbance, abnormal epigenetic modification, effects of maternal glucocorticoid overexposure on fetal lymphocytes and effects of the fetal hypothalamic–pituitary–adrenal axis on the immune system. Although the phenomena have already been clearly implicated in epidemiologic and experimental studies, new studies investigating the mechanisms of these effects may provide new avenues for exploiting these pathways for disease prevention. PMID:27226490

Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

EPA Pesticide Factsheets

Background: Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies.Objective: In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system.Methods: We used U.S. EPA??s animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA??s in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features. Results: A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network. Conclusion: Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarch

Screening Chemical Effects on Steroidogenesis in H295R Human Adrenocortical Carcinoma Cells (SOT)

EPA Science Inventory

Proper endocrine function requires steroid hormone biosynthesis and metabolism (steroidogenesis). Disruption of steroidogenesis by environmental chemicals can result in altered hormone levels causing adverse reproductive and developmental effects. This study is the first to estab...

Future Directions in Childhood Adversity and Youth Psychopathology.

PubMed

McLaughlin, Katie A

2016-01-01

Despite long-standing interest in the influence of adverse early experiences on mental health, systematic scientific inquiry into childhood adversity and developmental outcomes has emerged only recently. Existing research has amply demonstrated that exposure to childhood adversity is associated with elevated risk for multiple forms of youth psychopathology. In contrast, knowledge of developmental mechanisms linking childhood adversity to the onset of psychopathology-and whether those mechanisms are general or specific to particular kinds of adversity-remains cursory. Greater understanding of these pathways and identification of protective factors that buffer children from developmental disruptions following exposure to adversity is essential to guide the development of interventions to prevent the onset of psychopathology following adverse childhood experiences. This article provides recommendations for future research in this area. In particular, use of a consistent definition of childhood adversity, integration of studies of typical development with those focused on childhood adversity, and identification of distinct dimensions of environmental experience that differentially influence development are required to uncover mechanisms that explain how childhood adversity is associated with numerous psychopathology outcomes (i.e., multifinality) and identify moderators that shape divergent trajectories following adverse childhood experiences. A transdiagnostic model that highlights disruptions in emotional processing and poor executive functioning as key mechanisms linking childhood adversity with multiple forms of psychopathology is presented as a starting point in this endeavour. Distinguishing between general and specific mechanisms linking childhood adversity with psychopathology is needed to generate empirically informed interventions to prevent the long-term consequences of adverse early environments on children's development.

40 CFR 798.4350 - Inhalation developmental toxicity study.

Code of Federal Regulations, 2012 CFR

2012-07-01

...) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Specific Organ/Tissue... million (ppm). (6) “No-observed-effect level” is the maximum concentration in a test which produces no observed adverse effects. A no-observed-effect level is expressed in terms of weight or volume of test...

40 CFR 798.4350 - Inhalation developmental toxicity study.

Code of Federal Regulations, 2014 CFR

2014-07-01

...) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Specific Organ/Tissue... million (ppm). (6) “No-observed-effect level” is the maximum concentration in a test which produces no observed adverse effects. A no-observed-effect level is expressed in terms of weight or volume of test...

40 CFR 798.4350 - Inhalation developmental toxicity study.

Code of Federal Regulations, 2013 CFR

2013-07-01

...) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Specific Organ/Tissue... million (ppm). (6) “No-observed-effect level” is the maximum concentration in a test which produces no observed adverse effects. A no-observed-effect level is expressed in terms of weight or volume of test...

The Sea Urchin Embryo, an Invertebrate Model for Mammalian Developmental Neurotoxicity, Reveals Multiple Neurotransmitter Mechanisms for Effects of Chlorpyrifos: Therapeutic Interventions and a Comparison with the Monoamine Depleter, Reserpine

PubMed Central

Buznikov, Gennady A.; Nikitina, Lyudmila A.; Rakić, Ljubiša M.; Miloševi, Ivan; Bezuglov, Vladimir V.; Lauder, Jean M.; Slotkin, Theodore A.

2007-01-01

Lower organisms show promise for the screening of neurotoxicants that might target mammalian brain development. Sea urchins use neurotransmitters as embryonic growth regulatory signals, so that adverse effects on neural substrates for mammalian brain development can be studied in this simple organism. We compared the effects of the organophosphate insecticide, chlorpyrifos in sea urchin embryos with those of the monoamine depleter, reserpine, so as to investigate multiple neurotransmitter mechanisms involved in developmental toxicity and to evaluate different therapeutic interventions corresponding to each neurotransmitter system. Whereas reserpine interfered with all stages of embryonic development, the effects of chlorpyrifos did not emerge until the mid-blastula stage. After that point, the effects of the two agents were similar. Treatment with membrane permeable analogs of the monoamine neurotransmitters, serotonin and dopamine, prevented the adverse effects of either chlorpyrifos or reserpine, despite the fact that chlorpyrifos works simultaneously through actions on acetylcholine, monoamines and other neurotransmitter pathways. This suggests that different neurotransmitters, converging on the same downstream signaling events, could work together or in parallel to offset the developmental disruption caused by exposure to disparate agents. We tested this hypothesis by evaluating membrane permeable analogs of acetylcholine and cannabinoids, both of which proved effective against chlorpyrifos- or reserpine-induced teratogenesis. Invertebrate test systems can provide both a screening procedure for mammalian neuroteratogenesis and may uncover novel mechanisms underlying developmental vulnerability as well as possible therapeutic approaches to prevent teratogenesis. PMID:17720543

Unmet Health Services Needs Among US Children with Developmental Disabilities: Associations with Family Impact and Child Functioning.

PubMed

Lindly, Olivia J; Chavez, Alison E; Zuckerman, Katharine E

To determine associations of unmet needs for child or family health services with (1) adverse family financial and employment impacts and (2) child behavioral functioning problems among US children with autism spectrum disorder (ASD), developmental delay (DD), and/or intellectual disability (ID). This was a secondary analysis of parent-reported data from the 2009 to 2010 National Survey of Children with Special Health Care Needs linked to the 2011 Survey of Pathways to Diagnosis and Services. The study sample (n = 3,518) represented an estimated 1,803,112 US children aged 6 to 17 years with current ASD, DD, and/or ID (developmental disabilities). Dependent variables included adverse family financial and employment impacts, as well as child behavioral functioning problems. The independent variables of interest were unmet need for (1) child health services and (2) family health services. Multivariable logistic regression models were fit to examine associations. Unmet need for child and family health services, adverse family financial and employment impacts, and child behavioral functioning problems were prevalent among US children with developmental disabilities. Unmet needs were associated with an increased likelihood of adverse family employment and financial impacts. Unmet needs were associated with an increased likelihood of child behavioral functioning problems the following year; however, this association was not statistically significant. Unmet needs are associated with adverse impacts for children with developmental disabilities and their families. Increased access to and coordination of needed health services following ASD, DD, and/or ID diagnosis may improve outcomes for children with developmental disabilities and their families.

Evidence for non-acetylcholinesterase mechanisms in pesticide-induced developmental neurotoxicity#

EPA Science Inventory

Acetylcholinesterase inhibition is a well-established mode of action for adverse effects of organophosphorus and carbamate pesticides, and the use of this endpoint in regulatory considerations has been assumed to be protective of downstream cholinergic effects. It has been questi...

Evidence for non-acetylcholinesterase mechanisms in pesticide-induced developmental neurotoxicity

EPA Science Inventory

Acetyicholinesterase inhibition is a well-established mode of action for adverse effects of organophosphorus and carbamate pesticides, and the use of this endpoint in regulatory considerations has been assumed to be protective of downstream cholinergic effects. It has been questi...

High-throughput screening of chemical effects on steroidogenesis using H295R human adrenocortical carcinoma cells

EPA Science Inventory

Disruption of steroidogenesis by environmental chemicals can result in altered hormone levels causing adverse reproductive and developmental effects. A high-throughput assay using H295R human adrenocortical carcinoma cells was used to evaluate the effect of 2,060 chemical samples...

Developmental origins of inflammatory and immune diseases.

PubMed

Chen, Ting; Liu, Han-Xiao; Yan, Hui-Yi; Wu, Dong-Mei; Ping, Jie

2016-08-01

Epidemiological and experimental animal studies show that suboptimal environments in fetal and neonatal life exert a profound influence on physiological function and risk of diseases in adult life. The concepts of the 'developmental programming' and Developmental Origins of Health and Diseases (DOHaD) have become well accepted and have been applied across almost all fields of medicine. Adverse intrauterine environments may have programming effects on the crucial functions of the immune system during critical periods of fetal development, which can permanently alter the immune function of offspring. Immune dysfunction may in turn lead offspring to be susceptible to inflammatory and immune diseases in adulthood. These facts suggest that inflammatory and immune disorders might have developmental origins. In recent years, inflammatory and immune disorders have become a growing health problem worldwide. However, there is no systematic report in the literature on the developmental origins of inflammatory and immune diseases and the potential mechanisms involved. Here, we review the impacts of adverse intrauterine environments on the immune function in offspring. This review shows the results from human and different animal species and highlights the underlying mechanisms, including damaged development of cells in the thymus, helper T cell 1/helper T cell 2 balance disturbance, abnormal epigenetic modification, effects of maternal glucocorticoid overexposure on fetal lymphocytes and effects of the fetal hypothalamic-pituitary-adrenal axis on the immune system. Although the phenomena have already been clearly implicated in epidemiologic and experimental studies, new studies investigating the mechanisms of these effects may provide new avenues for exploiting these pathways for disease prevention. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Developmental toxicity of nicotine: A transdisciplinary synthesis and implications for emerging tobacco products

PubMed Central

England, Lucinda J.; Aagaard, Kjersti; Bloch, Michele; Conway, Kevin; Cosgrove, Kelly; Grana, Rachel; Gould, Thomas J.; Hatsukami, Dorothy; Jensen, Frances; Kandel, Denise; Lanphear, Bruce; Leslie, Frances; Pauly, James R.; Neiderhiser, Jenae; Rubinstein, Mark; Slotkin, Theodore A.; Spindel, Eliot; Stroud, Laura; Wakschlag, Lauren

2018-01-01

While the health risks associated with adult cigarette smoking have been well described, effects of nicotine exposure during periods of developmental vulnerability are often overlooked. Using MEDLINE and PubMed literature searches, books, reports and expert opinion, a transdisciplinary group of scientists reviewed human and animal research on the health effects of exposure to nicotine during pregnancy and adolescence. A synthesis of this research supports that nicotine contributes critically to adverse effects of gestational tobacco exposure, including reduced pulmonary function, auditory processing defects, impaired infant cardiorespiratory function, and may contribute to cognitive and behavioral deficits in later life. Nicotine exposure during adolescence is associated with deficits in working memory, attention, and auditory processing, as well as increased impulsivity and anxiety. Finally, recent animal studies suggest that nicotine has a priming effect that increases addiction liability for other drugs. The evidence that nicotine adversely affects fetal and adolescent development is sufficient to warrant public health measures to protect pregnant women, children, and adolescents from nicotine exposure. PMID:27890689

Developmental toxicity of nicotine: A transdisciplinary synthesis and implications for emerging tobacco products.

PubMed

England, Lucinda J; Aagaard, Kjersti; Bloch, Michele; Conway, Kevin; Cosgrove, Kelly; Grana, Rachel; Gould, Thomas J; Hatsukami, Dorothy; Jensen, Frances; Kandel, Denise; Lanphear, Bruce; Leslie, Frances; Pauly, James R; Neiderhiser, Jenae; Rubinstein, Mark; Slotkin, Theodore A; Spindel, Eliot; Stroud, Laura; Wakschlag, Lauren

2017-01-01

While the health risks associated with adult cigarette smoking have been well described, effects of nicotine exposure during periods of developmental vulnerability are often overlooked. Using MEDLINE and PubMed literature searches, books, reports and expert opinion, a transdisciplinary group of scientists reviewed human and animal research on the health effects of exposure to nicotine during pregnancy and adolescence. A synthesis of this research supports that nicotine contributes critically to adverse effects of gestational tobacco exposure, including reduced pulmonary function, auditory processing defects, impaired infant cardiorespiratory function, and may contribute to cognitive and behavioral deficits in later life. Nicotine exposure during adolescence is associated with deficits in working memory, attention, and auditory processing, as well as increased impulsivity and anxiety. Finally, recent animal studies suggest that nicotine has a priming effect that increases addiction liability for other drugs. The evidence that nicotine adversely affects fetal and adolescent development is sufficient to warrant public health measures to protect pregnant women, children, and adolescents from nicotine exposure. Published by Elsevier Ltd.

Developmental Regression and Autism Reported to the Vaccine Adverse Event Reporting System

ERIC Educational Resources Information Center

Woo, Emily Jane; Ball, Robert; Landa, Rebecca; Zimmerman, Andrew W.; Braun, M. Miles

2007-01-01

We report demographic and clinical characteristics of children reported to the US Vaccine Adverse Event Reporting System (VAERS) as having autism or another developmental disorder after vaccination. We completed 124 interviews with parents and reviewed medical records for 31 children whose records contained sufficient information to evaluate the…

Future Directions in Childhood Adversity and Youth Psychopathology

PubMed Central

McLaughlin, Katie A.

2016-01-01

Despite long-standing interest in the influence of adverse early experiences on mental health, systematic scientific inquiry into childhood adversity and developmental outcomes has emerged only recently. Existing research has amply demonstrated that exposure to childhood adversity is associated with elevated risk for multiple forms of youth psychopathology. In contrast, knowledge of developmental mechanisms linking childhood adversity to the onset of psychopathology—and whether those mechanisms are general or specific to particular kinds of adversity—remains cursory. Greater understanding of these pathways and identification of protective factors that buffer children from developmental disruptions following exposure to adversity is essential to guide the development of interventions to prevent the onset of psychopathology following adverse childhood experiences. This article provides recommendations for future research in this area. In particular, use of a consistent definition of childhood adversity, integration of studies of typical development with those focused on childhood adversity, and identification of distinct dimensions of environmental experience that differentially influence development are required to uncover mechanisms that explain how childhood adversity is associated with numerous psychopathology outcomes (i.e., multifinality) and identify moderators that shape divergent trajectories following adverse childhood experiences. A transdiagnostic model that highlights disruptions in emotional processing and poor executive functioning as key mechanisms linking childhood adversity with multiple forms of psychopathology is presented as a starting point in this endeavour. Distinguishing between general and specific mechanisms linking childhood adversity with psychopathology is needed to generate empirically informed interventions to prevent the long-term consequences of adverse early environments on children’s development. PMID:26849071

N-acetylcysteine prevents ketamine-induced adverse effects on development, heart rate and monoaminergic neurons in zebrafish.

PubMed

Robinson, Bonnie; Dumas, Melanie; Gu, Qiang; Kanungo, Jyotshna

2018-06-08

N-acetylcysteine, a precursor molecule of glutathione, is an antioxidant. Ketamine, a pediatric anesthetic, has been implicated in cardiotoxicity and neurotoxicity including modulation of monoaminergic systems in mammals and zebrafish. Here, we show that N-acetylcysteine prevents ketamine's adverse effects on development and monoaminergic neurons in zebrafish embryos. The effects of ketamine and N-acetylcysteine alone or in combination were measured on the heart rate, body length, brain serotonergic neurons and tyrosine hydroxylase-immunoreactive (TH-IR) neurons. In the absence of N-acetylcysteine, a concentration of ketamine that produces an internal embryo exposure level comparable to human anesthetic plasma concentrations significantly reduced heart rate and body length and those effects were prevented by N-acetylcysteine co-treatment. Ketamine also reduced the areas occupied by serotonergic neurons in the brain, whereas N-acetylcysteine co-exposure counteracted this effect. TH-IR neurons in the embryo brain and TH-IR cells in the trunk were significantly reduced with ketamine treatment, but not in the presence of N-acetylcysteine. In our continued search for compounds that can prevent ketamine toxicity, this study using specific endpoints of developmental toxicity, cardiotoxicity and neurotoxicity, demonstrates protective effects of N-acetylcysteine against ketamine's adverse effects. This is the first study that shows the protective effects of N-acetylcysteine on ketamine-induced developmental defects of monoaminergic neurons as observed in a whole organism. Published by Elsevier B.V.

Developmental Stability Covaries with Genome-Wide and Single-Locus Heterozygosity in House Sparrows

PubMed Central

Vangestel, Carl; Mergeay, Joachim; Dawson, Deborah A.; Vandomme, Viki; Lens, Luc

2011-01-01

Fluctuating asymmetry (FA), a measure of developmental instability, has been hypothesized to increase with genetic stress. Despite numerous studies providing empirical evidence for associations between FA and genome-wide properties such as multi-locus heterozygosity, support for single-locus effects remains scant. Here we test if, and to what extent, FA co-varies with single- and multilocus markers of genetic diversity in house sparrow (Passer domesticus) populations along an urban gradient. In line with theoretical expectations, FA was inversely correlated with genetic diversity estimated at genome level. However, this relationship was largely driven by variation at a single key locus. Contrary to our expectations, relationships between FA and genetic diversity were not stronger in individuals from urban populations that experience higher nutritional stress. We conclude that loss of genetic diversity adversely affects developmental stability in P. domesticus, and more generally, that the molecular basis of developmental stability may involve complex interactions between local and genome-wide effects. Further study on the relative effects of single-locus and genome-wide effects on the developmental stability of populations with different genetic properties is therefore needed. PMID:21747940

Effects of ToxCast Phase I Chemicals on Steroidogenesis in H295R Human Adrenocortical Carcinoma cells (SOT)

EPA Science Inventory

Steroid hormones are essential for proper development and reproduction. Disruption of steroidogenesis by environmental toxicants results in altered hormone levels causing adverse reproductive and developmental effects. H295R human adrenocortical carcinoma cells were used to evalu...

Virtual Tissue Models in Developmental Toxicity Research

EPA Science Inventory

Prenatal exposure to drugs and chemicals may perturb, directly or indirectly, core developmental processes in the embryo (patterning, morphogenesis, proliferation and apoptosis, and cell differentiation), leading to adverse developmental outcomes. Because embryogenesis entails a...

A Population-based Study Evaluating the Association between Surgery in Early Life and Child Development at Primary School Entry.

PubMed

O'Leary, James D; Janus, Magdalena; Duku, Eric; Wijeysundera, Duminda N; To, Teresa; Li, Ping; Maynes, Jason T; Crawford, Mark W

2016-08-01

It is unclear whether exposure to surgery in early life has long-term adverse effects on child development. The authors aimed to investigate whether surgery in early childhood is associated with adverse effects on child development measured at primary school entry. The authors conducted a population-based cohort study in Ontario, Canada, by linking provincial health administrative databases to children's developmental outcomes measured by the Early Development Instrument (EDI). From a cohort of 188,557 children, 28,366 children who underwent surgery before EDI completion (age 5 to 6 yr) were matched to 55,910 unexposed children. The primary outcome was early developmental vulnerability, defined as any domain of the EDI in the lowest tenth percentile of the population. Subgroup analyses were performed based on age at first surgery (less than 2 and greater than or equal to 2 yr) and frequency of surgery. Early developmental vulnerability was increased in the exposed group (7,259/28,366; 25.6%) compared with the unexposed group (13,957/55,910; 25.0%), adjusted odds ratio, 1.05; 95% CI, 1.01 to 1.08. Children aged greater than or equal to 2 yr at the time of first surgery had increased odds of early developmental vulnerability compared with unexposed children (odds ratio, 1.05; 95% CI, 1.01 to 1.10), but children aged less than 2 yr at the time of first exposure were not at increased risk (odds ratio, 1.04; 95% CI, 0.98 to 1.10). There was no increase in odds of early developmental vulnerability with increasing frequency of exposure. Children who undergo surgery before primary school age are at increased risk of early developmental vulnerability, but the magnitude of the difference between exposed and unexposed children is small.

Comparative Developmental Toxicity of Flavonoids Using an Integrative Zebrafish System

PubMed Central

Bugel, Sean M.; Bonventre, Josephine A.; Tanguay, Robert L.

2016-01-01

Flavonoids are a large, structurally diverse class of bioactive naturally occurring chemicals commonly detected in breast milk, soy based infant formulas, amniotic fluid, and fetal cord blood. The potential for pervasive early life stage exposures raises concerns for perturbation of embryogenesis, though developmental toxicity and bioactivity information is limited for many flavonoids. Therefore, we evaluated a suite of 24 flavonoid and flavonoid-like chemicals using a zebrafish embryo-larval toxicity bioassay—an alternative model for investigating developmental toxicity of environmentally relevant chemicals. Embryos were exposed to 1–50 µM of each chemical from 6 to 120 h postfertilization (hpf), and assessed for 26 adverse developmental endpoints at 24, 72, and 120 hpf. Behavioral changes were evaluated in morphologically normal animals at 24 and 72 hpf, at 120 hpf using a larval photomotor response (LPR) assay. Gene expression was comparatively evaluated for all compounds for effects on biomarker transcripts indicative of AHR (cyp1a) and ER (cyp19a1b, esr1, lhb, vtg) pathway bioactivity. Overall, 15 of 24 flavonoids elicited adverse effects on one or more of the developmental or behavioral endpoints. Hierarchical clustering and principle component analyses compared toxicity profiles and identified 3 distinct groups of bioactive flavonoids. Despite robust induction of multiple estrogen-responsive biomarkers, co-exposure with ER and GPER antagonists did not ameliorate toxicity, suggesting ER-independence and alternative modes of action. Taken together, these studies demonstrate that development is sensitive to perturbation by bioactive flavonoids in zebrafish that are not related to traditional estrogen receptor mode of action pathways. This integrative zebrafish platform provides a useful framework for evaluating flavonoid developmental toxicity and hazard prioritization. PMID:27492224

Recommendation of an Occupational Exposure Level for Perfluro-N-Butyl Iodide

DTIC Science & Technology

2006-09-01

Clinical signs observed in some dogs, but not all dogs exposed to PFBI included salivation, limb and/or muscle tension, and non-specific signs of...Symposium 2003 considered, “…developmental deficits or delays, and goiter and other effects of frank hypothyroid condition to be adverse effects

Romantic Relationships and Adjustment Problems in China: The Moderating Effect of Classroom Romantic Context

ERIC Educational Resources Information Center

Hou, Jinqin; Natsuaki, Misaki N.; Zhang, Jianxin; Guo, Fei; Huang, Zheng; Wang, Mianbo; Chen, Zhiyan

2013-01-01

Theoretical and empirical research has shown that adolescent romantic relationships are associated with a wide range of developmental outcomes, including adverse consequences. The present study used a hierarchical linear model to examine the moderating effect of classroom romantic context on the association between adolescent romantic…

Born early and born poor: An eco-bio-developmental model for poverty and preterm birth.

PubMed

Brumberg, H L; Shah, S I

2015-01-01

Poverty is associated with adverse long-term cognitive outcomes in children. Poverty is also linked with preterm delivery which, in turn, is associated with adverse cognitive outcomes. However, the extent of the effect of poverty on preterm delivery, as well as proposed mechanisms by which they occur, have not been well described. Further, the impact of poverty on preterm school readiness has not been reviewed. As the childhood poverty level continues to increase in the U.S., we examine the evidence around physiological, neurological, cognitive and learning outcomes associated with prematurity in the context of poverty. We use the evidence gathered to suggest an Eco-Bio-Developmental model, emphasizing poverty as a toxic stress which predisposes preterm birth and which, via epigenetic forces, can continue into the next generation. Continued postnatal social disadvantage for these developmentally high-risk preterm infants is strongly linked with poor neurodevelopmental outcomes, decreased school readiness, and decreased educational attainment which can perpetuate the poverty cycle. We suggest social remedies aimed at decreasing the impact of poverty on mothers, fathers, and children which may be effective in reducing the burden of preterm birth.

Prenatal stress accelerates offspring growth to compensate for reduced maternal investment across mammals

PubMed Central

Berghänel, Andreas; Heistermann, Michael; Schülke, Oliver; Ostner, Julia

2017-01-01

Across mammals, prenatal maternal stress (PREMS) affects many aspects of offspring development, including offspring growth. However, how PREMS translates to offspring growth is inconsistent, even within species. To explain the full range of reported effects of prenatal adversity on offspring growth, we propose an integrative hypothesis: developmental constraints and a counteracting adaptive growth plasticity work in opposition to drive PREMS effects on growth. Mothers experiencing adversity reduce maternal investment leading to stunted growth (developmental constraints). Concomitantly, the pace of offspring life history is recalibrated to partly compensate for these developmental constraints (adaptive growth plasticity). Moreover, the relative importance of each process changes across ontogeny with increasing offspring independence. Thus, offspring exposed to PREMS may grow at the same rate as controls during gestation and lactation, but faster after weaning when direct maternal investment has ceased. We tested these predictions with a comparative analysis on the outcomes of 719 studies across 21 mammal species. First, the observed growth changes in response to PREMS varied across offspring developmental periods as predicted. We argue that the observed growth acceleration after weaning is not “catch-up growth,” because offspring that were small for age grew slower. Second, only PREMS exposure early during gestation produced adaptive growth plasticity. Our results suggest that PREMS effects benefit the mother’s future reproduction and at the same time accelerate offspring growth and possibly maturation and reproductive rate. In this sense, PREMS effects on offspring growth allow mother and offspring to make the best of a bad start. PMID:29180423

Potential of chromium(III) picolinate for reproductive or developmental toxicity following exposure of male CD-1 mice prior to mating.

PubMed

McAdory, DeAna; Rhodes, Nicholas R; Briggins, Felicia; Bailey, Melissa M; Di Bona, Kristin R; Goodwin, Craig; Vincent, John B; Rasco, Jane F

2011-12-01

Chromium(III) picolinate, [Cr(pic)(3)], is a commonly used nutritional supplement in humans, which has also been approved for use in animals. Health concerns have arisen over the use of [Cr(pic)(3)]. At high [Cr(pic)(3)] doses, developmental toxicity tests in female mice have shown a higher litter incidence of split cervical arch in exposed fetuses, but this was not consistently reproducible. In the current study, male CD-1 mice were used to further assess the potential for reproductive or developmental toxicity. Four weeks prior to mating, the males were fed a diet providing 200 mg/kg/day [Cr(pic)(3)] for comparison with untreated controls. Females were not treated. Each male was mated with two females, which were sacrificed on gestation day 17, and their litters were examined for adverse effects. Mating and fertility indices were not significantly altered by treatment. Male exposure to [Cr(pic)(3)] also had no effect on prenatal mortality, fetal weight, or gross or skeletal morphology. These results suggest that paternal dietary exposure to chromium(III) picolinate has little potential for adverse reproductive effects, even at exposure levels considerably higher than expected human exposures from nutritional supplements (1 mg of Cr per day or less).

Long-Term Safety and Adverse Events of Risperidone in Children, Adolescents, and Adults with Pervasive Developmental Disorders

ERIC Educational Resources Information Center

Hellings, Jessica A.; Cardona, Alicia M.; Schroeder, Stephen R.

2010-01-01

The objective of this study was to examine long-term adverse events of risperidone in 19 children, adolescents, and adults with Pervasive Developmental Disorders and intellectual disability, continuing risperidone for a mean of 186.5 weeks, following a 46-week risperidone study. Nineteen individuals continued long-term follow-up after our…

Novel quantitative methods for characterization of chemical induced functional alteration in developing neuronal cultures

EPA Science Inventory

ABSTRACT BODY: Thousands of chemicals lack adequate testing for adverse effects on nervous system development, stimulating research into alternative methods to screen chemicals for potential developmental neurotoxicity. Microelectrode arrays (MEA) collect action potential spiking...

DISINFECTION BY-PRODUCTS AND OTHER EMERGING CONTAMINANTS IN DRINKING WATER

EPA Science Inventory

Although drinking water disinfection by-products (DBPs) have been studied for the last 30 years, significant, new concerns have arisen. These concerns include adverse reproductive and developmental effects recently observed in human populations, concerns that the types of cancer...

Developmental neurotoxicity testing: Past, present and future.

EPA Science Inventory

Adverse effects on the nervous system following exposure to environmental contaminants during development have been well documented. Indeed, in a number of cases (e.g., lead, methyl mercury) the developing human nervous system appears to be a highly susceptible target. There ar...

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

Dose related shifts in the developmental progress of chick embryos exposed to mobile phone induced electromagnetic fields.

PubMed

Zareen, Nusrat; Khan, Muhammad Yunus; Minhas, Liaqat Ali

2009-01-01

The possible adverse effects of Electromagnetic Fields (EMFs) emitted from mobile phones present a major public concern today. Some studies indicate EMFs effects on genes, free radical production, immunological and carcinogenic effects. On the other hand there are studies which do not support the hypothesis of any biological impacts of EMFs. This study was designed to observe the effects of mobile phone induced EMFs on survival and general growth and development of chick embryo, investigating dose-response relationship if any. This was an experimental study in which developing chick embryos were exposed to different doses of mobile phone induced EMFs. For this purpose a mobile phone was placed in the incubator in the centre of fertilised eggs in silent ringing mode and was 'rung' upon from any other line or cell phone. After incubation for 10 or 15 days the eggs were opened and the developmental mile-stones of the surviving embryos were compared with the non exposed subgroup. EMFs exposure significantly decreased the survivability of the chick embryos. The lower doses of EMFs caused growth retardation. However, this effect of growth retardation reallocated to partial growth enhancement on increasing the dose of EMFs and shifted over to definite growth enhancement on further raising the dose. There is an adverse effect of EMFs exposure on embryo survivability. Chick embryos developmental process is influenced by EMFs. However, these effects are variable depending upon the dose of EMFs exposure.

Influence of Study Design on Developmental and Reproductive Toxicology Study Outcomes.

PubMed

Foster, Paul M D

2017-01-01

Regulatory studies of developmental and reproductive toxicity (DART) studies have remained largely unchanged for decades, with exposures occurring at various phases of the reproductive cycle and toxicity evaluations at different ages/times depending on the study purpose. The National Toxicology Program has conducted studies examining the power to detect adverse effects where there is a prenatal exposure, but evaluations occur postnatally. In these studies, examination is required of only 1 male and female pup from each litter beyond weaning. This provides poor resolving power to detect rare events (e.g., reproductive tract malformations). If an adverse effect is detected, there is little confidence in the shape of the dose-response curve (and the Benchmark Dose or No Observed Adverse Effect Level [NOAEL]). We have developed a new protocol to evaluate DART, the modified one generation study, with exposure commencing with pregnant animals and retention of 4 males and females from each litter beyond weaning to improve statistical power. These animals can be allocated to specific cohorts that examine subchronic toxicity, teratology, littering, and neurobehavioral toxicity in the same study. This approach also results in a reduction in animal numbers used, compared with individual stand-alone studies, and offers increased numbers of end points evaluated compared with recent Organization for Economic Cooperation and Development proposals.

Prenatal stress and development: beyond the single cause and effect paradigm.

PubMed

Hamlin, Heather J

2012-12-01

Our awareness of the causes of stress-induced developmental dysfunction has increased dramatically over the past decade, and it is becoming increasingly clear that a number of factors can have considerable impacts on the developing fetus. Although there is a tendency in investigations of developmental teratogens to attribute specific causes to adverse fetal outcomes, it is important we recognize that for most developmental dysfunctions it is unlikely a single cause, but yet a series of environmental insults combined with genetic predisposition that ultimately leads to a disease state. Nonetheless, a number of developmental teratogens, such as maternal psychological stress and chemical exposures, have been shown to increase the likelihood of developmental defects. These defects can manifest during development, leading to observable birth defects, or could become evident long after birth, even into adulthood. In addition, epigenetic mutations in the germline can alter the phenotype of successive generations through transgenerational inheritance, and in this way environmental factors can alter the developmental outcomes and disease predispositions of future generations. Understanding this complexity is essential to interpretations of causality in the studies of stress-induced developmental dysfunction and needs to be fully considered to more effectively interpret potential outcomes. Copyright © 2013 Wiley Periodicals, Inc.

Mental Health, Behavioral and Developmental Issues for Youth in Foster Care.

PubMed

Deutsch, Stephanie A; Lynch, Amy; Zlotnik, Sarah; Matone, Meredith; Kreider, Amanda; Noonan, Kathleen

2015-10-01

Youth in foster care represent a unique population with complex mental and behavioral health, social-emotional, and developmental needs. For this population with special healthcare needs, the risk for adverse long-term outcomes great if needs go unaddressed or inadequately addressed while in placement. Although outcomes are malleable and effective interventions exist, there are barriers to optimal healthcare delivery. The general pediatrician as advocate is paramount to improve long-term outcomes. Copyright © 2015 Mosby, Inc. All rights reserved.

Effects of therapeutic interventions for foster children on behavioral problems, caregiver attachment, and stress regulatory neural systems.

PubMed

Fisher, Philip A; Gunnar, Megan R; Dozier, Mary; Bruce, Jacqueline; Pears, Katherine C

2006-12-01

Young children in foster care are exposed to high levels of stress. These experiences place foster children at risk for poor social, academic, and mental heath outcomes. The role of adverse events in stimulating neurobiological stress responses presumably plays a role in shaping neural systems that contribute to these problems. Systematic and developmentally well-timed interventions might have the potential to change developmental trajectories and promote resilience. Moreover, understanding how specific dimensions of early adversity affect underlying stress response systems and how alterations in these systems are related to later psychosocial outcomes might facilitate more precise and targeted interventions. Data are drawn from two ongoing randomized trials involving foster infants/toddlers and preschoolers. Consistent with prior animal models of early adversity, these studies have shown that early adversity-particularly neglect, younger age at first foster placement, and higher number of placements-is associated with altered hypothalamic-pituitary-adrenal (HPA) axis function. The interventions under investigation have produced evidence that it is possible to impact many areas that have been negatively affected by early stress, including HPA axis activity, behavior, and attachment to caregivers.

Development of Children at Risk for Adverse Outcomes Participating in Early Intervention in Developing Countries: A Randomized Controlled Trial

ERIC Educational Resources Information Center

Wallander, Jan L.; Bann, Carla M.; Biasini, Fred J.; Goudar, Shivaprasad S.; Pasha, Omrana; Chomba, Elwyn; McClure, Elizabeth; Carlo, Waldemar A.

2014-01-01

Background: Previous research has indicated positive effects of early developmental intervention (EDI) on the development of children in developing countries. Few studies, however, have examined longitudinally when differential treatment effects may be observed and whether differential outcomes are associated with exposure to different risk…

Reproductive failure of the red shiner (Cyprinella lutrensis) after exposure to an exogenous estrogen

USGS Publications Warehouse

McGree, M.M.; Winkelman, D.L.; Vieira, N.K.M.; Vajda, A.M.

2010-01-01

Endocrine disrupting chemicals (EDCs) have been detected in surface waters worldwide and can lead to developmental and reproductive disruption in exposed fishes. In the US Great Plains, EDCs are impacting streams and rivers and may be causing adverse reproductive effects. To examine how estrogenic EDCs might affect reproductive success of plains fishes, we experimentally exposed male red shiners (Cyprinella lutrensis) to exogenous 17b-estradiol. We characterized the effects of estradiol on male gonadal histology and secondary sexual characteristics, determined whether exposure reduced reproductive success, and examined the effects of depuration. Adults were exposed to a mean concentration of 70 ng L-1 estradiol, a solvent control, or a water control for at least 83 days. Male exposure to estradiol resulted in elevated plasma vitellogenin concentrations, changes in spermatogenesis, reduced mating coloration and tubercles, altered mating behaviors, and reduced reproductive success with no viable progeny produced. Reproductive endpoints improved upon depuration (28 days). Exposure to estradiol had significant adverse effects on red shiners, indicating that wild populations may face developmental and reproductive difficulties if they are chronically exposed to estradiol.

Developmental exposure to environmental estrogens alters microbiota structure in zebrafish

EPA Science Inventory

Exposure to Bisphenol A (BPA), a widespread environmental contaminant, has been associated with adverse endocrine and neurodevelopmental effects. Growing public concern over the safety of BPA has resulted in swift replacement with a suite of alternatives that uniformly lack suffi...

NTP-CERHR EXPERT PANEL UPDATE ON THE REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF DI(2-ETHYLHEXYL) PHTHALATE.

EPA Science Inventory

The purpose of the Center is to provide timely, unbiased, scientifically sound evaluations of human and experimental evidence for adverse effects on reproduction and development caused by agents to which humans may be exposed.

A BIOLOGICALLY BASED MODEL FOR THE HORMONAL CONTROL OF THE MENSTRUAL CYCLE

EPA Science Inventory

Recent studies suggest that environmental substances that mimic endogenous estrogens (eg. estradiol) may disrupt the endocrine system. While high-level exposures to estrogenic substances are believed to contribute to such adverse effects as cancer, developmental disorders, and fe...

Concentrations and trends of Perfluorinated chemicals in potential indoor sources from 2007 through 2011 in the US

EPA Science Inventory

Certain perfluorinated chemicals in consumer products have been associated with developmental toxicity and other adverse health effects. Temporal trends in the concentrations of selected perfluorinated chemicals (PFCs), including perfluorooctanoic acid (PFOA) and other perfluoroc...

Strengths of Farming Communities in Fostering Resilience in Children.

ERIC Educational Resources Information Center

Larson, Nancy C.; Dearmont, Melissa

2002-01-01

Explores the unique values and characteristics of rural communities and farm families, particularly individual, family, and community factors that may protect children from potentially negative developmental effects of chronic stress or adversity. Considers community strengths in supporting children's healthy development. Identifies implications…

H295R Human Adrenocortical Carcinoma Cells as a Screening Platform for Steroidogenesis (NC SOT)

EPA Science Inventory

Proper biosynthesis and metabolism of steroid hormones is essential for development and reproduction. Disruption of steroidogenesis by environmental toxicants results in altered hormone levels causing adverse reproductive and developmental effects. H295R human adrenocortical carc...

NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Di-n-Butyl Phthalate (DBP).

PubMed

2003-04-01

TThe National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for di-n-butyl phthalate (DBP) to cause adverse effects on reproduction and development in humans. DBP is one of 7 phthalate chemicals evaluated by the NTP CERHR Phthalates Expert Panel. These phthalates were selected for evaluation because of high production volume, extent of human exposures, use in children's products, and/or published evidence of reproductive or developmental toxicity. Unlike many phthalates, DBP is not currently used as a plasticizer in polyvinyl chloride plastics. DBP is a component of latex adhesives and is used in cosmetics and other personal care products, as a plasticizer in cellulose plastics, and as a solvent for dyes. The results of this evaluation on DBP are published in a NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of Di-n-Butyl Phthalate, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to DBP on human development and reproduction. First, although DBP could possibly affect human reproduction and development if exposures are sufficiently high, the NTP concludes that there is negligible concern for reproductive toxicity in exposed adults. Second, the NTP concludes that there is minimal concern for developmental effects when pregnant women are exposed to DBP levels estimated by the panel (2-10 mug/kg body weight/day). There is no direct evidence that exposure of people to DBP adversely affects reproduction or development, but studies reviewed by the expert panel show that oral exposure to high doses of DBP (>/=100 mg/kg body weight/day) may adversely affect the prenatal and early postnatal development in rodents. Finally, based on exposure estimates in women of reproductive age, the NTP concludes that there is some concern for DBP causing adverse effects to human development, particularly development of the male reproductive system. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available electronically in PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

Prenatal Dexamethasone Augments the Sex-Selective Developmental Neurotoxicity of Chlorpyrifos: Implications for Vulnerability after Pharmacotherapy for Preterm Labor

PubMed Central

Slotkin, Theodore A.; Card, Jennifer; Infante, Alice; Seidler, Frederic J.

2013-01-01

Glucocorticoids are routinely given in preterm labor and are also elevated by maternal stress; organophosphate exposures are virtually ubiquitous, so coexposures to these two agents are pervasive. We administered dexamethasone to pregnant rats on gestational days 17–19 at a standard therapeutic dose (0.2 mg/kg); offspring were then given chlorpyrifos on postnatal days 1–4, at a dose (1 mg/kg) that produces barely-detectable (<10%) inhibition of brain cholinesterase activity. We evaluated indices for acetylcholine (ACh) synaptic function throughout adolescence, young adulthood and later adulthood, in brain regions possessing the majority of ACh projections and cell bodies; we measured nicotinic ACh receptor binding, hemicholinium-3 binding to the presynaptic choline transporter and choline acetyltransferase activity, all known targets for the adverse developmental effects of dexamethasone and chlorpyrifos given individually. Dexamethasone did not enhance the systemic toxicity of chlorpyrifos, as evidenced by weight gain and measurements of cholinesterase inhibition during chlorpyrifos treatment. Nevertheless, it enhanced the loss of presynaptic ACh function selectively in females, who ordinarily show sparing of organophosphate developmental neurotoxicity relative to males. Females receiving the combined treatment showed decrements in choline transporter binding and choline acetyltransferase activity that were unique (not found with either treatment alone), as well as additive decrements in nicotinic receptor binding. On the other hand, males given dexamethasone showed no augmentation of the effects of chlorpyrifos. Our findings indicate that prior dexamethasone exposure could create a subpopulation that is especially vulnerable to the adverse effects of organophosphates or other developmental neurotoxicants. PMID:23416428

Change in Gene Expression in Zebrafish as an Endpoint for Developmental Neurotoxicity Screening

EPA Science Inventory

Chemicals that adversely affect the developing nervous system may have long-term consequences on human health. Little information exists on a large number of environmental chemicals to guide the risk assessments for developmental neurotoxicity (DNT). As traditional developmental ...

Comprehensive assessment of a chlorinated drinking water concentrate in a rat multigenerational reproductive toxicity study

EPA Science Inventory

Some epidemiological studies report associations between drinking water disinfection by-products (DBPs) and adverse reproductive and developmental effects, e.g., low birth weight, spontaneous abortion, stillbirth, and birth defects. To address concerns raised by these studies, w...

Comprehensive Assessment of a Chlorinated Drinking Water Concentrate in a Rat Multigenerational Reproductive Toxicity Study##

EPA Science Inventory

Some epidemiological studies report associations between drinking water disinfection by-products (DBPs) and adverse reproductive and developmental effects, e.g., low birth weight, spontaneous abortion, stillbirth, and birth defects. To address concerns raised by these studies, w...

Toxicological effects of mainstream whole smoke solutions on embryonic movements of the developing embryo.

PubMed

Ejaz, Sohail; Seok, Kim Bum; Woong, Lim Chae

2005-01-01

Cigarette smoking is unrivaled among developmental toxicants in terms of total adverse impact on the human population. Maternal tobacco use during pregnancy adversely affects prenatal and postnatal growth and increases the risk of behavioral and developmental defects in children and adolescents. In the current study, the effects of different preparations of nicotine and mainstream whole smoke solutions (MSWSS) on embryonic movements during neonatal development were examined in vivo, using the chicken embryo model, recorded in real-time by a video camera. It was observed that low doses of nicotine induced hyperactivity and higher doses induced hypoactivity. Accordingly, a significant (p < 0.01) decrease in movements was observed by application of 10 microg of nicotine and different preparations of MSWSS. A dose-dependent decrease in embryonic movements was observed, which did not recover by the end of experiment. It was concluded that nicotine could alter embryonic movements, which are important during embryogenesis for differentiation and maturation of the body systems.

AN ASSESSMENT OF THE EFFECTS OF GESTATIONAL AND LACTATIONAL EXPOSURE TO ETHINYL ESTRADIOL (EE) AND BISPHENOL A (BPA) ON REPRODUCTIVE MORPHOLOGY AND BEHAVIOR IN FEMALE AND MALE LONG EVANS HOODED RAT

EPA Science Inventory

Anthropogenic estrogens are pervasive in the environment. Although the effects of these 'xenoestrogens' are controversial in humans, some fish species are adversely affected in contaminated ecosystems. The current project focuses on the effects of developmental exposure to two ...

Effects of an Early Family Intervention on Children's Memory: The Mediating Effects of Cortisol Levels

ERIC Educational Resources Information Center

Bugental, Daphne Blunt; Schwartz, Alex; Lynch, Colleen

2010-01-01

Developmental psychologists have long been concerned with the ways that early adversity influences children's long-term outcomes. In the current study, activity of the hypothalamic-pituitary-adrenal axis of medically at-risk (e.g., preterm) infants was measured as a result of maternal participation in a novel cognitively based home visitation…

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.

Cytotoxic effects of propiconazole and its metabolites in mouse and human hepatoma cells and primary mouse hepatocytes

EPA Science Inventory

Abstract: Propiconazole is a triazole-containing fungicide that is used agriculturally on grasses, fruits, grains, seeds, hardwoods, and conifers. Propiconazole is a mouse liver hepatotoxicant and a hepatocarcinogen and has adverse reproductive and developmental toxicities in exp...

DISINFECTION BY-PRODUCTS OF EMERGING CONCERN: RESULTS OF A U.S. NATIONWIDE OCCURRENCE STUDY

EPA Science Inventory

Drinking water disinfection by-products (DBPs) are of concern because some epidemiologic studies have shown that some DBPs are associated with cancer or adverse reproductive/developmental effects in human populations and other studies have shown that certain DBPs cause similar he...

Alterations in microbiota structure and neurobehavior in zebrafish following developmental exposure to estrogenic compounds

EPA Science Inventory

Exposure to Bisphenol A (BPA), a high-production volume chemical and widespread environmental contaminant, has been associated with adverse endocrine and neurodevelopmental effects. Growing public concern over the safety of BPA has resulted in swift replacement with a suite of al...

NTP-CERHR EXPERT PANEL REPORT ON REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF METHYLPHENIDATE.

EPA Science Inventory

A manuscript describes the results of an expert panel meeting of the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR). The purpose CERHR is to provide timely, unbiased, scientifically sound evaluations of human and experimental evidence for adverse effects on...

Maternal Sensitivity and Communication Styles: Mothers with Depression

ERIC Educational Resources Information Center

Hwa-Froelich, Deborah A.; Loveland Cook, Cynthia A.; Flick, Louise H.

2008-01-01

Women living in poverty are at increased risk for depression, especially during their childbearing years. Whereas poverty has known adverse effects on children's cognitive, social, and communication development, maternal depression may place these children at additional risk of developmental delays. The maternal sensitivity of mothers with and…

Effects of exposure to azaarenes on emergence and mouthpart development in the midge Chironomus riparius (Diptera: Chironomidae)

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

Bleeker, E.A.J.; Leslie, H.A.; Groenendijk, D.

1999-08-01

Adverse effects of azaarenes on emergence and mouthpart development of the midge Chironomus riparius were analyzed using six closely related three-ringed isomers and metabolites. Effects on growth rate were examined by comparing the average day of emergence of exposed midges with that of controls. Fluctuating asymmetry (FA) in the pecten epipharyngis was examined as a measure of developmental abnormality. Delayed emergence was found at concentrations as low as 2% of the acute LC50, so emergence day appears to be a useful sensitive parameter to quantity life cycle effects. No differences in FA were found between exposed and control larvae, although,more » in other studies, all compounds have been proven to be genotoxic. The differences in FA were found between exposed and control larvae, although, in other studies, all compounds have been proven to be genotoxic. The differences in the genotoxic and FA-inducing properties of these compounds indicate that different mechanisms are involved in expressing these adverse effects. This study also illustrates that the choice of the morphological parameter strongly influences the results of developmental disturbance analyses and thus the risk qualification of a potentially hazardous compound.« less

Financial well-being of single, working-age mothers of children with developmental disabilities.

PubMed

Parish, Susan L; Rose, Roderick A; Swaine, Jamie G; Dababnah, Sarah; Mayra, Ellen Tracy

2012-09-01

Understanding the financial well-being of single mothers who care for children with developmental disabilities is important to ensure that public policies can be effectively targeted to support these vulnerable families. The authors analyze data from the Survey of Income and Program Participation to describe income poverty, asset poverty, income, net worth, and liquid assets of U.S. single, working-age mothers (n  =  242) of children and adult children with developmental disabilities. The well-being of these mothers was compared to the situation of married mothers of children with developmental disabilities (n  =  345) and of single mothers who did not have children with developmental disabilities (n  =  6,547). Compared with both married mothers of children with developmental disabilities and single mothers without children with developmental disabilities, single mothers of children with developmental disabilities had markedly worse financial well-being across a range of income- and asset-based measures. Single mothers caring for children with developmental disabilities face adverse financial well-being as compared with other mothers. Policy makers should consider targeted measures to improve the financial well-being of these parents.

PPTOX III: environmental stressors in the developmental origins of disease--evidence and mechanisms.

PubMed

Schug, Thaddeus T; Barouki, Robert; Gluckman, Peter D; Grandjean, Philippe; Hanson, Mark; Heindel, Jerold J

2013-02-01

Fetal and early postnatal development constitutes the most vulnerable time period of human life in regard to adverse effects of environmental hazards. Subtle effects during development can lead to functional deficits and increased disease risk later in life. The hypothesis stating that environmental exposures leads to altered programming and, thereby, to increased susceptibility to disease or dysfunction later in life has garnered much support from both experimental and epidemiological studies. Similar observations have been made on the long-term impact of nutritional unbalance during early development. In an effort to bridge the fields of nutritional and environmental developmental toxicity, the Society of Toxicology sponsored this work. This report summarizes novel findings in developmental toxicity as reported by select invited experts and meeting attendees. Recommendations for the application and improvement of current and future research efforts are also presented.

Reproductive and Developmental Toxicity of Dioxin in Fish1

PubMed Central

King-Heiden, Tisha C.; Mehta, Vatsal; Xiong, Kong M.; Lanham, Kevin A.; Antkiewicz, Dagmara S.; Ganser, Alissa; Heideman, Warren

2011-01-01

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD or dioxin) is a global environmental contaminant and the prototypical ligand for investigating aryl hydrocarbon receptor (AHR)-mediated toxicity. Environmental exposure to TCDD results in developmental and reproductive toxicity in fish, birds and mammals. To resolve the ecotoxicological relevance and human health risks posed by exposure to dioxin-like AHR agonists, a vertebrate model is needed that allows for toxicity studies at various levels of biological organization, assesses adverse reproductive and developmental effects and establishes appropriate integrative correlations between different levels of effects. Here we describe the reproductive and developmental toxicity of TCDD in feral fish species and summarize how using the zebrafish model to investigate TCDD toxicity has enabled us to characterize the AHR signaling in fish and to better understand how dioxin-like chemicals induce toxicity. We propose that such studies can be used to predict the risks that AHR ligands pose to feral fish populations and provide a platform for integrating risk assessments for both ecologically relevant organisms and humans. PMID:21958697

Beyond Cumulative Risk: A Dimensional Approach to Childhood Adversity.

PubMed

McLaughlin, Katie A; Sheridan, Margaret A

2016-08-01

Children who have experienced environmental adversity-such as abuse, neglect, or poverty-are more likely to develop physical and mental health problems, perform poorly at school, and have difficulties in social relationships than children who have not encountered adversity. What is less clear is how and why adverse early experiences exert such a profound influence on children's development. Identifying developmental processes that are disrupted by adverse early environments is the key to developing better intervention strategies for children who have experienced adversity. Yet, much existing research relies on a cumulative risk approach that is unlikely to reveal these mechanisms. This approach tallies the number of distinct adversities experienced to create a risk score. This risk score fails to distinguish between distinct types of environmental experience, implicitly assuming that very different experiences influence development through the same underlying mechanisms. We advance an alternative model. This novel approach conceptualizes adversity along distinct dimensions, emphasizes the central role of learning mechanisms, and distinguishes between different forms of adversity that might influence learning in distinct ways. A key advantage of this approach is that learning mechanisms provide clear targets for interventions aimed at preventing negative developmental outcomes in children who have experienced adversity.

Impulsivity as a mechanism linking child abuse and neglect with substance use in adolescence and adulthood.

PubMed

Oshri, Assaf; Kogan, Steve M; Kwon, Josephine A; Wickrama, K A S; Vanderbroek, Lauren; Palmer, Abraham A; MacKillop, James

2018-05-01

Emerging developmental perspectives suggest that adverse rearing environments promote neurocognitive adaptations that heighten impulsivity and increase vulnerability to risky behavior. Although studies document links between harsh rearing environments and impulsive behavior on substance use, the developmental hypothesis that impulsivity acts as mechanism linking adverse rearing environments to downstream substance use remains to be investigated. The present study investigated the role of impulsivity in linking child abuse and neglect with adult substance use using data from (a) a longitudinal sample of youth (Study 1, N = 9,421) and (b) a cross-sectional sample of adults (Study 2, N = 1,011). In Study 1, the links between child abuse and neglect and young adult smoking and marijuana use were mediated by increases in adolescent impulsivity. In Study 2, indirect links between child abuse and neglect and substance use were evidenced via delayed reward discounting and impulsivity traits. Among impulsivity subcomponents, robust indirect effects connecting childhood experiences to cigarette use emerged for negative urgency. Negative urgency, positive urgency, and sensation seeking mediated the effect of child abuse and neglect on cannabis and alcohol use. Results suggest that child abuse and neglect increases risk for substance use in part, due to effects on impulsivity. Individuals with adverse childhood experiences may benefit from substance use preventive intervention programs that target impulsive behaviors.

Effects of Perfluorooctanoic Acid on Mouse Mammary Gland Development and Differentiation Resulting from Cross-Foster and Restricted Gestational Exposures

EPA Science Inventory

The adverse consequences of developmental exposures to perfluorooctanoic acid (PFOA) have been established, and include impaired development of the offspring mammary gland (MG). However, the relationship between the timing or route of exposure, and the phenotypic consequences in ...

CHANGES IN PROTEOMIC PROFILES OF CEREBELLUM FOLLOWING DEVELOPMENTAL EXPOSURE TO AROCLOR 1254 OR DE-71.

EPA Science Inventory

Chronic low level exposure to polychlorinated biphenyls (PCBs) has been shown to adversely affect human health, including learning and memory. Polybromiated diphenyl ethers (PBDEs) are structurally similar to PCBs and have been shown to have neurotoxic effects in vitro and in viv...

DISINFECTION BY-PRODUCTS OF HEALTH CONCERN IN DRINKING WATER: RESULTS OF A U.S. NATIONWIDE OCCURRENCE STUDY

EPA Science Inventory

Drinking water disinfection by-products (DBPs) are of concern because some epidemiologic studies have shown that some DBPs are associated with cancer or adverse reproductive/developmental effects in human populations, and other studies have shown that certain DBPs cause similar h...

DISINFECTION BY-PRODUCTS OF HEALTH CONCERN IN DRINKING WATER: RESULTS OF A NATIONWIDE OCCURRENCE STUDY

EPA Science Inventory

Drinking water disinfection by-products (DBPs) are of concern because some epidemiologic studies have shown that some DBPs are associated with cancer or adverse reproductive/developmental effects in human populations, and other studies have shown that certain DBPs cause similar h...

NTP-CERHR Expert Panel Report on the Reproductive and Developmental Toxicity of Bisphenol A

EPA Science Inventory

The National Toxicology Program (NTP)1 established the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) in June 1998. The purpose of the CERHR is to provide timely, unbiased, scientifically sound evaluations of the potential for adverse effects on reproduction...

COMPARATIVE EMBRYONIC AND LARVAL DEVELOPMENTAL RESPONSES OF THE ESTUARINE GRASS SHRIMP (PALAEMONETES PUGIO) TO THE JUVENILE HORMONE AGONIST FENOXYCARB

EPA Science Inventory

This work was undertaken in order to develop a sensitive bioassay which indicates adverse effects of estuarine-applied insecticides on nontarget species. Newly developed 'third generation' insecticides are designed to act as hormone agonists and bind to endogenous insect hormone...

THE POWER TO DETECT A DIFFERENCE: DETERMINING SAMPLE SIZE REQUIREMENTS FOR EVALUATION OF REPRODUCTIVE/DEVELOPMENTAL EFFECTS FROM EXPOSURE TO COMPLEX MIXTURES OF DISINFECTION BYPRODUCTS

EPA Science Inventory

Toxicological assessment of environmentally-realistic complex mixtures of drinking-water disinfection byproducts (DBPs) are needed to address concerns raised by some epidemiological studies showing associations between exposure to chemically disinfected water and adverse reproduc...

NTP-CERHR EXPERT PANEL REPORT ON THE REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF AMPHETAMINE AND METHAMPHETAMINE.

EPA Science Inventory

A manuscript describes the results of an expert panel meeting of the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR). The purpose CERHR is to provide timely, unbiased, scientifically sound evaluations of human and experimental evidence for adverse effects ...

Using Analogies to Facilitate Conceptual Change in Mathematics Learning

ERIC Educational Resources Information Center

Vamvakoussi, Xenia

2017-01-01

The problem of adverse effects of prior knowledge in mathematics learning has been amply documented and theorized by mathematics educators as well as cognitive/developmental psychologists. This problem emerges when students' prior knowledge about a mathematical notion comes in contrast with new information coming from instruction, giving rise to…

DEVELOPMENTAL EXPOSURE TO DI-N-BUTYLTIN DICHLORIDE (DBTC): IMMUNOTOXIC AND NEUROTOXIC EVALUATION

EPA Science Inventory

Organotins are incorporated as stabilizers in PVC water supply pipe. Particularly when new, mono- and di-substituted methyl- and butyltins leach from the pipe and are thus of regulatory concern to EPA. These contaminants have adverse effects on both the immune and nervous systems...

Screening for angiogenic inhibitors in zebrafish to evaluate a predictive model for developmental vascular toxicity

EPA Science Inventory

Chemically-induced vascular toxicity during embryonic development may cause a wide range of adverse effects. To identify putative vascular disrupting chemicals (pVDCs), a predictive signature was constructed from U.S. EPA ToxCast high-throughput screening (HTS) assays that map to...

The Protective Effects of Family Support on the Relationship between Official Intervention and General Delinquency across the Life Course.

PubMed

Dong, Beidi; Krohn, Marvin D

2017-03-01

Previous research on the labeling perspective has identified mediational processes and the long-term effects of official intervention in the life course. However, it is not yet clear what factors may moderate the relationship between labeling and subsequent offending. The current study integrates Cullen's (1994) social support theory to examine how family social support conditions the criminogenic, stigmatizing effects of official intervention on delinquency and whether such protective effects vary by developmental stage. Using longitudinal data from the Rochester Youth Development Study, we estimated negative binomial regression models to investigate the relationships between police arrest, family social support, and criminal offending during both adolescence and young adulthood. Police arrest is a significant predictor of self-reported delinquency in both the adolescent and adult models. Expressive family support exhibits main effects in the adolescent models; instrumental family support exhibits main effects at both developmental stages. Additionally, instrumental family support diminishes some of the predicted adverse effects of official intervention in adulthood. Perception of family support can be critical in reducing general delinquency as well as buffering against the adverse effects of official intervention on subsequent offending. Policies and programs that work with families subsequent to a criminal justice intervention should emphasize the importance of providing a supportive environment for those who are labeled.

Larval starvation improves metabolic response to adult starvation in honey bees (Apis mellifera L.).

PubMed

Wang, Ying; Campbell, Jacob B; Kaftanoglu, Osman; Page, Robert E; Amdam, Gro V; Harrison, Jon F

2016-04-01

Environmental changes during development have long-term effects on adult phenotypes in diverse organisms. Some of the effects play important roles in helping organisms adapt to different environments, such as insect polymorphism. Others, especially those resulting from an adverse developmental environment, have a negative effect on adult health and fitness. However, recent studies have shown that those phenotypes influenced by early environmental adversity have adaptive value under certain (anticipatory) conditions that are similar to the developmental environment, though evidence is mostly from morphological and behavioral observations and it is still rare at physiological and molecular levels. In the companion study, we applied a short-term starvation treatment to fifth instar honey bee larvae and measured changes in adult morphology, starvation resistance, hormonal and metabolic physiology and gene expression. Our results suggest that honey bees can adaptively respond to the predicted nutritional stress. In the present study, we further hypothesized that developmental starvation specifically improves the metabolic response of adult bees to starvation instead of globally affecting metabolism under well-fed conditions. Here, we produced adult honey bees that had experienced a short-term larval starvation, then we starved them for 12 h and monitored metabolic rate, blood sugar concentrations and metabolic reserves. We found that the bees that experienced larval starvation were able to shift to other fuels faster and better maintain stable blood sugar levels during starvation. However, developmental nutritional stress did not change metabolic rates or blood sugar levels in adult bees under normal conditions. Overall, our study provides further evidence that early larval starvation specifically improves the metabolic responses to adult starvation in honey bees. © 2016. Published by The Company of Biologists Ltd.

The Relationship between the Severity of Eating Problems and Intellectual Developmental Deficit Level

ERIC Educational Resources Information Center

Gal, Eynat; Hardal-Nasser, Reem; Engel-Yeger, Batya

2011-01-01

Nutrition, essential in the daily living functions promoting life quality of persons with intellectual developmental deficits (IDD), is adversely affected by the highly prevalent eating problems in these persons. The current study explores the characteristics of eating problems in population of children with intellectual developmental disorders.…

Is Intake of Flavonoid-Based Food Supplements During Pregnancy Safe for the Developing Child? A Literature Review.

PubMed

Barenys, Marta; Masjosthusmann, Stefan; Fritsche, Ellen

2017-01-01

Due to potential health benefits and the general assumption that natural products are safe, there is an increasing trend in the general population - including pregnant women - to supplement their diet with flavonoid-based food supplements. In addition, preclinical studies aim to prevent developmental adverse effects induced by toxic substances, infections, maternal or genetic diseases of the unborn child by administration of flavonoids at doses far above those reached by normal diets. Because these substances do not undergo classical risk assessment processes, our aim was to review the available literature on the potential adverse effects of maternal diet supplementation with flavonoid-based products for the developing child. A systematic literature search was performed in three databases and screened following four exclusion criteria. Selected studies were classified into two groups: 1. Studies on the developmental toxicity of single flavonoids in vitro or in animals in vivo, and 2. Studies on the developmental toxicity of single flavonoids or on flavonoid-mixtures in humans. The data collected indicate that there is a concern for the safety of some flavonoids within realistic human exposure scenarios. This concern is accompanied by a tremendous lack of studies on safety of these compounds during development making definite safety decisions impossible. Besides studies of survival, especially the more specific developmental processes like nervous system development need to be addressed experimentally. Before new high-dose, flavonoid-based therapeutic strategies are developed for pregnant women further research on the safety of these compounds is clearly needed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Developmental regression and autism reported to the Vaccine Adverse Event Reporting System.

PubMed

Woo, Emily Jane; Ball, Robert; Landa, Rebecca; Zimmerman, Andrew W; Braun, M Miles

2007-07-01

We report demographic and clinical characteristics of children reported to the US Vaccine Adverse Event Reporting System (VAERS) as having autism or another developmental disorder after vaccination. We completed 124 interviews with parents and reviewed medical records for 31 children whose records contained sufficient information to evaluate the child's developmental history. Medical record review indicated that 27 of 31 (87%) children had autism/ASD and 19 (61.3%) had evidence of developmental regression (loss of social, language, or motor skills). The proportion of VAERS cases of autism with regression was greater than that reported in population-based studies, based on the subset of VAERS cases with medical record confirmation. This difference may reflect preferential reporting to VAERS of autism with regression. In other respects, the children in this study appear to be similar to other children with autism. Further research might determine whether the pathogenesis of autism with developmental regression differs from that of autism without regression.

Developmental Neurotoxicology: History and Outline of ...

EPA Pesticide Factsheets

The present work provides a brief review of basic concepts in developmental neurotoxicology, as well as current representative testing guidelines for evaluating developmental neurotoxicity (DNT) of xenobiotics. Historically, DNT was initially recognized as a “functional” teratogenicity: the main concern was that prenatal and/or early postnatal exposures to chemicals during critical periods of central nervous system (CNS) development would cause later functional abnormalities of the brain. Current internationally harmonized DNT study guidelines are thus intended to predict adverse effects of test compounds on the developing CNS by observing such postnatal parameters as motor activity, startle response, and learning and memory, as well as neropathological alterations. The reliability of current DNT study guidelines and sensitivity of testing methodologies recommended in these guidelines have been confirmed by retrospective evaluations of the many international and domestic collaborative validation studies in developed nations including Japan. Invited review with brief review of basic concepts in developmental neurotoxicology, as well as current representative testing guidelines for evaluating developmental neurotoxicity (DNT) of xenobiotics.

Characterization of a developmental toxicity dose-response model.

PubMed Central

Faustman, E M; Wellington, D G; Smith, W P; Kimmel, C A

1989-01-01

The Rai and Van Ryzin dose-response model proposed for teratology experiments has been characterized for its appropriateness and applicability in modeling the dichotomous response data from developmental toxicity studies. Modifications were made in the initial probability statements to reflect more accurately biological events underlying developmental toxicity. Data sets used for the evaluation were obtained from the National Toxicology Program and U.S. EPA laboratories. The studies included developmental evaluations of ethylene glycol, diethylhexyl phthalate, di- and triethylene glycol dimethyl ethers, and nitrofen in rats, mice, or rabbits. Graphic examination and statistical evaluation demonstrate that this model is sensitive to the data when compared to directly measured experimental outcomes. The model was used to interpolate to low-risk dose levels, and comparisons were made between the values obtained and the no-observed-adverse-effect levels (NOAELs) divided by an uncertainty factor. Our investigation suggests that the Rai and Van Ryzin model is sensitive to the developmental toxicity end points, prenatal deaths, and malformations, and appears to model closely their relationship to dose. PMID:2707204

NTP-CERHR monograph on the potential human reproductive and developmental effects of amphetamines.

PubMed

2005-07-01

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for amphetamines to cause adverse effects on reproduction and development in humans. Amphetamines evaluated were D- and D,L-amphetamine and methamphetamine. Amphetamine is approved by the U.S. Food and Drug Administration for the treatment of attention deficit hyperactivity disorder (ADHD) in persons over 3 years of age and narcolepsy; methamphetamine is approved for the treatment of ADHD in persons 6 years of age and older and for short-term treatment of obesity. Amphetamines were selected for evaluation because of 1) widespread usage in children, 2) availability of developmental studies in children and experimental animals, and 3) public concern about the effect of this stimulant on child development. The results of this evaluation on amphetamines are published in an NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of Methylphenidate, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to methylphenidate on human development and reproduction. First, there is some concern for developmental effects, specifically for potential neurobehavioral alterations, from prenatal amphetamine exposure in humans both in therapeutic and non-therapeutic settings. After prenatal exposure to therapeutic doses of amphetamine, rat pups demonstrated neurobehavioral alterations. Data from human and animal studies were judged insufficient for an evaluation of the effect of amphetamine exposure on growth and other related developmental effects. Second, there is concern for methamphetamine-induced adverse developmental effects, specifically on growth and neurobehavioral development, in therapeutic and non-therapeutic settings. This conclusion is based on evidence from studies in experimental animals that prenatal and postnatal exposures to methamphetamine produce neurobehavioral alterations, small litter size, and low birth weight. Results from studies in humans suggest that methamphetamine may cause low birth weight and shortened gestation, but study confounders such as possible multiple drug usage prevent a definite conclusion. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available in electronic PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

Developmental toxicity of prenatal exposure to toluene.

PubMed

Bowen, Scott E; Hannigan, John H

2006-01-01

Organic solvents have become ubiquitous in our environment and are essential for industry. Many women of reproductive age are increasingly exposed to solvents such as toluene in occupational settings (ie, long-term, low-concentration exposures) or through inhalant abuse (eg, episodic, binge exposures to high concentrations). The risk for teratogenic outcome is much less with low to moderate occupational solvent exposure compared with the greater potential for adverse pregnancy outcomes, developmental delays, and neurobehavioral problems in children born to women exposed to high concentrations of abused organic solvents such as toluene, 1,1,1-trichloroethane, xylenes, and nitrous oxide. Yet the teratogenic effects of abuse patterns of exposure to toluene and other inhalants remain understudied. We briefly review how animal models can aid substantially in clarifying the developmental risk of exposure to solvents for adverse biobehavioral outcomes following abuse patterns of use and in the absence of associated health problems and co-drug abuse (eg, alcohol). Our studies also begin to establish the importance of dose (concentration) and critical perinatal periods of exposure to specific outcomes. The present results with our clinically relevant animal model of repeated, brief, high-concentration binge prenatal toluene exposure demonstrate the dose-dependent effect of toluene on prenatal development, early postnatal maturation, spontaneous exploration, and amphetamine-induced locomotor activity. The results imply that abuse patterns of toluene exposure may be more deleterious than typical occupational exposure on fetal development and suggest that animal models are effective in studying the mechanisms and risk factors of organic solvent teratogenicity.

The international society for developmental psychobiology Sackler symposium: early adversity and the maturation of emotion circuits--a cross-species analysis.

PubMed

Callaghan, Bridget L; Sullivan, Regina M; Howell, Brittany; Tottenham, Nim

2014-12-01

Early-life caregiving shapes the architecture and function of the developing brain. The fact that the infant-caregiver relationship is critically important for infant functioning across all altricial species, and that the anatomical circuits supporting emotional functioning are highly preserved across different species, suggests that the results of studies examining the role of early adversity and emotional functioning should be translatable across species. Here we present findings from four different research laboratories, using three different species, which have converged on a similar finding: adversity accelerates the developmental trajectory of amygdala-prefrontal cortex (PFC) development and modifies emotional behaviors. First, a rodent model of attachment learning associated with adversity is presented showing precocial disruption of attachment learning and emergence of heightened fear learning and emotionality. Second, a model of infant-mother separation is presented in which early adversity is shown to accelerate the developmental emergence of adult-like fear retention and extinction. Third, a model of early life adversity in Rhesus monkeys is presented in which a naturally occurring variation in maternal-care (abuse) is shown to alter the functioning of emotion circuits. Finally, a human model of maternal deprivation is presented in which children born into orphanages and then adopted abroad exhibit aberrant development of emotion circuits. The convergence of these cross-species studies on early life adversity suggests that adversity targets the amygdala and PFC and has immediate impact on infant behavior with the caregiver, and emotional reactions to the world. These results provide insight into mechanisms responsible for caregiver induced mental health trajectory alterations. © 2014 Wiley Periodicals, Inc.

Maternal and offspring outcomes in women with intellectual and developmental disabilities: a population-based cohort study.

PubMed

Brown, H K; Cobigo, V; Lunsky, Y; Vigod, S N

2017-04-01

To compare the risks for adverse maternal and offspring outcomes in women with and without intellectual and developmental disabilities. Population-based cohort study. Ontario, Canada. Singleton obstetrical deliveries to 18- to 49-year-old women with and without intellectual and developmental disabilities (n = 3932 in the exposed cohort, n = 382 774 in the unexposed cohort; 2002-2011 fiscal years). Women with intellectual and developmental disabilities were identified based on diagnoses in health administrative data or receipt of disability income support. The unexposed cohort comprised women without intellectual and developmental disabilities. Modified Poisson regression was used to compute adjusted relative risks (aRR) and 95% confidence intervals (CI) comparing the two cohorts. Primary maternal outcomes were: gestational diabetes, gestational hypertension, pre-eclampsia, eclampsia, and venous thromboembolism. Primary offspring outcomes were: preterm birth, small for gestational age, and large for gestational age. The exposed cohort, compared with the unexposed cohort, had increased risks for pre-eclampsia (aRR 1.47, 95% CI 1.11-1.93) and venous thromboembolism (aRR 1.60, 95% CI 1.17-2.19). Their offspring had increased risks for preterm birth (aRR 1.63, 95% CI 1.47-1.80) and small for gestational age (aRR 1.35, 95% CI 1.25-1.45). These findings suggest that there is a need to address modifiable risk factors for adverse outcomes among women with intellectual and developmental disabilities prior to and during pregnancy. Moreover, there is a need to enhance monitoring for maternal and offspring complications in this population. Large cohort study: intellectual and developmental disabilities predispose women/babies to adverse outcomes. © 2016 Royal College of Obstetricians and Gynaecologists.

Potential developmental neurotoxicity of pesticides used in Europe

PubMed Central

Bjørling-Poulsen, Marina; Andersen, Helle Raun; Grandjean, Philippe

2008-01-01

Pesticides used in agriculture are designed to protect crops against unwanted species, such as weeds, insects, and fungus. Many compounds target the nervous system of insect pests. Because of the similarity in brain biochemistry, such pesticides may also be neurotoxic to humans. Concerns have been raised that the developing brain may be particularly vulnerable to adverse effects of neurotoxic pesticides. Current requirements for safety testing do not include developmental neurotoxicity. We therefore undertook a systematic evaluation of published evidence on neurotoxicity of pesticides in current use, with specific emphasis on risks during early development. Epidemiologic studies show associations with neurodevelopmental deficits, but mainly deal with mixed exposures to pesticides. Laboratory experimental studies using model compounds suggest that many pesticides currently used in Europe – including organophosphates, carbamates, pyrethroids, ethylenebisdithiocarbamates, and chlorophenoxy herbicides – can cause neurodevelopmental toxicity. Adverse effects on brain development can be severe and irreversible. Prevention should therefore be a public health priority. The occurrence of residues in food and other types of human exposures should be prevented with regard to the pesticide groups that are known to be neurotoxic. For other substances, given their widespread use and the unique vulnerability of the developing brain, the general lack of data on developmental neurotoxicity calls for investment in targeted research. While awaiting more definite evidence, existing uncertainties should be considered in light of the need for precautionary action to protect brain development. PMID:18945337

Early Adversity and Developmental Outcomes: Interaction Between Genetics, Epigenetics, and Social Experiences Across the Life Span.

PubMed

Champagne, Frances A

2010-09-01

Longitudinal studies in humans demonstrate the association between prenatal and postnatal experiences of adversity and long-term changes in neurodevelopment. These studies raise the question of how experiences become incorporated at a biological level to induce persistent changes in functioning. Laboratory studies using animal models and recent analyses in human cohorts implicate epigenetic mechanisms as a possible route through which these environmental effects are achieved. In particular, there is evidence that changes in DNA methylation are associated with early life experiences with consequences for gene expression and behavior. Despite the potential stability of DNA methylation, it is apparent that this epigenetic mark can be dynamically modified through pharmacological targeting and behavioral experiences. Developmental plasticity may also be achieved through modification of the juvenile environment. Although these juvenile experiences may lead to common endpoints, there is evidence suggesting that the effects of early and later life experiences may be achieved by different molecular pathways. This review discusses evidence for the role of epigenetic mechanisms in shaping developmental trajectories in response to early life experience as well as the potential plasticity that can occur beyond the perinatal period. These studies have implications for approaches to intervention and suggest the importance of considering individual differences in genetic and epigenetic vulnerability in developing treatment strategies. © The Author(s) 2010.

Using Human-Derived Neural Cells as an In Vitro Model for Developmental Neurotoxicity Following Exposure to Pesticides

EPA Science Inventory

Agricultural, industrial and commercial use of pesticides continues to increase with an estimated annual usage nearing a billion lbs/year. Many of these compounds target the nervous system of nuisance animals and due to their lack of selectivity, casue adverse effects in non-targ...

SEXUALLY DIMORPHIC LORDOSIS BEHAVIOR IS MORE SENSITIVE TO DISRUPTION BY DEVELOPMENTAL EXPOSURE TO ETHINYL ESTRADIOL THAN IS REPRODUCTIVE MORPHOLOGY IN THE LONG EVANS FEMALE RAT.

EPA Science Inventory

Anthropogenic estrogens are pervasive in the environment. Although the effects of these xenoestrogens are controversial in humans, some fish species are adversely affected in contaminated ecosystems. While studies investigating endocrine disruptors typically focus on reproducti...

CHRONIC EXPOSURE TO DI(2-ETHYLHEXYL) PHTHALATE (DEHP) DELAYS PUBERTY AND REDUCES ANDROGEN-DEPENDENT TISSUE WEIGHTS IN THE MALE RAT

EPA Science Inventory

DEHP, dibutyl (DBP)-, and benzyl butyl (BBP)- phthalate are plasticizers that cause adverse developmental reproductive effects in laboratory animals. They alter sexual differentiation in the rat by reducing fetal Leydig cell testosterone synthesis and insl3 mRNA levels, which in ...

CHLORINATED VS. CHLORAMINATED DRINKING WATER: TOXICITY-BASED IDENTIFICATION OF DISINFECTION BY-PRODUCTS USING ESI-MS AND ESI-MS/MS

EPA Science Inventory

Drinking water disinfection by-products (DBPs) are of concern because some epidemiologic studies have shown that some DBPs are associated with cancer or adverse reproductive/developmental effects in human populations, and other studies have shown that certain DBPs cause similar h...

Working with the Young Child: Clinical Implications of Contemporary Developmental Science

ERIC Educational Resources Information Center

Gold, Claudia M.

2017-01-01

The recognition that adverse childhood experiences have long-term negative effects parallels the explosion of evidence demonstrating how early experience gets into the body and brain. This knowledge, in turn, has significant implications for treatment of emotional and behavioral problems in early childhood. In this article, I offer a guide to…

The Influence of Parental Separation and Divorce on Adolescent Academic Achievement: Developmental Issues.

ERIC Educational Resources Information Center

Nisivoccia, Joseph Dominick

Parental separation and divorce can have a critically adverse effect on the academic performance and achievement of adolescent students. The psychological and social disadvantages can significantly interfere with students reaching their full potential for success in school. Information is provided on the scope of divorce in society and its…

MEETING IN CHINA: CHLORINATED VS. CHLORAMINATED DRINKING WATER: TOXICITY-BASED IDENTIFICATION OF DISINFECTION BY-PRODUCTS USING ESI-MS AND ESI-MS/MS

EPA Science Inventory

Drinking water disinfection by-products (DBPs) are of concern because epidemiologic studies have shown that they are associated with bladder cancer and adverse reproductive/developmental effects in human populations, and some cause cancer in laboratory animals. As a result, the U...

Meeting in Canada: Chlorinated vs. Chloraminated Drinking Water: Toxicity-Based Identification of Disinfection By-Products Using ESI-MS and ESI-MS/MS

EPA Science Inventory

Drinking water disinfection by-products (DBPs) are of concern because epidemiologic studies have shown that they are associated with bladder cancer and adverse reproductive/developmental effects in human populations. There is almost no information on high molecular weight DBPs (>...

MEETING IN INDIANAPOLIS: CHLORINATED VS. CHLORAMINATED DRINKING WATER: TOXICITY-BASED IDENTIFICATION OF DBPS USING ESI-MS AND ESI-MS/MS

EPA Science Inventory

Drinking water disinfection by-products (DBPs) are of concern because some epidemiologic studies have shown that they are associated with cancer or adverse reproductive/developmental effects in human populations. While more than 500 DBPs have been reported in drinking water, the...

Developmental Programming of Cardiovascular Disease Following Intrauterine Growth Restriction: Findings Utilising A Rat Model of Maternal Protein Restriction

PubMed Central

Zohdi, Vladislava; Lim, Kyungjoon; Pearson, James T.; Black, M. Jane

2014-01-01

Over recent years, studies have demonstrated links between risk of cardiovascular disease in adulthood and adverse events that occurred very early in life during fetal development. The concept that there are embryonic and fetal adaptive responses to a sub-optimal intrauterine environment often brought about by poor maternal diet that result in permanent adverse consequences to life-long health is consistent with the definition of “programming”. The purpose of this review is to provide an overview of the current knowledge of the effects of intrauterine growth restriction (IUGR) on long-term cardiac structure and function, with particular emphasis on the effects of maternal protein restriction. Much of our recent knowledge has been derived from animal models. We review the current literature of one of the most commonly used models of IUGR (maternal protein restriction in rats), in relation to birth weight and postnatal growth, blood pressure and cardiac structure and function. In doing so, we highlight the complexity of developmental programming, with regards to timing, degree of severity of the insult, genotype and the subsequent postnatal phenotype. PMID:25551250

Biomarkers of adult and developmental neurotoxicity

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

Slikker, William; Bowyer, John F.

2005-08-07

Neurotoxicity may be defined as any adverse effect on the structure or function of the central and/or peripheral nervous system by a biological, chemical, or physical agent. A multidisciplinary approach is necessary to assess adult and developmental neurotoxicity due to the complex and diverse functions of the nervous system. The overall strategy for understanding developmental neurotoxicity is based on two assumptions: (1) significant differences in the adult versus the developing nervous system susceptibility to neurotoxicity exist and they are often developmental stage dependent; (2) a multidisciplinary approach using neurobiological, including gene expression assays, neurophysiological, neuropathological, and behavioral function is necessarymore » for a precise assessment of neurotoxicity. Application of genomic approaches to developmental studies must use the same criteria for evaluating microarray studies as those in adults including consideration of reproducibility, statistical analysis, homogenous cell populations, and confirmation with non-array methods. A study using amphetamine to induce neurotoxicity supports the following: (1) gene expression data can help define neurotoxic mechanism(s) (2) gene expression changes can be useful biomarkers of effect, and (3) the site-selective nature of gene expression in the nervous system may mandate assessment of selective cell populations.« less

Identifying genomic and developmental causes of adverse drug reactions in children

PubMed Central

Becker, Mara L; Leeder, J Steven

2011-01-01

Adverse drug reactions are a concern for all clinicians who utilize medications to treat adults and children; however, the frequency of adult and pediatric adverse drug reactions is likely to be under-reported. In this age of genomics and personalized medicine, identifying genetic variation that results in differences in drug biotransformation and response has contributed to significant advances in the utilization of several commonly used medications in adults. In order to better understand the variability of drug response in children however, we must not only consider differences in genotype, but also variation in gene expression during growth and development, namely ontogeny. In this article, recommendations for systematically approaching pharmacogenomic studies in children are discussed, and several examples of studies that investigate the genomic and developmental contribution to adverse drug reactions in children are reviewed. PMID:21121777

Xenon ventilation during therapeutic hypothermia in neonatal encephalopathy: a feasibility study.

PubMed

Dingley, John; Tooley, James; Liu, Xun; Scull-Brown, Emma; Elstad, Maja; Chakkarapani, Ela; Sabir, Hemmen; Thoresen, Marianne

2014-05-01

Therapeutic hypothermia has become standard of care in newborns with moderate and severe neonatal encephalopathy; however, additional interventions are needed. In experimental models, breathing xenon gas during cooling offers long-term additive neuroprotection. This is the first xenon feasibility study in cooled infants. Xenon is expensive, requiring a closed-circuit delivery system. Cooled newborns with neonatal encephalopathy were eligible for this single-arm, dose-escalation study if clinically stable, under 18 hours of age and requiring less than 35% oxygen. Xenon duration increased stepwise from 3 to 18 hours in 14 subjects; 1 received 25% xenon and 13 received 50%. Respiratory, cardiovascular, neurologic (ie, amplitude-integrated EEG, seizures), and inflammatory (C-reactive protein) effects were examined. The effects of starting or stopping xenon rapidly or slowly were studied. Three matched control subjects per xenon treated subject were selected from our cooling database. Follow-up was at 18 months using mental developmental and physical developmental indexes of the Bayley Scales of Infant Development II. No adverse respiratory or cardiovascular effects, including post-extubation stridor, were seen. Xenon increased sedation and suppressed seizures and background electroencephalographic activity. Seizures sometimes occurred during rapid weaning of xenon but not during slow weaning. C-reactive protein levels were similar between groups. Hourly xenon consumption was 0.52 L. Three died, and 7 of 11 survivors had mental and physical developmental index scores ≥70 at follow-up. Breathing 50% xenon for up to 18 hours with 72 hours of cooling was feasible, with no adverse effects seen with 18 months' follow-up. Copyright © 2014 by the American Academy of Pediatrics.

Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

PubMed Central

Leung, Maxwell C.K.; Phuong, Jimmy; Baker, Nancy C.; Sipes, Nisha S.; Klinefelter, Gary R.; Martin, Matthew T.; McLaurin, Keith W.; Setzer, R. Woodrow; Darney, Sally Perreault; Judson, Richard S.; Knudsen, Thomas B.

2015-01-01

Background: Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies. Objective: In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system. Methods: We used U.S. EPA’s animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA’s in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features. Results: A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network. Conclusion: Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarchy across animal studies consistent with the human TDS hypothesis. We confirmed the known role of estrogen and androgen signaling pathways in rodent TDS, and importantly, broadened the list of molecular targets to include retinoic acid signaling, vascular remodeling proteins, G-protein coupled receptors (GPCRs), and cytochrome P450s. Citation: Leung MC, Phuong J, Baker NC, Sipes NS, Klinefelter GR, Martin MT, McLaurin KW, Setzer RW, Darney SP, Judson RS, Knudsen TB. 2016. Systems toxicology of male reproductive development: profiling 774 chemicals for molecular targets and adverse outcomes. Environ Health Perspect 124:1050–1061; http://dx.doi.org/10.1289/ehp.1510385 PMID:26662846

Characterization of neural development in zebrafish embryos using real-time quantitative PCR.

EPA Science Inventory

Chemicals adversely affecting the developing nervous system may cause long-term consequences on human health. Little information exists on a large number of environmental compounds to guide developmental neurotoxicity risk assessments. Because developmental neurotoxicity studies ...

The long arm of community: the influence of childhood community contexts across the early life course.

PubMed

Wickrama, K A S; Noh, Samuel

2010-08-01

This study examines the longitudinal effects of childhood community contexts on young adult outcomes. The study uses a sample of 14,000 adolescents (52% female) derived from the 1990 US Census and the National Longitudinal Study of Adolescent Health (Addhealth). The study examines whether community and family environments exert separate and/or joint long-term influences on young adult achievement and depression. We found both direct and indirect long-term influences of childhood community adversity on young adult educational attainment. The indirect influences of childhood community adversity operated through family and individual-level factors. The long-term influence of childhood community adversity on young adult depression was only indirect. Overall, community influences on young adult achievement outcomes were mediated by family context and by the adolescents' adjustments and transitions, including adolescent depression, school adjustment, and disruptive transitional events. The moderating effect of childhood community adversity suggests that the protective effects of family resources on young adult outcomes dissipate significantly in extremely adverse neighborhoods. The findings demonstrate the importance of integrating multiple theoretical perspectives for longitudinal research to capture pathways of community influence on adolescent developmental and young adulthood outcomes.

Neighborhood Qualification of the Association between Parenting and Problem Behavior Trajectories among Mexican-origin Father-Adolescent Dyads

PubMed Central

White, Rebecca M. B.; Liu, Yu; Gonzales, Nancy A.; Knight, George P.; Tein, Jenn-Yun

2016-01-01

To address the combined importance of fathers and neighborhoods for adolescent adjustment, we examined whether associations between fathers' parenting and adolescents' problem behaviors were qualified by neighborhood adversity. We captured both mainstream (e.g., authoritative) and alternative (e.g., no-nonsense, reduced involvement) parenting styles and examined parenting and neighborhood effects on changes over time in problem behaviors among a sample of Mexican-origin father-adolescent dyads (N = 462). Compared to their counterparts in low-adversity neighborhoods, adolescents in high-adversity neighborhoods experienced greater initial benefits from authoritative fathering, greater long-term benefits from no-nonsense fathering, and fewer costs associated with reduced involvement fathering. The combined influences of alternative paternal parenting styles and neighborhood adversity may set ethnic and racial minority adolescents on different developmental pathways to competence. PMID:28453217

The Protective Effects of Family Support on the Relationship between Official Intervention and General Delinquency across the Life Course

PubMed Central

Dong, Beidi; Krohn, Marvin D.

2016-01-01

Purpose Previous research on the labeling perspective has identified mediational processes and the long-term effects of official intervention in the life course. However, it is not yet clear what factors may moderate the relationship between labeling and subsequent offending. The current study integrates Cullen’s (1994) social support theory to examine how family social support conditions the criminogenic, stigmatizing effects of official intervention on delinquency and whether such protective effects vary by developmental stage. Methods Using longitudinal data from the Rochester Youth Development Study, we estimated negative binomial regression models to investigate the relationships between police arrest, family social support, and criminal offending during both adolescence and young adulthood. Results Police arrest is a significant predictor of self-reported delinquency in both the adolescent and adult models. Expressive family support exhibits main effects in the adolescent models; instrumental family support exhibits main effects at both developmental stages. Additionally, instrumental family support diminishes some of the predicted adverse effects of official intervention in adulthood. Conclusions Perception of family support can be critical in reducing general delinquency as well as buffering against the adverse effects of official intervention on subsequent offending. Policies and programs that work with families subsequent to a criminal justice intervention should emphasize the importance of providing a supportive environment for those who are labeled. PMID:28729962

Adolescent Family Adversity and Mental Health Problems: The Role of Adaptive Self-Regulation Capacities. The TRAILS Study

ERIC Educational Resources Information Center

Bakker, Martin Paul; Ormel, Johan; Verhulst, Frank C.; Oldehinkel, Albertine J.

2011-01-01

Adolescent family adversity is a considerable adaptive challenge in an increasingly turbulent developmental period. Using data from a prospective population cohort of 2230 Dutch adolescents, we tested risk-buffering interactions between adolescent family adversity and self-regulation capacities on mental health. We used two adaptive…

Social Adversity and Antisocial Behavior: Mediating Effects of Autonomic Nervous System Activity.

PubMed

Fagan, Shawn E; Zhang, Wei; Gao, Yu

2017-11-01

The display of antisocial behaviors in children and adolescents has been of interest to criminologists and developmental psychologists for years. Exposure to social adversity is a well-documented predictor of antisocial behavior. Additionally, measures of autonomic nervous system (ANS) activity, including heart rate variability (HRV), pre-ejection period (PEP), and heart rate, have been associated with antisocial behaviors including rule-breaking and aggression. Social neuroscience research has begun to investigate how neurobiological underpinnings affect the relationship between social adversity and antisocial/psychopathic behavior in children and adolescents. This study investigated the potential mediating effects of ANS activity on the relationship between social adversity and antisocial behavior in a group of 7- to 10-year-old children from the community (N = 339; 48.2% male). Moderated multiple mediation analyses revealed that low resting heart rate, but not PEP or HRV, mediated the relationship between social adversity and antisocial behavior in males only. Social adversity but not ANS measures were associated with antisocial behavior in females. Findings have implications for understanding the neural influences that underlie antisocial behavior, illustrate the importance of the social environment regarding the expression of these behaviors, and highlight essential gender differences.

Promoting Healthy Transition to College through Mindfulness Training with First-Year College Students: Pilot Randomized Controlled Trial

ERIC Educational Resources Information Center

Dvoráková, Kamila; Kishida, Moé; Li, Jacinda; Elavsky, Steriani; Broderick, Patricia C.; Agrusti, Mark R.; Greenberg, Mark T.

2017-01-01

Objective: Given the importance of developmental transitions on young adults' lives and the high rates of mental health issues among U.S. college students, first-year college students can be particularly vulnerable to stress and adversity. This pilot study evaluated the effectiveness and feasibility of mindfulness training aiming to promote…

Effects of Three Levels of Early Intervention Services on Children Prenatally Exposed to Cocaine

ERIC Educational Resources Information Center

Claussen, Angelika H.; Scott, Keith G.; Mundy, Peter C.; Katz, Lynne F.

2004-01-01

Cocaine use during pregnancy is a high-risk indicator for adverse developmental outcomes. Three levels of intervention (center, home, and primary care) were compared in a full service, birth to age 3, early intervention program serving children exposed to cocaine prenatally. Data were collected on 130 children from urban, predominantly poor,…

Prenatal and Family Risks of Children Born to Mothers with Epilepsy: Effects on Cognitive Development

ERIC Educational Resources Information Center

Titze, Karl; Koch, Sabine; Helge, Hans; Lehmkuhl, Ulrike; Rauh, Hellgard; Steinhausen, Hans-Christoph

2008-01-01

The offspring of mothers with epilepsy are considered to be at developmental risk during pregnancy from: (1) generalized maternal seizures (hypoxia); (2) teratogenicity of antiepileptic drugs (AEDs); and (3) adverse socio-familial conditions associated with having a chronically sick mother. Sixty-seven children of mothers with epilepsy and 49…

Job Demands and Job Control as Predictors of Depressive Symptoms: Moderating Effects of Negative Childhood Socioemotional Experiences.

PubMed

Pulkki-Råback, Laura; Elovainio, Marko; Virtanen, Marianna; Kivimäki, Mika; Hintsanen, Mirka; Hintsa, Taina; Jokela, Markus; Puttonen, Sampsa; Joensuu, Matti; Lipsanen, Jari; Raitakari, Olli T; Keltikangas-Järvinen, Liisa

2016-10-01

There have been calls to know more about vulnerability factors that may predispose to adverse health outcomes at work. We examined if childhood adverse experiences would affect vulnerability to psychosocial stress factors at work. A nationally representative sample of 1546 Finnish men and women was followed up from childhood to adulthood. Childhood adverse experiences consisted of socioeconomic and emotional factors. Job demands and job control were measured 21 years later, and depressive symptoms were measured 21 and 27 years after the childhood measurements. Job demands predicted depressive symptoms over 6 years, and the association was modified by childhood emotional adversity. Participants with three or more emotional adversities in childhood had more depressive symptoms in response to high job demands compared with participants with zero or one emotional adversities in childhood (Betas = -1.40 and -2.01, ps < 0.05 and <0.01). No such moderating effect by childhood adverse experiences was found for the association between job control and depressive symptoms. Although modest in effect size, these findings provide a developmental viewpoint for understanding the role of childhood experiences in work-related stress factors. Such knowledge can enhance understanding of individual differences in vulnerability to the demands of working life. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Media use by children younger than 2 years.

PubMed

Brown, Ari

2011-11-01

In 1999, the American Academy of Pediatrics (AAP) issued a policy statement addressing media use in children. The purpose of that statement was to educate parents about the effects that media--both the amount and the content--may have on children. In one part of that statement, the AAP recommended that "pediatricians should urge parents to avoid television viewing for children under the age of two years." The wording of the policy specifically discouraged media use in this age group, although it is frequently misquoted by media outlets as no media exposure in this age group. The AAP believed that there were significantly more potential negative effects of media than positive ones for this age group and, thus, advised families to thoughtfully consider media use for infants. This policy statement reaffirms the 1999 statement with respect to media use in infants and children younger than 2 years and provides updated research findings to support it. This statement addresses (1) the lack of evidence supporting educational or developmental benefits for media use by children younger than 2 years, (2) the potential adverse health and developmental effects of media use by children younger than 2 years, and (3) adverse effects of parental media use (background media) on children younger than 2 years.

Early adversity and risk for moderate to severe unipolar depressive disorder in adolescence and adulthood: A register-based study of 978,647 individuals.

PubMed

Dahl, Signe Kirk; Larsen, Janne Tidselbak; Petersen, Liselotte; Ubbesen, Mads Bonde; Mortensen, Preben Bo; Munk-Olsen, Trine; Musliner, Katherine Louise

2017-05-01

Early adversity is a known risk factor for unipolar depression. We examined the impact of 9 types of early adversity on risk for moderate to severe unipolar depression in adolescence or adulthood, and evaluated whether these effects were moderated by gender and adversity timing. We conducted a prospective, population-based cohort study using Danish national registers. The sample included all individuals born in Denmark between 1980 and 1998 (N=978,647). Exposure to early adversity was assessed from ages 0-15. Types of adversity included parental illness, incarceration, death, disability, and psychiatric diagnosis; family disruption; out-of-home care; and childhood abuse. Individuals were followed from age 15 until first in- or outpatient depression diagnosis (ICD-10 codes F32, F33) in a psychiatric hospital, death, emigration, or December 31st, 2013, whichever came first. Hazard ratios (HRs) were calculated using Cox regressions. All adversities were significantly associated with increased risk for moderate to severe adolescent/adult depression (HR range: 1.30-2.72), although the effects were attenuated after mutual adjustment (adjusted HR range: 1.06-1.70). None of the effects were moderated by gender. The effect of family disruption was strongest between ages 0-4 (HR=1.66, 95% CI=1.61-1.71), while the effect of out-of-home care was strongest between ages 10-14 (HR=2.45, 95% CI=2.28-2.64). Untreated and primary-care treated depression were not measured. Our results support past findings that multiple types of early adversity increase risk for moderate to severe unipolar depression in adolescence and adulthood. Certain adversities may be more harmful if they occur during specific developmental time periods. Copyright © 2017 Elsevier B.V. All rights reserved.

Childhood sexual abuse and adult developmental outcomes: findings from a 30-year longitudinal study in New Zealand.

PubMed

Fergusson, David M; McLeod, Geraldine F H; Horwood, L John

2013-09-01

Childhood sexual abuse (CSA) has been associated with many adverse medical, psychological, behavioral and socioeconomic outcomes in adulthood. This study aims to examine the linkages between CSA and a wide range of developmental outcomes over a protracted time period to age 30. Data from over 900 members of the New Zealand birth cohort the Christchurch Health and Development Study were examined. CSA prior to age 16 was assessed at ages 18 and 21 years, in addition to: mental health, psychological wellbeing, sexual risk-taking behaviors, physical health and socioeconomic outcomes to age 30. After statistical adjustment for confounding by 10 covariates spanning socio-demographic, family functioning and child factors, extent of exposure to CSA was associated with increased rates of (B, SE, p): major depression (0.426, 0.094, <.001); anxiety disorder (0.364, 0.089, <.001); suicidal ideation (0.395, 0.089, <.001); suicide attempt (1.863, 0.403, <.001); alcohol dependence (0.374, 0.118, <.002); and illicit drug dependence (0.425, 0.113, <.001). In addition, at age 30 CSA was associated with higher rates of PTSD symptoms (0.120, 0.051, .017); decreased self-esteem (-0.371, 0.181, .041); and decreased life satisfaction (-0.510, 0.189, .007). Childhood sexual abuse was also associated with decreased age of onset of sexual activity (-0.381, 0.091, <.001), increased number of sexual partners (0.175, 0.035, <.001); increased medical contacts for physical health problems (0.105, 0.023, <.001); and welfare dependence (0.310, 0.099, .002). Effect sizes (Cohen's d) for the significant outcomes from all domains ranged from .14 to .53, while the attributable risks for the mental health outcomes ranged from 5.7% to 16.6%. CSA is a traumatic childhood life event in which the negative consequences increase with increasing severity of abuse. CSA adversely influences a number of adult developmental outcomes that span: mental disorders, psychological wellbeing, sexual risk-taking, physical health and socioeconomic wellbeing. While the individual effect sizes for CSA typically range from small to moderate, it is clear that accumulative adverse effects on adult developmental outcomes are substantial. Copyright © 2013 Elsevier Ltd. All rights reserved.

Adversity in Preschool-Aged Children: Effects on Salivary Interleukin-1β

PubMed Central

Tyrka, Audrey R.; Parade, Stephanie H.; Valentine, Thomas R.; Eslinger, Nicole M.; Seifer, Ronald

2016-01-01

Exposure to early life adversity is linked to impaired affective, cognitive, and behavioral functioning and increases risk for various psychiatric and medical conditions. Stress-induced increases in pro-inflammatory cytokines may be a biological mechanism of these effects. Few studies have examined cytokine levels in children experiencing early life adversity, and very little research has investigated cytokines or other markers of inflammation in saliva. In the present study, we examined salivary IL-1β and C-reactive protein (CRP) levels in relation to stress exposure in 40 children aged 3 to 5 years who were enrolled in a larger study of early life adversity. Childhood maltreatment status was assessed via review of child welfare records, and contextual stress exposure, traumatic life event history, and symptoms of psychopathology were assessed via caregiver interviews at a home visit. In a subsequent visit, salivary IL-1β and CRP were obtained before and after participation in four emotion-eliciting tasks. Number of past month contextual stressors, lifetime contextual stressors, and traumatic life events each demonstrated a significant main effect on IL-1β. Baseline IL-1β was positively associated with each of the significant main-effect adversities. Post-challenge IL-1β displayed positive associations with each adversity variable, but were not significant. CRP was not significantly associated with any of the adversity variables. Given evidence suggesting involvement of IL-1β in the neuropathology of psychiatric conditions, these results may have important implications for developmental outcomes. PMID:25997772

Childhood personality as a harbinger of competence and resilience in adulthood.

PubMed

Shiner, Rebecca L; Masten, Ann S

2012-05-01

This study examined the significance of childhood Big Five personality traits for competence and resilience in early adulthood. Resilience was defined in terms of adaptive success in age-salient developmental tasks despite significant adversity throughout childhood/adolescence. The Project Competence Longitudinal Study tracked 205 young people from childhood (around age 10) to emerging adulthood (EA, age 20) and young adulthood (YA, age 30; 90% retention). Multimethod composites were created for personality traits, adversity exposure, and adult outcomes of academic achievement, work, rule-abiding conduct, friendship, and romantic relationships. Regressions showed significant main effects of childhood personality predicting adult outcomes, controlling for adversity, with few interaction effects. In person-focused analyses, the resilient group in EA and YA (high competence, high adversity) showed higher childhood conscientiousness, agreeableness, and openness and lower neuroticism than the maladaptive group (low competence, high adversity). The competent (high competence, low adversity) and resilient groups showed similar childhood traits. Turnaround cases, who changed from the maladaptive group in EA to the resilient group in YA, exhibited higher childhood conscientiousness than persistently maladaptive peers. Findings suggest that children on pathways to success in adulthood, whether facing low or high adversity, have capacities for emotion regulation, empathy and connection, dedication to schoolwork, and mastery and exploration.

Maternal Obesity: Lifelong Metabolic Outcomes for Offspring from Poor Developmental Trajectories During the Perinatal Period.

PubMed

Zambrano, Elena; Ibáñez, Carlos; Martínez-Samayoa, Paola M; Lomas-Soria, Consuelo; Durand-Carbajal, Marta; Rodríguez-González, Guadalupe L

2016-01-01

The prevalence of obesity in women of reproductive age is increasing in developed and developing countries around the world. Human and animal studies indicate that maternal obesity adversely impacts both maternal health and offspring phenotype, predisposing them to chronic diseases later in life including obesity, dyslipidemia, type 2 diabetes mellitus, and hypertension. Several mechanisms act together to produce these adverse health effects including programming of hypothalamic appetite-regulating centers, increasing maternal, fetal and offspring glucocorticoid production, changes in maternal metabolism and increasing maternal oxidative stress. Effective interventions during human pregnancy are needed to prevent both maternal and offspring metabolic dysfunction due to maternal obesity. This review addresses the relationship between maternal obesity and its negative impact on offspring development and presents some maternal intervention studies that propose strategies to prevent adverse offspring metabolic outcomes. Copyright © 2016 IMSS. Published by Elsevier Inc. All rights reserved.

Early childhood adversity, toxic stress, and the role of the pediatrician: translating developmental science into lifelong health.

PubMed

Garner, Andrew S; Shonkoff, Jack P

2012-01-01

Advances in a wide range of biological, behavioral, and social sciences are expanding our understanding of how early environmental influences (the ecology) and genetic predispositions (the biologic program) affect learning capacities, adaptive behaviors, lifelong physical and mental health, and adult productivity. A supporting technical report from the American Academy of Pediatrics (AAP) presents an integrated ecobiodevelopmental framework to assist in translating these dramatic advances in developmental science into improved health across the life span. Pediatricians are now armed with new information about the adverse effects of toxic stress on brain development, as well as a deeper understanding of the early life origins of many adult diseases. As trusted authorities in child health and development, pediatric providers must now complement the early identification of developmental concerns with a greater focus on those interventions and community investments that reduce external threats to healthy brain growth. To this end, AAP endorses a developing leadership role for the entire pediatric community-one that mobilizes the scientific expertise of both basic and clinical researchers, the family-centered care of the pediatric medical home, and the public influence of AAP and its state chapters-to catalyze fundamental change in early childhood policy and services. AAP is committed to leveraging science to inform the development of innovative strategies to reduce the precipitants of toxic stress in young children and to mitigate their negative effects on the course of development and health across the life span.

Towards Building an AOP-based Prenatal Developmental Toxicity Ontology (CEFIC LRI Workshop - Brussels)

EPA Science Inventory

Ontologies are a way to formalize domain-specific scientific knowledge. A developmental ontology would help researchers describe the pathways and processes critical to embryonic development and provide a way to link their chemical disruption to adverse outcomes. Designing one for...

Application of Signaling Pathway-Based Adverse Outcome Pathways and High Throughput Toxicokinetic-PBPK for Developmental Cardiac Malformations

EPA Science Inventory

Associating putative molecular initiating events (MIE) with downstream cell signaling pathways and modeling fetal exposure kinetics is an important challenge for integration in developmental systems toxicology. Here, we describe an integrative systems toxicology model for develop...

Vulnerability of the neural circuitry underlying sexual behavior to chronic adult exposure to oral bisphenol a in male mice.

PubMed

Picot, Marie; Naulé, Lydie; Marie-Luce, Clarisse; Martini, Mariangela; Raskin, Kalina; Grange-Messent, Valérie; Franceschini, Isabelle; Keller, Matthieu; Mhaouty-Kodja, Sakina

2014-02-01

There are human reproduction concerns associated with extensive use of bisphenol A (BPA)-containing plastic and, in particular, the leaching of BPA into food and beverages. In this context, it remains unclear whether and how exposure to BPA interferes with the developmental organization and adult activation of male sexual behavior by testosterone. We evaluated the developmental and adult exposure to oral BPA at doses equivalent to the no-observed-adverse-effect-level (5 mg/kg body weight per day) and tolerable daily intake (TDI) (50 μg/kg body weight per day) on mouse sexual behavior and the potential mechanisms underlying BPA effects. Adult exposure to BPA reduced sexual motivation and performance at TDI dose only. Exposed males took longer to initiate mating and reach ejaculation despite normal olfactory chemoinvestigation. This deficiency was not restored by sexual experience and was associated with unchanged circulating levels of testosterone. By contrast, developmental exposure to BPA at TDI or no-observed-adverse-effect-level dose did not reduce sexual behavior or alter the neuroanatomical organization of the preoptic area. Disrupting the neural androgen receptor resulted in behavioral and neuroanatomical effects similar to those induced by adult exposure to TDI dose. Moreover, adult exposure of mutant males to BPA at TDI dose did not trigger additional alteration of sexual behavior, suggesting that BPA and neural androgen receptor mutation share a common mechanism of action. This shows, for the first time, that the neural circuitry underlying male sexual behavior is vulnerable to chronic adult exposure to low dose of BPA and suggests that BPA could act in vivo as an antiandrogenic compound.

Metabolomics approach reveals metabolic disorders and potential biomarkers associated with the developmental toxicity of tetrabromobisphenol A and tetrachlorobisphenol A

NASA Astrophysics Data System (ADS)

Ye, Guozhu; Chen, Yajie; Wang, Hong-Ou; Ye, Ting; Lin, Yi; Huang, Qiansheng; Chi, Yulang; Dong, Sijun

2016-10-01

Tetrabromobisphenol A and tetrachlorobisphenol A are halogenated bisphenol A (H-BPA), and has raised concerns about their adverse effects on the development of fetuses and infants, however, the molecular mechanisms are unclear, and related metabolomics studies are limited. Accordingly, a metabolomics study based on gas chromatography-mass spectrometry was employed to elucidate the molecular developmental toxicology of H-BPA using the marine medaka (Oryzias melastigmas) embryo model. Here, we revealed decreased synthesis of nucleosides, amino acids and lipids, and disruptions in the TCA (tricarboxylic acid) cycle, glycolysis and lipid metabolism, thus inhibiting the developmental processes of embryos exposed to H-BPA. Unexpectedly, we observed enhanced neural activity accompanied by lactate accumulation and accelerated heart rates due to an increase in dopamine pathway and a decrease in inhibitory neurotransmitters following H-BPA exposure. Notably, disorders of the neural system, and disruptions in glycolysis, the TCA cycle, nucleoside metabolism, lipid metabolism, glutamate and aspartate metabolism induced by H-BPA exposure were heritable. Furthermore, lactate and dopa were identified as potential biomarkers of the developmental toxicity of H-BPA and related genetic effects. This study has demonstrated that the metabolomics approach is a useful tool for obtaining comprehensive and novel insights into the molecular developmental toxicity of environmental pollutants.

Effects of gamma radiation on the early developmental stages of Zebrafish (Danio rerio).

PubMed

Praveen Kumar, M K; Shyama, S K; Kashif, Shamim; Dubey, S K; Avelyno, D'costa; Sonaye, B H; Kadam Samit, B; Chaubey, R C

2017-08-01

The zebrafish is gaining importance as a popular vertebrate model organism and is widely employed in ecotoxicological studies, especially for the biomonitoring of pollution in water bodies. There is limited data on the genetic mechanisms governing the adverse health effects in regards to an early developmental exposure to gamma radiation. In the present study zebrafish (Danio rerio) embryos were exposed to 1, 2.5, 5, 7.5 and 10Gy of gamma radiation at 3h post fertilization (hpf). Different developmental toxicity endpoints were investigated. Further, expression of genes associated with the development and DNA damage i.e. (sox2 sox19a and p53) were evaluated using Quantitative PCR (qPCR). The significant changes in the expression of sox2 sox19a and p53 genes were observed. This data was supported the developmental defects observed in the zebrafish embryo exposed to gamma radiation such as i.e. increased DNA damage, decreased hatching rate, increase in median hatching time, decreased body length, increased mortality rate, increased morphological deformities. Further, study shows that the potential ecotoxicological threat of gamma radiation on the early developmental stages of zebrafish. Further, it revealed that the above parameters can be used as predictive biomarkers of gamma radiation exposure. Copyright © 2017. Published by Elsevier Inc.

Neighborhood Qualification of the Association Between Parenting and Problem Behavior Trajectories Among Mexican-Origin Father-Adolescent Dyads.

PubMed

White, Rebecca M B; Liu, Yu; Gonzales, Nancy A; Knight, George P; Tein, Jenn-Yun

2016-12-01

To address the combined importance of fathers and neighborhoods for adolescent adjustment, we examined whether associations between fathers' parenting and adolescents' problem behaviors were qualified by neighborhood adversity. We captured both mainstream (e.g., authoritative) and alternative (e.g., no-nonsense, reduced involvement) parenting styles and examined parenting and neighborhood effects on changes over time in problem behaviors among a sample of Mexican-origin father-adolescent dyads (N = 462). Compared to their counterparts in low-adversity neighborhoods, adolescents in high-adversity neighborhoods experienced greater initial benefits from authoritative fathering, greater long-term benefits from no-nonsense fathering, and fewer costs associated with reduced involvement fathering. The combined influences of alternative paternal parenting styles and neighborhood adversity may set ethnic and racial minority adolescents on different developmental pathways to competence. © 2016 The Authors. Journal of Research on Adolescence © 2016 Society for Research on Adolescence.

Strategies for Reversing the Effects of Metabolic Disorders Induced as a Consequence of Developmental Programming

PubMed Central

Vickers, M. H.; Sloboda, D. M.

2012-01-01

Obesity and the metabolic syndrome have reached epidemic proportions worldwide with far-reaching health care and economic implications. The rapid increase in the prevalence of these disorders suggests that environmental and behavioral influences, rather than genetic causes, are fueling the epidemic. The developmental origins of health and disease hypothesis has highlighted the link between the periconceptual, fetal, and early infant phases of life and the subsequent development of metabolic disorders in later life. In particular, the impact of poor maternal nutrition on susceptibility to later life metabolic disease in offspring is now well documented. Several studies have now shown, at least in experimental animal models, that some components of the metabolic syndrome, induced as a consequence of developmental programming, are potentially reversible by nutritional or targeted therapeutic interventions during windows of developmental plasticity. This review will focus on critical windows of development and possible therapeutic avenues that may reduce metabolic and obesogenic risk following an adverse early life environment. PMID:22783205

Application of Sholl analysis to quantify changes in growth and development in rat mammary gland whole mounts.

PubMed

Stanko, Jason P; Easterling, Michael R; Fenton, Suzanne E

2015-07-01

Studies that utilize the rodent mammary gland (MG) as an endpoint for assessing the developmental toxicity of chemical exposures typically employ either basic dimensional measurements or developmental scoring of morphological characteristics as a means to quantify MG development. There are numerous means by which to report these developmental changes, leading to inconsistent translation across laboratories. The Sholl analysis is a method historically used for quantifying neuronal dendritic patterns. The present study describes the use of the Sholl analysis to quantify MG branching characteristics. Using this method, we were able to detect significant differences in branching density in MG of peripubertal female Sprague Dawley rats that had been exposed to vehicle or a potent estrogen. These data suggest the Sholl analysis can be an effective tool for quantitatively measuring an important characteristic of MG development and for examining associations between MG growth and density and adverse effects in the breast. Published by Elsevier Inc.

Effects of microplastics on juveniles of the common goby (Pomatoschistus microps): confusion with prey, reduction of the predatory performance and efficiency, and possible influence of developmental conditions.

PubMed

Carlos de Sá, Luís; Luís, Luís G; Guilhermino, Lúcia

2015-01-01

Microplastics (MP) are ubiquitous contaminants able to cause adverse effects on organisms. Three hypotheses were tested here: early Pomatoschistus microps juveniles can ingest MP; the presence of MP may reduce fish predatory performance and efficiency; developmental conditions may influence the preyselection capability of fish. Predatory bioassays were carried out with juveniles from two estuaries with differences in environmental conditions: Minho (M-est) and Lima (L-est) Rivers (NW Iberian coast). Polyethylene MP spheres (3 types) alone and in combination with Artemia nauplii were offered as prey.All the MP types were ingested, suggesting confusion with food. Under simultaneous exposure to MP and Artemia, L-est fish showed a significant reduction of the predatory performance (65%) and efficiency (upto 50%), while M-est fish did not, suggesting that developmental conditions may influence the preyselection capability of fish. The MP-induced reduction of food intake may decrease individual and population fitness.

Sex-specific effects of nicotine exposure on developmental programming of blood pressure and vascular reactivity in the C57Bl/6J mouse.

PubMed

Fox, Karin A; Longo, Monica; Tamayo, Esther; Gamble, Phyllis; Makhlouf, Michel; Mateus, Julio F; Saade, George R

2012-09-01

The objective of the study was to determine whether perinatal nicotine exposure adversely affects cardiovascular health in adulthood. C57Bl/6J female mice were randomized to 200 μg/mL nicotine in 2% saccharin or 2% saccharin alone from 2 weeks before breeding until weaning. Offspring weight, vital signs, and carotid artery vascular reactivity were studied. A second cohort was subjected to shaker stress on day 4 of 7 days. Selected mediators of vascular tone were evaluated by molecular studies. Student t or Mann-Whitney U test was performed for statistical analysis (significance: P < .05). Nicotine-exposed compared with control female offspring had significantly elevated mean blood pressure under normal and stress conditions. Nicotine females lacked heart rate elevation after stress. Nicotine males had higher mean heart rate and a blunted contractile response to phenylephrine compared with controls, without an increase in blood pressure. Perinatal nicotine exposure has an impact on the developmental programming of future cardiovascular health, with adverse effects more evident in female offspring. Copyright © 2012 Mosby, Inc. All rights reserved.

Long-term adverse effects of neonatal exposure to bisphenol A on the murine female reproductive tract.

PubMed

Newbold, Retha R; Jefferson, Wendy N; Padilla-Banks, Elizabeth

2007-01-01

The developing fetus is uniquely sensitive to perturbation by chemicals with hormone-like activity. The adverse effects of prenatal diethylstilbestrol (DES) exposure are a classic example. Since concern has been mounting regarding the human health and environmental effects of bisphenol A (BPA), a high-production-volume chemical with estrogenic activity used in the synthesis of plastics, we investigated its long-term effects in an experimental animal model that was previously shown useful in studying the adverse effects of developmental exposure to DES. Outbred female CD-1 mice were treated on days 1-5 with subcutaneous injections of BPA (10, 100 or 1000 microg/kg/day) dissolved in corn oil or corn oil alone (Control). At 18 months, ovaries and reproductive tract tissues were examined. There was a statistically significant increase in cystic ovaries and cystic endometrial hyperplasia (CEH) in the BPA-100 group as compared to Controls. Progressive proliferative lesion (PPL) of the oviduct and cystic mesonephric (Wolffian) duct remnants were also seen in all of the BPA groups. More severe pathologies of the uterus following neonatal BPA treatment included adenomyosis, leiomyomas, atypical hyperplasia, and stromal polyps. These data suggest that BPA causes long-term adverse effects if exposure occurs during critical periods of differentiation.

Long-term Adverse Effects of Neonatal Exposure to Bisphenol A on the Murine Female Reproductive Tract

PubMed Central

Newbold, Retha R.; Jefferson, Wendy N.; Banks, Elizabeth Padilla

2007-01-01

The developing fetus is uniquely sensitive to perturbation by chemicals with hormone-like activity. The adverse effects of prenatal diethylstilbestrol (DES) exposure are a classic example. Since concern has been mounting regarding the human health and environmental effects of bisphenol A (BPA), a high-production-volume chemical with estrogenic activity used in the synthesis of plastics, we investigated its long-term effects in an experimental animal model that was previously shown useful in studying the adverse effects of developmental exposure to DES. Outbred female CD-1 mice were treated on days 1-5 with subcutaneous injections of BPA (10, 100 or 1000 μg/kg/day) dissolved in corn oil or corn oil alone (Control). At 18 months, ovaries and reproductive tract tissues were examined. There was a statistically significant increase in cystic ovaries and cystic endometrial hyperplasia (CEH) in the BPA-100 group as compared to Controls. Progressive proliferative lesion (PPL) of the oviduct and cystic mesonephric (Wolffian) duct remnants were also seen in all of the BPA groups. More severe pathologies of the uterus following neonatal BPA treatment included adenomyosis, leiomyomas, atypical hyperplasia, and stromal polyps. These data suggest that BPA causes long-term adverse effects if exposure occurs during critical periods of differentiation. PMID:17804194

Origins of Children's Externalizing Behavior Problems in Low-Income Families: Toddlers’ Willing Stance toward their Mothers as the Missing Link

PubMed Central

Kochanska, Grazyna; Kim, Sanghag; Boldt, Lea J.

2013-01-01

Although children's active role in socialization has been long acknowledged, relevant research has typically focused on children's difficult temperament or negative behaviors that elicit coercive and adversarial processes, largely overlooking their capacity to act as positive, willing, even enthusiastic, active socialization agents. We studied the willing, receptive stance toward their mothers in 186 24-44-month-old children in a low-income sample. Confirmatory Factor Analysis supported a latent construct of willing stance, manifested as children's responsiveness to mothers in naturalistic interactions, responsive imitation in teaching contexts, and committed compliance with maternal prohibitions, all observed in the laboratory. Structural Equation Modeling analyses confirmed that ecological adversity undermined maternal responsiveness and responsiveness, in turn, was linked to children's willing stance. A compromised willing stance predicted externalizing behavior problems, assessed 10 months later, and fully mediated the links between maternal responsiveness and those outcomes. Ecological adversity had a direct, unmediated effect on internalizing behavior problems. Considering children's active role as willing, receptive agents capable of embracing parental influence can lead to a more complete understanding of detrimental mechanisms that link ecological adversity with antisocial developmental pathways. It can also inform research on the normative socialization process, consistent with the objectives of developmental psychopathology. PMID:24229537

TOXICOLOGICAL HIGHLIGHT: SCREENING FOR DEVELOPMENTAL TOXICITY OF TOBACCO SMOKE CONSTITUENTS

EPA Science Inventory

Abstract
Cigarette smoking is unrivaled among developmental toxicants in terms of total adverse impact on the human population. According to the American Lung Association, smoking during pregnancy is estimated to account for 20 to 30 percent of low-weight babies, up to 14 per...

The potential of AOP networks for reproductive and developmental toxicity assay development

EPA Science Inventory

Historically, the prediction of reproductive and early developmental toxicity has largely relied on the use of animals. The Adverse Outcome Pathway (AOP) framework forms a basis for the development of new non-animal test methods. It also provides biological context for mechanisti...

Identification of Putative Cardiovascular System Developmental Toxicants using a Classification Model based on Signaling Pathway-Adverse Outcome Pathways

EPA Science Inventory

An important challenge for an integrative approach to developmental systems toxicology is associating putative molecular initiating events (MIEs), cell signaling pathways, cell function and modeled fetal exposure kinetics. We have developed a chemical classification model based o...

DOSIMETRY AND REPRODUCTIVE/DEVELOPMENTAL STUDY DESIGN AND INTERPRETATION FOR RISK OR SAFETY ASSESSMENT

EPA Science Inventory

Increasingly reproductive and developmental toxicity studies are utilized in assessing the potential for adverse affects in pregnant women, nursing infants, and children. These studies largely have been utilized based upon the dose to the mother due to the complexity of describin...

Alternative Test Methods for Developmental Neurotoxicity: A History and Path Forward (OECD EFSA workshop)

EPA Science Inventory

Exposure to environmental contaminants is well documented to adversely impact the development of the nervous system. However, the time, animal and resource intensive EPA and OECD testing guideline methods for developmental neurotoxicity (DNT) are not a viable solution to characte...

Adverse Reproductive and Developmental Health Outcomes Following Prenatal Exposure to a Hydraulic Fracturing Chemical Mixture in Female C57Bl/6 Mice.

PubMed

Kassotis, Christopher D; Bromfield, John J; Klemp, Kara C; Meng, Chun-Xia; Wolfe, Andrew; Zoeller, R Thomas; Balise, Victoria D; Isiguzo, Chiamaka J; Tillitt, Donald E; Nagel, Susan C

2016-09-01

Unconventional oil and gas operations using hydraulic fracturing can contaminate surface and groundwater with endocrine-disrupting chemicals. We have previously shown that 23 of 24 commonly used hydraulic fracturing chemicals can activate or inhibit the estrogen, androgen, glucocorticoid, progesterone, and/or thyroid receptors in a human endometrial cancer cell reporter gene assay and that mixtures can behave synergistically, additively, or antagonistically on these receptors. In the current study, pregnant female C57Bl/6 dams were exposed to a mixture of 23 commonly used unconventional oil and gas chemicals at approximately 3, 30, 300, and 3000 μg/kg·d, flutamide at 50 mg/kg·d, or a 0.2% ethanol control vehicle via their drinking water from gestational day 11 through birth. This prenatal exposure to oil and gas operation chemicals suppressed pituitary hormone concentrations across experimental groups (prolactin, LH, FSH, and others), increased body weights, altered uterine and ovary weights, increased heart weights and collagen deposition, disrupted folliculogenesis, and other adverse health effects. This work suggests potential adverse developmental and reproductive health outcomes in humans and animals exposed to these oil and gas operation chemicals, with adverse outcomes observed even in the lowest dose group tested, equivalent to concentrations reported in drinking water sources. These endpoints suggest potential impacts on fertility, as previously observed in the male siblings, which require careful assessment in future studies.

Adverse Reproductive and Developmental Health Outcomes Following Prenatal Exposure to a Hydraulic Fracturing Chemical Mixture in Female C57Bl/6 Mice

PubMed Central

Kassotis, Christopher D.; Bromfield, John J.; Klemp, Kara C.; Meng, Chun-Xia; Wolfe, Andrew; Zoeller, R. Thomas; Balise, Victoria D.; Isiguzo, Chiamaka J.; Tillitt, Donald E.

2016-01-01

Unconventional oil and gas operations using hydraulic fracturing can contaminate surface and groundwater with endocrine-disrupting chemicals. We have previously shown that 23 of 24 commonly used hydraulic fracturing chemicals can activate or inhibit the estrogen, androgen, glucocorticoid, progesterone, and/or thyroid receptors in a human endometrial cancer cell reporter gene assay and that mixtures can behave synergistically, additively, or antagonistically on these receptors. In the current study, pregnant female C57Bl/6 dams were exposed to a mixture of 23 commonly used unconventional oil and gas chemicals at approximately 3, 30, 300, and 3000 μg/kg·d, flutamide at 50 mg/kg·d, or a 0.2% ethanol control vehicle via their drinking water from gestational day 11 through birth. This prenatal exposure to oil and gas operation chemicals suppressed pituitary hormone concentrations across experimental groups (prolactin, LH, FSH, and others), increased body weights, altered uterine and ovary weights, increased heart weights and collagen deposition, disrupted folliculogenesis, and other adverse health effects. This work suggests potential adverse developmental and reproductive health outcomes in humans and animals exposed to these oil and gas operation chemicals, with adverse outcomes observed even in the lowest dose group tested, equivalent to concentrations reported in drinking water sources. These endpoints suggest potential impacts on fertility, as previously observed in the male siblings, which require careful assessment in future studies. PMID:27560547

Bisphenol A and human health: a review of the literature.

PubMed

Rochester, Johanna R

2013-12-01

There is growing evidence that bisphenol A (BPA) may adversely affect humans. BPA is an endocrine disruptor that has been shown to be harmful in laboratory animal studies. Until recently, there were relatively few epidemiological studies examining the relationship between BPA and health effects in humans. However, in the last year, the number of these studies has more than doubled. A comprehensive literature search found 91 studies linking BPA to human health; 53 published within the last year. This review outlines this body of literature, showing associations between BPA exposure and adverse perinatal, childhood, and adult health outcomes, including reproductive and developmental effects, metabolic disease, and other health effects. These studies encompass both prenatal and postnatal exposures, and include several study designs and population types. While it is difficult to make causal links with epidemiological studies, the growing human literature correlating environmental BPA exposure to adverse effects in humans, along with laboratory studies in many species including primates, provides increasing support that environmental BPA exposure can be harmful to humans, especially in regards to behavioral and other effects in children. Copyright © 2013 Elsevier Inc. All rights reserved.

The Effects of Childhood and Adolescent Adversity on Substance Use Disorders and Poor Health in Early Adulthood

PubMed Central

Wolitzky-Taylor, Kate; Sewart, Amy; Vrshek-Schallhorn, Suzanne; Zinbarg, Richard; Mineka, Susan; Hammen, Constance; Bobova, Lyuba; Adam, Emma K.; Craske, Michelle G.

2016-01-01

Childhood and adolescent adversity have been shown to predict later mental and physical health outcomes. Understanding which aspects and developmental timings of adversity are important, and the mechanisms by which they have their impact may help guide intervention approaches. A large subset of adolescents (N = 457; Female 68.9%) from the 10-year longitudinal Youth Emotion Project was examined to better understand the associations among childhood/adolescent adversity, substance use disorder, and later health quality. Adolescent (but not childhood) adversities were associated with poorer health in late adolescence/early adulthood, adolescent adversities were associated with subsequent onset of substance use disorder, and adolescent adversities continued to be associated with poorer health in late adolescence/early adulthood after accounting for the variance explained by substance use disorder onset. These associations were observed after statistically accounting for emotional disorders and socioeconomic status. Specific domains of adversity uniquely predicted substance use disorder and poorer health outcomes. In contrast with current recent research, our findings suggest the association between childhood/adolescent adversity and poorer health outcomes in late adolescence and emerging adulthood are not entirely accounted for by substance use disorder, suggesting efforts to curtail family-based adolescent adversity may have downstream health benefits. PMID:27613006

The Effects of Childhood and Adolescent Adversity on Substance Use Disorders and Poor Health in Early Adulthood.

PubMed

Wolitzky-Taylor, Kate; Sewart, Amy; Vrshek-Schallhorn, Suzanne; Zinbarg, Richard; Mineka, Susan; Hammen, Constance; Bobova, Lyuba; Adam, Emma K; Craske, Michelle G

2017-01-01

Childhood and adolescent adversity have been shown to predict later mental and physical health outcomes. Understanding which aspects and developmental timings of adversity are important, and the mechanisms by which they have their impact may help guide intervention approaches. A large subset of adolescents (N = 457; Female 68.9 %) from the 10-year longitudinal Youth Emotion Project was examined to better understand the associations among childhood/adolescent adversity, substance use disorder, and later health quality. Adolescent (but not childhood) adversities were associated with poorer health in late adolescence/early adulthood, adolescent adversities were associated with subsequent onset of substance use disorder, and adolescent adversities continued to be associated with poorer health in late adolescence/early adulthood after accounting for the variance explained by substance use disorder onset. These associations were observed after statistically accounting for emotional disorders and socioeconomic status. Specific domains of adversity uniquely predicted substance use disorder and poorer health outcomes. In contrast with current recent research, our findings suggest the association between childhood/adolescent adversity and poorer health outcomes in late adolescence and emerging adulthood are not entirely accounted for by substance use disorder, suggesting efforts to curtail family-based adolescent adversity may have downstream health benefits.

The effects of drought and disturbance on the growth and developmental instability of loblolly pine (Pinus taeda L.)

USGS Publications Warehouse

Graham, John H.; Duda, Jeffrey J.; Brown, Michelle L.; Kitchen, Stanley G.; Emlen, John M.; Malol, Jagadish; Bankstahl, Elizabeth; Krzysik, Anthony J.; Balbach, Harold E.; Freeman, D. Carl

2012-01-01

Ecological indicators provide early warning of adverse environmental change, helping land managers adaptively manage their resources while minimizing costly remediation. In 1999 and 2000, we studied two such indicators, growth and developmental instability, of loblolly pine (Pinus taeda L.) influenced by mechanized infantry training at Fort Benning, Georgia. Disturbed areas were used for military training; tracked and wheeled vehicles damaged vegetation and soils. Highly disturbed sites had fewer trees, diminished ground cover, warmer soils in the summer, and more compacted soils with a shallower A-horizon. We hypothesized that disturbance would decrease the growth of needles, branches, and tree rings, increase the complexity of tree rings, and increase the developmental instability of needles. Contrary to our expectations, however, disturbance enhanced growth in the first year of the study, possibly by reducing competition. In the second year, a drought reduced growth of branches and needles, eliminating the stimulatory effect of disturbance. Growth-ring widths increased with growing-season precipitation, and decreased with growing-season temperature over the last 40 years. Disturbance had no effect on tree-ring complexity, as measured by the Hurst exponent. Within-fascicle variation of current-year needle length, a measure of developmental instability, differed among the study populations, but appeared unrelated to mechanical disturbance or drought.

Phenotypic screening for developmental neurotoxicity ...

EPA Pesticide Factsheets

There are large numbers of environmental chemicals with little or no available information on their toxicity, including developmental neurotoxicity. Because of the resource-intensive nature of traditional animal tests, high-throughput (HTP) methods that can rapidly evaluate chemicals for the potential to affect the developing brain are being explored. Typically, HTP screening uses biochemical and molecular assays to detect the interaction of a chemical with a known target or molecular initiating event (e.g., the mechanism of action). For developmental neurotoxicity, however, the mechanism(s) is often unknown. Thus, we have developed assays for detecting chemical effects on the key events of neurodevelopment at the cellular level (e.g., proliferation, differentiation, neurite growth, synaptogenesis, network formation). Cell-based assays provide a test system at a level of biological complexity that encompasses many potential neurotoxic mechanisms. For example, phenotypic assessment of neurite outgrowth at the cellular level can detect chemicals that target kinases, ion channels, or esterases at the molecular level. The results from cell-based assays can be placed in a conceptual framework using an Adverse Outcome Pathway (AOP) which links molecular, cellular, and organ level effects with apical measures of developmental neurotoxicity. Testing a wide range of concentrations allows for the distinction between selective effects on neurodevelopmental and non-specific

Developmental effects of 3,4-methylenedioxymethamphetamine: a review.

PubMed

Skelton, Matthew R; Williams, Michael T; Vorhees, Charles V

2008-03-01

+/-3,4-Methylenedioxymethamphetamine (MDMA) is a chemical derivative of amphetamine that has become a popular drug of abuse and has been shown to deplete serotonin in the brains of users and animals exposed to it. To date, most studies have investigated the effects of MDMA on adult animals. With a majority of users of MDMA being young adults, the chances of the users becoming pregnant and exposing the fetuses to MDMA are also a concern. Evidence to date has shown that developmental exposure to MDMA results in learning and memory impairments in the Morris water maze, a task known to be sensitive to hippocampal disruption, when the animals are tested as adults. Developmental MDMA exposure leads to hypoactivity in the offspring as adults but does not affect outcome on tests of anxiety. MDMA administration decreases pup weight, increases corticosterone and brain-derived neurotrophic factor levels during treatment while decreasing brain levels of serotonin; a decrease that initially dissipates and then reappears in adulthood. Neonatal MDMA exposure increases the sensitivity of the serotonin 1A receptor, a possible mechanism underlying the learning and memory deficits seen. Taken together, the evidence shows that MDMA exposure has adverse effects on the developing brain and behavior. The animal and human data on developmental MDMA exposure are reviewed and their public health implications discussed.

Early developmental characteristics and features of major depressive disorder among child psychiatric patients in Hungary.

PubMed

Kapornai, Krisztina; Gentzler, Amy L; Tepper, Ping; Kiss, Eniko; Mayer, László; Tamás, Zsuzsanna; Kovacs, Maria; Vetró, Agnes

2007-06-01

We investigate the relations of early atypical characteristics (perinatal problems, developmental delay, and difficult temperament) and onset-age (as well as severity of) first major depressive disorder (MDD) and first internalizing disorder in a clinical sample of depressed children in Hungary. Participants were 371 children (ages 7-14) with MDD, and their biological mothers, recruited through multiple clinical sites. Diagnoses (via DSM-IV criteria) and onset dates of disorders were finalized "best estimate" psychiatrists, and based on multiple information sources. Mothers provided developmental data in a structured interview. Difficult temperament predicted earlier onset of MDD and first internalizing disorder, but its effect was ameliorated if the family was intact during early childhood. Further, the importance of difficult temperament decreased as a function of time. Perinatal problems and developmental delay did not impact onset ages of disorders, and none of the early childhood characteristics associated with MDD episode severity. Children with MDD may have added disadvantage of earlier onset if they had a difficult temperament in infancy. Because early temperament mirrors physiological reactivity and regulatory capacity, it can affect various areas of functioning related to psychopathology. Early caregiver stability may attenuate some adverse effects of difficult infant temperament.

Differential Susceptibility to the Environment: Are Developmental Models Compatible with the Evidence from Twin Studies?

ERIC Educational Resources Information Center

Del Giudice, Marco

2016-01-01

According to models of differential susceptibility, the same neurobiological and temperamental traits that determine increased sensitivity to stress and adversity also confer enhanced responsivity to the positive aspects of the environment. Differential susceptibility models have expanded to include complex developmental processes in which genetic…

Acute, subchronic, and developmental toxicological properties of lubricating oil base stocks.

PubMed

Dalbey, Walden E; McKee, Richard H; Goyak, Katy Olsavsky; Biles, Robert W; Murray, Jay; White, Russell

2014-01-01

Lubricating oil base stocks (LOBs) are substances used in the manufacture of finished lubricants and greases. They are produced from residue remaining after atmospheric distillation of crude oil that is subsequently fractionated by vacuum distillation and additional refining steps. Initial LOB streams that have been produced by vacuum distillation but not further refined may contain polycyclic aromatic compounds (PACs) and may present carcinogenic hazards. In modern refineries, LOBs are further refined by multistep processes including solvent extraction and/or hydrogen treatment to reduce the levels of PACs and other undesirable constituents. Thus, mildly (insufficiently) refined LOBs are potentially more hazardous than more severely (sufficiently) refined LOBs. This article discusses the evaluation of LOBs using statistical models based on content of PACs; these models indicate that insufficiently refined LOBs (potentially carcinogenic LOBs) can also produce systemic and developmental effects with repeated dermal exposure. Experimental data were also obtained in ten 13-week dermal studies in rats, eight 4-week dermal studies in rabbits, and seven dermal developmental toxicity studies with sufficiently refined LOBs (noncarcinogenic and commonly marketed) in which no observed adverse effect levels for systemic toxicity and developmental toxicity were 1000 to 2000 mg/kg/d with dermal exposures, typically the highest dose tested. Results in both oral and inhalation developmental toxicity studies were similar. This absence of toxicologically relevant findings was consistent with lower PAC content of sufficiently refined LOBs. Based on data on reproductive organs with repeated dosing and parameters in developmental toxicity studies, sufficiently refined LOBs are likely to have little, if any, effect on reproductive parameters.

Adverse Childhood Experiences among Direct Support Professionals

ERIC Educational Resources Information Center

Keesler, John M.

2018-01-01

Direct support professionals (DSPs) provide integral support to many individuals with intellectual and developmental disabilities (IDD). Yet, individuals' access to qualified DSPs is often compromised as organizations struggle to hire and retain DSPs. Despite a vast body of research exploring factors associated with turnover, adverse childhood…

A systematic review of possible serious adverse health effects of nicotine replacement therapy.

PubMed

Lee, Peter N; Fariss, Marc W

2017-04-01

We conducted a systematic literature review to identify and critically evaluate studies of serious adverse health effects (SAHEs) in humans using nicotine replacement therapy (NRT) products. Serious adverse health effects refer to adverse events, leading to substantial disruption of the ability to conduct normal life functions. Strength of evidence evaluations and conclusions were also determined for the identified SAHEs. We evaluated 34 epidemiological studies and clinical trials, relating NRT use to cancer, reproduction/development, CVD, stroke and/or other SAHEs in patients, and four meta-analyses on effects in healthy populations. The overall evidence suffers from many limitations, the most significant being the short-term exposure (≤12 weeks) and follow-up to NRT product use in most of the studies, the common failure to account for changes in smoking behaviour following NRT use, and the sparse information on SAHEs by type of NRT product used. The only SAHE from NRT exposure we identified was an increase in respiratory congenital abnormalities reported in one study. Limited evidence indicated a lack of effect between NRT exposure and SAHEs for CVD and various reproduction/developmental endpoints. For cancer, stroke and other SAHEs, the evidence was inadequate to demonstrate any association with NRT use. Our conclusions agree with recent statements from authoritative bodies.

Ecological School Counseling in High-Poverty Elementary Schools: Counselors' Backgrounds and Perceptions Regarding the Effects of Poverty, Importance of Advocacy and School-Based Mental Health Programs

ERIC Educational Resources Information Center

Brown, La Vera C.

2016-01-01

Elementary school counselors working in high-poverty schools experience several challenges due to the multiple barriers associated with serving children from low-SES families. Research shows that children from low-SES families are at risk of adverse consequences to their developmental and psychological progress due to negative environmental…

What Are the Most Effective Early Response Strategies and Interventions to Assess and Address the Immediate Needs of Children outside of Family Care?

ERIC Educational Resources Information Center

Boothby, Neil; Wessells, Mike; Williamson, John; Huebner, Gillian; Canter, Kelly; Rolland, Eduardo Garcia; Kutlesic, Vesna; Bader, Farah; Diaw, Lena; Levine, Maya; Malley, Anita; Michels, Kathleen; Patel, Sonali; Rasa, Tanya; Ssewamala, Fred; Walker, Vicki

2012-01-01

Objectives: Children outside of family care face increased risk of threats to their well-being, have lower educational achievement, and experience adverse developmental outcomes. While it is generally accepted that early response and intervention is critical to reducing the risk of harm for children who have been separated from their families, it…

Epigenetic mechanisms in alcohol- and adversity-induced developmental origins of neurobehavioral functioning.

PubMed

Boschen, K E; Keller, S M; Roth, T L; Klintsova, A Y

The long-term effects of developmental alcohol and stress exposure are well documented in both humans and non-human animal models. Damage to the brain and attendant life-long impairments in cognition and increased risk for psychiatric disorders are debilitating consequences of developmental exposure to alcohol and/or psychological stress. Here we discuss evidence for a role of epigenetic mechanisms in mediating these consequences. While we highlight some of the common ways in which stress or alcohol impact the epigenome, we point out that little is understood of the epigenome's response to experiencing both stress and alcohol exposure, though stress is a contributing factor as to why women drink during pregnancy. Advancing our understanding of this relationship is of critical concern not just for the health and well-being of individuals directly exposed to these teratogens, but for generations to come. Copyright © 2018 Elsevier Inc. All rights reserved.

Adverse Childhood Experiences and Criminal Extremity: New Evidence for Sexual Homicide.

PubMed

DeLisi, Matt; Beauregard, Eric

2018-03-01

Adverse childhood experiences are associated with a wide range of behavioral, health, and psychiatric deficits and have recently been used to study the development of serious offending careers. Unfortunately, this research paradigm has largely ignored forensic populations. This study utilized the adverse childhood experiences framework to examine the associations between exposure to violence, victimization, and total adverse childhood experiences on sexual homicide using a sample of 616 incarcerated adult male sexual offenders from Canada 85 of whom committed sexual homicide. Epidemiological tables of odds revealed that a gradient of adverse childhood experiences was associated with sexual homicide, but that the most significant risks were for offenders who had the most extensive abuse histories. In adjusted models, exposure to violence, victimization, and total adverse childhood experiences increased the odds of sexual homicide by 334%, 249%, and 546%, respectively. These effects intensified in models adjusted for childhood enuresis, cruelty to animals, parental abandonment, deviant sexual behaviors, poor self-image, and sexual problems to 559%, 326%, and 849%, respectively. The adverse childhood experiences framework is a systematic way to organize the criminogenic developmental sequela in sexual homicide. © 2017 American Academy of Forensic Sciences.

Programmed Effects in Neurobehavior and Antioxidative Physiology in Zebrafish Embryonically Exposed to Cadmium: Observations and Hypothesized Adverse Outcome Pathway Framework.

PubMed

Ruiter, Sander; Sippel, Josefine; Bouwmeester, Manon C; Lommelaars, Tobias; Beekhof, Piet; Hodemaekers, Hennie M; Bakker, Frank; van den Brandhof, Evert-Jan; Pennings, Jeroen L A; van der Ven, Leo T M

2016-11-02

Non-communicable diseases (NCDs) are a major cause of premature mortality. Recent studies show that predispositions for NCDs may arise from early-life exposure to low concentrations of environmental contaminants. This developmental origins of health and disease (DOHaD) paradigm suggests that programming of an embryo can be disrupted, changing the homeostatic set point of biological functions. Epigenetic alterations are a possible underlying mechanism. Here, we investigated the DOHaD paradigm by exposing zebrafish to subtoxic concentrations of the ubiquitous contaminant cadmium during embryogenesis, followed by growth under normal conditions. Prolonged behavioral responses to physical stress and altered antioxidative physiology were observed approximately ten weeks after termination of embryonal exposure, at concentrations that were 50-3200-fold below the direct embryotoxic concentration, and interpreted as altered developmental programming. Literature was explored for possible mechanistic pathways that link embryonic subtoxic cadmium to the observed apical phenotypes, more specifically, the probability of molecular mechanisms induced by cadmium exposure leading to altered DNA methylation and subsequently to the observed apical phenotypes. This was done using the adverse outcome pathway model framework, and assessing key event relationship plausibility by tailored Bradford-Hill analysis. Thus, cadmium interaction with thiols appeared to be the major contributor to late-life effects. Cadmium-thiol interactions may lead to depletion of the methyl donor S -adenosyl-methionine, resulting in methylome alterations, and may, additionally, result in oxidative stress, which may lead to DNA oxidation, and subsequently altered DNA methyltransferase activity. In this way, DNA methylation may be affected at a critical developmental stage, causing the observed apical phenotypes.

Developmental influences on fertility decisions by women: an evolutionary perspective

PubMed Central

Tickner, M.; McAllister, L. S.; Sheppard, P.

2016-01-01

Developmental environments are crucial for shaping our life course. Elements of the early social and biological environments have been consistently associated with reproduction in humans. To date, a strong focus has been on the relationship between early stress, earlier menarche and first child birth in women. These associations, found predominately in high-income countries, have been usefully interpreted within life-history theory frameworks. Fertility, on the other hand—a missing link between an individual's early environment, reproductive strategy and fitness—has received little attention. Here, we synthesize this literature by examining the associations between early adversity, age at menarche and fertility and fecundity in women. We examine the evidence that potential mechanisms such as birth weight, childhood body composition, risky health behaviours and developmental influences on attractiveness link the early environment and fecundity and fertility. The evidence that menarche is associated with fertility and fecundity is good. Currently, owing to the small number of correlational studies and mixed methodologies, the evidence that early adversity predicts fecundity and fertility is not conclusive. This area of research is in its infancy; studies examining early adversity and adult fertility decisions that can also examine likely biological, social and psychological pathways present opportunities for future fertility research. PMID:27022073

A systematic evaluation of chemicals in hydraulic-fracturing fluids and wastewater for reproductive and developmental toxicity.

PubMed

Elliott, Elise G; Ettinger, Adrienne S; Leaderer, Brian P; Bracken, Michael B; Deziel, Nicole C

2017-01-01

Hydraulic-fracturing fluids and wastewater from unconventional oil and natural gas development contain hundreds of substances with the potential to contaminate drinking water. Challenges to conducting well-designed human exposure and health studies include limited information about likely etiologic agents. We systematically evaluated 1021 chemicals identified in hydraulic-fracturing fluids (n=925), wastewater (n=132), or both (n=36) for potential reproductive and developmental toxicity to triage those with potential for human health impact. We searched the REPROTOX database using Chemical Abstract Service registry numbers for chemicals with available data and evaluated the evidence for adverse reproductive and developmental effects. Next, we determined which chemicals linked to reproductive or developmental toxicity had water quality standards or guidelines. Toxicity information was lacking for 781 (76%) chemicals. Of the remaining 240 substances, evidence suggested reproductive toxicity for 103 (43%), developmental toxicity for 95 (40%), and both for 41 (17%). Of these 157 chemicals, 67 had or were proposed for a federal water quality standard or guideline. Our systematic screening approach identified a list of 67 hydraulic fracturing-related candidate analytes based on known or suspected toxicity. Incorporation of data on potency, physicochemical properties, and environmental concentrations could further prioritize these substances for future drinking water exposure assessments or reproductive and developmental health studies.

Validating Functional Measures of Physical Ability for Aging People with Intellectual Developmental Disability

ERIC Educational Resources Information Center

Maring, Joyce R.; Costello, Ellen; Birkmeier, Marisa C.; Richards, Maggie; Alexander, Lisa M.

2013-01-01

Unlike the aging population without intellectual and developmental disabilities (IDD), few standardized performance measures exist to assess physical function and risk for adverse outcomes such as nonfatal, unintentional injuries. We modified 3 selected standardized performance tools in the areas of general fitness (2-Minute Walk Test), balance…

Prenatal Tobacco Exposure: Developmental Outcomes in the Neonatal Period

ERIC Educational Resources Information Center

Espy, Kimberly Andrews; Fang, Hua; Johnson, Craig; Stopp, Christian; Wiebe, Sandra A.; Respass, Jennifer

2011-01-01

Smoking during pregnancy is a persistent public health problem that has been linked to later adverse outcomes. The neonatal period--the first month of life--carries substantial developmental change in regulatory skills and is the period when tobacco metabolites are cleared physiologically. Studies to date mostly have used cross-sectional designs…

Developmental neurotoxicants in e-waste: an emerging health concern.

PubMed

Chen, Aimin; Dietrich, Kim N; Huo, Xia; Ho, Shuk-mei

2011-04-01

Electronic waste (e-waste) has been an emerging environmental health issue in both developed and developing countries, but its current management practice may result in unintended developmental neurotoxicity in vulnerable populations. To provide updated information about the scope of the issue, presence of known and suspected neurotoxicants, toxicologic mechanisms, and current data gaps, we conducted this literature review. We reviewed original articles and review papers in PubMed and Web of Science regarding e-waste toxicants and their potential developmental neurotoxicity. We also searched published reports of intergovernmental and governmental agencies and nongovernmental organizations on e-waste production and management practice. We focused on the potential exposure to e-waste toxicants in vulnerable populations-that is, pregnant women and developing children-and neurodevelopmental outcomes. In addition, we summarize experimental evidence of developmental neurotoxicity and mechanisms. In developing countries where most informal and primitive e-waste recycling occurs, environmental exposure to lead, cadmium, chromium, polybrominated diphenyl ethers, polychlorinated biphenyls, and polycyclic aromatic hydrocarbons is prevalent at high concentrations in pregnant women and young children. Developmental neurotoxicity is a serious concern in these regions, but human studies of adverse effects and potential mechanisms are scarce. The unprecedented mixture of exposure to heavy metals and persistent organic pollutants warrants further studies and necessitates effective pollution control measures. Pregnant women and young children living close to informal e-waste recycling sites are at risk of possible perturbations of fetus and child neurodevelopment.

Behavioral toxicology, risk assessment, and chlorinated hydrocarbons.

PubMed Central

Evangelista de Duffard, A M; Duffard, R

1996-01-01

Behavioral end points are being used with greater frequency in neurotoxicology to detect and characterize the adverse effects of chemicals on the nervous system. Behavioral measures are particularly important for neurotoxicity risk assessment since many known neurotoxicants do not result in neuropathology. The chlorinated hydrocarbon class consists of a wide variety of chemicals including polychlorinated biphenyls, clioquinol, trichloroethylene, hexachlorophene, organochlorine insecticides (DDT, dicofol, chlordecone,dieldrin, and lindane), and phenoxyherbicides. Each of these chemicals has effects on motor, sensory, or cognitive function that are detectable using functional measures such as behavior. Furthermore, there is evidence that if exposure occurs during critical periods of development, many of the chlorinated hydrocarbons are developmental neurotoxicants. Developmental neurotoxicity is frequently expressed as alterations in motor function or cognitive abilities or changes in the ontogeny of sensorimotor reflexes. Neurotoxicity risk assessment should include assessments of the full range of possible neurotoxicological effects, including both structural and functional indicators of neurotoxicity. PMID:9182042

NTP-CERHR monograph on the potential human reproductive and developmental effects of hydroxyurea.

PubMed

2008-10-01

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for hydroxyurea to cause adverse effects on reproduction and development in humans. Hydroxyurea is a drug used to treat cancer, sickle cell disease, and thalassemia. It is the only treatment for sickle cell disease in children, aside from blood transfusion and, in severe cases, hematopoietic stem cell transplantation. Hydroxyurea is FDA-approved for use in adults with sickle cell anemia to reduce the frequency of painful crises and the need for blood transfusions. Hydroxyurea may be given to children and adults with sickle cell disease for an extended period of time or for repeated cycles of therapy. Treatment with hydroxyurea is associated with known side effects such as cytotoxicity and myelosuppression, and hydroxyurea is genotoxic (can damage DNA). CERHR selected hydroxyurea for evaluation because of: its increasing use for treatment of sickle cell disease in children and adults, knowledge that it inhibits DNA synthesis and is cytotoxic, and published evidence of reproductive and developmental toxicity in rodents. The results of this evaluation are published in the NTP-CERHR Monograph on Hydroxyurea, which includes the NTP Brief and Expert Panel Report on the Reproductive and Developmental Toxicity of Hydroxyurea. Additional information related to the evaluation process, including public comments received on the draft NTP Brief and the final expert panel report, are available on the CERHR website (http:// cerhr.niehs.nih.gov/). See hydroxyurea under "CERHR Chemicals" on the homepage or go directly to http://cerhr.niehs.nih.gov/chemicals/hydroxyurea/hydroxyurea-eval.html). The NTP reached the following conclusions on the possible effects of exposure to hydroxyurea on human reproduction or development. The possible levels of concern, from lowest to highest, are negligible concern, minimal concern, some concern, concern, and serious concern. The NTP expresses serious concern that exposure of men to therapeutic doses of hydroxyurea may adversely affect sperm production. This level of concern is for all males who have reached puberty. The NTP concurs with the Expert Panel that there is concern that exposure of pregnant women to hydroxyurea may result in birth defects, abnormalities of fetal growth, or abnormal postnatal development in offspring. The NTP concurs with the Expert Panel that there is minimal concern that exposure of children to therapeutic doses of hydroxyurea at 5 -15 years of age will adversely affect growth. NTP will transmit the NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Hydroxyurea to federal and state agencies, interested parties, and the public and make it available in electronic PDF format on the CERHR web site (http://cerhr niehs nih gov) and in printed text or CD from CERHR.

Early Adversity, Elevated Stress Physiology, Accelerated Sexual Maturation, and Poor Health in Females

ERIC Educational Resources Information Center

Belsky, Jay; Ruttle, Paula L.; Boyce, W. Thomas; Armstrong, Jeffrey M.; Essex, Marilyn J.

2015-01-01

Evolutionary-minded developmentalists studying predictive-adaptive-response processes linking childhood adversity with accelerated female reproductive development and health scientists investigating the developmental origins of health and disease (DOoHaD) may be tapping the same process, whereby longer-term health costs are traded off for…

Neurodevelopment and Thyroid Hormone Synthesis Inhibition in the Rat: Quantitative Understanding Within the Adverse Outcome Pathway Framework

EPA Science Inventory

Adequate levels of thyroid hormones (TH) are needed for proper brain development, deficiencies may lead to adverse neurological outcomes in humans and animal models. Environmental chemicals have been linked to TH disruption, yet the relationship between developmental exposures an...

Disparities in adverse childhood experiences among sexual minority and heterosexual adults: results from a multi-state probability-based sample.

PubMed

Andersen, Judith P; Blosnich, John

2013-01-01

Adverse childhood experiences (e.g., physical, sexual and emotional abuse, neglect, exposure to domestic violence, parental discord, familial mental illness, incarceration and substance abuse) constitute a major public health problem in the United States. The Adverse Childhood Experiences (ACE) scale is a standardized measure that captures multiple developmental risk factors beyond sexual, physical and emotional abuse. Lesbian, gay, and bisexual (i.e., sexual minority) individuals may experience disproportionately higher prevalence of adverse childhood experiences. To examine, using the ACE scale, prevalence of childhood physical, emotional, and sexual abuse and childhood household dysfunction among sexual minority and heterosexual adults. Analyses were conducted using a probability-based sample of data pooled from three U.S. states' Behavioral Risk Factor Surveillance System (BRFSS) surveys (Maine, Washington, Wisconsin) that administered the ACE scale and collected information on sexual identity (n = 22,071). Compared with heterosexual respondents, gay/lesbian and bisexual individuals experienced increased odds of six of eight and seven of eight adverse childhood experiences, respectively. Sexual minority persons had higher rates of adverse childhood experiences (IRR = 1.66 gay/lesbian; 1.58 bisexual) compared to their heterosexual peers. Sexual minority individuals have increased exposure to multiple developmental risk factors beyond physical, sexual and emotional abuse. We recommend the use of the Adverse Childhood Experiences scale in future research examining health disparities among this minority population.

Life course pathways of adverse childhood experiences toward adult psychological well-being: A stress process analysis.

PubMed

Nurius, Paula S; Green, Sara; Logan-Greene, Patricia; Borja, Sharon

2015-07-01

Growing evidence suggests that toxic stressors early in life not only convey developmental impacts but also augment risk of proliferating chains of additional stressors that can overwhelm individual coping and undermine recovery and health. Examining trauma within a life course stress process perspective, we posit that early childhood adversity carries a unique capacity to impair adult psychological well-being both independent of and cumulative with other contributors, including social disadvantage and stressful adult experiences. This study uses data from a representative population-based health survey (N=13,593) to provide one of the first multivariate assessments of unique, cumulative, and moderated effects of adverse childhood experiences (ACEs) toward explaining 3 related yet distinct measures of adult mental health: perceived well-being, psychological distress, and impaired daily activities. Results demonstrate support for each set of hypothesized associations, including exacerbation and amelioration of ACEs effects by adult stress and resilience resources, respectively. Implications for services and future research are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Life Course Pathways of Adverse Childhood Experiences Toward Adult Psychological Well-Being: A Stress Process Analysis

PubMed Central

Nurius, Paula S.; Green, Sara; Logan-Greene, Patricia; Borja, Sharon

2015-01-01

Growing evidence suggests that toxic stressors early in life not only convey developmental impacts but also augment risk of proliferating chains of additional stressors that can overwhelm individual coping and undermine recovery and health. Examining trauma within a life course stress process perspective, we posit that early childhood adversity carries a unique capacity to impair adult psychological well-being both independent of and cumulative with other contributors, including social disadvantage and stressful adult experiences. This study uses data from a representative population-based health survey (N = 13,593) to provide one of the first multivariate assessments of unique, cumulative, and moderated effects of adverse childhood experiences (ACEs) toward explaining 3 related yet distinct measures of adult mental health: perceived well-being, psychological distress, and impaired daily activities. Results demonstrate support for each set of hypothesized associations, including exacerbation and amelioration of ACEs effects by adult stress and resilience resources, respectively. Implications for services and future research are discussed. PMID:25846195

Systematic review of pediatric health outcomes associated with childhood adversity.

PubMed

Oh, Debora Lee; Jerman, Petra; Silvério Marques, Sara; Koita, Kadiatou; Purewal Boparai, Sukhdip Kaur; Burke Harris, Nadine; Bucci, Monica

2018-02-23

Early detection of and intervention in childhood adversity has powerful potential to improve the health and well-being of children. A systematic review was conducted to better understand the pediatric health outcomes associated with childhood adversity. PubMed, PsycArticles, and CINAHL were searched for relevant articles. Longitudinal studies examining various adverse childhood experiences and biological health outcomes occurring prior to age 20 were selected. Mental and behavioral health outcomes were excluded, as were physical health outcomes that were a direct result of adversity (i.e. abusive head trauma). Data were extracted and risk of bias was assessed by 2 independent reviewers. After identifying 15940 records, 35 studies were included in this review. Selected studies indicated that exposure to childhood adversity was associated with delays in cognitive development, asthma, infection, somatic complaints, and sleep disruption. Studies on household dysfunction reported an effect on weight during early childhood, and studies on maltreatment reported an effect on weight during adolescence. Maternal mental health issues were associated with elevated cortisol levels, and maltreatment was associated with blunted cortisol levels in childhood. Furthermore, exposure to childhood adversity was associated with alterations of immune and inflammatory response and stress-related accelerated telomere erosion. Childhood adversity affects brain development and multiple body systems, and the physiologic manifestations can be detectable in childhood. A history of childhood adversity should be considered in the differential diagnosis of developmental delay, asthma, recurrent infections requiring hospitalization, somatic complaints, and sleep disruption. The variability in children's response to adversity suggests complex underlying mechanisms and poses a challenge in the development of uniform diagnostic guidelines. More large longitudinal studies are needed to better understand how adversity, its timing and severity, and the presence of individual genetic, epigenetic, and protective factors affects children's health and development.

Identification of novel uncertainty factors and thresholds of toxicological concern for health hazard and risk assessment: Application to cleaning product ingredients.

PubMed

Wang, Zhen; Scott, W Casan; Williams, E Spencer; Ciarlo, Michael; DeLeo, Paul C; Brooks, Bryan W

2018-04-01

Uncertainty factors (UFs) are commonly used during hazard and risk assessments to address uncertainties, including extrapolations among mammals and experimental durations. In risk assessment, default values are routinely used for interspecies extrapolation and interindividual variability. Whether default UFs are sufficient for various chemical uses or specific chemical classes remains understudied, particularly for ingredients in cleaning products. Therefore, we examined publicly available acute median lethal dose (LD50), and reproductive and developmental no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) values for the rat model (oral). We employed probabilistic chemical toxicity distributions to identify likelihoods of encountering acute, subacute, subchronic and chronic toxicity thresholds for specific chemical categories and ingredients in cleaning products. We subsequently identified thresholds of toxicological concern (TTC) and then various UFs for: 1) acute (LD50s)-to-chronic (reproductive/developmental NOAELs) ratios (ACRs), 2) exposure duration extrapolations (e.g., subchronic-to-chronic; reproductive/developmental), and 3) LOAEL-to-NOAEL ratios considering subacute/acute developmental responses. These ratios (95% CIs) were calculated from pairwise threshold levels using Monte Carlo simulations to identify UFs for all ingredients in cleaning products. Based on data availability, chemical category-specific UFs were also identified for aliphatic acids and salts, aliphatic alcohols, inorganic acids and salts, and alkyl sulfates. In a number of cases, derived UFs were smaller than default values (e.g., 10) employed by regulatory agencies; however, larger UFs were occasionally identified. Such UFs could be used by assessors instead of relying on default values. These approaches for identifying mammalian TTCs and diverse UFs represent robust alternatives to application of default values for ingredients in cleaning products and other chemical classes. Findings can also support chemical substitutions during alternatives assessment, and data dossier development (e.g., read across), identification of TTCs, and screening-level hazard and risk assessment when toxicity data is unavailable for specific chemicals. Copyright © 2018 Elsevier Ltd. All rights reserved.

Adverse reproductive and developmental health outcomes following prenatal exposure to a 2 hydraulic fracturing chemical mixture in female C57Bl/6 mice

USGS Publications Warehouse

Kassotis, Christopher D.; Bromfield, John J.; Klemp, Kara C.; Meng, Chun-Xia; Wolfe, Andrew R.; Zoeller, Thomas; Balise, Victoria D.; Isiguzo, Chiamaka J.; Tillitt, Donald E.; Nagel, Susan C.

2016-01-01

Unconventional oil and gas operations using hydraulic fracturing can contaminate surface and groundwater with endocrine-disrupting chemicals. We have previously shown that 23 of 24 commonly used hydraulic fracturing chemicals can activate or inhibit the estrogen, androgen, glucocorticoid, progesterone, and/or thyroid receptors in a human endometrial cancer cell reporter gene assay and that mixtures can behave synergistically, additively, or antagonistically on these receptors. In the current study, pregnant female C57Bl/6 dams were exposed to a mixture of 23 commonly used unconventional oil and gas chemicals at approximately 3, 30, 300, and 3000 μg/kg·d, flutamide at 50 mg/kg·d, or a 0.2% ethanol control vehicle via their drinking water from gestational day 11 through birth. This prenatal exposure to oil and gas operation chemicals suppressed pituitary hormone concentrations across experimental groups (prolactin, LH, FSH, and others), increased body weights, altered uterine and ovary weights, increased heart weights and collagen deposition, disrupted folliculogenesis, and other adverse health effects. This work suggests potential adverse developmental and reproductive health outcomes in humans and animals exposed to these oil and gas operation chemicals, with adverse outcomes observed even in the lowest dose group tested, equivalent to concentrations reported in drinking water sources. These endpoints suggest potential impacts on fertility, as previously observed in the male siblings, which require careful assessment in future studies. - See more at: http://press.endocrine.org/doi/10.1210/en.2016-1242#sthash.9kqfLvXg.dpuf

Neurodevelopmental Low-dose Bisphenol A Exposure Leads to Early Life-stage Hyperactivity and Learning Deficits in Adult Zebrafish

PubMed Central

Saili, Katerine S.; Corvi, Margaret M.; Weber, Daniel N.; Patel, Ami U.; Das, Siba R.; Przybyla, Jennifer; Anderson, Kim A.; Tanguay, Robert L.

2011-01-01

Developmental bisphenol A (BPA) exposure has been implicated in adverse behavior and learning deficits. The mode of action underlying these effects is unclear. The zebrafish model was employed to investigate the neurobehavioral effects of developmental bisphenol A (BPA) exposure. The objectives of this study were to identify whether low-dose, developmental BPA exposure affects larval zebrafish locomotor behavior and whether learning deficits occur in adults exposed during development. Two control compounds, 17β-estradiol (an estrogen receptor ligand) and GSK4716 (a synthetic estrogen related receptor gamma ligand), were included. Larval toxicity assays were used to determine appropriate BPA, 17β-estradiol, and GSK4716 concentrations for behavior testing. BPA tissue uptake was analyzed using HPLC and lower doses were extrapolated using a linear regression analysis. Larval behavior tests were conducted using a ViewPoint Zebrabox. Adult learning tests were conducted using a custom-built T-maze. BPA exposure to ≤30 μM was nonteratogenic in zebrafish. Neurodevelopmental BPA exposure to 0.01, 0.1, or 1 μM led to larval hyperactivity or learning deficits in adult zebrafish. Exposure to 0.1 μM 17β-estradiol or GSK4716 also led to larval hyperactivity. This study demonstrates the efficacy of using the larval zebrafish model for studying the neurobehavioral effects of low-dose developmental BPA exposure. PMID:22108044

Behavioral Approaches to the Treatment of Sleep Problems in Children with Developmental Disorders: What Is the State of the Art?

ERIC Educational Resources Information Center

Richdale, Amanda; Wiggs, Luci

2005-01-01

This paper reviews behavioral treatments for sleep problems in children with a developmental disorder (DD). Sleep problems are common in children with a DD and children's sleep problems may be associated with adverse consequences including behaviour problems, compromised daytime functioning and family stress. However, the sleep intervention…

Adolescents' Precocious and Developmentally Appropriate Contributions to Their Families' Well-Being and Resilience in Five Countries

ERIC Educational Resources Information Center

Ungar, Michael; Theron, Linda; Didkowsky, Nora

2011-01-01

An exploratory qualitative study of 16 disadvantaged youth in 5 countries suggests that making both precocious and developmentally appropriate contributions to their families' well-being is advantageous to adolescents coping with chronic adversity. All youth were known to be doing well (as identified by community advisors) and showed patterns of…

Rejected by Peers--Attracted to Antisocial Media Content: Rejection-Based Anger Impairs Moral Judgment among Adolescents

ERIC Educational Resources Information Center

Plaisier, Xanthe S.; Konijn, Elly A.

2013-01-01

Adolescence is an important developmental stage during which both peers and the media have a strong influence. Both peer rejection and the use of morally adverse media are associated with negative developmental outcomes. This study examines processes by which peer rejection might drive adolescents to select antisocial media content by tying…

Present and future of developmental neuropsychopharmacology.

PubMed

Arango, Celso

2015-05-01

The field of child and adolescent psychiatry has always lagged behind adult psychiatry. With recent evidence that the vast majority of mental disorders, even when they emerge in adulthood, cause abnormal neurodevelopment and resultant emphasis on prevention and early intervention, there is a need to put child psychiatry at the top of the agenda in mental health research. This should also be the case for developmental neuropsychopharmacology. The target of drug discovery should shift toward a population younger than the one that is typically included in clinical trials. This is not only a matter of trying to replicate what has been found in individuals with mature brains; it is about searching for new strategies that address developing brains while the therapeutic window for their effect is still open. At present, major concerns in developmental psychopharmacology are over-prescription rates and use of psychotropic medications for conditions with a particularly underdeveloped evidence base, as well as adverse effects, especially potentially life-shortening cardiometabolic effects and suicidal ideation. The future of research in this area should focus on the use of drugs for primary and secondary prevention that would modify abnormal brain development. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

Understanding the Interplay of Individual and Social-Developmental Factors in the Progression of Substance Use and Mental Health from Childhood to Adulthood

PubMed Central

Jones, Tiffany M.; Hill, Karl G.; Epstein, Marina; Lee, Jungeun Olivia; Hawkins, J. David; Catalano, Richard F.

2016-01-01

This study examines the interplay between individual and social-developmental factors in the development of positive functioning, substance use problems, and mental health problems. This interplay is nested within positive and negative developmental cascades that span childhood, adolescence, the transition to adulthood, and adulthood. Data are drawn from the Seattle Social Development Project, a gender-balanced, ethnically diverse community sample of 808 participants interviewed 12 times from ages 10 to 33. Path modeling showed short- and long-term cascading effects of positive social environments, family history of depression, and substance using social environments throughout development. Positive family social environments set a template for future partner social environment interaction and had positive influences on proximal individual functioning, both in the next developmental period and long term. Family history of depression adversely affected mental health functioning throughout adulthood. Family substance use began a cascade of substance-specific social environments across development, which was the pathway through which increasing severity of substance use problems flowed. The model also indicated that adolescent, but not adult, individual functioning influenced selection into positive social environments, and significant cross-domain effects were found in which substance using social environments affected subsequent mental health. PMID:27427802

Zebrafish model systems for developmental neurobehavioral toxicology.

PubMed

Bailey, Jordan; Oliveri, Anthony; Levin, Edward D

2013-03-01

Zebrafish offer many advantages that complement classic mammalian models for the study of normal development as well as for the teratogenic effects of exposure to hazardous compounds. The clear chorion and embryo of the zebrafish allow for continuous visualization of the anatomical changes associated with development, which, along with short maturation times and the capability of complex behavior, makes this model particularly useful for measuring changes to the developing nervous system. Moreover, the rich array of developmental, behavioral, and molecular benefits offered by the zebrafish have contributed to an increasing demand for the use of zebrafish in behavioral teratology. Essential for this endeavor has been the development of a battery of tests to evaluate a spectrum of behavior in zebrafish. Measures of sensorimotor plasticity, emotional function, cognition and social interaction have been used to characterize the persisting adverse effects of developmental exposure to a variety of chemicals including therapeutic drugs, drugs of abuse and environmental toxicants. In this review, we present and discuss such tests and data from a range of developmental neurobehavioral toxicology studies using zebrafish as a model. Zebrafish provide a key intermediate model between high throughput in vitro screens and the classic mammalian models as they have the accessibility of in vitro models and the complex functional capabilities of mammalian models. Copyright © 2013 Wiley Periodicals, Inc.

Zebrafish Model Systems for Developmental Neurobehavioral Toxicology

PubMed Central

Bailey, Jordan; Oliveri, Anthony; Levin, Edward D.

2014-01-01

Zebrafish offer many advantages that complement classic mammalian models for the study of normal development as well as for the teratogenic effects of exposure to hazardous compounds. The clear chorion and embryo of the zebrafish allow for continuous visualization of the anatomical changes associated with development, which, along with short maturation times and the capability of complex behavior, makes this model particularly useful for measuring changes to the developing nervous system. Moreover, the rich array of developmental, behavioral, and molecular benefits offered by the zebrafish have contributed to an increasing demand for the use of zebrafish in behavioral teratology. Essential for this endeavor has been the development of a battery of tests to evaluate a spectrum of behavior in zebrafish. Measures of sensorimotor plasticity, emotional function, cognition and social interaction have been used to characterize the persisting adverse effects of developmental exposure to a variety of chemicals including therapeutic drugs, drugs of abuse and environmental toxicants. In this review, we present and discuss such tests and data from a range of developmental neurobehavioral toxicology studies using zebrafish as a model. Zebrafish provide a key intermediate model between high throughput in vitro screens and the classic mammalian models as they have the accessibility of in vitro models and the complex functional capabilities of mammalian models. PMID:23723169

Understanding the interplay of individual and social-developmental factors in the progression of substance use and mental health from childhood to adulthood.

PubMed

Jones, Tiffany M; Hill, Karl G; Epstein, Marina; Lee, Jungeun Olivia; Hawkins, J David; Catalano, Richard F

2016-08-01

This study examines the interplay between individual and social-developmental factors in the development of positive functioning, substance use problems, and mental health problems. This interplay is nested within positive and negative developmental cascades that span childhood, adolescence, the transition to adulthood, and adulthood. Data are drawn from the Seattle Social Development Project, a gender-balanced, ethnically diverse community sample of 808 participants interviewed 12 times from ages 10 to 33. Path modeling showed short- and long-term cascading effects of positive social environments, family history of depression, and substance-using social environments throughout development. Positive family social environments set a template for future partner social environment interaction and had positive influences on proximal individual functioning, both in the next developmental period and long term. Family history of depression adversely affected mental health functioning throughout adulthood. Family substance use began a cascade of substance-specific social environments across development, which was the pathway through which increasing severity of substance use problems flowed. The model also indicated that adolescent, but not adult, individual functioning influenced selection into positive social environments, and significant cross-domain effects were found in which substance-using social environments affected subsequent mental health.

Gene expression profiles in the cerebellum and hippocampus following exposure to a neurotoxicant, Aroclor 1254: Developmental effects

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

Royland, Joyce E.; Wu, Jinfang; Zawia, Nasser H.

2008-09-01

The developmental consequences of exposure to the polychlorinated biphenyls (PCBs) have been widely studied, making PCBs a unique model to understand issues related to environmental mixture of persistent chemicals. PCB exposure in humans adversely affects neurocognitive development, causes psychomotor difficulties, and contributes to attention deficits in children, all of which seem to be associated with altered patterns of neuronal connectivity. In the present study, we examined gene expression profiles in the rat nervous system following PCB developmental exposure. Pregnant rats (Long-Evans) were dosed perinatally with 0 or 6 mg/kg/day of Aroclor 1254 from gestation day 6 through postnatal day (PND)more » 21. Gene expression in cerebellum and hippocampus from PND7 and PND14 animals was analyzed with an emphasis on developmental aspects. Changes in gene expression ({>=} 1.5 fold) in control animals identified normal developmental changes. These basal levels of expression were compared to data from Aroclor 1254-treated animals to determine the impact of gestational PCB exposure on developmental parameters. The results indicate that the expression of a number of developmental genes related to cell cycle, synaptic function, cell maintenance, and neurogenesis is significantly altered from PND7 to PND14. Aroclor 1254 treatment appears to dampen the overall growth-related gene expression levels in both regions with the effect being more pronounced in the cerebellum. Functional analysis suggests that Aroclor 1254 delays maturation of the developing nervous system, with the consequences dependent on the ontological state of the brain area and the functional role of the individual gene. Such changes may underlie learning and memory deficits observed in PCB exposed animals and humans.« less

USE OF CASE REPORTS IN ASSESSING ADVERSE OUTCOMES OF HUMAN PRENATAL DRUG EXPOSURES: AN APPROACH

EPA Science Inventory

The use of case reports for assessing the developmental consequences of prenatal drug exposure is limited by the inability to determine the incidence of adverse outcomes and by the high likelihood for bias. Yet, because it is impossible to conduct clinical trials for the assessme...

The joint contribution of maternal history of early adversity and adulthood depression to socioeconomic status and potential relevance for offspring development.

PubMed

Bouvette-Turcot, Andrée-Anne; Unternaehrer, Eva; Gaudreau, Hélène; Lydon, John E; Steiner, Meir; Meaney, Michael J

2017-01-01

We examined the interactive effects of maternal childhood adversity and later adulthood depression on subsequent socioeconomic status (SES). Our community sample ranged from 230 to 243 mothers (across measures) drawn from a prospective, longitudinal cohort study. Maternal childhood adversity scores were derived using an integrated measure derived from the Childhood Trauma Questionnaire (CTQ) and the Parental Bonding Index (PBI). Maternal depression was measured in the prenatal period with the Center for Epidemiologic Studies Depression Scale (CES-D). SES measures included maternal highest level of education and family income as obtained prenatally. The analyses yielded significant interaction effects between maternal childhood adversity and prenatal depression that predicted income, prenatally. Women who reported higher levels of childhood adversity combined with higher levels of self-reported depressive symptoms were significantly more likely to live in low SES environments. Results also showed that level of education was predicted by childhood adversity independent of maternal symptoms of depression. The results suggest that SES is influenced by a life course pathway that begins in childhood and includes adversity-related mental health outcomes. Since child health and development is influenced by both maternal mental health and SES, this pathway may also contribute to the intergenerational transmission of the risk for psychopathology in the offspring. The results also emphasize the importance of studying potential precursors of low SES, a well-documented environmental risk factor for poor developmental outcomes in the offspring. Copyright © 2016. Published by Elsevier B.V.

Developmental influences on fertility decisions by women: an evolutionary perspective.

PubMed

Coall, D A; Tickner, M; McAllister, L S; Sheppard, P

2016-04-19

Developmental environments are crucial for shaping our life course. Elements of the early social and biological environments have been consistently associated with reproduction in humans. To date, a strong focus has been on the relationship between early stress, earlier menarche and first child birth in women. These associations, found predominately in high-income countries, have been usefully interpreted within life-history theory frameworks. Fertility, on the other hand--a missing link between an individual's early environment, reproductive strategy and fitness--has received little attention. Here, we synthesize this literature by examining the associations between early adversity, age at menarche and fertility and fecundity in women. We examine the evidence that potential mechanisms such as birth weight, childhood body composition, risky health behaviours and developmental influences on attractiveness link the early environment and fecundity and fertility. The evidence that menarche is associated with fertility and fecundity is good. Currently, owing to the small number of correlational studies and mixed methodologies, the evidence that early adversity predicts fecundity and fertility is not conclusive. This area of research is in its infancy; studies examining early adversity and adult fertility decisions that can also examine likely biological, social and psychological pathways present opportunities for future fertility research. © 2016 The Author(s).

Disparities in Adverse Childhood Experiences among Sexual Minority and Heterosexual Adults: Results from a Multi-State Probability-Based Sample

PubMed Central

Andersen, Judith P; Blosnich, John

2013-01-01

Background Adverse childhood experiences (e.g., physical, sexual and emotional abuse, neglect, exposure to domestic violence, parental discord, familial mental illness, incarceration and substance abuse) constitute a major public health problem in the United States. The Adverse Childhood Experiences (ACE) scale is a standardized measure that captures multiple developmental risk factors beyond sexual, physical and emotional abuse. Lesbian, gay, and bisexual (i.e., sexual minority) individuals may experience disproportionately higher prevalence of adverse childhood experiences. Purpose To examine, using the ACE scale, prevalence of childhood physical, emotional, and sexual abuse and childhood household dysfunction among sexual minority and heterosexual adults. Methods Analyses were conducted using a probability-based sample of data pooled from three U.S. states’ Behavioral Risk Factor Surveillance System (BRFSS) surveys (Maine, Washington, Wisconsin) that administered the ACE scale and collected information on sexual identity (n = 22,071). Results Compared with heterosexual respondents, gay/lesbian and bisexual individuals experienced increased odds of six of eight and seven of eight adverse childhood experiences, respectively. Sexual minority persons had higher rates of adverse childhood experiences (IRR = 1.66 gay/lesbian; 1.58 bisexual) compared to their heterosexual peers. Conclusions Sexual minority individuals have increased exposure to multiple developmental risk factors beyond physical, sexual and emotional abuse. We recommend the use of the Adverse Childhood Experiences scale in future research examining health disparities among this minority population. PMID:23372755

Programmed Effects in Neurobehavior and Antioxidative Physiology in Zebrafish Embryonically Exposed to Cadmium: Observations and Hypothesized Adverse Outcome Pathway Framework

PubMed Central

Ruiter, Sander; Sippel, Josefine; Bouwmeester, Manon C.; Lommelaars, Tobias; Beekhof, Piet; Hodemaekers, Hennie M.; Bakker, Frank; van den Brandhof, Evert-Jan; Pennings, Jeroen L. A.; van der Ven, Leo T. M.

2016-01-01

Non-communicable diseases (NCDs) are a major cause of premature mortality. Recent studies show that predispositions for NCDs may arise from early-life exposure to low concentrations of environmental contaminants. This developmental origins of health and disease (DOHaD) paradigm suggests that programming of an embryo can be disrupted, changing the homeostatic set point of biological functions. Epigenetic alterations are a possible underlying mechanism. Here, we investigated the DOHaD paradigm by exposing zebrafish to subtoxic concentrations of the ubiquitous contaminant cadmium during embryogenesis, followed by growth under normal conditions. Prolonged behavioral responses to physical stress and altered antioxidative physiology were observed approximately ten weeks after termination of embryonal exposure, at concentrations that were 50–3200-fold below the direct embryotoxic concentration, and interpreted as altered developmental programming. Literature was explored for possible mechanistic pathways that link embryonic subtoxic cadmium to the observed apical phenotypes, more specifically, the probability of molecular mechanisms induced by cadmium exposure leading to altered DNA methylation and subsequently to the observed apical phenotypes. This was done using the adverse outcome pathway model framework, and assessing key event relationship plausibility by tailored Bradford-Hill analysis. Thus, cadmium interaction with thiols appeared to be the major contributor to late-life effects. Cadmium-thiol interactions may lead to depletion of the methyl donor S-adenosyl-methionine, resulting in methylome alterations, and may, additionally, result in oxidative stress, which may lead to DNA oxidation, and subsequently altered DNA methyltransferase activity. In this way, DNA methylation may be affected at a critical developmental stage, causing the observed apical phenotypes. PMID:27827847

Developmental milestones at one year for the offspring of mothers with congenital hypothyroidism: a population-based study

PubMed

Léger, Juliane; Forhan, Anne; Dos Santos, Sophie; Larroque, Béatrice; Ecosse, Emmanuel; Charles, Marie-Aline; Heude, Barbara

2018-05-01

Maternal thyroid dysfunction during pregnancy is associated with neurodevelopmental impairment in the offspring. No data are currently available for the offspring of patients treated early for congenital hypothyroidism (CH). The aim of this study was to investigate motor and language milestones at one year of age in a population-based registry of children born to young women with CH. We assessed 110 children born to mothers with CH, and 1367 children from the EDEN French population-based birth cohort study prospectively, at the age of one year, with identical questionnaires. Outcomes were assessed in terms of scores for childhood developmental milestones relating to mobility, motor coordination, communication, motricity and language skills. After adjustment for confounding factors, children born to mothers with CH were found to have a higher risk of poor motor coordination than those of the EDEN cohort (OR: 4.18, 95% CI: 2.52-6.93). No differences were identified for the other four domains investigated. Children born to mothers with gestational diabetes have a higher risk of low motor coordination score than their peers (OR: 2.10, 95% CI: 1.21-3.66). Children born to mothers with TSH ≥ 10 IU/L during the first six months of pregnancy were more likely to have low motricity or communication skills scores than those born to mothers with lower TSH concentrations (56% vs 21% for each score, P  < 0.04). Maternal CH may have slight adverse effects on some developmental milestones in the child at one year of age, particularly for children born to mothers with uncontrolled hypothyroidism. However, it remains unclear whether these adverse effects modify subsequent neurodevelopment. © 2018 European Society of Endocrinology.

Developmental immunotoxicity of chemicals in rodents and its possible regulatory impact.

PubMed

Hessel, Ellen V S; Tonk, Elisa C M; Bos, Peter M J; van Loveren, Henk; Piersma, Aldert H

2015-01-01

Around 25% of the children in developed countries are affected with immune-based diseases. Juvenile onset diseases such as allergic, inflammatory and autoimmune diseases have shown increasing prevalences in the last decades. The role of chemical exposures in these phenomena is unclear. It is thought that the developmental immune system is more susceptible to toxicants than the mature situation. Developmental immunotoxicity (DIT) testing is nowadays not or minimally included in regulatory toxicology requirements. We reviewed whether developmental immune parameters in rodents would provide relatively sensitive endpoints of toxicity, whose inclusion in regulatory toxicity testing might improve hazard identification and risk assessment of chemicals. For each of the nine reviewed toxicants, the developing immune system was found to be at least as sensitive or more sensitive than the general (developmental) toxicity parameters. Functional immune (antigen-challenged) parameters appear more affected than structural (non-challenged) immune parameters. Especially, antibody responses to immune challenges with keyhole limpet hemocyanine or sheep red blood cells and delayed-type hypersensitivity responses appear to provide sensitive parameters of developmental immune toxicity. Comparison with current tolerable daily intakes (TDI) and their underlying overall no observed adverse effect levels showed that for some of the compounds reviewed, the TDI may need reconsideration based on developmental immune parameters. From these data, it can be concluded that the developing immune system is very sensitive to the disruption of toxicants independent of study design. Consideration of including functional DIT parameters in current hazard identification guidelines and wider application of relevant study protocols is warranted.

Developmental Neurotoxicants in E-Waste: An Emerging Health Concern

PubMed Central

Chen, Aimin; Dietrich, Kim N.; Huo, Xia; Ho, Shuk-mei

2011-01-01

Objective Electronic waste (e-waste) has been an emerging environmental health issue in both developed and developing countries, but its current management practice may result in unintended developmental neurotoxicity in vulnerable populations. To provide updated information about the scope of the issue, presence of known and suspected neurotoxicants, toxicologic mechanisms, and current data gaps, we conducted this literature review. Data sources We reviewed original articles and review papers in PubMed and Web of Science regarding e-waste toxicants and their potential developmental neurotoxicity. We also searched published reports of intergovernmental and governmental agencies and nongovernmental organizations on e-waste production and management practice. Data extraction We focused on the potential exposure to e-waste toxicants in vulnerable populations—that is, pregnant women and developing children—and neurodevelopmental outcomes. In addition, we summarize experimental evidence of developmental neurotoxicity and mechanisms. Data synthesis In developing countries where most informal and primitive e-waste recycling occurs, environmental exposure to lead, cadmium, chromium, polybrominated diphenyl ethers, polychlorinated biphenyls, and polycyclic aromatic hydrocarbons is prevalent at high concentrations in pregnant women and young children. Developmental neurotoxicity is a serious concern in these regions, but human studies of adverse effects and potential mechanisms are scarce. The unprecedented mixture of exposure to heavy metals and persistent organic pollutants warrants further studies and necessitates effective pollution control measures. Conclusions Pregnant women and young children living close to informal e-waste recycling sites are at risk of possible perturbations of fetus and child neurodevelopment. PMID:21081302

Early Developmental Conditioning of Later Health and Disease: Physiology or Pathophysiology?

PubMed Central

Hanson, M. A.; Gluckman, P. D.

2014-01-01

Extensive experimental animal studies and epidemiological observations have shown that environmental influences during early development affect the risk of later pathophysiological processes associated with chronic, especially noncommunicable, disease (NCD). This field is recognized as the developmental origins of health and disease (DOHaD). We discuss the extent to which DOHaD represents the result of the physiological processes of developmental plasticity, which may have potential adverse consequences in terms of NCD risk later, or whether it is the manifestation of pathophysiological processes acting in early life but only becoming apparent as disease later. We argue that the evidence suggests the former, through the operation of conditioning processes induced across the normal range of developmental environments, and we summarize current knowledge of the physiological processes involved. The adaptive pathway to later risk accords with current concepts in evolutionary developmental biology, especially those concerning parental effects. Outside the normal range, effects on development can result in nonadaptive processes, and we review their underlying mechanisms and consequences. New concepts concerning the underlying epigenetic and other mechanisms involved in both disruptive and nondisruptive pathways to disease are reviewed, including the evidence for transgenerational passage of risk from both maternal and paternal lines. These concepts have wider implications for understanding the causes and possible prevention of NCDs such as type 2 diabetes and cardiovascular disease, for broader social policy and for the increasing attention paid in public health to the lifecourse approach to NCD prevention. PMID:25287859

Bio-potency of a 21 kDa Kunitz-type trypsin inhibitor from Tamarindus indica seeds on the developmental physiology of H. armigera.

PubMed

Pandey, Prabhash K; Jamal, Farrukh

2014-11-01

A trypsin inhibitor purified from the seeds of Tamarindus indica by Sephadex G-75, DEAE-Sepharose and Trypsin-Sepharose CL-4B columns was studied for its antifeedant, larvicidal, pupicidal and growth inhibitory activities against Helicoverpa armigera larvae. Tamarindus trypsin inhibitor (TTI) exhibited inhibitory activity towards total gut proteolytic enzymes of H. armigera (~87%) and bovine trypsin (~84%). Lethal doses which caused mortality and weight reduction by 50% were 1% w/w and 0.50% w/w, respectively. IC50 of TTI against Helicoverpa midgut proteases and bovine trypsin were ~2.10 µg/ml and 1.68 µg/ml respectively. In larval feeding studies the 21 kDa Kunitz-type protein was found to retard growth and development, prolonged the larval-pupal development durations along with adversely affecting the fertility and fecundity of H. armigera. In artificial diet at 0.5% w/w TTI, the efficiency of conversion of ingested food as well as of digested food, relative growth rate, growth index declined whereas approximate digestibility, metabolic cost, relative consumption rate, consumption index and total developmental period enhanced for H. armigera larvae. These results suggest that TTI has toxic and adverse effect on the developmental physiology of H. armigera and could be useful in controlling the pest H. armigera. Copyright © 2014 Elsevier Inc. All rights reserved.

Promoting healthy transition to college through mindfulness training with first-year college students: Pilot randomized controlled trial.

PubMed

Dvořáková, Kamila; Kishida, Moé; Li, Jacinda; Elavsky, Steriani; Broderick, Patricia C; Agrusti, Mark R; Greenberg, Mark T

2017-01-01

Given the importance of developmental transitions on young adults' lives and the high rates of mental health issues among U.S. college students, first-year college students can be particularly vulnerable to stress and adversity. This pilot study evaluated the effectiveness and feasibility of mindfulness training aiming to promote first-year college students' health and wellbeing. 109 freshmen were recruited from residential halls (50% Caucasian, 66% female). Data collection was completed in November 2014. A randomized control trial was conducted utilizing the Learning to BREATHE (L2B) program, a universal mindfulness program adapted to match the developmental tasks of college transition. Participation in the pilot intervention was associated with significant increase in students' life satisfaction, and significant decrease in depression and anxiety. Marginally significant decrease was found for sleep issues and alcohol consequences. Mindfulness-based programs may be an effective strategy to enhance a healthy transition into college.

Epigenetic Vestiges of Early Developmental Adversity: Childhood Stress Exposure and DNA Methylation in Adolescence

ERIC Educational Resources Information Center

Essex, Marilyn J.; Boyce, W. Thomas; Hertzman, Clyde; Lam, Lucia L.; Armstrong, Jeffrey M.; Neumann, Sarah M. A.; Kobor, Michael S.

2013-01-01

Fifteen-year-old adolescents (N = 109) in a longitudinal study of child development were recruited to examine differences in DNA methylation in relation to parent reports of adversity during the adolescents' infancy and preschool periods. Microarray technology applied to 28,000 cytosine-guanine dinucleotide sites within DNA derived from buccal…

Pre-Adoption Adversity and Self-Reported Behavior Problems in 7 Year-Old International Adoptees

ERIC Educational Resources Information Center

Gagnon-Oosterwaal, Noemi; Cossette, Louise; Smolla, Nicole; Pomerleau, Andree; Malcuit, Gerard; Chicoine, Jean-Francois; Jeliu, Gloria; Belhumeur, Celine; Berthiaume, Claude

2012-01-01

To further investigate the long-term impact of pre-adoption adversity on international adoptees, externalizing and internalizing symptoms were assessed using a self-report measure at school-age in addition to mothers' reports. The sample consisted of 95 adopted children and their mothers. Children's health and developmental status were assessed…

2,2′,3,5′,6-PENTACHLOROBIPHENYL (PCB 95) AND ITS HYDROXYLATED METABOLITES ARE ENANTIOMERICALLY ENRICHED IN FEMALE MICE

PubMed Central

Kania-Korwel, Izabela; Barnhart, Christopher D.; Stamou, Marianna; Truong, Kim M.; El-Komy, Mohammed H.M.E.; Lein, Pamela J.; Veng-Pedersen, Peter; Lehmler, Hans-Joachim

2012-01-01

Epidemiological and laboratory studies link polychlorinated biphenyls and their metabolites to adverse neurodevelopmental outcomes. Several neurotoxic PCB congeners are chiral and undergo enantiomeric enrichment in mammalian species, which may modulate PCB developmental neurotoxicity. This study measures levels and enantiomeric enrichment of PCB 95 and its hydroxylated metabolites (OH-PCBs) in adult female C57Bl/6 mice following subchronic exposure to racemic PCB 95. Tissue levels of PCB 95 and OH-PCBs increased with increasing dose. Dose-dependent enantiomeric enrichment of PCB 95 was observed in brain and other tissues. OH-PCBs also displayed enantiomeric enrichment in blood and liver, but were not detected in adipose and brain. In light of data suggesting enantioselective effects of chiral PCBs on molecular targets linked to PCB developmental neurotoxicity, our observations highlight the importance of accounting for PCB and OH-PCB enantiomeric enrichment in the assessment of PCB developmental neurotoxicity. PMID:22974126

Endocrine active agents: implications of adverse and non-adverse changes.

PubMed

Foster, Paul M D; McIntyre, Barry S

2002-01-01

The US Environmental Protection Agency (EPA) is currently in the process of developing screening and testing methodologies for the assessment of agents that may possess endocrine-like activity--the so-called endocrine disruptors. Moreover, the EPA has signaled its intention of placing information arising from such studies on the worldwide web. This has created significant interest in how such information may be used in risk assessment and by policymakers and the public in the potential regulation or deselection of specific chemical agents. The construction of lists of endocrine disruptors, although fulfilling the requirements of some parties, is really of little use when the nature of the response, the dose level employed, and the lifestage of the test species used are not given. Thus, we have already seen positive in vitro information available on the interaction with a receptor being used as a key indicator when the results of large, high quality in vivo studies showing no adverse changes have been ignored. Clearly a number of in vitro systems are available to ascertain chemical interaction with specific (mainly steroid) hormone receptors including a number of reporter gene assays. These assays only provide indicators of potential problems and should not be, in isolation, indicators of toxicity. Likewise, short-term in vivo screens such as the uterotrophic and Hershberger studies are frequently conducted in castrated animals and thus indicate the potential for a pharmacological response in vivo rather than an adverse effect. A number of new end points have been added to standard rodent testing protocols in the belief of providing more sensitivity to detect endocrine related changes. These include the measurement of anogenital distance (AGD), developmental landmarks [vaginal opening (VO), preputial separation (PPS)], and in some studies the counting of nipples and areolae on males. AGD, VO, and PPS are all affected by the size of the pup in which they are measured and should always be compared using bodyweight as a covariate. The historical control database for such changes is gradually growing, albeit that if pups are not individually identified it becomes problematic to associate any change with a specific malformation or to assess whether a delay or advance in, for example, developmental landmarks is biologically significant. Agents that significantly reduce AGD in males (it is an androgen-dependent variable) frequently have other more adverse changes associated with this end point (eg, reproductive tract malformations), but a 2 to 3% change in AGD although measurable is unlikely to be biologically of importance and in isolation would not necessarily be considered adverse. Retention of thoracic nipples in male rat pups is also an indicator of impaired androgen status. Recent studies have also shown that this retention for some endocrine active chemicals is permanent. Thus, the presence of a permanent structural change that is rarely found in adult control animals could be considered a malformation and therefore a developmental adverse effect on which risk assessment decisions could be made. The advent of multigeneration reproduction studies as the definitive studies for the assessment of the dose-response relationships and risk assessment for endocrine disruptors has shown that current testing protocols may be inadequate to reliably detect the adverse effects of concern as only 1 adult/sex/litter is examined. A number of the effects on reproductive development although, due to an in utero exposure, will not be manifest until after puberty or at adulthood. The use of only a limited number of animals to examine such changes, particularly for weaker acting materials indicates that some agents may have been examined in well-conducted, modern protocols but have insufficient power to detect low incidence phenomena (eg, a 5% incidence of malformations).

First preliminary results of an observation of Panax ginseng treatment in patients with autistic disorder.

PubMed

Niederhofer, Helmut

2009-01-01

Autism is a pervasive developmental disorder, with impairments in reciprocal social interaction and verbal and nonverbal communication. There is often the need of psychopharmacological intervention in addition to psychobehavioral therapies, but benefits are limited by adverse side effects. For that reason, Panax ginseng, which is comparable with Piracetam, a substance effective in the treatment of autism, was investigated for possible improvement of autistic symptoms. There was some improvement, which suggests some benefits of Panax ginseng, at least as an add-on therapy.

Adverse and adaptive childhood experiences are associated with parental reflective functioning in mothers with substance use disorder.

PubMed

Håkansson, Ulrika; Watten, Reidulf; Söderström, Kerstin; Skårderud, Finn; Øie, Merete Glenne

2018-07-01

Mothers with a substance use disorder (SUD) are at risk for maladaptive parenting practices, and have heightened likelihood of having experienced childhood adversity themselves. In addition, parental reflective functioning (PRF), a capacity underlying sensitive caregiving, is often low in mothers with SUD. This study examines the relationship between PRF and aversive (emotional, physical, sexual abuse and neglect) and adaptive (safety and competence) experiences, in different developmental phases (early childhood, latency, and adolescence) in mothers with a SUD. A sample of 43 mothers with small children were interviewed with the Parental Developmental Interview to assess PRF, and they completed the Traumatic Antecedents Questionnaire regarding aversive and adaptive experiences. In addition, we used the Hopkins Symptoms Checklist-10 to control for mental health status and a battery of neuropsychological tests to control for executive functions. Results indicated that adaptive experiences in early childhood were positively related to PRF, and that experience of emotional abuse was negatively related to PRF. When separating the group of mothers in two sub-groups based on PRF level, results showed that mothers with negative to low PRF had significantly more experiences of adversities in early childhood and latency, and significantly less adaptive experiences in early childhood, latency and adolescence, compared to mothers with moderate to high PRF. In addition, mothers with adequate to high PRF reported experiencing significantly more types of adaptive experiences, and significantly less adversities compared to mothers with negative to low PRF. Results are discussed in relation to developmental trauma, resilience, epistemic trust and mistrust. Copyright © 2018 Elsevier Ltd. All rights reserved.

Improvement in metabolic effects by dietary intervention is dependent on the precise nature of the developmental programming challenge.

PubMed

Bautista, C J; Guzmán, C; Rodríguez-González, G L; Zambrano, E

2015-08-01

Predisposition to offspring metabolic dysfunction due to poor maternal nutrition differs with the developmental stage at exposure. Post-weaning nutrition also influences offspring phenotype in either adverse or beneficial ways. We studied a well-established rat maternal protein-restriction model to determine whether post-weaning dietary intervention improves adverse outcomes produced by a deficient maternal nutritional environment in pregnancy. Pregnant rats were fed a controlled diet (C, 20% casein) during pregnancy and lactation (CC) or were fed a restricted diet (R, 10% casein isocaloric diet) during pregnancy and C diet during lactation (RC). After weaning, the offspring were fed the C diet. At postnatal day (PND) 70 (young adulthood), female offspring either continued with the C diet (CCC and RCC) or were fed commercial Chow Purina 5001 (I) to further divide the animals into dietary intervention groups CCI and RCI. Another group of mothers and offspring were fed I throughout (III). Offspring food intake was averaged between PND 95-110 and 235-250 and carcass and liver compositions were measured at PND 25 and 250. Leptin (PND 110 and 250) and serum glucose, triglycerides and cholesterol (PND 250) levels were measured. Statistical analysis was carried out using ANOVA. At PND 25, body and liver weights were similar between groups; however, CCC and RCC carcass protein:fat ratios were lower compared with III diet. At PND 110 and 250, offspring CCC and RCC had higher body weight, food intake and serum leptin compared with CCI and RCI. CCI had lower carcass fat and increased protein compared with CCC and improved fasting glucose and triglycerides. Adult dietary intervention partially overcomes adverse effects of programming. Further studies are needed to determine the mechanisms involved.

Leveraging the biology of adversity to address the roots of disparities in health and development

PubMed Central

Shonkoff, Jack P.

2012-01-01

Extensive evidence that personal experiences and environmental exposures are embedded biologically (for better or for worse) and the cumulative knowledge of more than four decades of intervention research provide a promising opportunity to mobilize evolving scientific insights to catalyze a new era of more effective early childhood policy and practice. Drawing on emerging hypotheses about causal mechanisms that link early adversity with lifelong impairments in learning, behavior, and health, this paper proposes an enhanced theory of change to promote better outcomes for vulnerable, young children by strengthening caregiver and community capacities to reduce or mitigate the impacts of toxic stress, rather than simply providing developmental enrichment for the children and parenting education for their mothers. PMID:23045654

When Satisfaction Is Not Directly Related to the Support Services Received: Understanding Parents' Varied Experiences with Specialised Services for Children with Developmental Disabilities

ERIC Educational Resources Information Center

Robert, Marie; Leblanc, Line; Boyer, Thierry

2015-01-01

Parents of children with developmental disabilities (autism or intellectual disabilities) are more susceptible to stress and have a greater burden of adversity than other parents. Their well-being and satisfaction greatly depend on the system's response of finding them formal support and the help they need. This study proposes an interpretive…

The Stress Acceleration Hypothesis of Nightmares

PubMed Central

Nielsen, Tore

2017-01-01

Adverse childhood experiences can deleteriously affect future physical and mental health, increasing risk for many illnesses, including psychiatric problems, sleep disorders, and, according to the present hypothesis, idiopathic nightmares. Much like post-traumatic nightmares, which are triggered by trauma and lead to recurrent emotional dreaming about the trauma, idiopathic nightmares are hypothesized to originate in early adverse experiences that lead in later life to the expression of early memories and emotions in dream content. Accordingly, the objectives of this paper are to (1) review existing literature on sleep, dreaming and nightmares in relation to early adverse experiences, drawing upon both empirical studies of dreaming and nightmares and books and chapters by recognized nightmare experts and (2) propose a new approach to explaining nightmares that is based upon the Stress Acceleration Hypothesis of mental illness. The latter stipulates that susceptibility to mental illness is increased by adversity occurring during a developmentally sensitive window for emotional maturation—the infantile amnesia period—that ends around age 3½. Early adversity accelerates the neural and behavioral maturation of emotional systems governing the expression, learning, and extinction of fear memories and may afford short-term adaptive value. But it also engenders long-term dysfunctional consequences including an increased risk for nightmares. Two mechanisms are proposed: (1) disruption of infantile amnesia allows normally forgotten early childhood memories to influence later emotions, cognitions and behavior, including the common expression of threats in nightmares; (2) alterations of normal emotion regulation processes of both waking and sleep lead to increased fear sensitivity and less effective fear extinction. These changes influence an affect network previously hypothesized to regulate fear extinction during REM sleep, disruption of which leads to nightmares. This network consists of a fear circuit that includes amygdala, hippocampus, and medial prefrontal cortex and whose substantial overlap with the stress acceleration findings allows the latter to be incorporated into a wider, more developmentally coherent framework. PMID:28620339

Tests of the Attachment and Developmental Dynamic Systems Theory of Crime (ADDSTOC): Toward a Differential RDoC Diagnostic and Treatment Approach.

PubMed

Lindberg, Marc A; Zeid, Dana

2018-01-01

The Attachment and Developmental Dynamic Systems Theory of Crime was tested on 206 male inmates. They completed measures tapping attachments, clinical issues, adverse childhood events, peer crime, and crime addictions. A significant path model was found, going from insecure parental attachments to adverse childhood events, and then on to the behavioral crime addiction and criminal peers scales. Peer crime was also predicted by insecure parent attachments and the crime addiction scale. Finally, the crime addiction, peer crime, and insecure parental attachment scales predicted frequencies of criminal behavior. The model also fit a sample of 239 female inmates. The notions of crime addiction, in this context of adverse events and insecure parental attachments, offered newer and more powerful explanations than previously offered by social learning theories on why some individuals are more likely to associate with peers engaging in criminal behavior, and also how these combine to predict degrees of criminal behavior. By moving beyond main effects models, it was found that a focus on systems of interactions was robust in theory and application. However, profile data from the Attachment and Clinical Issues Questionnaire showed that individual differences in Research Domain Criteria diagnoses are fundamental to treatment settings. Such approaches to reducing rates of recidivism and substance abuse should also enhance outcomes in many domains, including HIV prevention, costs to health care, and at the same time increase overall public safety.

Reproductive Toxicity of T Cells in Early Life: Abnormal Immune Development and Postnatal Diseases.

PubMed

Liu, Han-Xiao; Jiang, Aifang; Chen, Ting; Qu, Wen; Yan, Hui-Yi; Ping, Jie

2017-01-01

Immunity is a balanced status with adequate biological defenses to recognize and fight "non-self", as well as adequate tolerance to recognize "self". To maintain this immune homeostasis, a well-organized T cell immune network is required, which in part depends on the well-controlled development of alternative effector T cells, with different cytokine repertoires. Recent researches have pointed that developing fetal T cells network is a remarkably sensitive toxicological target for adverse factors in early life. Epidemiological and experimental studies showed an inseparable relationship between T cell developmental toxicity and immune diseases in adults. Considering that the inflammatory and immune disorders have become a growing health problem worldwide, increasing attention is now being paid to the T cell developmental toxicity. We propose that adverse factors may have programming effects on the crucial functions of immune system during early life which is critical for fetal T cell development and the establishment of the distinct T cell repertoires balance. The permanently disturbed intrathymic or peripheral T cell development may in turn lead to the immune disorders in later life. In this manuscript, we reviewed how adverse factors affected T cell development in early-life with the consequence of the immune dysfunction and immune diseases, and further elucidate the mechanisms. These mechanisms will be helpful in prevention and treatment of the increased prevalence of immune diseases by interfering those pathways. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Developmental plasticity in schistosomes and other helminths

PubMed Central

Davies, Stephen J.; McKerrow, James H.

2010-01-01

Developmental plasticity in helminth life cycles serves, in most cases, to increase the probability of transmission between hosts, suggesting that the necessity to achieve transmission is a prominent selective pressure in the evolution of this phenomenon. Some evidence suggests that digenean trematodes from the genus Schistosoma are also capable of limited developmental responses to host factors. Here we review the currently available data on this phenomenon and attempt to draw comparisons with similar processes in the life cycles of other helminths. At present the biological significance of developmental responses by schistosomes under laboratory conditions remains unclear. Further work is needed to determine whether developmental plasticity plays any role in increasing the probability of schistosome transmission and life cycle propagation under adverse conditions, as it does in other helminth life cycles. PMID:13678642

Comparing rat and rabbit embryo-fetal developmental toxicity ...

EPA Pesticide Factsheets

A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (Cmax) at the developmental adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n=283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and Cmax exposures. For 13.5% of the compounds the rabbit was more sensitive and for 3.5% of compounds the rat was more sensitive when compared based on AUC exposures. For 12% of the compounds the rabbit was more sensitive and for 1.3% of compounds the rat was more sensitive based on Cmax exposures. When evaluated based on human equivalent dose (HED) conversion using standard factors, the rat and rabbit were equally sensitive. The relative extent of embryo-fetal toxicity in the presence of maternal toxicity was not different between species. Overall effect severity incidences were distributed similarly in rat and rabbit studies. Individual rat and rabbit strains did not show a different general distribution of systemic exposure LOAELs as compared to all strains combined for each species. There were no apparent species differences in the occurrence of embryo-fetal variations. Based on power of detection and given differences in the nature of developmental effects betwe

Methyl parathion inhibits the nuclear maturation, decreases the cytoplasmic quality in oocytes and alters the developmental potential of embryos of Swiss albino mice

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

Nair, Ramya; Singh, Vikram Jeet; Salian, Sujith Raj

Methyl parathion (MP) is one of the most commonly used and extremely toxic organophosphorous group of pesticide. A large number of studies in the literature suggest that it has adverse effects on the male reproductive system. However, there is limited information about its toxicity to the female reproductive system. In the present study we report the toxic effects of methyl parathion on the female reproductive system using Swiss albino mice as the experimental model. The female mice were administered orally with 5, 10 and 20 mg/kg of MP. One week later, the mice were superovulated with pregnant mare serum gonadotrophinmore » (PMSG) and human chorionic gonadotrophin (hCG) to study the quality of the oocytes, spindle organization, developmental potential of early embryos and the DNA integrity in blastocysts. MP exposure resulted in a non-significant decrease in the number of primordial follicles and increased DNA damage in granulosa cells. Though MP did not have any effect on the ovulation it had a significant inhibitory effect on the nuclear maturity of oocytes which was associated with spindle deformity. In addition, the oocytes had higher cytoplasmic abnormalities with depleted glutathione level. Even though it did not have any effect on the fertilization and blastocyst rate at lower doses, at 20 mg/kg MP it resulted in a significant decrease in blastocyst hatching, decrease in cell number and high DNA damage. While low body weight gain was observed in F1 generation from 5 mg/kg group, at higher dose, the body weight in F1 generation was marginally higher than control. Post-natal death in F1 generation was observed only in mice treated with 20 mg/kg MP. In conclusion, we report that MP has adverse effects on the oocyte quality, developmental potential of the embryo and reproductive outcome. - Highlights: • Methyl parathion induces severe cytoplasmic abnormalities in oocytes. • Inhibits nuclear maturation and spindle damage • Poor blastocyst quality and high DNA damage.« less

Aneuploidy: a common and early evidence-based biomarker for carcinogens and reproductive toxicants.

PubMed

Mandrioli, Daniele; Belpoggi, Fiorella; Silbergeld, Ellen K; Perry, Melissa J

2016-10-12

Aneuploidy, defined as structural and numerical aberrations of chromosomes, continues to draw attention as an informative effect biomarker for carcinogens and male reproductive toxicants. It has been well documented that aneuploidy is a hallmark of cancer. Aneuploidies in oocytes and spermatozoa contribute to infertility, pregnancy loss and a number of congenital abnormalities, and sperm aneuploidy is associated with testicular cancer. It is striking that several carcinogens induce aneuploidy in somatic cells, and also adversely affect the chromosome compliment of germ cells. In this paper we review 1) the contributions of aneuploidy to cancer, infertility, and developmental abnormalities; 2) techniques for assessing aneuploidy in precancerous and malignant lesions and in sperm; and 3) the utility of aneuploidy as a biomarker for integrated chemical assessments of carcinogenicity, and reproductive and developmental toxicity.

Developmental Deltamethrin Exposure Causes Persistent Changes in Dopaminergic Gene Expression, Neurochemistry, and Locomotor Activity in Zebrafish.

PubMed

Kung, Tiffany S; Richardson, Jason R; Cooper, Keith R; White, Lori A

2015-08-01

Pyrethroids are commonly used insecticides that are considered to pose little risk to human health. However, there is an increasing concern that children are more susceptible to the adverse effects of pesticides. We used the zebrafish model to test the hypothesis that developmental exposure to low doses of the pyrethroid deltamethrin results in persistent alterations in dopaminergic gene expression, neurochemistry, and locomotor activity. Zebrafish embryos were treated with deltamethrin (0.25-0.50 μg/l), at concentrations below the LOAEL, during the embryonic period [3-72 h postfertilization (hpf)], after which transferred to fresh water until the larval stage (2-weeks postfertilization). Deltamethrin exposure resulted in decreased transcript levels of the D1 dopamine (DA) receptor (drd1) and increased levels of tyrosine hydroxylase at 72 hpf. The reduction in drd1 transcripts persisted to the larval stage and was associated with decreased D2 dopamine receptor transcripts. Larval fish, exposed developmentally to deltamethrin, had increased levels of homovanillic acid, a DA metabolite. Since the DA system is involved in locomotor activity, we measured the swim activity of larval fish following a transition to darkness. Developmental exposure to deltamethrin significantly increased larval swim activity which was attenuated by concomitant knockdown of the DA transporter. Acute exposure to methylphenidate, a DA transporter inhibitor, increased swim activity in control larva, while reducing swim activity in larva developmentally exposed to deltamethrin. Developmental exposure to deltamethrin causes locomotor deficits in larval zebrafish, which is likely mediated by dopaminergic dysfunction. This highlights the need to understand the persistent effects of low-dose neurotoxicant exposure during development. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Developmental Deltamethrin Exposure Causes Persistent Changes in Dopaminergic Gene Expression, Neurochemistry, and Locomotor Activity in Zebrafish

PubMed Central

Kung, Tiffany S.; Richardson, Jason R.; Cooper, Keith R.; White, Lori A.

2015-01-01

Pyrethroids are commonly used insecticides that are considered to pose little risk to human health. However, there is an increasing concern that children are more susceptible to the adverse effects of pesticides. We used the zebrafish model to test the hypothesis that developmental exposure to low doses of the pyrethroid deltamethrin results in persistent alterations in dopaminergic gene expression, neurochemistry, and locomotor activity. Zebrafish embryos were treated with deltamethrin (0.25–0.50 μg/l), at concentrations below the LOAEL, during the embryonic period [3–72 h postfertilization (hpf)], after which transferred to fresh water until the larval stage (2-weeks postfertilization). Deltamethrin exposure resulted in decreased transcript levels of the D1 dopamine (DA) receptor (drd1) and increased levels of tyrosine hydroxylase at 72 hpf. The reduction in drd1 transcripts persisted to the larval stage and was associated with decreased D2 dopamine receptor transcripts. Larval fish, exposed developmentally to deltamethrin, had increased levels of homovanillic acid, a DA metabolite. Since the DA system is involved in locomotor activity, we measured the swim activity of larval fish following a transition to darkness. Developmental exposure to deltamethrin significantly increased larval swim activity which was attenuated by concomitant knockdown of the DA transporter. Acute exposure to methylphenidate, a DA transporter inhibitor, increased swim activity in control larva, while reducing swim activity in larva developmentally exposed to deltamethrin. Developmental exposure to deltamethrin causes locomotor deficits in larval zebrafish, which is likely mediated by dopaminergic dysfunction. This highlights the need to understand the persistent effects of low-dose neurotoxicant exposure during development. PMID:25912032

[Effects of postnatal growth retardation on early neurodevelopment in premature infants with intrauterine growth retardation].

PubMed

Cai, Yue-Ju; Song, Yan-Yan; Huang, Zhi-Jian; Li, Jian; Qi, Jun-Ye; Xiao, Xu-Wen; Wang, Lan-Xiu

2015-09-01

To study the effects of postnatal growth retardation on early neurodevelopment in premature infants with intrauterine growth retardation (IUGR). A retrospective analysis was performed on the clinical data of 171 premature infants who were born between May 2008 and May 2012 and were followed up until a corrected gestational age of 6 months. These infants were classified into two groups: IUGR group (n=40) and appropriate for gestational age (AGA) group (n=131). The growth retardation rates at the corrected gestational ages of 40 weeks, 3 months, and 6 months, as well as the neurodevelopmental outcome (evaluated by Gesell Developmental Scale) at corrected gestational ages of 3 and 6 months, were compared between the two groups. The growth retardation rate in the IUGR group was significantly higher than in the AGA group at the corrected gestational ages of 40 weeks, 3 months, and 6 months. All five developmental quotients evaluated by Gesell Developmental Scale (gross motor, fine motor, language, adaptability and individuality) in the IUGR group were significantly lower than in the AGA group at the corrected gestational ages of 3 months. At the corrected gestational age of 6 months, the developmental quotients of fine motor and language in the IUGR group were significantly lower than in the AGA group, however, there were no significant differences in the developmental quotients of gross motor, adaptability and individuality between the two groups. All five developmental quotients in IUGR infants with catch-up lag in weight were significantly lower than in IUGR and AGA infants who had caught up well. Growth retardation at early postnatal stages may adversely affect the early neurodevelopment in infants with IUGR.

Computational Modeling and Simulation of Developmental ...

EPA Pesticide Factsheets

Standard practice for assessing developmental toxicity is the observation of apical endpoints (intrauterine death, fetal growth retardation, structural malformations) in pregnant rats/rabbits following exposure during organogenesis. EPA’s computational toxicology research program (ToxCast) generated vast in vitro cellular and molecular effects data on >1858 chemicals in >600 high-throughput screening (HTS) assays. The diversity of assays has been increased for developmental toxicity with several HTS platforms, including the devTOX-quickPredict assay from Stemina Biomarker Discovery utilizing the human embryonic stem cell line (H9). Translating these HTS data into higher order-predictions of developmental toxicity is a significant challenge. Here, we address the application of computational systems models that recapitulate the kinematics of dynamical cell signaling networks (e.g., SHH, FGF, BMP, retinoids) in a CompuCell3D.org modeling environment. Examples include angiogenesis (angiodysplasia) and dysmorphogenesis. Being numerically responsive to perturbation, these models are amenable to data integration for systems Toxicology and Adverse Outcome Pathways (AOPs). The AOP simulation outputs predict potential phenotypes based on the in vitro HTS data ToxCast. A heuristic computational intelligence framework that recapitulates the kinematics of dynamical cell signaling networks in the embryo, together with the in vitro profiling data, produce quantitative predic

Systematic review of the potential adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children.

PubMed

Wikoff, Daniele; Welsh, Brian T; Henderson, Rayetta; Brorby, Gregory P; Britt, Janice; Myers, Esther; Goldberger, Jeffrey; Lieberman, Harris R; O'Brien, Charles; Peck, Jennifer; Tenenbein, Milton; Weaver, Connie; Harvey, Seneca; Urban, Jonathan; Doepker, Candace

2017-11-01

To date, one of the most heavily cited assessments of caffeine safety in the peer-reviewed literature is that issued by Health Canada (Nawrot et al., 2003). Since then, >10,000 papers have been published related to caffeine, including hundreds of reviews on specific human health effects; however, to date, none have compared the wide range of topics evaluated by Nawrot et al. (2003). Thus, as an update to this foundational publication, we conducted a systematic review of data on potential adverse effects of caffeine published from 2001 to June 2015. Subject matter experts and research team participants developed five PECO (population, exposure, comparator, and outcome) questions to address five types of outcomes (acute toxicity, cardiovascular toxicity, bone and calcium effects, behavior, and development and reproduction) in four healthy populations (adults, pregnant women, adolescents, and children) relative to caffeine intake doses determined not to be associated with adverse effects by Health Canada (comparators: 400 mg/day for adults [10 g for lethality], 300 mg/day for pregnant women, and 2.5 mg/kg/day for children and adolescents). The a priori search strategy identified >5000 articles that were screened, with 381 meeting inclusion/exclusion criteria for the five outcomes (pharmacokinetics was addressed contextually, adding 46 more studies). Data were extracted by the research team and rated for risk of bias and indirectness (internal and external validity). Selected no- and low-effect intakes were assessed relative to the population-specific comparator. Conclusions were drawn for the body of evidence for each outcome, as well as endpoints within an outcome, using a weight of evidence approach. When the total body of evidence was evaluated and when study quality, consistency, level of adversity, and magnitude of response were considered, the evidence generally supports that consumption of up to 400 mg caffeine/day in healthy adults is not associated with overt, adverse cardiovascular effects, behavioral effects, reproductive and developmental effects, acute effects, or bone status. Evidence also supports consumption of up to 300 mg caffeine/day in healthy pregnant women as an intake that is generally not associated with adverse reproductive and developmental effects. Limited data were identified for child and adolescent populations; the available evidence suggests that 2.5 mg caffeine/kg body weight/day remains an appropriate recommendation. The results of this systematic review support a shift in caffeine research to focus on characterizing effects in sensitive populations and establishing better quantitative characterization of interindividual variability (e.g., epigenetic trends), subpopulations (e.g., unhealthy populations, individuals with preexisting conditions), conditions (e.g., coexposures), and outcomes (e.g., exacerbation of risk-taking behavior) that could render individuals to be at greater risk relative to healthy adults and healthy pregnant women. This review, being one of the first to apply systematic review methodologies to toxicological assessments, also highlights the need for refined guidance and frameworks unique to the conduct of systematic review in this field. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Early-Life Exposure to Non-Nutritive Sweeteners and the Developmental Origins of Childhood Obesity: Global Evidence from Human and Rodent Studies.

PubMed

Archibald, Alyssa J; Dolinsky, Vernon W; Azad, Meghan B

2018-02-10

Non-nutritive sweeteners (NNS) are increasingly consumed by children and pregnant women around the world, yet their long-term health impact is unclear. Here, we review an emerging body of evidence suggesting that early-life exposure to NNS may adversely affect body composition and cardio-metabolic health. Some observational studies suggest that children consuming NNS are at increased risk for obesity-related outcomes; however, others find no association or provide evidence of confounding. Fewer studies have examined prenatal NNS exposure, with mixed results from different analytical approaches. There is a paucity of RCTs evaluating NNS in children, yielding inconsistent results that can be difficult to interpret due to study design limitations (e.g., choice of comparator, multifaceted interventions). The majority of this research has been conducted in high-income countries. Some rodent studies demonstrate adverse metabolic effects from NNS, but most have used extreme doses that are not relevant to humans, and few have distinguished prenatal from postnatal exposure. Most studies focus on synthetic NNS in beverages, with few examining plant-derived NNS or NNS in foods. Overall, there is limited and inconsistent evidence regarding the impact of early-life NNS exposure on the developmental programming of obesity and cardio-metabolic health. Further research and mechanistic studies are needed to elucidate these effects and inform dietary recommendations for expectant mothers and children worldwide.

Fetal Alcohol Spectrum Disorders.

PubMed

Williams, Janet F; Smith, Vincent C

2015-11-01

Prenatal exposure to alcohol can damage the developing fetus and is the leading preventable cause of birth defects and intellectual and neurodevelopmental disabilities. In 1973, fetal alcohol syndrome was first described as a specific cluster of birth defects resulting from alcohol exposure in utero. Subsequently, research unequivocally revealed that prenatal alcohol exposure causes a broad range of adverse developmental effects. Fetal alcohol spectrum disorder (FASD) is the general term that encompasses the range of adverse effects associated with prenatal alcohol exposure. The diagnostic criteria for fetal alcohol syndrome are specific, and comprehensive efforts are ongoing to establish definitive criteria for diagnosing the other FASDs. A large and growing body of research has led to evidence-based FASD education of professionals and the public, broader prevention initiatives, and recommended treatment approaches based on the following premises:▪ Alcohol-related birth defects and developmental disabilities are completely preventable when pregnant women abstain from alcohol use.▪ Neurocognitive and behavioral problems resulting from prenatal alcohol exposure are lifelong.▪ Early recognition, diagnosis, and therapy for any condition along the FASD continuum can result in improved outcomes.▪ During pregnancy:◦no amount of alcohol intake should be considered safe;◦there is no safe trimester to drink alcohol;◦all forms of alcohol, such as beer, wine, and liquor, pose similar risk; and◦binge drinking poses dose-related risk to the developing fetus. Copyright © 2015 by the American Academy of Pediatrics.

Developmental programming of the metabolic syndrome - critical windows for intervention

PubMed Central

Vickers, Mark H

2011-01-01

Metabolic disease results from a complex interaction of many factors, including genetic, physiological, behavioral and environmental influences. The recent rate at which these diseases have increased suggests that environmental and behavioral influences, rather than genetic causes, are fuelling the present epidemic. In this context, the developmental origins of health and disease hypothesis has highlighted the link between the periconceptual, fetal and early infant phases of life and the subsequent development of adult obesity and the metabolic syndrome. Although the mechanisms are yet to be fully elucidated, this programming was generally considered an irreversible change in developmental trajectory. Recent work in animal models suggests that developmental programming of metabolic disorders is potentially reversible by nutritional or targeted therapeutic interventions during the period of developmental plasticity. This review will discuss critical windows of developmental plasticity and possible avenues to ameliorate the development of postnatal metabolic disorders following an adverse early life environment. PMID:21954418

Safety assessment of boron by application of new uncertainty factors and their subdivision.

PubMed

Hasegawa, Ryuichi; Hirata-Koizumi, Mutsuko; Dourson, Michael L; Parker, Ann; Ono, Atsushi; Hirose, Akihiko

2013-02-01

The available toxicity information for boron was reevaluated and four appropriate toxicity studies were selected in order to derive a tolerable daily intake (TDI) using newly proposed uncertainty factors (UFs) presented in Hasegawa et al. (2010). No observed adverse effect levels (NOAELs) of 17.5 and 8.8 mgB/kg/day for the critical effect of testicular toxicity were found in 2-year rat and dog feeding studies. Also, the 95% lower confidence limit of the benchmark doses for 5% reduction of fetal body weight (BMDL(05)) was calculated as 44.9 and 10.3 mgB/kg/day in mouse and rat developmental toxicity studies, respectively. Measured values available for differences in boron clearance between rats and humans and variability in the glomerular filtration rate (GFR) in pregnant women were used to derive chemical specific UFs. For the remaining uncertainty, newly proposed default UFs, which were derived from the latest applicable information with a probabilistic approach, and their subdivided factors for toxicokinetic and toxicodynamic variability were applied. Finally, overall UFs were calculated as 68 for rat testicular toxicity, 40 for dog testicular toxicity, 247 for mouse developmental toxicity and 78 for rat developmental toxicity. It is concluded that 0.13 mgB/kg/day is the most appropriate TDI for boron, based on rat developmental toxicity. Copyright © 2012 Elsevier Inc. All rights reserved.

BRAIN DEVELOPMENT AND METHYLMERCURY: UNDERESTIMATION OF NEUROTOXICITY

PubMed Central

Grandjean, Philippe; Herz, Katherine T.

2011-01-01

Methylmercury is now recognized as an important developmental neurotoxicant, though this insight developed slowly over many decades. Developmental neurotoxicity was first reported in a Swedish case report in 1952, and from a serious outbreak in Minamata, Japan a few years later. While the infant suffered congenital poisoning, the mother was barely harmed, thus reflecting a unique vulnerability of the developing nervous system. Nonetheless, exposure limits for this environmental chemical were based solely on adult toxicity until 50 years after the first report on developmental neurotoxicity. Even current evidence is affected by uncertainty, most importantly by imprecision of the exposure assessment in epidemiological studies. Detailed calculations suggest that the relative imprecision may be as much as 50%, or greater, thereby substantially biasing the results toward the null. In addition, as methylmercury exposure usually originates from fish and seafood that also contains essential nutrients, so-called negative confounding may occur. Thus, the beneficial effects of the nutrients may appear to dampen the toxicity, unless proper adjustment is included in the analysis to reveal the true extent of adverse effects. These problems delayed the recognition of low-level methylmercury neurotoxicity. However, such problems are not unique, and many other industrial compounds are thought to cause developmental neurotoxicity, mostly with less epidemiological support than methylmercury. The experience obtained with methylmercury should therefore be taken into account when evaluating the evidence for other substances suspected of being neurotoxic. PMID:21259267

Reproductive disorders associated with pesticide exposure.

PubMed

Frazier, Linda M

2007-01-01

Exposure of men or women to certain pesticides at sufficient doses may increase the risk for sperm abnormalities, decreased fertility, a deficit of male children, spontaneous abortion, birth defects or fetal growth retardation. Pesticides from workplace or environmental exposures enter breast milk. Certain pesticides have been linked to developmental neurobehavioral problems, altered function of immune cells and possibly childhood leukemia. In well-designed epidemiologic studies, adverse reproductive or developmental effects have been associated with mixed pesticide exposure in occupational settings, particularly when personal protective equipment is not used. Every class of pesticides has at least one agent capable of affecting a reproductive or developmental endpoint in laboratory animals or people, including organophosphates, carbamates, pyrethroids, herbicides, fungicides, fumigants and especially organochlorines. Many of the most toxic pesticides have been banned or restricted in developed nations, but high exposures to these agents are still occurring in the most impoverished countries around the globe. Protective clothing, masks and gloves are more difficult to tolerate in hot, humid weather, or may be unavailable or unaffordable. Counseling patients who are concerned about reproductive and developmental effects of pesticides often involves helping them assess their exposure levels, weigh risks and benefits, and adopt practices to reduce or eliminate their absorbed dose. Patients may not realize that by the first prenatal care visit, most disruptions of organogenesis have already occurred. Planning ahead provides the best chance of lowering risk from pesticides and remediating other risk factors before conception.

Is decabromodiphenyl ether (BDE-209) a developmental neurotoxicant?

PubMed Central

Costa, Lucio G.; Giordano, Gennaro

2011-01-01

Polybrominated diphenyl ether (PBDE) flame retardants have become ubiquitous environmental pollutants. The relatively higher body burden in toddlers and children has reaised concern for their potential developmental neurotoxicity, which has been suggested by animal studies, in vitro experiments, and recent human epidemiological evidence. While lower brominated PBDEs have been banned in several countries, the fully brominated decaBDE (BDE-209) is still utilized, though manufacturers will discontinue production in the U.S.A. in 2013. The recent decision by the U.S. Environmental Protection Agency to base the Reference Dose (RfD) for BDE-209 on a developmental neurotoxicity study has generated some controversy. Because of its bulky configuration, BDE-209 is poorly absorbed and does not easily penetrate the cell wall. Its acute and chronic toxicities are relatively low, with the liver and the thyroid as the primary targets, though there is some evidence of carcinogenicity. A few animal studies have indicated that BDE-209 may cause developmental neurotoxicity, affecting motor and cognitive domains, as seen for other PBDEs. Limited in vivo and in vitro studies have also evidenced effects of BDE-209 on thyroid hormone homeostasis and direct effects on nervous cells, again similar to what found with other lower brominated PBDEs. In contrast, a recent developmental neurotoxicity study, carried out according to international guidelines, has provided no evidence of adverse effects on neurodevelopment, and this should be considered in a future re-evaluation of BDE-209. While estimated exposure to BDE-209 in children is believed to be several orders of magnitude below the most conservative RfD proposed by the USEPA, questions remain on the extent and relevance of BDE-209 metabolism to lower brominated PBDEs in the environment and in humans. PMID:21182867

BDE-47 causes developmental retardation with down-regulated expression profiles of ecdysteroid signaling pathway-involved nuclear receptor (NR) genes in the copepod Tigriopus japonicus.

PubMed

Hwang, Dae-Sik; Han, Jeonghoon; Won, Eun-Ji; Kim, Duck-Hyun; Jeong, Chang-Bum; Hwang, Un-Ki; Zhou, Bingsheng; Choe, Joonho; Lee, Jae-Seong

2016-08-01

2,2',4,4'-Tetrabromodiphenyl ether (BDE-47) is a persistent organic pollutant (POP) in marine environments. Despite its adverse effects (e.g. developmental retardation) in ecdysozoa, the effects of BDE-47 on transcription of ecdysteroid signaling pathway-involved-nuclear receptor (NR) genes and metamorphosis-related genes have not been examined in copepods. To examine the deleterious effect of BDE-47 on copepod molting and metamorphosis, BDE-47 was exposed to the harpacticoid copepod Tigriopus japonicus, followed by monitoring developmental retardation and transcriptional alteration of NR genes. The developmental rate was significantly inhibited (P<0.05) in response to BDE-47 and the agricultural insecticide gamma-hexachlorocyclohexane. Conversely, the ecdysteroid agonist ponasterone A (PoA) led to decreased molting and metamorphosis time (P<0.05) from the nauplius stage to the adult stage. In particular, expression profiles of all NR genes were the highest at naupliar stages 5-6 except for SVP, FTZ-F1, and HR96 genes. Nuclear receptor USP, HR96, and FTZ-F1 genes also showed significant sex differences (P<0.05) in gene expression levels over different developmental stages, indicating that these genes may be involved in vitellogenesis. NR gene expression patterns showed significant decreases (P<0.05) in response to BDE-47 exposure, implying that molting and metamorphosis retardation is likely associated with NR gene expression. In summary, BDE-47 leads to molting and metamorphosis retardation and suppresses transcription of NR genes. This information will be helpful in understanding the molting and metamorphosis delay mechanism in response to BDE-47 exposure. Copyright © 2016 Elsevier B.V. All rights reserved.

Evaluation of Epidemiology and Animal Data for Risk Assessment: Chlorpyrifos Developmental Neurobehavioral Outcomes

PubMed Central

Li, Abby A.; Lowe, Kimberly A.; McIntosh, Laura J.; Mink, Pamela J.

2012-01-01

Developmental neurobehavioral outcomes attributed to exposure to chlorpyrifos (CPF) obtained from epidemiologic and animal studies published before June 2010 were reviewed for risk assessment purposes. For epidemiological studies, this review considered (1) overall strength of study design, (2) specificity of CPF exposure biomarkers, (3) potential for bias, and (4) Hill guidelines for causal inference. In the case of animal studies, this review focused on evaluating the consistency of outcomes for developmental neurobehavioral endpoints from in vivo mammalian studies that exposed dams and/or offspring to CPF prior to weaning. Developmental neuropharmacologic and neuropathologic outcomes were also evaluated. Experimental design and methods were examined as part of the weight of evidence. There was insufficient evidence that human developmental exposures to CPF produce adverse neurobehavioral effects in infants and children across different cohort studies that may be relevant to CPF exposure. In animals, few behavioral parameters were affected following gestational exposures to 1 mg/kg-d but were not consistently reported by different laboratories. For postnatal exposures, behavioral effects found in more than one study at 1 mg/kg-d were decreased errors on a radial arm maze in female rats and increased errors in males dosed subcutaneously from postnatal day (PND) 1 to 4. A similar finding was seen in rats exposed orally from PND 1 to 21 with incremental dose levels of 1, 2, and 4 mg/kg-d, but not in rats dosed with constant dose level of 1 mg/kg-d. Neurodevelopmental behavioral, pharmacological, and morphologic effects occurred at doses that produced significant brain or red blood cell acetylcholinesterase inhibition in dams or offspring. PMID:22401178

Early-life nutritional effects on the female reproductive system.

PubMed

Chan, K A; Tsoulis, M W; Sloboda, D M

2015-02-01

There is now considerable epidemiological and experimental evidence indicating that early-life environmental conditions, including nutrition, affect subsequent development in later life. These conditions induce highly integrated responses in endocrine-related homeostasis, resulting in persistent changes in the developmental trajectory producing an altered adult phenotype. Early-life events trigger processes that prepare the individual for particular circumstances that are anticipated in the postnatal environment. However, where the intrauterine and postnatal environments differ markedly, such modifications to the developmental trajectory may prove maladaptive in later life. Reproductive maturation and function are similarly influenced by early-life events. This should not be surprising, because the primordial follicle pool is established early in life and is thus vulnerable to early-life events. Results of clinical and experimental studies have indicated that early-life adversity is associated with a decline in ovarian follicular reserve, changes in ovulation rates, and altered age at onset of puberty. However, the underlying mechanisms regulating the relationship between the early-life developmental environment and postnatal reproductive development and function are unclear. This review examines the evidence linking early-life nutrition and effects on the female reproductive system, bringing together clinical observations in humans and experimental data from targeted animal models. © 2015 Society for Endocrinology.

Investigation of repeated dose (90 day) oral toxicity, reproductive/developmental toxicity and mutagenic potential of 'Calebin A'.

PubMed

Majeed, Muhammed; Nagabhushanam, Kalyanam; Natarajan, Sankaran; Bani, Sarang; Pandey, Anjali; Karri, Suresh Kumar

2015-01-01

The present work investigated repeated dose and reproductive toxicity of Calebin A in Wistar rats. A study for assessing the mutagenic potential of Calebin A through an AMES test is also described. Calebin A was orally administered to groups of 10 male and/or 10 female Wistar rats each, assigned to three dose levels (20, 50 and 100 mg/kg/body weight) once daily for 90 consecutive days. None of the animals in any of the treatment/control groups exhibited any abnormal clinical signs/behavioral changes, reproductive as well as developmental parameters, or gross and microscopic changes in both male and female rats. Calebin A was also evaluated for its ability to induce reverse mutations at selected loci of Salmonella typhimurium in the presence and absence of Aroclor 1254 induced rat liver S9 cell lines. In conclusion, 100 mg/kg/d of Calebin A is not likely to produce any significant toxic effects in male and female Wistar rats and no reproductive or developmental toxicity was observed at the same dose and hence Calebin A at 100 mg/kg was determined as "No Observed Adverse Effect Level (NOAEL)" under the test conditions.

[Predictive value of qualitative assessment of general movements for adverse outcomes at 24 months of age in infants with asphyxia].

PubMed

Chen, Nan; Wen, Xiao-Hong; Huang, Jin-Hua; Wang, Shui-Yun; Zhu, Yue-E

2015-12-01

To investigate the predictive value of the qualitative assessment of general movements (GMs) for adverse outcomes at 24 months of age in full-term infants with asphyxia. A total of 114 full-term asphyxiated infants, who were admitted to the neonatal intensive care unit between 2009 and 2012 and took part in follow-ups after discharge were included in the study. All of them received the qualitative assessment of GMs within 3 months after birth. The development quotient was determined with the Bayley Scales of Infant Development at 24 months of age. The results of the qualitative assessment of GMs within 3 months after birth showed that among 114 infants, 20 (17.5%) had poor repertoire movements and 7 (6.1%) had cramped-synchronized movements during the writhing movements period; 8 infants (7.0%) had the absence of fidgety movements during the fidgety movements period. The results of development quotient at 24 months of age showed that 7 infants (6.1%) had adverse developmental outcomes: 6 cases of cerebral palsy and mental retardation and 1 case of mental retardation. There was a poor consistency between poor repertoire movements during the writhing movements period and the developmental outcomes at 24 months of age (Kappa=-0.019; P>0.05). There was a high consistency between cramped-synchronized movements during the writhing movements period and the developmental outcomes at 24 months of age (Kappa=0.848; P<0.05), and the results of predictive values of cramped-synchronized movements were shown as follows: predictive validity 98.2%, sensitivity 85.7%, specificity 99.1%, positive predictive value 85.7%, and negative predictive value 99.1%. There was a high consistency between the absence of fidgety movements during the fidgety movements period and the developmental outcomes at 24 months of age (Kappa=0.786; P<0.05), and its predictive values were expressed as follows: predictive validity 97.4%, sensitivity 85.7%, specificity 98.1%, positive predictive value 75.0%, and negative predictive value 99.1%. Cramped-synchronized movements and absence of fidgety movements can predict adverse developmental outcomes at 24 months of age in full-term infants with asphyxia.

Linking Prenatal Maternal Adversity to Developmental Outcomes in Infants: The Role of Epigenetic Pathways

PubMed Central

Monk, Catherine; Spicer, Julie; Champagne, Frances A.

2013-01-01

Prenatal exposure to maternal stress, anxiety, and depression can have lasting effects on infant development with consequences for risk of psychopathology. Though the impact of prenatal maternal distress has been well documented, the potential mechanisms through which maternal psychosocial variables shape development have yet to be fully elucidated. Advances in molecular biology have highlighted the role of epigenetic mechanisms in regulating gene activity, neurobiology, and behavior and the potential role of environmentally-induced epigenetic variation in linking early life exposures to long-term biobehavioral outcomes. In this review, we discuss evidence illustrating the association between maternal prenatal distress and both fetal and infant developmental trajectories and the potential role of epigenetic mechanisms in mediating these effects. Postnatal experiences may have a critical moderating influence on prenatal effects, and here we review findings illustrating prenatal-postnatal interplay and the developmental and epigenetic consequences of postnatal mother-infant interactions. The in utero environment is regulated by placental function and there is emerging evidence that the placenta is highly susceptible to maternal distress and a target of epigenetic dysregulation. Integrating studies of prenatal exposures, placental function, and postnatal maternal care with the exploration of epigenetic mechanisms may provide novel insights into the pathophysiology induced by maternal distress. PMID:23062303

Reproductive Health Risks Associated with Occupational Exposures to Antineoplastic Drugs in Health Care Settings: A Review of the Evidence

PubMed Central

Connor, Thomas H.; Lawson, Christina C.; Polovich, Martha; McDiarmid, Melissa A.

2015-01-01

Objectives Antineoplastic drugs are known reproductive and developmental toxicants. Our objective was to review the existing literature of reproductive health risks to workers who handle antineoplastic drugs. Methods A structured literature review of 18 peer-reviewed, English language publications of occupational exposure and reproductive outcomes was performed. Results While effect sizes varied with study size and population, occupational exposure to antineoplastic drugs appears to raise the risk of both congenital malformations and miscarriage. Studies of infertility and time-to-pregnancy also suggested an increased risk for sub-fertility. Conclusions Antineoplastic drugs are highly toxic in patients receiving treatment and adverse reproductive effects have been well documented in these patients. Healthcare workers with chronic, low level occupational exposure to these drugs also appear to have an increased risk of adverse reproductive outcomes. Additional precautions to prevent exposure should be considered. PMID:25153300

Developmental origins of non-communicable disease: Implications for research and public health

PubMed Central

2012-01-01

This White Paper highlights the developmental period as a plastic phase, which allows the organism to adapt to changes in the environment to maintain or improve reproductive capability in part through sustained health. Plasticity is more prominent prenatally and during early postnatal life, i.e., during the time of cell differentiation and specific tissue formation. These developmental periods are highly sensitive to environmental factors, such as nutrients, environmental chemicals, drugs, infections and other stressors. Nutrient and toxicant effects share many of the same characteristics and reflect two sides of the same coin. In both cases, alterations in physiological functions can be induced and may lead to the development of non-communicable conditions. Many of the major diseases – and dysfunctions – that have increased substantially in prevalence over the last 40 years seem to be related in part to developmental factors associated with either nutritional imbalance or exposures to environmental chemicals. The Developmental Origins of Health and Disease (DOHaD) concept provides significant insight into new strategies for research and disease prevention and is sufficiently robust and repeatable across species, including humans, to require a policy and public health response. This White Paper therefore concludes that, as early development (in utero and during the first years of postnatal life) is particularly sensitive to developmental disruption by nutritional factors or environmental chemical exposures, with potentially adverse consequences for health later in life, both research and disease prevention strategies should focus more on these vulnerable life stages. PMID:22715989

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.

Cumulative early life adversity predicts longevity in wild baboons

PubMed Central

Tung, Jenny; Archie, Elizabeth A.; Altmann, Jeanne; Alberts, Susan C.

2016-01-01

In humans and other animals, harsh circumstances in early life predict morbidity and mortality in adulthood. Multiple adverse conditions are thought to be especially toxic, but this hypothesis has rarely been tested in a prospective, longitudinal framework, especially in long-lived mammals. Here we use prospective data on 196 wild female baboons to show that cumulative early adversity predicts natural adult lifespan. Females who experience ≥3 sources of early adversity die a median of 10 years earlier than females who experience ≤1 adverse circumstances (median lifespan is 18.5 years). Females who experience the most adversity are also socially isolated in adulthood, suggesting that social processes partially explain the link between early adversity and adult survival. Our results provide powerful evidence for the developmental origins of health and disease and indicate that close ties between early adversity and survival arise even in the absence of health habit and health care-related explanations. PMID:27091302

Building a developmental toxicity ontology.

PubMed

Baker, Nancy; Boobis, Alan; Burgoon, Lyle; Carney, Edward; Currie, Richard; Fritsche, Ellen; Knudsen, Thomas; Laffont, Madeleine; Piersma, Aldert H; Poole, Alan; Schneider, Steffen; Daston, George

2018-04-03

As more information is generated about modes of action for developmental toxicity and more data are generated using high-throughput and high-content technologies, it is becoming necessary to organize that information. This report discussed the need for a systematic representation of knowledge about developmental toxicity (i.e., an ontology) and proposes a method to build one based on knowledge of developmental biology and mode of action/ adverse outcome pathways in developmental toxicity. This report is the result of a consensus working group developing a plan to create an ontology for developmental toxicity that spans multiple levels of biological organization. This report provide a description of some of the challenges in building a developmental toxicity ontology and outlines a proposed methodology to meet those challenges. As the ontology is built on currently available web-based resources, a review of these resources is provided. Case studies on one of the most well-understood morphogens and developmental toxicants, retinoic acid, are presented as examples of how such an ontology might be developed. This report outlines an approach to construct a developmental toxicity ontology. Such an ontology will facilitate computer-based prediction of substances likely to induce human developmental toxicity. © 2018 Wiley Periodicals, Inc.

Developmental Neurotoxicity Study of Dietary Bisphenol A in Sprague-Dawley Rats

PubMed Central

Stump, Donald G.; Beck, Melissa J.; Radovsky, Ann; Garman, Robert H.; Freshwater, Lester L.; Sheets, Larry P.; Marty, M. Sue; Waechter, John M.; Dimond, Stephen S.; Van Miller, John P.; Shiotsuka, Ronald N.; Beyer, Dieter; Chappelle, Anne H.; Hentges, Steven G.

2010-01-01

This study was conducted to determine the potential of bisphenol A (BPA) to induce functional and/or morphological effects to the nervous system of F1 offspring from dietary exposure during gestation and lactation according to the Organization for Economic Cooperation and Development and U.S. Environmental Protection Agency guidelines for the study of developmental neurotoxicity. BPA was offered to female Sprague-Dawley Crl:CD (SD) rats (24 per dose group) and their litters at dietary concentrations of 0 (control), 0.15, 1.5, 75, 750, and 2250 ppm daily from gestation day 0 through lactation day 21. F1 offspring were evaluated using the following tests: detailed clinical observations (postnatal days [PNDs] 4, 11, 21, 35, 45, and 60), auditory startle (PNDs 20 and 60), motor activity (PNDs 13, 17, 21, and 61), learning and memory using the Biel water maze (PNDs 22 and 62), and brain and nervous system neuropathology and brain morphometry (PNDs 21 and 72). For F1 offspring, there were no treatment-related neurobehavioral effects, nor was there evidence of neuropathology or effects on brain morphometry. Based on maternal and offspring body weight reductions, the no-observed-adverse-effect level (NOAEL) for systemic toxicity was 75 ppm (5.85 and 13.1 mg/kg/day during gestation and lactation, respectively), with no treatment-related effects at lower doses or nonmonotonic dose responses observed for any parameter. There was no evidence that BPA is a developmental neurotoxicant in rats, and the NOAEL for developmental neurotoxicity was 2250 ppm, the highest dose tested (164 and 410 mg/kg/day during gestation and lactation, respectively). PMID:20164145

Mechanistic insight into neurotoxicity induced by developmental insults

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

Tamm, Christoffer; Ceccatelli, Sandra

Epidemiological and/or experimental studies have shown that unfavorable prenatal environmental factors, such as stress or exposure to certain neurotoxic environmental contaminants, may have adverse consequences for neurodevelopment. Alterations in neurogenesis can have harmful effects not only for the developing nervous system, but also for the adult brain where neurogenesis is believed to play a role in learning, memory, and even in depression. Many recent advances in the understanding of the complex process of nervous system development can be integrated into the field of neurotoxicology. In the past 15 years we have been using cultured neural stem or progenitor cells tomore » investigate the effects of neurotoxic stimuli on cell survival, proliferation and differentiation, with special focus on heritable effects. This is an overview of the work performed by our group in the attempt to elucidate the mechanisms of developmental neurotoxicity and possibly provide relevant information for the understanding of the etiopathogenesis of complex brain disorders. - Highlights: • The developing nervous system is highly sensitive to toxic insults. • Neural stem cells are relevant models for mechanistic studies as well as for identifying heritable effects due to epigenetic changes. • Depending on the dose, the outcome of exposure to neurotoxicants ranges from altered proliferation and differentiation to cell death. • The elucidation of neurotoxicity mechanisms is relevant for understanding the etiopathogenesis of developmental and adult nervous system disorders.« less

Games for Health for Children—Current Status and Needed Research

PubMed Central

Blumberg, Fran; Buday, Richard; DeSmet, Ann; Fiellin, Lynn E.; Green, C. Shawn; Kato, Pamela M.; Lu, Amy Shirong; Maloney, Ann E.; Mellecker, Robin; Morrill, Brooke A.; Peng, Wei; Shegog, Ross; Simons, Monique; Staiano, Amanda E.; Thompson, Debbe; Young, Kimberly

2016-01-01

Abstract Videogames for health (G4H) offer exciting, innovative, potentially highly effective methods for increasing knowledge, delivering persuasive messages, changing behaviors, and influencing health outcomes. Although early outcome results are promising, additional research is needed to determine the game design and behavior change procedures that best promote G4H effectiveness and to identify and minimize possible adverse effects. Guidelines for ideal use of different types of G4H by children and adolescents should be elucidated to enhance effectiveness and minimize adverse effects. G4H stakeholders include organizational implementers, policy makers, players and their families, researchers, designers, retailers, and publishers. All stakeholders should be involved in G4H development and have a voice in setting goals to capitalize on their insights to enhance effectiveness and use of the game. In the future, multiple targeted G4H should be available to meet a population's diverse health needs in developmentally appropriate ways. Substantial, consistent, and sophisticated research with appropriate levels of funding is needed to realize the benefits of G4H. PMID:26262772

Games for Health for Children-Current Status and Needed Research.

PubMed

Baranowski, Tom; Blumberg, Fran; Buday, Richard; DeSmet, Ann; Fiellin, Lynn E; Green, C Shawn; Kato, Pamela M; Lu, Amy Shirong; Maloney, Ann E; Mellecker, Robin; Morrill, Brooke A; Peng, Wei; Shegog, Ross; Simons, Monique; Staiano, Amanda E; Thompson, Debbe; Young, Kimberly

2016-02-01

Videogames for health (G4H) offer exciting, innovative, potentially highly effective methods for increasing knowledge, delivering persuasive messages, changing behaviors, and influencing health outcomes. Although early outcome results are promising, additional research is needed to determine the game design and behavior change procedures that best promote G4H effectiveness and to identify and minimize possible adverse effects. Guidelines for ideal use of different types of G4H by children and adolescents should be elucidated to enhance effectiveness and minimize adverse effects. G4H stakeholders include organizational implementers, policy makers, players and their families, researchers, designers, retailers, and publishers. All stakeholders should be involved in G4H development and have a voice in setting goals to capitalize on their insights to enhance effectiveness and use of the game. In the future, multiple targeted G4H should be available to meet a population's diverse health needs in developmentally appropriate ways. Substantial, consistent, and sophisticated research with appropriate levels of funding is needed to realize the benefits of G4H.

Toxicological relevance of pharmaceuticals in drinking water.

PubMed

Bruce, Gretchen M; Pleus, Richard C; Snyder, Shane A

2010-07-15

Interest in the public health significance of trace levels of pharmaceuticals in potable water is increasing, particularly with regard to the effects of long-term, low-dose exposures. To assess health risks and establish target concentrations for water treatment, human health risk-based screening levels for 15 pharmaceutically active ingredients and four metabolites were compared to concentrations detected at 19 drinking water treatment plants across the United States. Compounds were selected based on rate of use, likelihood of occurrence, and potential for toxicity. Screening levels were established based on animal toxicity data and adverse effects at therapeutic doses, focusing largely on reproductive and developmental toxicity and carcinogenicity. Calculated drinking water equivalent levels (DWELs) ranged from 0.49 microg/L (risperidone) to 20,000 microg/L (naproxen). None of the 10 detected compounds exceeded their DWEL. Ratios of DWELs to maximum detected concentrations ranged from 110 (phenytoin) to 6,000,000 (sulfamethoxazole). Based on this evaluation, adverse health effects from targeted pharmaceuticals occurring in U.S. drinking water are not expected.

Developmental effects of antiepileptic drugs and the need for improved regulations

PubMed Central

Loring, David W.

2016-01-01

Antiepileptic drugs (AEDs) are among the most common teratogenic drugs prescribed to women of childbearing age. AEDs can induce both anatomical (malformations) and behavioral (cognitive/behavioral deficits) teratogenicity. Only in the last decade have we begun to truly discriminate differential AED developmental effects. Fetal valproate exposure carries a special risk for both anatomical and behavioral teratogenic abnormalities, but the mechanisms and reasons for individual variability are unknown. Intermediate anatomical risks exist for phenobarbital and topiramate. Several AEDs (e.g., lamotrigine and levetiracetam) appear to possess low risks for both anatomical and behavioral teratogenesis. Despite advances in the past decade, our knowledge of the teratogenic risks for most AEDs and the underlying mechanisms remain inadequate. Further, the long-term effects of AEDs in neonates and older children remain uncertain. The pace of progress is slow given the lifelong consequences of diminished developmental outcomes, exposing children unnecessarily to potential adverse effects. It is imperative that new approaches be employed to determine risks more expediently. Our recommendations include a national reporting system for congenital malformations, federal funding of the North American AED Pregnancy Registry, routine meta-analyses of cohort studies to detect teratogenic signals, monitoring of AED prescription practices for women, routine preclinical testing of all new AEDs for neurodevelopmental effects, more specific Food and Drug Administration requirements to establish differential AED cognitive effects in children, and improved funding of basic and clinical research to fully delineate risks and underlying mechanisms for AED-induced anatomical and behavioral teratogenesis. PMID:26519545

Resilience as Regulation of Developmental and Family Processes

PubMed Central

MacPhee, David; Lunkenheimer, Erika; Riggs, Nathaniel

2015-01-01

Resilience can be defined as establishing equilibrium subsequent to disturbances to a system caused by significant adversity. When families experience adversity or transitions, multiple regulatory processes may be involved in establishing equilibrium, including adaptability, regulation of negative affect, and effective problem-solving skills. The authors’ resilience-as-regulation perspective integrates insights about the regulation of individual development with processes that regulate family systems. This middle-range theory of family resilience focuses on regulatory processes across levels that are involved in adaptation: whole-family systems such as routines and sense of coherence; coregulation of dyads involving emotion regulation, structuring, and reciprocal influences between social partners; and individual self-regulation. Insights about resilience-as-regulation are then applied to family-strengthening interventions that are designed to promote adaptation to adversity. Unresolved issues are discussed in relation to resilience-as-regulation in families, in particular how risk exposure is assessed, interrelations among family regulatory mechanisms, and how families scaffold the development of children’s resilience. PMID:26568647

Embryonic vascular disruption adverse outcomes: Linking high-throughput signaling signatures with functional consequences.

PubMed

Ellis-Hutchings, Robert G; Settivari, Raja S; McCoy, Alene T; Kleinstreuer, Nicole; Franzosa, Jill; Knudsen, Thomas B; Carney, Edward W

2017-04-13

Embryonic vascular disruption is an important adverse outcome pathway (AOP) as chemical disruption of cardiovascular development induces broad prenatal defects. High-throughput screening (HTS) assays aid AOP development although linking in vitro data to in vivo apical endpoints remains challenging. This study evaluated two anti-angiogenic agents, 5HPP-33 and TNP-470, across the ToxCastDB HTS assay platform and anchored the results to complex in vitro functional assays: the rat aortic explant assay (AEA), rat whole embryo culture (WEC), and the zebrafish embryotoxicity (ZET) assay. Both were identified as putative vascular disruptive compounds (pVDCs) in ToxCastDB and disrupted angiogenesis and embryogenesis in the functional assays. Differences were observed in potency and adverse effects: 5HPP-33 was embryolethal (WEC and ZET); TNP-470 produced caudal defects at lower concentrations. This study demonstrates how a tiered approach using HTS signatures and complex functional in vitro assays might be used to prioritize further in vivo developmental toxicity testing. Copyright © 2017 Elsevier Inc. All rights reserved.

Embryonic vascular disruption adverse outcomes: Linking high throughput signaling signatures with functional consequences.

PubMed

Ellis-Hutchings, Robert G; Settivari, Raja S; McCoy, Alene T; Kleinstreuer, Nicole; Franzosa, Jill; Knudsen, Thomas B; Carney, Edward W

2017-06-01

Embryonic vascular disruption is an important adverse outcome pathway (AOP) as chemical disruption of cardiovascular development induces broad prenatal defects. High throughput screening (HTS) assays aid AOP development although linking in vitro data to in vivo apical endpoints remains challenging. This study evaluated two anti-angiogenic agents, 5HPP-33 and TNP-470, across the ToxCastDB HTS assay platform and anchored the results to complex in vitro functional assays: the rat aortic explant assay (AEA), rat whole embryo culture (WEC), and the zebrafish embryotoxicity (ZET) assay. Both were identified as putative vascular disruptive compounds (pVDCs) in ToxCastDB and disrupted angiogenesis and embryogenesis in the functional assays. Differences were observed in potency and adverse effects: 5HPP-33 was embryolethal (WEC and ZET); TNP-470 produced caudal defects at lower concentrations. This study demonstrates how a tiered approach using HTS signatures and complex functional in vitro assays might be used to prioritize further in vivo developmental toxicity testing. Copyright © 2017 Elsevier Inc. All rights reserved.

Pre- and Postnatal Exposure to Low Dose Glufosinate Ammonium Induces Autism-Like Phenotypes in Mice

PubMed Central

Laugeray, Anthony; Herzine, Ameziane; Perche, Olivier; Hébert, Betty; Aguillon-Naury, Marine; Richard, Olivier; Menuet, Arnaud; Mazaud-Guittot, Séverine; Lesné, Laurianne; Briault, Sylvain; Jegou, Bernard; Pichon, Jacques; Montécot-Dubourg, Céline; Mortaud, Stéphane

2014-01-01

Glufosinate ammonium (GLA) is one of the most widely used herbicides in agriculture. As is the case for most pesticides, potential adverse effects of GLA have not been studied from the perspective of developmental neurotoxicity. Early pesticides exposure may weaken the basic structure of the developing brain and cause permanent changes leading to a wide range of lifelong effects on health and/or behavior. Here, we addressed the developmental impact of GLA by exposing female mice to low dose GLA during both pre- and postnatal periods and analyzed potential developmental and behavioral changes of the offspring during infancy and adulthood. A neurobehavioral test battery revealed significant effects of GLA maternal exposure on early reflex development, pup communication, affiliative behaviors, and preference for social olfactory cues, but emotional reactivity and emotional memory remained unaltered. These behavioral alterations showed a striking resemblance to changes seen in animal models of Autistic Spectrum Disorders. At the brain level, GLA maternal exposure caused some increase in relative brain weight of the offspring. In addition, reduced expression of Pten and Peg3 – two genes implicated in autism-like deficits – was observed in the brain of GLA-exposed pups at postnatal day 15. Our work thus provides new data on the link between pre- and postnatal exposure to the herbicide GLA and the onset of autism-like symptoms later in life. It also raises fundamental concerns about the ability of current safety testing to assess risks of pesticide exposure during critical developmental periods. PMID:25477793

Developmental origins of polycystic ovary syndrome (PCOS), a case control study comparing birth weight in women with PCOS and control group.

PubMed

Sadrzadeh, Sheda; Painter, Rebecca C; Lambalk, Cornelis B

2016-10-01

Evidence from various epidemiological studies and experimental animal studies has linked adverse intrauterine circumstances with health problems in adult life. This field of investigation is known as Developmental Origins of Health and Disease (DOHaD). Studies investigating the relation between developing polycystic ovary syndrome (PCOS) in adulthood and birth weight have yielded inconsistent results: PCOS is described more often in women with low birth weight and high birth weight, while other studies have failed to establish any relation. In this retrospective case-control study, we evaluated whether women diagnosed with PCOS had lower birth weight compared to women with a regular menstrual cycle (controls). Binary logistic regression models were used to analyze the data and correct for known confounders. About 65 women with PCOS and 96 controls were recruited for this purpose. The average birth weight of PCOS women (3357 g) did not differ from the average birth weight of controls (3409 g). Mean age at menarche differed significantly between groups, 13.7  years and 12.8  years (p = 0.006), respectively, for PCOS women and controls. In conclusion, we could not confirm the effect of adverse intrauterine conditions, reflected in birth weight, on developing PCOS.

Systems Toxicology of Male Reproductive Development ...

EPA Pesticide Factsheets

Adverse trends in male reproductive health have been reported for increased rates of testicular germ cell tumor, low semen quality, cryptorchidism, and hypospadias. An association with prenatal environmental exposure has been inferred from human and animal studies underlying male reproductive developmental defects. The present study established the links between environmental chemicals, molecular targets, and adverse outcomes using U.S. EPA animal study (ToxRefDB) and high-throughput screening (ToxCast) databases. This systems-based approach revealed a phenotypic hierarchy across 63 chemicals and a pleiotropic in vitro bioactivity profile. Although estrogenic and anti-androgenic activities have been extensively studied in male reproductive developmental toxicity, the present study showed these receptor targets to be only a subset of the potential landscape of molecular targets. A variety of chemical (e.g. phthalates, conazoles, carbamates, and phenol compounds) and bioactivity (e.g. nuclear receptors, vascular remodeling proteins, and cytochrome-P450 reductases) clusters further suggested multiple pathways leading to the adverse outcomes. This points to the need for multi-scale systems models to predict whether the occurrence of one adverse outcome may predict the risk of another. Imbalances in androgen and estrogen signaling have been a general focus in male reproductive toxicology research. While a number of recent studies have demonstrated that both hormonal

Growth and development in internationally adopted children: extent and timing of recovery after early adversity.

PubMed

Palacios, Jesús; Román, Maite; Camacho, Carlos

2011-03-01

Following initial adversity, internationally adopted children arrive with significant growth and developmental delays. Post-placement recovery has been widely documented, but little has been known about its extent and timing several years after placement and in children with diverse pre-adoptive experiences. A total of 289 children adopted from six countries into Spanish families were studied. Growth and psychological development were considered on arrival and after an average of over 3 years. Growth and developmental initial delays affected a substantial percentage of the children. Post-adoption recovery seemed quicker and more complete in weight and height than in head circumference and psychological development. Initial and later values were correlated, but growth-development relation on arrival subsequently lost significance. Most of the catch-up happened in the first three post-adoption years. Adoption offers an impressive opportunity for recovery after previous adversity, although continuity between past and present persists. The improvement is more marked in some areas than in others and more substantial in the first post-adoption years. © 2010 Blackwell Publishing Ltd.

AMP-Activated Protein Kinase as a Reprogramming Strategy for Hypertension and Kidney Disease of Developmental Origin.

PubMed

Tain, You-Lin; Hsu, Chien-Ning

2018-06-12

Suboptimal early-life conditions affect the developing kidney, resulting in long-term programming effects, namely renal programming. Adverse renal programming increases the risk for developing hypertension and kidney disease in adulthood. Conversely, reprogramming is a strategy aimed at reversing the programming processes in early life. AMP-activated protein kinase (AMPK) plays a key role in normal renal physiology and the pathogenesis of hypertension and kidney disease. This review discusses the regulation of AMPK in the kidney and provides hypothetical mechanisms linking AMPK to renal programming. This will be followed by studies targeting AMPK activators like metformin, resveratrol, thiazolidinediones, and polyphenols as reprogramming strategies to prevent hypertension and kidney disease. Further studies that broaden our understanding of AMPK isoform- and tissue-specific effects on renal programming are needed to ultimately develop reprogramming strategies. Despite the fact that animal models have provided interesting results with regard to reprogramming strategies targeting AMPK signaling to protect against hypertension and kidney disease with developmental origins, these results await further clinical translation.

Caregiver Training in Mindfulness-Based Positive Behavior Supports (MBPBS): Effects on Caregivers and Adults with Intellectual and Developmental Disabilities

PubMed Central

Singh, Nirbhay N.; Lancioni, Giulio E.; Karazsia, Bryan T.; Myers, Rachel E.

2016-01-01

Caregivers often manage the aggressive behavior of individuals with intellectual and developmental disabilities that reside in community group homes. Sometimes this results in adverse outcomes for both the caregivers and the care recipients. We provided a 7-day intensive Mindfulness-Based Positive Behavior Support (MBPBS) training to caregivers from community group homes and assessed the outcomes in terms of caregiver variables, individuals’ behaviors, and an administrative outcome. When compared to pre-MBPBS training, the MBPBS training resulted in the caregivers using significantly less physical restraints, and staff stress and staff turnover were considerably reduced. The frequency of injury to caregivers and peers caused by the individuals was significantly reduced. A benefit-cost analysis showed substantial financial savings due to staff participation in the MBPBS program. This study provides further proof-of-concept for the effectiveness of MBPBS training for caregivers, and strengthens the call for training staff in mindfulness meditation. PMID:26903906

Adverse childhood experiences and psychosocial well-being of women who were in foster care as children.

PubMed

Bruskas, Delilah; Tessin, Dale H

2013-01-01

Research has shown that many children in foster care later have psychosocial problems as adults; this is often attributed to cumulative adversities and a lack of supportive caregivers. The risk factors associated with foster care, such as maternal separation and multiple placements, often counteract many protective factors that can ameliorate the effects of childhood adversities. This study assessed the relationship between adverse childhood experiences (ACEs) and psychosocial well-being in women who were in foster care as children. A total of 101 women aged 18-71 years (mean, 36.83 [12.95] years) completed an anonymous online survey based on the 10-item ACE Questionnaire, the Sense of Coherence questionnaire, and the General Health Questionnaire. More than 56% of respondents were identified as experiencing current psychological distress. Sense of coherence scores (mean, 54.26 [15.35]) showed a significant inverse association with both General Health Questionnaire (mean, 14.83 [5.88]) and ACE (mean, 5.68 [2.90]) scores (r = -0.64 and -0.31, respectively) and 97% reported at least 1 ACE, 70% reported ≥ 5 and 33% reported ≥ 8. Linear regressions indicated that ACEs reported to occur before foster care were associated with lower levels of sense of coherence (8%) and higher levels of psychological distress (6%). Physical neglect and living in a dysfunctional household (parental loss, maternal abuse, or household member associated with substance abuse or prison) significantly decreased during foster care by 16 and 19 percentage points, respectively. Rates of emotional and physical abuse did not change. The number of ACEs was associated with the level of psychological distress. Our findings suggest that children entering the foster care system are already vulnerable and at risk of experiencing ACEs during foster care and psychological distress during adulthood. Measures implemented to protect children must not cause more harm than good. Social services that preserve and strengthen the family unit and reduce the number of ACEs both before and during foster care are recommended. Social workers and clinicians who are trained to address and manage the unique developmental needs of children in foster care may help reduce the effects of ACEs and optimize developmental health.

Multigeneration reproductive and developmental toxicity study of bar gene inserted into genetically modified potato on rats.

PubMed

Rhee, Gyu Seek; Cho, Dae Hyun; Won, Yong Hyuck; Seok, Ji Hyun; Kim, Soon Sun; Kwack, Seung Jun; Lee, Rhee Da; Chae, Soo Yeong; Kim, Jae Woo; Lee, Byung Mu; Park, Kui Lea; Choi, Kwang Sik

2005-12-10

Each specific protein has an individual gene encoding it, and a foreign gene introduced to a plant can be used to synthesize a new protein. The identification of potential reproductive and developmental toxicity from novel proteins produced by genetically modified (GM) crops is a difficult task. A science-based risk assessment is needed in order to use GM crops as a conventional foodstuff. In this study, the specific characteristics of GM food and low-level chronic exposure were examined using a five-generation animal study. In each generation, rats were fed a solid pellet containing 5% GM potato and non-GM potato for 10 wk prior to mating in order to assess the potential reproductive and developmental toxic effects. In the multigeneration animal study, there were no GM potato-related changes in body weight, food consumption, reproductive performance, and organ weight. Polymerase chain reaction (PCR) was carried out using extracted genomic DNA to examine the possibility of gene persistence in the organ tissues after a long-term exposure to low levels of GM feed. In each generation, the gene responsible for bar was not found in any of the reproductive organs of the GM potato-treated male and female rats, and the litter-related indexes did not show any genetically modified organism (GMO)-related changes. The results suggest that genetically modified crops have no adverse effects on the multigeneration reproductive-developmental ability.

Lasting effect of intimate partner violence exposure during preschool on aggressive behavior and prosocial skills.

PubMed

Holmes, Megan R; Voith, Laura A; Gromoske, Andrea N

2015-06-01

Intimate partner violence (IPV) exposure can negatively affect children's social behavior. However, it is unknown if the negative effects of IPV exposure during the preschool years are sustained through the early school years, if maladaptive behavior in one domain (e.g., aggressive behavior) is linked to subsequent maladaptive behavior in a different developmental domain (e.g., prosocial skill deficits), and if these relations differ by gender. This study addresses these gaps by using data from a sample of 1,125 children aged 3 to 4 at Time 1 and aged 5 to 7 at Time 2 from the National Survey of Child and Adolescent Well-Being. A series of nested longitudinal structural equation models were tested. Aggressive behavior and prosocial skills were stable across time. Time 1 IPV was associated with increased aggressive behavior at Time 1, which in turn was related to increased Time 2 aggressive behavior. Gender differences emerged; Time 2 IPV was associated with prosocial skills deficits for girls but not boys. A cross-domain relation existed between Time 1 aggressive behavior and Time 2 prosocial skills deficits for boys but not girls. These findings support that behavioral problems demonstrated later in childhood may emerge from earlier adverse developmental experiences and that difficulties in one domain may spill over into other developmental domains. Gender-specific interventions to promote competence in children may contribute to diverting children from maladaptive developmental outcomes. © The Author(s) 2014.

Developmental toxicity of PAH mixtures in fish early life stages. Part II: adverse effects in Japanese medaka.

PubMed

Le Bihanic, Florane; Clérandeau, Christelle; Le Menach, Karyn; Morin, Bénédicte; Budzinski, Hélène; Cousin, Xavier; Cachot, Jérôme

2014-12-01

In aquatic environments, polycyclic aromatic hydrocarbons (PAHs) mostly occur as complex mixtures, for which risk assessment remains problematic. To better understand the effects of PAH mixture toxicity on fish early life stages, this study compared the developmental toxicity of three PAH complex mixtures. These mixtures were extracted from a PAH-contaminated sediment (Seine estuary, France) and two oils (Arabian Light and Erika). For each fraction, artificial sediment was spiked at three different environmental concentrations roughly equivalent to 0.5, 4, and 10 μg total PAH g(-1) dw. Japanese medaka embryos were incubated on these PAH-spiked sediments throughout their development, right up until hatching. Several endpoints were recorded at different developmental stages, including acute endpoints, morphological abnormalities, larvae locomotion, and genotoxicity (comet and micronucleus assays). The three PAH fractions delayed hatching, induced developmental abnormalities, disrupted larvae swimming activity, and damaged DNA at environmental concentrations. Differences in toxicity levels, likely related to differences in PAH proportions, were highlighted between fractions. The Arabian Light and Erika petrogenic fractions, containing a high proportion of alkylated PAHs and low molecular weight PAHs, were more toxic to Japanese medaka early life stages than the pyrolytic fraction. This was not supported by the toxic equivalency approach, which appeared unsuitable for assessing the toxicity of the three PAH fractions to fish early life stages. This study highlights the potential risks posed by environmental mixtures of alkylated and low molecular weight PAHs to early stages of fish development.

Developmental effects of magnetic field (50 Hz) in combination with ionizing radiation and chemical teratogens.

PubMed

Pafková, H; Jerábek, J; Tejnorová, I; Bednár, V

1996-11-01

The influence of a 50 Hz magnetic field (MF) on avian and mammalian embryogenesis, the MF level and vector, as well as the effect of exposure to MF (50 Hz, 10 mT) in combination with X-rays has been recently reported [2,3]. No significant alterations of chick or rat embryogenesis were found after repeated exposures to 50 Hz MF at 10 mT or 6 microT or with different vectors. However, X-ray chick embryotoxicity was significantly affected by repeated exposures of developing organisms to MF. A strong dependence of effect on the type of interaction was revealed. A decrease of X-ray induced teratogenicity was observed when MF preceded X-ray exposure (indirect interaction), while MF exposure applied immediately after X-ray radiation (direct interaction) non-significantly potentiated adverse developmental effects of ionizing radiation. This study deals with the effects of MF in combination with insulin or tetracycline. Exposure of chick embryos to MF influenced the sensitivity of embryonic morphogenetic systems to the subsequently administered chemical teratogens, insulin and/or tetracycline. A protective effect of MF was detected similarly as in the case of indirect interaction with ionizing radiation.

Effects of Estrogen in Gender-dependent Fetal Programming of Adult Cardiovascular Dysfunction.

PubMed

Chen, Zewen; Wang, Lei; Ke, Jun; Xiao, DaLiao

2018-03-01

Epidemiological studies and experimental studies have demonstrated that intrauterine adverse environment increases the risk of cardiovascular disease (CVD) in adulthood. However, whether an individual develops a cardiovascular dysfunctional phenotype may depend on genetic background, age, and sex. In this review, we summarize some of the recent experimental animal studies in the developmental programming of adult CVD with an emphasis on sex differences and the potential role of estrogen in mediating sexual dimorphism. Few epidemiological studies report the effect of sex on the developmental programming of CVD. However, numerous experimental animal studies have shown a sex difference in fetal programming of adult cardiovascular dysfunction. Most of the animal studies indicate that male offspring develop cardiovascular dysfunction and CVD in adulthood, whereas adult females appear to be protected. Estrogen is one of the key factors that contributes to the sex difference of adult CVD. Estrogen/its receptor (ER) may interact with the RAS system by changes of DNA methylation patterns at the target gene promoter, serve as an antioxidant to counteract the prenatal insults-induced heightened ROS, and function as an eNOS activator to increase vasodilation, resulting in the protection of female offspring from the development of hypertension and other CVDs. These studies suggest that estrogen/ER may contribute to sex differences in cardiovascular response to an adverse intrauterine environment and play a significant role in modulating the cardiovascular response in adulthood. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Seizure disorders and developmental disorders: impact on life of affected families-a structured interview.

PubMed

Spindler, Ulrike Petra; Hotopp, Lena Charlott; Bach, Vivien Angela; Hornemann, Frauke; Syrbe, Steffen; Andreas, Anna; Merkenschlager, Andreas; Kiess, Wieland; Bernhard, Matthias Karl; Bertsche, Thilo; Neininger, Martina Patrizia; Bertsche, Astrid

2017-08-01

Seizure disorder and developmental disorder are two of the most common chronic disorders in childhood. Data on perceived parental burden and specific effects on daily life is scarce. We performed a structured interview, consecutively talking to all parents of pediatric outpatients of our university hospital diagnosed with seizure or developmental disorder. Three hundred seven parents (of 317 affected children: 53 with seizure disorder, 44 with specific developmental disorder, 35 with learning disorder, 71 with intellectual disability, 15 with seizure + specific developmental disorder, 23 with seizure + learning disorder, 76 with seizure disorder + intellectual disability) were interviewed. Parents of children with both seizure disorder and intellectual disability stated the highest constraints in daily life, regarding friends, hobbies, emotional pressure, occupation, partnership, habitation, and financial burden. Due to diagnosis of seizure or developmental disorder, 155/307 (51%) parents reduced their working hours/stopped working, 62/307 (20%) changed their habitation, and 46/307 (15%) broke up. As judged by parents, 148/317 (47%) children are being discriminated against, even own family/friends and educators are held responsible. Parents perceive changes in their daily life and discrimination of their children due to their children's seizure and developmental disorders. An intellectual disability combined with seizure disorder caused the highest constraint. What is Known: • Seizure and/or developmental disorders of children may adversely influence quality of life for affected parents. • Caring for a child with special health care needs can take complete attention and own parental needs may therefore be difficult to meet. What is New: • Two out of three parents stated changes of their daily life such as quitting work, change of habitation, or breakup of partnership due to their child's diagnosis. • As judged by the parents, one in two children with developmental disorder of any kind is being discriminated against, even teachers and own family are held responsible.

Developmental toxicity evaluation of inhaled tertiary amyl methyl ether in mice and rats.

PubMed

Welsch, Frank; Elswick, Barbara; James, R Arden; Marr, Melissa C; Myers, Christina B; Tyl, Rochelle W

2003-01-01

This evaluation was part of a much more comprehensive testing program to characterize the mammalian toxicity potential of the gasoline oxygenator additive tertiary amyl methyl ether (TAME), and was initiated upon a regulatory agency mandate. A developmental toxicity hazard identification study was conducted by TAME vapor inhalation exposure in two pregnant rodent species. Timed-pregnant CD(Sprague-Dawley) rats and CD-1 mice, 25 animals per group, inhaled TAME vapors containing 0, 250, 1500 or 3500 ppm for 6 h a day on gestational days 6-16 (mice) or 6-19 (rats). The developmental toxicity hazard potential was evaluated following the study design draft guidelines and end points proposed by the United States Environmental Protection Agency. Based on maternal body weight changes during pregnancy, the no-observable-adverse-effect level (NOAEL) was 250 ppm for maternal toxicity in rats and 1500 ppm for developmental toxicity in rats using the criterion of near-term fetal body weights. In mice, more profound developmental toxicity was present than in rats, at both 1500 and 3500 ppm. At the highest concentration, mouse litters revealed more late fetal deaths, significantly reduced fetal body weights per litter and increased incidences of cleft palate (classified as an external malformation), as well as enlarged lateral ventricles of the cerebrum (a visceral variation). At 1500 ppm, mouse fetuses also exhibited an increased incidence of cleft palate and the dam body weights were reduced. Therefore, the NOAEL for the mouse maternal and developmental toxicity was 250 ppm under the conditions of this study. Copyright 2003 John Wiley & Sons, Ltd.

Maternal PUFA status but not prenatal methylmercury exposure is associated with children's language functions at age five years in the Seychelles.

PubMed

Strain, J J; Davidson, Philip W; Thurston, Sally W; Harrington, Donald; Mulhern, Maria S; McAfee, Alison J; van Wijngaarden, Edwin; Shamlaye, Conrad F; Henderson, Juliette; Watson, Gene E; Zareba, Grazyna; Cory-Slechta, Deborah A; Lynch, Miranda; Wallace, Julie M W; McSorley, Emeir M; Bonham, Maxine P; Stokes-Riner, Abbie; Sloane-Reeves, Jean; Janciuras, Joanne; Wong, Rosa; Clarkson, Thomas W; Myers, Gary J

2012-11-01

Evidence from the Seychelles Child Development Nutrition Study suggests that maternal nutritional status can modulate the relationship between prenatal methylmercury (MeHg) exposure and developmental outcomes in children. The aim of this study was to investigate whether maternal PUFA status was a confounding factor in any possible associations between prenatal MeHg exposure and developmental outcomes at 5 y of age in the Republic of Seychelles. Maternal status of (n-3) and (n-6) PUFA were measured in serum collected at 28 wk gestation and delivery. Prenatal MeHg exposure was determined in maternal hair collected at delivery. At 5 y of age, the children completed a comprehensive range of sensitive developmental assessments. Complete data from 225 mothers and their children were available for analysis. Multiple linear regression analyses revealed Preschool Language Scale scores of the children improved with increasing maternal serum DHA [22:6(n-3)] concentrations and decreased with increasing arachidonic acid [20:4(n-6)] concentrations, albeit verbal intelligence improved with increasing (n-6) PUFA concentrations in maternal serum. There were no adverse associations between MeHg exposure and developmental outcomes. These findings suggest that higher fish consumption, resulting in higher maternal (n-3) PUFA status, during pregnancy is associated with beneficial developmental effects rather than detrimental effects resulting from the higher concomitant exposures of the fetus to MeHg. The association of maternal (n-3) PUFA status with improved child language development may partially explain the authors' previous finding of improving language scores, as prenatal MeHg exposure increased in an earlier mother-child cohort in the Seychelles where maternal PUFA status was not measured.

Evaluation of developmental toxicity in rats exposed to the environmental estrogen bisphenol A during pregnancy.

PubMed

Kim, J C; Shin, H C; Cha, S W; Koh, W S; Chung, M K; Han, S S

2001-10-19

Bisphenol A (BPA) is an essential component of epoxy resins used in the lacquer lining of metal food cans, as a component of polycarbonates, and in dental sealants. The present study was conducted in an attempt to evaluate the adverse effects of the environmental estrogen BPA on initiation and maintenance of pregnancy and embryofetal development after maternal exposure during the entire period of pregnancy in Sprague-Dawley rats. The test chemical was administered by gavage to mated females from days 1 to 20 of gestation (sperm in varginal lavage = day 0) at dose levels of 0, 100, 300, and 1000 mg/kg. All females were subjected to caesarean section on day 21 of gestation and their fetuses were examined for external, visceral and skeletal abnormalities. In the 1000 mg/kg group, significant toxic effects including abnormal clinical signs, decreased maternal body weight and body weight gain, and reduced food consumption were observed in pregnant rats. An increase in pregnancy failure was also found in the successfully mated females. In addition, increased number of embryonal deaths, increased postimplantation loss, reduced litter size and fetal body weight, and decreased number of fetal ossification centers of several skeletal districts were seen. On the contrary, no significant changes induced by BPA were detected in the number of corpora lutea and implantation sites and by fetal morphological examinations. In the 300 mg/kg group, suppressed maternal body weight and body weight gain, decreased food intake and reduced body weight of male fetuses were seen. There were no adverse signs of either maternal toxicity or developmental toxicity in the 100 mg/kg group. It was concluded that BPA administration during the entire period of pregnancy in rats produced pregnancy failure, pre- and postimplantation loss, fetal developmental delay and severe maternal toxicity, but no embryo-fetal dysmorphogenesis at an oral exposure level of 1000 mg/kg.

Iron deficiency anemia: adverse effects on infant psychomotor development.

PubMed

Walter, T; De Andraca, I; Chadud, P; Perales, C G

1989-07-01

In a double-blind, placebo-control prospective cohort study of 196 infants from birth to 15 months of age, assessment was made at 12 months of age of the relationship between iron status and psychomotor development, the effect of a short-term (10-day) trial of oral iron vs placebo, and the effect of long-term (3 months) oral iron therapy. Development was assessed with the mental and psychomotor indices and the infant behavior record of the Bayley Scales of Infant Development in 39 anemic, 30 control, and 127 nonanemic iron-deficient children. Anemic infants had significantly lower Mental and Psychomotor Developmental Index scores than control infants or nonanemic iron-deficient infants (one-way analysis of variance, P less than .0001). Control infants and nonanemic iron-deficient infants performed comparably. No difference was noted between the effect of oral administration of iron or placebo after 10 days or after 3 months of iron therapy. Among anemic infants a hemoglobin concentration less than 10.5 g/dL and duration of anemia of greater than 3 months were correlated with significantly lower motor and mental scores (P less than .05). Anemic infants failed specifically in language capabilities and body balance-coordination skills when compared with controls. These results, in a design in which intervening variables were closely controlled, suggest that when iron deficiency progresses to anemia, but not before, adverse influences in the performance of developmental tests appear and persist for at least 3 months despite correction of anemia with iron therapy. If these impairments prove to be long standing, prevention of iron deficiency anemia in early infancy becomes the only way to avoid them.

Developmental neurotoxicity and autism: A potential link between indoor neuroactive pollutants and the curious birth order risk factor.

PubMed

Gray, Wesley A; Billock, Vincent A

2017-11-01

Epidemiological and demographic studies find an increased risk of autism among first-borns. Toxicological studies show that some semi-volatile substances found in infant products produce adverse effects in neural and endocrine systems of animals, including behavioral and developmental effects. Several factors elevate the exposure of human infants to these chemicals. The highest exposures found in infants are comparable to the exposures that induce neural toxicity in animals. A review of these literatures suggests a linking hypothesis that could bridge the epidemiological and toxicological lines of evidence: an infant's exposure to neuroactive compounds emitted by infant products is increased by product newness and abundance; exposure is likely maximized for first-born children in families that can afford new products. Exposure is reduced for subsequently-born children who reuse these now neuroactive-depleted products. The presence of neuroactive chemical emissions from infant products has implications for birth-order effects and for other curious risk factors in autism, including gender, socioeconomic status, and season-of-birth risk factors. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

Maternal exposure to di(2-ethylhexyl)phthalate (DEHP) promotes the transgenerational inheritance of adult-onset reproductive dysfunctions through the female germline in mice

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

Pocar, Paola, E-mail: paola.pocar@unimi.it; Fianda

Endocrine disruptors (EDs) are compounds known to promote transgenerational inheritance of adult-onset disease in subsequent generations after maternal exposure during fetal gonadal development. This study was designed to establish whether gestational and lactational exposure to the plasticizer di(2-ethylhexyl)phthalate (DEHP) at environmental doses promotes transgenerational effects on reproductive health in female offspring, as adults, over three generations in the mouse. Gestating F0 mouse dams were exposed to 0, 0.05, 5 mg/kg/day DEHP in the diet from gestational day 0.5 until the end of lactation. The incidence of adult-onset disease in reproductive function was recorded in F1, F2 and F3 female offspring.more » In adult F1 females, DEHP exposure induced reproductive adverse effects with: i) altered ovarian follicular dynamics with reduced primordial follicular reserve and a larger growing pre-antral follicle population, suggesting accelerated follicular recruitment; ii) reduced oocyte quality and embryonic developmental competence; iii) dysregulation of the expression profile of a panel of selected ovarian and pre-implantation embryonic genes. F2 and F3 female offspring displayed the same altered reproductive morphological phenotype and gene expression profiles as F1, thus showing transgenerational transmission of reproductive adverse effects along the female lineage. These findings indicate that in mice exposure to DEHP at doses relevant to human exposure during gonadal sex determination significantly perturbs the reproductive indices of female adult offspring and subsequent generations. Evidence of transgenerational transmission has important implications for the reproductive health and fertility of animals and humans, significantly increasing the potential biohazards of this toxicant. - Highlights: • Maternal exposure to DEHP transgenerationally affects female reproductive health. • DEHP reduced ovarian follicular reserve up to the third generation. • DEHP reduced oocyte and blastocyst developmental competence up to F3. • DEHP altered expression levels for key genes in ovary and blastocysts up to F4. • DEHP's adverse effects were observed at doses relevant for human exposure.« less

Revolutionizing Toxicity Testing For Predicting Developmental Outcomes (DNT4)

EPA Science Inventory

Characterizing risk from environmental chemical exposure currently requires extensive animal testing; however, alternative approaches are being researched to increase throughput of chemicals screened, decrease reliance on animal testing, and improve accuracy in predicting adverse...

Predictive Models and Computational Embryology

EPA Science Inventory

EPA’s ‘virtual embryo’ project is building an integrative systems biology framework for predictive models of developmental toxicity. One schema involves a knowledge-driven adverse outcome pathway (AOP) framework utilizing information from public databases, standardized ontologies...

Early postnatal exposure to ultrafine particulate matter air pollution: persistent ventriculomegaly, neurochemical disruption, and glial activation preferentially in male mice.

PubMed

Allen, Joshua L; Liu, Xiufang; Pelkowski, Sean; Palmer, Brian; Conrad, Katherine; Oberdörster, Günter; Weston, Douglas; Mayer-Pröschel, Margot; Cory-Slechta, Deborah A

2014-09-01

Air pollution has been associated with adverse neurological and behavioral health effects in children and adults. Recent studies link air pollutant exposure to adverse neurodevelopmental outcomes, including increased risk for autism, cognitive decline, ischemic stroke, schizophrenia, and depression. We sought to investigate the mechanism(s) by which exposure to ultrafine concentrated ambient particles (CAPs) adversely influences central nervous system (CNS) development. We exposed C57BL6/J mice to ultrafine (< 100 nm) CAPs using the Harvard University Concentrated Ambient Particle System or to filtered air on postnatal days (PNDs) 4-7 and 10-13, and the animals were euthanized either 24 hr or 40 days after cessation of exposure. Another group of males was exposed at PND270, and lateral ventricle area, glial activation, CNS cytokines, and monoamine and amino acid neurotransmitters were quantified. We observed ventriculomegaly (i.e., lateral ventricle dilation) preferentially in male mice exposed to CAPs, and it persisted through young adulthood. In addition, CAPs-exposed males generally showed decreases in developmentally important CNS cytokines, whereas in CAPs-exposed females, we observed a neuroinflammatory response as indicated by increases in CNS cytokines. We also saw changes in CNS neurotransmitters and glial activation across multiple brain regions in a sex-dependent manner and increased hippocampal glutamate in CAPs-exposed males. We observed brain region- and sex-dependent alterations in cytokines and neurotransmitters in both male and female CAPs-exposed mice. Lateral ventricle dilation (i.e., ventriculomegaly) was observed only in CAPs-exposed male mice. Ventriculomegaly is a neuropathology that has been associated with poor neurodevelopmental outcome, autism, and schizophrenia. Our findings suggest alteration of developmentally important neurochemicals and lateral ventricle dilation may be mechanistically related to observations linking ambient air pollutant exposure and adverse neurological/neurodevelopmental outcomes in humans.

Nutritional status of foster children in the U.S.: Implications for cognitive and behavioral development☆

PubMed Central

Tooley, Ursula A.; Makhoul, Zeina; Fisher, Philip A.

2016-01-01

Objective Children in foster care are at greater risk for poor health, physical, cognitive, behavioral, and developmental outcomes than are children in the general population. Considerable research links early nutrition to later cognitive and behavioral outcomes. The aim of this narrative review is to examine the prevalence of poor nutrition and its relation to subsequent health and development in foster children. Method Relevant studies for inclusion were identified from numerous sources (e.g., PubMed, Google Scholar, and reference sections). Inclusion criteria were studies published between 1990 and 2016 of (i) the nutritional status of children in foster care or (ii) the nutritional status of children exposed to early adversity (e.g., low-income and internationally adopted children) or (iii) the developmental effects of poor nutrition and micronutrient deficiencies. Results Two key findings that have adverse implications for cognitive development emerged: (i) the prevalence of anemia and iron-deficiency anemia is higher among foster children than among the general population of children in the U.S., and (ii) the developmental demands of catch-up growth post-placement may lead to micronutrient deficiencies even after children have begun sufficient dietary intake of these nutrients. Moreover, there is a paucity of recent studies on the nutritional status of children in foster care, despite the multiple factors that may place them at risk for malnutrition. Conclusion Attention to nutritional status among care providers and medical professionals may remove one of the possible negative influences on foster children's development and in turn significantly alter their trajectories and place them on a more positive path early in life. Recommendations for further research, policy, and practice are discussed. PMID:28626279

Development assessment of HIV exposed children aged 6-18 months: a cohort study from North India.

PubMed

Rajan, Remya; Seth, Anju; Mukherjee, Sharmila B; Chandra, Jagdish

2017-11-01

HIV exposed children are vulnerable to developmental delay irrespective of their HIV status due to combined effect of risk factors like poverty, prenatal drug exposure, stress and chronic illness in family and malnutrition. This cohort study assessed the development of 50 HIV exposed children aged 6-18 months at a Pediatric Centre of Excellence in HIV care in India. The development was assessed using Development Assessment Scale for Indian Infants (DASII) at enrolment, 3 and 6 months later. The development quotient (DQ) scores and proportion of children with developmental delay (DQ ≤ 70) were compared among two sub-groups, HIV infected (HI) and HIV exposed uninfected (HEU) children. The various social and clinical factors affecting development were studied by univariate and multivariate analysis. Prevalence of developmental delay was 2.4% in the HEU (n = 41), and 33.3% in HI (n = 9). The DQ of HI was significantly lower than that of HEU at all three assessments. The DQ of HI were also significantly lower compared to the HEU at ages 12.1-18 months (83.37 ± 20.73 vs 94.68 ± 5.13, p = 0.005) and 18.1-24 months (84.55 ± 15.35 vs 94.63 ± 5.86, p = 0.006) respectively. The development of HEU was adversely affected by lower socioeconomic status and presence of wasting. In addition, development of HI was also adversely influenced by presence of stunting and opportunistic infections, advanced disease stage and shorter ART duration. We conclude that with optimum care, HEU can have a normal development, while a considerable proportion of HI may continue to have delayed development.

Nutritional status of foster children in the U.S.: Implications for cognitive and behavioral development.

PubMed

Tooley, Ursula A; Makhoul, Zeina; Fisher, Philip A

2016-11-01

Children in foster care are at greater risk for poor health, physical, cognitive, behavioral, and developmental outcomes than are children in the general population. Considerable research links early nutrition to later cognitive and behavioral outcomes. The aim of this narrative review is to examine the prevalence of poor nutrition and its relation to subsequent health and development in foster children. Relevant studies for inclusion were identified from numerous sources (e.g., PubMed, Google Scholar, and reference sections). Inclusion criteria were studies published between 1990 and 2016 of (i) the nutritional status of children in foster care or (ii) the nutritional status of children exposed to early adversity (e.g., low-income and internationally adopted children) or (iii) the developmental effects of poor nutrition and micronutrient deficiencies. Two key findings that have adverse implications for cognitive development emerged: (i) the prevalence of anemia and iron-deficiency anemia is higher among foster children than among the general population of children in the U.S., and (ii) the developmental demands of catch-up growth post-placement may lead to micronutrient deficiencies even after children have begun sufficient dietary intake of these nutrients. Moreover, there is a paucity of recent studies on the nutritional status of children in foster care, despite the multiple factors that may place them at risk for malnutrition. Attention to nutritional status among care providers and medical professionals may remove one of the possible negative influences on foster children's development and in turn significantly alter their trajectories and place them on a more positive path early in life. Recommendations for further research, policy, and practice are discussed.

The toxicological properties of petroleum gases.

PubMed

McKee, Richard H; Herron, Deborah; Saperstein, Mark; Podhasky, Paula; Hoffman, Gary M; Roberts, Linda

2014-01-01

To characterize the toxicological hazards of petroleum gases, 90-day inhalation toxicity (Organization for Economic Cooperation and Development [OECD] 413) and developmental toxicity (OECD 414) tests were conducted with liquefied propane gas (LPG) at concentrations of 1000, 5000, or 10,000 ppm. A micronucleus test (OECD 474) of LPG was also conducted. No systemic or developmental effects were observed; the overall no observed adverse effect concentration (NOAEC) was 10,000 ppm. Further, there was no effect of LPG exposure at levels up to 10,000 ppm on micronucleus induction and no evidence of bone marrow toxicity. Other alkane gases (ethane, propane, n-butane, and isobutane) were then evaluated in combined repeated exposure studies with reproduction/development toxicity screening tests (OECD 422). There were no toxicologically important changes in parameters relating to systemic toxicity or neurotoxicity for any of these gases at concentrations ranging from 9000 to 16,000 ppm. There was no evidence of effects on developmental or reproductive toxicity in the studies of ethane, propane, or n-butane at the highest concentrations tested. However, there was a reduction in mating in the high-exposure group (9000 ppm) of the isobutane study, which although not significantly different was outside the range previously observed in the testing laboratory. Assuming the reduction in mating to have been toxicologically significant, the NOAEC for the isobutane reproductive toxicity screening test was 3000 ppm (7125 mg/m(3)). A method is proposed by which the toxicity of any of the 106 complex petroleum gas streams can be estimated from its composition.

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

A data-driven weighting scheme for multivariate phenotypic endpoints recapitulates zebrafish developmental cascades

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

Zhang, Guozhu, E-mail: gzhang6@ncsu.edu

Zebrafish have become a key alternative model for studying health effects of environmental stressors, partly due to their genetic similarity to humans, fast generation time, and the efficiency of generating high-dimensional systematic data. Studies aiming to characterize adverse health effects in zebrafish typically include several phenotypic measurements (endpoints). While there is a solid biomedical basis for capturing a comprehensive set of endpoints, making summary judgments regarding health effects requires thoughtful integration across endpoints. Here, we introduce a Bayesian method to quantify the informativeness of 17 distinct zebrafish endpoints as a data-driven weighting scheme for a multi-endpoint summary measure, called weightedmore » Aggregate Entropy (wAggE). We implement wAggE using high-throughput screening (HTS) data from zebrafish exposed to five concentrations of all 1060 ToxCast chemicals. Our results show that our empirical weighting scheme provides better performance in terms of the Receiver Operating Characteristic (ROC) curve for identifying significant morphological effects and improves robustness over traditional curve-fitting approaches. From a biological perspective, our results suggest that developmental cascade effects triggered by chemical exposure can be recapitulated by analyzing the relationships among endpoints. Thus, wAggE offers a powerful approach for analysis of multivariate phenotypes that can reveal underlying etiological processes. - Highlights: • Introduced a data-driven weighting scheme for multiple phenotypic endpoints. • Weighted Aggregate Entropy (wAggE) implies differential importance of endpoints. • Endpoint relationships reveal developmental cascade effects triggered by exposure. • wAggE is generalizable to multi-endpoint data of different shapes and scales.« less

Income poverty, poverty co-factors, and the adjustment of children in elementary school.

PubMed

Ackerman, Brian P; Brown, Eleanor D

2006-01-01

Since 1990, there have been great advances in how developmental researchers construct poverty. These advances are important because they may help inform social policy at many levels and help frame how American culture constructs poverty for children, both symbolically and in the opportunities children and families get to escape from poverty. Historically, developmental perspectives have embodied social address and main effects models, snapshot views of poverty effects at single points in time, and a rather narrow focus on income as the symbolic marker of the ecology of disadvantage. More recent views, in contrast, emphasize the diverse circumstances of disadvantaged families and diverse outcomes of disadvantaged children, the multiple sources of risk and the multiple determinants of poor outcomes for these children, dynamic aspects of that ecology, and change as well as continuity in outcome trajectories. The advances also consist of more powerful frames for understanding the ecology of disadvantage and the risk it poses for child outcomes. Most developmental researchers still tend to frame causal variables ultimately in terms of the dichotomy between social causation and social selection views, with a primary emphasis on the former. In part, this framing has reflected limitations of sample size and design, because the theoretical and empirical power of reciprocal selection models is clear (Kim et al., 2003). The conceptual advances that prompt such models include widespread acknowledgement of third variable problems in interpreting effects, of the clear need for multivariate approaches, and the need to pursue mechanisms and moderators of the relations between causal candidates and child outcomes. In the context of these advances, one of the core goals of our research program has been to construct robust representations of environmental adversity for disadvantaged families. Most of our research focuses on contextual co-factors at a family level (e.g., maternal relationship instability), which either have not been described by many researchers or have been described in a way that does not fit the ecology of disadvantage (e.g., marital status). We found that income poverty, key contextual co-factors, and endogenous child attributes tend to show independent and selective associations with child academic competence and externalizing behavior, and that co-factor effects tend to be direct rather than mediated by harsh parenting, tend to have effects that are episodic and concurrent, and are easily- and well-represented by multiple risk indexes that bear powerful relations to child problem behaviors. A second core goal has been to better understand the developmental construction of poor outcomes for disadvantaged children, which requires consideration of dynamic aspects of the ecology and the potential importance of the timing of risk experiences. We found that family instability and change in environmental circumstances predict increases in problem behaviors, and that dose of adversity seems to matter for some variables if it is recent, and not for other variables. Through person-centered research, we also are beginning to understand some factors that seem to underlie the convergence of adjustment problems over grade in school. Many of our co-factor findings and many of our developmental findings seem both complex and double-edged. One edge is that they encourage a certain pessimism in showing how environmental adversity progressively constructs poor outcomes for disadvantaged children in school. Overall, for instance, we saw more problems and more multi-dimensional problems in fifth grade than in first grade, and the impact of environmental change was mostly negative. The other edge, however, is more positive in reflecting the possibility of discontinuity in child adjustment problems associated with positive changes in family circumstances. Findings for minimal persistence and for the strength of recent and concurrent effects argue that the possibility of self-righting and emergent competence in school is robust through the fifth grade even for the most problematic disadvantaged children.

The impact of epilepsy on the adolescent adolescent.

PubMed

Marin, Susana

2005-01-01

Epilepsy is the most common serious neurologic condition affecting adolescents, coinciding with a time of dramatic change in growth, hormones, psychology, and social situations. Adolescents with epilepsy are sensitive to peer norms and beliefs and may limit disclosure of their chronic illness to feel less different or stigmatized. They may also explore the world of alcohol and recreational drugs, like others in their peer group, as well as experiment with their own medications. The goal of treatment should be maintenance of a normal lifestyle with complete seizure control, minimal adverse effects, and achievement of normal adolescent milestones. Adolescents with epilepsy have an increased incidence of depression because of the combination of the unpredictable nature of epilepsy, a perceived lack of control, uncontrollable adverse events, and negative perceptions of themselves. The purpose of this article is to summarize the physical, developmental, emotional, and cognitive effects of epilepsy on adolescents. By increasing the awareness of healthcare providers, interventions designed to prevent further negative consequences can be considered for adolescents with epilepsy.

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

Presentations: Adverse Outcome Pathways for Abnormal Phenotypes

EPA Science Inventory

Birth defects affect many infants and the etiology for most are unknown. Although environmental factors are known to influence pregnancy outcome, thousands of chemicals, present in the environment, are untested for developmental toxicity potential. Application of computational p...

Predictive Models and Computational Toxicology (II IBAMTOX)

EPA Science Inventory

EPA’s ‘virtual embryo’ project is building an integrative systems biology framework for predictive models of developmental toxicity. One schema involves a knowledge-driven adverse outcome pathway (AOP) framework utilizing information from public databases, standardized ontologies...

Reproductive toxicity of carbon nanomaterials: a review

NASA Astrophysics Data System (ADS)

Vasyukova, I.; Gusev, A.; Tkachev, A.

2015-11-01

In the current review, we assembled the experimental evidences of an association between carbon nanomaterials including carbon black, graphite nanoplatelets, graphene, single- and multi-walled carbon nanotubes, and fullerene exposure and adverse reproductive and developmental effects, in vitro and in vivo studies. It is shown that carbon nanomaterials reveal toxic effect on reproductive system and offspring development of the animals of various system groups to a certain degree depending on carbon crystal structure. Although this paper provides initial information about the potential male and female reproductive toxicity of carbon nanomaterials, further studies, using characterized nanoparticles, relevant routes of administration, and doses closely reflecting all the expected levels of exposure are needed.

Toxic stress history and hypothalamic-pituitary-adrenal axis function in a social stress task: Genetic and epigenetic factors.

PubMed

Lapp, Hannah E; Ahmed, Sarah; Moore, Celia L; Hunter, Richard G

2018-02-21

Histories of early life stress (ELS) or social discrimination can reach levels of severity characterized as toxic to mental and physical health. Such toxic social stress during development has been linked to altered acute hypothalamic-pituitary-adrenal (HPA) response to social stress in adulthood. However, there are important individual differences in the size and direction of these effects. We explored developmental, genetic, epigenetic, and contextual sources of individual differences in the relationship between ELS, discrimination, and adult responses to acute social stress in a standard laboratory test. Additional measures included perceived status, social support, background activity of HPA axis, and genetic variants in aspects of the stress response system. Participants (n = 90) answered questions about historical and ongoing stress, provided a DNA sample to examine genetic polymorphisms and epigenetic marks, and underwent the Trier Social Stress Test (TSST) during which three saliva samples were collected to assess HPA function. Individuals who reported high levels of childhood adversity had a blunted salivary cortisol response to the TSST. Childhood adversity, discrimination experiences, and FKBP5 genotype were found to predict pretest cortisol levels. Following up on recent observations that the glucocorticoid receptor directly interacts with the mitochondrial genome, particularly the NADH dehydrogenase 6 (MT-ND6) gene, individuals who reported high childhood adversity were also found to have higher percent methylation across six CpG sites upstream of MT-ND6. These findings suggest multiple contributions across psychological, genetic, epigenetic, and social domains to vulnerability and resilience in hypothalamic-pituitary-adrenal axis regulation. Further study to examine how these multiple contributors affect developmental endpoints through integrated or independent pathways will be of use. Copyright © 2018 Elsevier Inc. All rights reserved.

Infant Parasympathetic and Sympathetic Activity during Baseline, Stress and Recovery: Interactions with Prenatal Adversity Predict Physical Aggression in Toddlerhood.

PubMed

Suurland, J; van der Heijden, K B; Huijbregts, S C J; van Goozen, S H M; Swaab, H

2018-05-01

Exposure to prenatal adversity is associated with aggression later in life. Individual differences in autonomic nervous system (ANS) functioning, specifically nonreciprocal activation of the parasympathetic (PNS) and sympathetic (SNS) nervous systems, increase susceptibility to aggression, especially in the context of adversity. Previous work examining interactions between early adversity and ANS functioning in infancy is scarce and has not examined interaction between PNS and SNS. This study examined whether the PNS and SNS moderate the relation between cumulative prenatal risk and early physical aggression in 124 children (57% male). Cumulative risk (e.g., maternal psychiatric disorder, substance (ab)use, and social adversity) was assessed during pregnancy. Parasympathetic respiratory sinus arrhythmia (RSA) and sympathetic pre-ejection period (PEP) at baseline, in response to and during recovery from emotional challenge were measured at 6 months. Physical aggression and non-physical aggression/oppositional behavior were measured at 30 months. The results showed that cumulative prenatal risk predicted elevated physical aggression and non-physical aggression/oppositional behavior in toddlerhood; however, the effects on physical aggression were moderated by PNS and SNS functioning. Specifically, the effects of cumulative risk on physical aggression were particularly evident in children characterized by low baseline PNS activity and/or by nonreciprocal activity of the PNS and SNS, characterized by decreased activity (i.e., coinhibition) or increased activity (i.e., coactivation) of both systems at baseline and/or in response to emotional challenge. These findings extend our understanding of the interaction between perinatal risk and infant ANS functioning on developmental outcome.

20170312 - Adverse Outcome Pathway (AOP) framework for ...

EPA Pesticide Factsheets

Vascular development commences with de novo assembly of a primary capillary plexus (vasculogenesis) followed by its expansion (angiogenesis) and maturation (angio-adaptation) into a hierarchical system of arteries and veins. These processes are tightly regulated by genetic signals and environmental factors linked to morphogenesis and microphysiology. Gestational exposure to some chemicals disrupts vascular development leading to adverse outcomes. To broadly assess consequences of gestational toxicant exposure on vascular development, an Adverse Outcome Pathway (AOP) framework was constructed that integrates data from ToxCast high-throughput screening (HTS) assays with pathway-level information from the literature and public databases. The AOP-based model resolved the ToxCast library (1065 compounds) into a matrix based on several dozen molecular functions critical for developmental angiogenesis. A sample of 38 ToxCast chemicals selected across the matrix tested model performance. Putative vascular disrupting chemical (pVDC) bioactivity was assessed by multiple laboratories utilizing diverse angiogenesis assays, including: transgenic zebrafish, complex human cell co-cultures, engineered microscale systems, and human-synthetic models. The ToxCast pVDC signature predicted vascular disruption in a manner that was chemical-specific and assay-dependent. An AOP for developmental vascular toxicity was constructed that focuses on inhibition of VEGF receptor (VEGFR2). Thi

Adverse Outcome Pathway (AOP) framework for embryonic ...

EPA Pesticide Factsheets

Vascular development commences with de novo assembly of a primary capillary plexus (vasculogenesis) followed by its expansion (angiogenesis) and maturation (angio-adaptation) into a hierarchical system of arteries and veins. These processes are tightly regulated by genetic signals and environmental factors linked to morphogenesis and microphysiology. Gestational exposure to some chemicals disrupts vascular development leading to adverse outcomes. To broadly assess consequences of gestational toxicant exposure on vascular development, an Adverse Outcome Pathway (AOP) framework was constructed that integrates data from ToxCast high-throughput screening (HTS) assays with pathway-level information from the literature and public databases. The AOP-based model resolved the ToxCast library (1065 compounds) into a matrix based on several dozen molecular functions critical for developmental angiogenesis. A sample of 38 ToxCast chemicals selected across the matrix tested model performance. Putative vascular disrupting chemical (pVDC) bioactivity was assessed by multiple laboratories utilizing diverse angiogenesis assays, including: transgenic zebrafish, complex human cell co-cultures, engineered microscale systems, and human-synthetic models. The ToxCast pVDC signature predicted vascular disruption in a manner that was chemical-specific and assay-dependent. An AOP for developmental vascular toxicity was constructed that focuses on inhibition of VEGF receptor (VEGFR2). Thi

Childhood exposure to violence and lifelong health: clinical intervention science and stress-biology research join forces.

PubMed

Moffitt, Terrie E

2013-11-01

Many young people who are mistreated by an adult, victimized by bullies, criminally assaulted, or who witness domestic violence react to this violence exposure by developing behavioral, emotional, or learning problems. What is less well known is that adverse experiences like violence exposure can lead to hidden physical alterations inside a child's body, alterations that may have adverse effects on life-long health. We discuss why this is important for the field of developmental psychopathology and for society, and we recommend that stress-biology research and intervention science join forces to tackle the problem. We examine the evidence base in relation to stress-sensitive measures for the body (inflammatory reactions, telomere erosion, epigenetic methylation, and gene expression) and brain (mental disorders, neuroimaging, and neuropsychological testing). We also review promising interventions for families, couples, and children that have been designed to reduce the effects of childhood violence exposure. We invite intervention scientists and stress-biology researchers to collaborate in adding stress-biology measures to randomized clinical trials of interventions intended to reduce effects of violence exposure and other traumas on young people.

34 CFR 300.8 - Child with a disability.

Code of Federal Regulations, 2010 CFR

2010-07-01

... development, communication development, social or emotional development, or adaptive development; and (2) Who... means a developmental disability significantly affecting verbal and nonverbal communication and social interaction, generally evident before age three, that adversely affects a child's educational performance...

Developmental telomere attrition predicts impulsive decision-making in adult starlings

PubMed Central

Bateson, Melissa; Brilot, Ben O.; Gillespie, Robert; Monaghan, Pat; Nettle, Daniel

2015-01-01

Animals in a poor biological state face reduced life expectancy, and as a consequence should make decisions that prioritize immediate survival and reproduction over long-term benefits. We tested the prediction that if, as has been suggested, developmental telomere attrition is a biomarker of state and future life expectancy, then individuals who have undergone greater developmental telomere attrition should display greater choice impulsivity as adults. We measured impulsive decision-making in a cohort of European starlings (Sturnus vulgaris) in which we had previously manipulated developmental telomere attrition by cross-fostering sibling chicks into broods of different sizes. We show that as predicted by state-dependent optimality models, individuals who had sustained greater developmental telomere attrition and who had shorter current telomeres made more impulsive foraging decisions as adults, valuing smaller, sooner food rewards more highly than birds with less attrition and longer telomeres. Our findings shed light on the biological embedding of early adversity and support a functional explanation for its consequences that could be applicable to other species, including humans. PMID:25473012

Enhancing the fathead minnow fish embryo toxicity test: Optimizing embryo production and assessing the utility of additional test endpoints.

PubMed

Roush, Kyle S; Krzykwa, Julie C; Malmquist, Jacob A; Stephens, Dane A; Sellin Jeffries, Marlo K

2018-05-30

The fathead minnow fish embryo toxicity (FET) test has been identified as a potential alternative to toxicity test methods that utilize older fish. However, several challenges have been identified with the fathead minnow FET test, including: 1) difficulties in obtaining appropriately-staged embryos for FET test initiation, 2) a paucity of data comparing fathead minnow FET test performance to the fathead minnow larval growth and survival (LGS) test and 3) a lack of sublethal endpoints that could be used to estimate chronic toxicity and/or predict adverse effects. These challenges were addressed through three study objectives. The first objective was to optimize embryo production by assessing the effect of breeding group composition (number of males and females) on egg production. Results showed that groups containing one male and four females produced the largest clutches, enhancing the likelihood of procuring sufficient numbers of embryos for FET test initiation. The second study objective was to compare the performance of the FET test to that of the fathead minnow LGS test using three reference toxicants. The FET and LGS tests were similar in their ability to predict the acute toxicity of sodium chloride and ethanol, but the FET test was found to be more sensitive than the LGS test for sodium dodecyl sulfate. The last objective of the study was to evaluate the utility and practicality of several sublethal metrics (i.e., growth, developmental abnormalities and growth- and stress-related gene expression) as FET test endpoints. Developmental abnormalities, including pericardial edema and hatch success, were found to offer the most promise as additional FET test endpoints, given their responsiveness, potential for predicting adverse effects, ease of assessment and low cost of measurement. Copyright © 2018 Elsevier Inc. All rights reserved.

Goldilocks' Determination of What New In Vivo Data are "Just Right" for Different Common Drug Development Scenarios, Part 1.

PubMed

Bowman, Christopher J; Chapin, Robert E

2016-08-01

As alternative models and scientific advancements improve the ability to predict developmental toxicity, the challenge is how to best use this information to support safe use of pharmaceuticals in humans. While in vivo experimental data are often expected, there are other important considerations that drive the impact of developmental toxicity data to human risk assessment and product labeling. These considerations include three key elements: (1) the drug's likelihood of producing off-target toxicities, (2) risk tolerance of adverse effects based on indication and patient population, and (3) how much is known about the effects of modulating the target in pregnancy and developmental biology. For example, there is little impact or value of a study in pregnant monkeys to inform the risk assessment for a highly specific monoclonal antibody indicated for a life-threatening indication against a target known to be critical for pregnancy maintenance and fetal survival. In contrast, a small molecule to a novel biological target for a chronic lifestyle indication would warrant more safety data than simply in vitro studies and a literature review. Rather than accounting for innumerable theoretical possibilities surrounding each potential submission's profile, we consolidated most of the typical situations into eight possible scenarios across these three elements, and present a discussion of these scenarios here. We hope that this framework will facilitate a rational approach to determining what new information is required to inform developmental toxicity risk of pharmaceuticals in context of the specific needs of each program while reducing animal use where possible. © 2016 Wiley Periodicals, Inc.

Cardiac Development in Zebrafish and Human Embryonic Stem Cells Is Inhibited by Exposure to Tobacco Cigarettes and E-Cigarettes

PubMed Central

Palpant, Nathan J.; Hofsteen, Peter; Pabon, Lil; Reinecke, Hans; Murry, Charles E.

2015-01-01

Background Maternal smoking is a risk factor for low birth weight and other adverse developmental outcomes. Objective We sought to determine the impact of standard tobacco cigarettes and e-cigarettes on heart development in vitro and in vivo. Methods Zebrafish (Danio rerio) were used to assess developmental effects in vivo and cardiac differentiation of human embryonic stem cells (hESCs) was used as a model for in vitro cardiac development. Results In zebrafish, exposure to both types of cigarettes results in broad, dose-dependent developmental defects coupled with severe heart malformation, pericardial edema and reduced heart function. Tobacco cigarettes are more toxic than e-cigarettes at comparable nicotine concentrations. During cardiac differentiation of hESCs, tobacco smoke exposure results in a delayed transition through mesoderm. Both types of cigarettes decrease expression of cardiac transcription factors in cardiac progenitor cells, suggesting a persistent delay in differentiation. In definitive human cardiomyocytes, both e-cigarette- and tobacco cigarette-treated samples showed reduced expression of sarcomeric genes such as MLC2v and MYL6. Furthermore, tobacco cigarette-treated samples had delayed onset of beating and showed low levels and aberrant localization of N-cadherin, reduced myofilament content with significantly reduced sarcomere length, and increased expression of the immature cardiac marker smooth muscle alpha-actin. Conclusion These data indicate a negative effect of both tobacco cigarettes and e-cigarettes on heart development in vitro and in vivo. Tobacco cigarettes are more toxic than E-cigarettes and exhibit a broader spectrum of cardiac developmental defects. PMID:25978043

Ultraviolet Photolysis of Chlorpyrifos: Developmental Neurotoxicity Modeled in PC12 Cells

PubMed Central

Slotkin, Theodore A.; Seidler, Frederic J.; Wu, Changlong; MacKillop, Emiko A.; Linden, Karl G.

2009-01-01

Background Ultraviolet photodegradation products from pesticides form both in the field and during water treatment. Objectives We evaluated the photolytic breakdown of the organophosphate pesticide chlorpyrifos (CPF) in terms of both the chemical entities generated by low-pressure ultraviolet C irradiation and their potential as developmental neurotoxicants. Methods We separated by-products using high-performance liquid chromatography and characterized them by gas chromatography/mass spectrometry. We assessed neurotoxicity in neuronotypic PC12 cells, both in the undifferentiated state and during differentiation. Results Photodegradation of CPF in methanol solution generated CPF oxon and trichloropyridinol, products known to retain developmental neurotoxicant actions, as well as a series of related organophosphate and phosphorothionate derivatives. Exposure conditions that led to 50% degradation of CPF thus did not reduce developmental neurotoxicity. The degradation mixture inhibited DNA synthesis in undifferentiated cells to the same extent as native CPF. In differentiating cells, the products likewise retained the full ability to elicit shortfalls in cell number and corresponding effects on cell growth and neurite formation. When the exposure was prolonged to the point where 70% of the CPF was degraded, the adverse effects on PC12 cells were no longer evident; however, these conditions were sufficiently severe to generate toxic products from the methanol vehicle. Conclusions Our results indicate that field conditions or remediation treatments that degrade a significant proportion of the CPF do not necessarily produce inactive products and, indeed, may elicit formation of even more toxic chemicals that are more water soluble and thus have greater field mobility than CPF itself. PMID:19337505

Chlorpyrifos-Oxon Disrupts Zebrafish Axonal Growth and Motor Behavior

PubMed Central

Yang, Dongren; Lauridsen, Holly; Buels, Kalmia; Chi, Lai-Har; La Du, Jane; Bruun, Donald A.; Olson, James R.; Tanguay, Robert L.; Lein, Pamela J.

2011-01-01

Axonal morphology is a critical determinant of neuronal connectivity, and perturbation of the rate or extent of axonal growth during development has been linked to neurobehavioral deficits in animal models and humans. We previously demonstrated that the organophosphorus pesticide (OP) chlorpyrifos (CPF) inhibits axonal growth in cultured neurons. In this study, we used a zebrafish model to determine whether CPF, its oxon metabolite (CPFO), or the excreted metabolite trichloro-2-pyridinol (TCPy) alter spatiotemporal patterns of axonal growth in vivo. Static waterborne exposure to CPFO, but not CPF or TCPy, at concentrations ≥ 0.03μM from 24- to 72-h post fertilization significantly inhibited acetylcholinesterase, and high-performance liquid chromatography detected significantly more TCPy in zebrafish exposed to 0.1μM CPFO versus 1.0μM CPF. These data suggest that zebrafish lack the metabolic enzymes to activate CPF during these early developmental stages. Consistent with this, CPFO, but not CPF, significantly inhibited axonal growth of sensory neurons, primary motoneurons, and secondary motoneurons at concentrations ≥ 0.1μM. Secondary motoneurons were the most sensitive to axonal growth inhibition by CPFO, which was observed at concentrations that did not cause mortality, gross developmental defects, or aberrant somatic muscle differentiation. CPFO effects on axonal growth correlated with adverse effects on touch-induced swimming behavior, suggesting the functional relevance of these structural changes. These data suggest that altered patterns of neuronal connectivity contribute to the developmental neurotoxicity of CPF and demonstrate the relevance of zebrafish as a model for studying OP developmental neurotoxicity. PMID:21346248

Brain Regions Related to Impulsivity Mediate the Effects of Early Adversity on Antisocial Behavior.

PubMed

Mackey, Scott; Chaarani, Bader; Kan, Kees-Jan; Spechler, Philip A; Orr, Catherine; Banaschewski, Tobias; Barker, Gareth; Bokde, Arun L W; Bromberg, Uli; Büchel, Christian; Cattrell, Anna; Conrod, Patricia J; Desrivières, Sylvane; Flor, Herta; Frouin, Vincent; Gallinat, Jürgen; Gowland, Penny; Heinz, Andreas; Ittermann, Bernd; Paillère Martinot, Marie-Laure; Artiges, Eric; Nees, Frauke; Papadopoulos-Orfanos, Dimitri; Poustka, Luise; Smolka, Michael N; Jurk, Sarah; Walter, Henrik; Whelan, Robert; Schumann, Gunter; Althoff, Robert R; Garavan, Hugh

2017-08-15

Individual differences in impulsivity and early adversity are known to be strong predictors of adolescent antisocial behavior. However, the neurobiological bases of impulsivity and their relation to antisocial behavior and adversity are poorly understood. Impulsivity was estimated with a temporal discounting task. Voxel-based morphometry was used to determine the brain structural correlates of temporal discounting in a large cohort (n = 1830) of 14- to 15-year-old children. Mediation analysis was then used to determine whether the volumes of brain regions associated with temporal discounting mediate the relation between adverse life events (e.g., family conflict, serious accidents) and antisocial behaviors (e.g., precocious sexual activity, bullying, illicit substance use). Greater temporal discounting (more impulsivity) was associated with 1) lower volume in frontomedial cortex and bilateral insula and 2) greater volume in a subcortical region encompassing the ventral striatum, hypothalamus and anterior thalamus. The volume ratio between these cortical and subcortical regions was found to partially mediate the relation between adverse life events and antisocial behavior. Temporal discounting is related to regions of the brain involved in reward processing and interoception. The results support a developmental imbalance model of impulsivity and are consistent with the idea that negative environmental factors can alter the developing brain in ways that promote antisocial behavior. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Factors affecting the causality assessment of adverse events following immunisation in paediatric clinical trials: An online survey.

PubMed

Voysey, Merryn; Tavana, Rahele; Farooq, Yama; Heath, Paul T; Bonhoeffer, Jan; Snape, Matthew D

2015-12-16

Serious adverse events (SAEs) in clinical trials require reporting within 24h, including a judgment of whether the SAE was related to the investigational product(s). Such assessments are an important component of pharmacovigilance, however classification systems for assigning relatedness vary across study protocols. This on-line survey evaluated the consistency of SAE causality assessment among professionals with vaccine clinical trial experience. Members of the clinical advisory forum of experts (CAFÉ), a Brighton Collaboration online-forum, were emailed a survey containing SAEs from hypothetical vaccine trials which they were asked to classify. Participants were randomised to either two classification options (related/not related to study immunisation) or three options (possibly/probably/unrelated). The clinical scenarios, were (i) leukaemia diagnosed 5 months post-immunisation with a live RSV vaccine, (ii) juvenile idiopathic arthritis (JIA) 3 months post-immunisation with a group A streptococcal vaccine, (iii) developmental delay diagnosed at age 10 months after infant capsular group B meningococcal vaccine, (iv) developmental delay diagnosed at age 10 months after maternal immunisation with a group B streptococcal vaccine. There were 140 respondents (72 two options, 68 three options). Across all respondents, SAEs were considered related to study immunisation by 28% (leukaemia), 74% (JIA), 29% (developmental delay after infant immunisation) and 42% (developmental delay after maternal immunisation). Having only two options made respondents significantly less likely to classify the SAE as immunisation-related for two scenarios (JIA p=0.0075; and maternal immunisation p=0.045). Amongst study investigators (n=43) this phenomenon was observed for three of the four scenarios: (JIA p=0.0236; developmental delay following infant immunisation p=0.0266; and developmental delay after maternal immunisation p=0.0495). SAE causality assessment is inconsistent amongst study investigators and can be influenced by the classification systems available to them. There is a pressing need for SAE classification systems to be standardised across study protocols. Copyright © 2015 Elsevier Ltd. All rights reserved.

Long-term effects of early life exposure to environmental estrogens on ovarian function: Role of epigenetics

PubMed Central

Cruz, Gonzalo; Foster, Warren; Paredes, Alfonso; Yi, Kun Don; Uzumcu, Mehmet

2014-01-01

Estrogens play an important role in development and function of the brain and reproductive tract. Accordingly, it is thought that developmental exposure to environmental estrogens can disrupt neural and reproductive tract development potentially resulting in long-term alterations in neurobehavior and reproductive function. Many chemicals have been shown to have estrogenic activity whereas others affect estrogen production and turnover resulting in disruption of estrogen signaling pathways. However, these mechanisms and the concentrations required to induce these effects cannot account for the myriad adverse effects of environmental toxicants on estrogen sensitive target tissues. Hence, alternative mechanisms are thought to underlie the adverse effects documented in experimental animal models and thus could be important to human health. In this review, the epigenetic regulation of gene expression is explored as a potential target of environmental toxicants including estrogenic chemicals. We suggest that toxicant-induced changes in epigenetic signatures are important mechanisms underlying disruption of ovarian follicular development. In addition, we discuss how exposure to environmental estrogens during early life can alter gene expression through effects on epigenetic control potentially leading to permanent changes in ovarian physiology. PMID:25040227

Long-term effects of early-life exposure to environmental oestrogens on ovarian function: role of epigenetics.

PubMed

Cruz, G; Foster, W; Paredes, A; Yi, K D; Uzumcu, M

2014-09-01

Oestrogens play an important role in development and function of the brain and reproductive tract. Accordingly, it is considered that developmental exposure to environmental oestrogens can disrupt neural and reproductive tract development, potentially resulting in long-term alterations in neurobehaviour and reproductive function. Many chemicals have been shown to have oestrogenic activity, whereas others affect oestrogen production and turnover, resulting in the disruption of oestrogen signalling pathways. However, these mechanisms and the concentrations required to induce these effects cannot account for the myriad adverse effects of environmental toxicants on oestrogen-sensitive target tissues. Hence, alternative mechanisms are assumed to underlie the adverse effects documented in experimental animal models and thus could be important to human health. In this review, the epigenetic regulation of gene expression is explored as a potential target of environmental toxicants including oestrogenic chemicals. We suggest that toxicant-induced changes in epigenetic signatures are important mechanisms underlying the disruption of ovarian follicular development. In addition, we discuss how exposure to environmental oestrogens during early life can alter gene expression through effects on epigenetic control potentially leading to permanent changes in ovarian physiology. © 2014 British Society for Neuroendocrinology.

Persistent organochlorinated pesticides and mechanisms of their toxicity.

PubMed

Mrema, Ezra J; Rubino, Federico M; Brambilla, Gabri; Moretto, Angelo; Tsatsakis, Aristidis M; Colosio, Claudio

2013-05-10

Persistent organic pollutants comprised of organic chemicals like polychlorinated biphenyls, dibenzo-p-dioxins, dibenzofurans and organochlorinated pesticides which have many characteristics in common. Once released in the environment they resist physical, biological, chemical and photochemical breakdown processes and thus persist in the environment. They are subject to long transboundary air pollution transport. They accumulate in the food chain due to their lipophilicity, bioaccumulation and biomagnification properties. Human exposure occurs through inhalation of air, ingestion of food and skin contact. Because most of them bioaccumulate and remain preferentially in fat, their long-term effects are still a matter of public health concern. They are condemned for health adverse effects such as cancer, reproductive defects, neurobehavioral abnormalities, endocrine and immunological toxicity. These effects can be elicited via a number of mechanisms among others include disruption of endocrine system, oxidation stress and epigenetic. However most of the mechanisms are not clear thus a number of studies are ongoing trying to elucidate them. In this review, the underlying possible mechanisms of action and their possible roles in adverse developmental and reproductive processes are discussed and where possible a linkage is made to some existing epidemiological data. Both genomic and nongenomic pathways are used to describe these effects. Understanding of these mechanisms will enable development of strategies to protect the public by reducing these adverse effects. This review is limited to persistent organochlorinated pesticides (OCPs) such as dichlorodiphenyltrichloroethane (DDT) and its metabolites, hexachlorobenzene (HCB), beta-hexachlorocyclohexane (β-HCH) and endosulfan. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Computer Simulation of Embryonic Systems: What can a ...

EPA Pesticide Factsheets

(1) Standard practice for assessing developmental toxicity is the observation of apical endpoints (intrauterine death, fetal growth retardation, structural malformations) in pregnant rats/rabbits following exposure during organogenesis. EPA’s computational toxicology research program (ToxCast) generated vast in vitro cellular and molecular effects data on >1858 chemicals in >600 high-throughput screening (HTS) assays. The diversity of assays has been increased for developmental toxicity with several HTS platforms, including the devTOX-quickPredict assay from Stemina Biomarker Discovery utilizing the human embryonic stem cell line (H9). Translating these HTS data into higher order-predictions of developmental toxicity is a significant challenge. Here, we address the application of computational systems models that recapitulate the kinematics of dynamical cell signaling networks (e.g., SHH, FGF, BMP, retinoids) in a CompuCell3D.org modeling environment. Examples include angiogenesis (angiodysplasia) and dysmorphogenesis. Being numerically responsive to perturbation, these models are amenable to data integration for systems Toxicology and Adverse Outcome Pathways (AOPs). The AOP simulation outputs predict potential phenotypes based on the in vitro HTS data ToxCast. A heuristic computational intelligence framework that recapitulates the kinematics of dynamical cell signaling networks in the embryo, together with the in vitro profiling data, produce quantitative pr

Hydrogen Sulfide in Hypertension and Kidney Disease of Developmental Origins.

PubMed

Hsu, Chien-Ning; Tain, You-Lin

2018-05-11

Adverse environments occurring during kidney development may produce long-term programming effects, namely renal programming, to create increased vulnerability to the development of later-life hypertension and kidney disease. Conversely, reprogramming is a strategy aimed at reversing the programming processes in early life, even before the onset of clinical symptoms, which may counter the rising epidemic of hypertension and kidney disease. Hydrogen sulfide (H₂S), the third gasotransmitter, plays a key role in blood pressure regulation and renal physiology. This review will first present the role of H₂S in the renal system and provide evidence for the links between H₂S signaling and the underlying mechanisms of renal programming, including the renin⁻angiotensin system, oxidative stress, nutrient-sensing signals, sodium transporters, and epigenetic regulation. This will be followed by potential H₂S treatment modalities that may serve as reprogramming strategies to prevent hypertension and kidney disease of developmental origins. These H₂S treatment modalities include precursors for H₂S synthesis, H₂S donors, and natural plant-derived compounds. Despite emerging evidence from experimental studies in support of reprogramming strategies targeting the H₂S signaling pathway to protect against hypertension and kidney disease of developmental origins, these results need further clinical translation.

The Role of Maternal Nutrition During the Periconceptional Period and Its Effect on Offspring Phenotype.

PubMed

Fleming, Tom P; Eckert, Judith J; Denisenko, Oleg

2017-01-01

The early preimplantation embryo has been rigorously studied for decades to understand inherent reproductive and developmental mechanisms driving its morphogenesis from before fertilisation through to and beyond implantation. Recent research has demonstrated that this short developmental window is also critical for the embryo's interaction with external, maternal factors, particularly nutritional status. Here, maternal dietary quality has been shown to alter the pattern of development in an enduring way that can influence health throughout the lifetime. Thus, using mouse models, maternal protein restriction exclusively during the preimplantation period with normal nutrition thereafter is sufficient to cause adverse cardiometabolic and neurological outcomes in adult offspring. Evidence for similar effects whereby environmental factors during the periconceptional window can programme postnatal disease risk can be found in human and large animal models and also in response to in vitro conditions such as assisted conception and related infertility treatments. In this review, using mouse malnutrition models, we evaluate the step-by-step mechanisms that lead from maternal poor diet consumption though to offspring disease. We consider how adverse programming within the embryo may be induced, what nutrient factors and signalling pathways may be involved, and how these cues act to change the embryo in distinct ways across placental and foetal lineage paths, leading especially to changes in the growth trajectory which in turn associate with later disease risk. These mechanisms straddle epigenetic, molecular, cellular and physiological levels of biology and suggest, for health outcomes, preimplantation development to be the most important time in our lives.

Drugs of abuse in pregnancy, poor neonatal development, and future neurodegeneration. Is oxidative stress the culprit?

PubMed

Neri, Margherita; Bello, Stefania; Turillazzi, Emanuela; Riezzo, Irene

2015-01-01

The abuse of licit and illicit drugs is a worldwide issue that is a cause for concern in pregnant women. It may lead to complications in pregnancy that may affect the mother, fetus, and /or neonate. The effects of any substance on the developing embryo and fetus are dependent upon dosing, timing, duration of drug exposure, and the extent of drug distribution. Teratogenic effects have been described when exposure takes place during the embryonic stage; however drugs have subtle effects, including abnormal growth and/or maturation, alterations in neurotransmitters and their receptors, and brain organization. The mechanisms by which intrauterine exposure to many substances may result in neuronal injury have not been completely elucidated. Oxidative stress and epigenetic changes have been recently implicated in the pathogenesis of long - term adverse health sequelae, and neuro-developmental impairment in the offspring of addicted mothers. Transgenerational epigenetics may also explain the alarming datum that developmental abnormalities, impairment in learning and memory, and attention deficit can occur even in the absence of direct fetal exposure, when drugs are consumed prior to conception. There is a growing body of evidence demonstrating a link between redox state unbalance, epigenetic markers, developmental anomalies, and neurodegeneration. The reviewed literature data uphold redox homeostasis disruption as an important factor in the pathogenesis of drug of abuse- induced neurodegeneration, and highlight the potential for new therapies that could prevent neurodegeneration through antioxidant and epigenetic modulatory mechanisms. This therefore reveals important targets for novel neuroprotective strategies.

Phthalate-Induced Pathology in the Foetal Testis Involves More Than Decreased Testosterone Production

EPA Science Inventory

Foetal exposure to phthalates is known to adversely impact male reproductive development and function. Developmental anomalies of reproductive tract have been attributed to impaired testosterone synthesis. However, species differences in the ability to produce testosterone have...

INCREASED SUSCEPTIBILITY OF ADULTS FOLLOWING DEVELOPMENT EXPOSURE TO NEUROTOXICANTS: ANOTHER SUSCEPTIBLE POPULATION?

EPA Science Inventory

There is considerable public and regulatory interest in the adverse outcomes of developmental exposure to toxicants. The 1996 Food Quality Protection Act spurred research on understanding potential neurotoxic, immunotoxic, and endocrine outcomes in susceptible populations, parti...

Adverse effects of ocean acidification on early development of squid (Doryteuthis pealeii).

PubMed

Kaplan, Maxwell B; Mooney, T Aran; McCorkle, Daniel C; Cohen, Anne L

2013-01-01

Anthropogenic carbon dioxide (CO2) is being absorbed into the ocean, altering seawater chemistry, with potentially negative impacts on a wide range of marine organisms. The early life stages of invertebrates with internal and external aragonite structures may be particularly vulnerable to this ocean acidification. Impacts to cephalopods, which form aragonite cuttlebones and statoliths, are of concern because of the central role they play in many ocean ecosystems and because of their importance to global fisheries. Atlantic longfin squid (Doryteuthis pealeii), an ecologically and economically valuable taxon, were reared from eggs to hatchlings (paralarvae) under ambient and elevated CO2 concentrations in replicated experimental trials. Animals raised under elevated pCO2 demonstrated significant developmental changes including increased time to hatching and shorter mantle lengths, although differences were small. Aragonite statoliths, critical for balance and detecting movement, had significantly reduced surface area and were abnormally shaped with increased porosity and altered crystal structure in elevated pCO2-reared paralarvae. These developmental and physiological effects could alter squid paralarvae behavior and survival in the wild, directly and indirectly impacting marine food webs and commercial fisheries.

Adverse Effects of Ocean Acidification on Early Development of Squid (Doryteuthis pealeii)

PubMed Central

Kaplan, Maxwell B.; Mooney, T. Aran; McCorkle, Daniel C.; Cohen, Anne L.

2013-01-01

Anthropogenic carbon dioxide (CO2) is being absorbed into the ocean, altering seawater chemistry, with potentially negative impacts on a wide range of marine organisms. The early life stages of invertebrates with internal and external aragonite structures may be particularly vulnerable to this ocean acidification. Impacts to cephalopods, which form aragonite cuttlebones and statoliths, are of concern because of the central role they play in many ocean ecosystems and because of their importance to global fisheries. Atlantic longfin squid (Doryteuthis pealeii), an ecologically and economically valuable taxon, were reared from eggs to hatchlings (paralarvae) under ambient and elevated CO2 concentrations in replicated experimental trials. Animals raised under elevated pCO2 demonstrated significant developmental changes including increased time to hatching and shorter mantle lengths, although differences were small. Aragonite statoliths, critical for balance and detecting movement, had significantly reduced surface area and were abnormally shaped with increased porosity and altered crystal structure in elevated pCO2-reared paralarvae. These developmental and physiological effects could alter squid paralarvae behavior and survival in the wild, directly and indirectly impacting marine food webs and commercial fisheries. PMID:23741298

Tavaborole, a Novel Boron-Containing Small Molecule Pharmaceutical Agent for Topical Treatment of Onychomycosis: I. Reproductive and Developmental Toxicity Studies.

PubMed

Ciaravino, Vic; Coronado, Dina; Lanphear, Cheryl; Hoberman, Alan; Chanda, Sanjay

2016-09-01

Tavaborole is a topical antifungal agent approved by the US Food and Drug Administration for the treatment of toenail onychomycosis. As part of the nonclinical development program, reproductive and developmental toxicity studies were conducted (rat oral fertility and early embryonic development, rat (oral) and rabbit (dermal) embryo-fetal development). There were no effects on fertility or reproductive performance at doses up to 300 mg/kg/d (107 times the maximum recommended human dose [MRHD] based on mean area under the plasma concentration-time curve comparisons). In the rat embryo-fetal development toxicity studies, teratogenicity was not observed at doses up to 100 mg/kg/d (29 times the MRHD). However, several treatment-related skeletal malformations and variations were observed at 300 mg/kg/d (570 times the MRHD). In rabbit embryo-fetal development toxicity studies dosed via oral or dermal administration, the no observable adverse effect level for maternal toxicity and embryo-fetal toxicity was 50 mg/kg/d (16 times the MRHD) and 5% (26 times the MRHD), respectively. © The Author(s) 2016.

Resilience in young children involved with child protective services.

PubMed

Sattler, Kierra M P; Font, Sarah A

2018-01-01

Child maltreatment increases the risk of poor developmental outcomes. However, some children display resilience, meaning they are high-functioning despite their adverse experiences. To date, few research studies have examined protective factors among very young maltreated children. Yet, domains of resilience, and the protective factors that promote resilience among maltreated children, are likely to differ by developmental stage. Drawing on ecological systems theory and life course theory, we examined how protective factors at multiple ecological levels across early childhood were related to social and cognitive resilience among very young children involved with child protective services. The results demonstrated that the buffering effects of protective factors varied by social or cognitive resilience and the cumulative effects of protective factors were more consistently related to later resilience than protective factors at specific time points. In addition, the influence of specific protective factors on resilience slightly varied by initial in-home or out-of-home placement. These findings have important policy and research implications for promoting optimal development among children involved in child protective services. Copyright © 2017 Elsevier Ltd. All rights reserved.

Linking Adverse Childhood Effects and Attachment: A Theory of Etiology for Sexual Offending.

PubMed

Grady, Melissa D; Levenson, Jill S; Bolder, Tess

2016-01-25

Sexual violence continues to be a significant public health problem affecting significant portions of the population. Unfortunately, an agreed upon theory of etiology remains elusive leading to challenges in developing effective prevention and treatment interventions. Recently, there is a growing body of literature examining the role of adverse childhood experiences (ACEs) in the development of sexually violent behavior. This research has begun to explore the rates of various types of child maltreatments and family dysfunction in individuals who have been convicted of a sexual crime. These empirical inquiries have been primarily descriptive in nature and have not yet provided a cohesive theoretical model as to why the presence of ACEs might contribute to sexually abusive behavior. This article suggests that attachment theory offers an explanatory link between early adversity and sexually abusive behavior in adulthood. We first summarize important attachment theory concepts, then integrate them with research in the area of developmental psychopathology and ACEs, and finally propose a model by which attachment can be used as an explanatory theory for subsequent sexualized coping and sexually abusive behaviors. Finally, this article explores the implications for practice, policy, and research using this explanatory theory as a framework for understanding sexual violence. © The Author(s) 2016.

Individual in Context: The Role of Impulse Control on the Association between the Home, School, and Neighborhood Developmental Contexts and Adolescent Delinquency.

PubMed

Fine, Adam; Mahler, Alissa; Steinberg, Laurence; Frick, Paul J; Cauffman, Elizabeth

2017-07-01

Social ecological theories and decades of supporting research suggest that contexts exert a powerful influence on adolescent delinquency. Individual traits, such as impulse control, also pose a developmental disadvantage to adolescents through increasing risk of delinquency. However, such individual differences may also predispose some youth to struggle more in adverse environments, but also to excel in enriched environments. Despite the prominence of impulse control in both developmental and criminological literatures, researchers are only beginning to consider impulse control as an individual characteristic that may affect developmental outcomes in response to environmental input. Using a racially diverse (Latino 46 %; Black 37 %; White 15 %; other race 2 %) sample of 1,216 first-time, male, juvenile offenders from the longitudinal Crossroads Study, this study examined key interactions between baseline impulse control and the home, school, and neighborhood contexts in relation to delinquency within the following 6 months. The results indicated that even after accounting for prior delinquency, youth in more negative home, school, and neighborhood contexts engaged in the same amount of delinquency in the following 6 months regardless of their level of impulse control. However, the effects of positive home, school, and neighborhood contexts on delinquency were stronger for youth with moderate or high impulse control and minimally affected youth with low impulse control. The findings suggest two risk factors for delinquency: low impulse control as a dispositional vulnerability that operates independently of developmental context, and a second that results from a contextual vulnerability.

Mounting evidence favoring single-family room neonatal intensive care.

PubMed

Stevens, D; Thompson, P; Helseth, C; Pottala, J

2015-01-01

Controversy regarding the optimal design for neonatal intensive care has existed for more than 20 years. Recent evidence confirms that in comparison with the traditional open-bay design, the single-room facility provides for improved control of excessive noise and light, improved staff and parental satisfaction with care and equal, or possibly reduced, cost of care. Single-room care was not associated with any increase in adverse outcomes. To optimize long term developmental outcomes, single-room care must be augmented with appropriate developmental therapy and programs to actively support parental involvement.

Toxic Environmental Chemicals: The Role of Reproductive Health Professionals In Preventing Harmful Exposures

PubMed Central

SUTTON, Patrice; WOODRUFF, Tracey J.; PERRON, Joanne; STOTLAND, Naomi; CONRY, Jeanne A.; MILLER, Mark D.; GIUDICE, Linda C.

2015-01-01

Every pregnant woman in the U.S. is exposed to many and varied environmental chemicals. Rapidly accumulating scientific evidence documents that widespread exposure to environmental chemicals at levels encountered in daily life can adversely impact reproductive and developmental health. Preconception and prenatal exposure to environmental chemicals are of particular import because they may have a profound and lasting impact on health across the life course. Thus, preventing developmental exposures to environmental chemicals would benefit greatly from the active participation of reproductive health professionals in clinical and policy arenas. PMID:22405527

Reproductive and developmental effects of disinfection by-products in drinking water.

PubMed Central

Reif, J S; Hatch, M C; Bracken, M; Holmes, L B; Schwetz, B A; Singer, P C

1996-01-01

Recent epidemiologic studies have reported associations between the consumption of chlorinated drinking water and reproductive and developmental effects. Here we review the available epidemiologic data, assess the hazard potential posed by exposure to disinfection by-products, identify critical data gaps, and offer recommendations for further research. The epidemiologic evidence supporting associations between exposure to water disinfection by-products (DBPs) and adverse pregnancy outcomes is sparse, and positive findings should be interpreted cautiously. The methods used during the early stages of research in this area have been diverse. Variability in exposure assessment and endpoints makes it difficult to synthesize or combine the available data. Exposure misclassification and unmeasured confounding may have lead to bias in risk estimation. Future studies of reproductive outcome and exposure to chlorinated water should use improved methods for exposure assessment to 1) assure selection of appropriate exposure markers, 2) assess seasonal and annual fluctuations in DBPs, 3) assess variability within the distribution system, and 4) assess exposure through multiple routes such as bathing and showering, as well as consumption. Population-based studies should be conducted to evaluate male and female fertility, conception delay, growth retardation, and specific birth defects. The reproductive and developmental effects of exposure to DBPs could be efficiently explored in ongoing investigations by incorporating valid exposure markers and relevant questionnaire information. Future studies should make use of naturally occurring variability in the concentrations of DBPs and may incorporate biomarkers of exposure and effect in their design. Epidemiologic investigations should be conducted in parallel with laboratory-based and animal studies in a coordinated, multidisciplinary approach. PMID:8930546

Screening for Developmental Neurotoxicity Using PC12 Cells: Comparisons of Organophosphates with a Carbamate, an Organochlorine, and Divalent Nickel

PubMed Central

Slotkin, Theodore A.; MacKillop, Emiko A.; Ryde, Ian T.; Tate, Charlotte A.; Seidler, Frederic J.

2007-01-01

Background In light of the large number of chemicals that are potential developmental neurotoxicants, there is a need to develop rapid screening techniques. Objectives We exposed undifferentiated and differentiating neuronotypic PC12 cells to different organophosphates (chlorpyrifos, diazinon, parathion), a carbamate (physostigmine), an organochlorine (dieldrin), and a metal (divalent nickel; Ni2+) and examined indices of cell replication and differentiation for both short- and long-term exposures. Results In undifferentiated cells, all the agents inhibited DNA synthesis, with the greatest effect for diazinon, but physostigmine eventually produced the largest deficits in the total number of cells after prolonged exposure. The onset of differentiation intensified the adverse effects on DNA synthesis and changed the rank order in keeping with a shift away from noncholinergic mechanisms and toward cholinergic mechanisms. Differentiation also worsened the effects of each agent on cell number after prolonged exposure, whereas cell growth was not suppressed, nor were there any effects on viability as assessed with trypan blue. Nevertheless, differentiating cells displayed signs of oxidative stress from all of the test compounds except Ni2+, as evidenced by measurements of lipid peroxidation. Finally, all of the toxicants shifted the transmitter fate of the cells away from the cholinergic phenotype and toward the catecholaminergic phenotype. Conclusions These studies point out the feasibility of developing cell-based screening methods that enable the detection of multiple end points that may relate to mechanisms associated with developmental neurotoxicity, revealing some common targets for disparate agents. PMID:17366826

Moderate Childhood Stress Buffers Against Depressive Response to Proximal Stressors: A Multi-Wave Prospective Study of Early Adolescents

PubMed Central

Shapero, Benjamin G.; Hamilton, Jessica L.; Stange, Jonathan P.; Liu, Richard T.; Y.Abramson, Lyn; Alloy, Lauren B.

2015-01-01

Although the majority of research in the field has focused on childhood stressors as a risk factor for psychopathology, a burgeoning body of literature has focused on the possible steeling effect of moderate types of stressful events. The current study investigated the effects of proximal life stressors on prospective changes in depressive symptoms, and whether a history of moderate childhood adversity would moderate this relationship in a multi-wave study of a diverse community sample of early adolescents (N = 163, 52% female, 51% Caucasian). Hierarchical linear modeling was run with four waves of data. Adolescents with greater moderately severe early life events evinced a blunted depressive symptom response to changes in proximal stressful events in the previous 9 months, compared to those with fewer early moderately severe experiences of adversity. These results held after controlling for between-subject factors such as race, gender, severe early life stress, and average stress over the four waves of data. Findings indicate that greater exposure to moderate childhood stressors may buffer against the negative effects of subsequent stressors, suggesting the importance of a nuanced developmental approach to studying the effects of early life stress. PMID:25911194

Adolescent Choline Supplementation Attenuates Working Memory Deficits in Rats Exposed to Alcohol During the Third Trimester Equivalent

PubMed Central

Schneider, Ronald D.; Thomas, Jennifer D.

2018-01-01

Background Children exposed to alcohol prenatally may suffer from behavioral and cognitive alterations that adversely affect their quality of life. Animal studies have shown that perinatal supplementation with the nutrient choline can attenuate ethanol’s adverse effects on development; however, it is not clear how late in development choline can be administered and still effectively reduce the consequences of prenatal alcohol exposure. Using a rodent model, this study examined whether choline supplementation is effective in mitigating alcohol’s teratogenic effects when administered during adolescence/young adulthood. Methods Sprague–Dawley rats were exposed to alcohol (5.25 g/kg/d) during the third trimester equivalent brain growth spurt, which occurs from postnatal day (PD) 4 to 9, via oral intubation. Sham-intubated and nontreated controls were included. Subjects were treated with 100 mg/kg/d choline chloride or vehicle from PD 40 to 60, a period equivalent to young adulthood in the rat. After the choline treatment had ceased, subjects were tested on a series of behavioral tasks: open field activity (PD 61 to 64), Morris water maze spatial learning (PD 65 to 73), and spatial working memory (PD 87 to 91). Results Ethanol-exposed subjects were overactive in the activity chambers and impaired on both the spatial and the working memory versions of the Morris water maze. Choline treatment failed to attenuate alcohol-related overactivity in the open field and deficits in Morris water maze performance. In contrast, choline supplementation significantly mitigated alcohol-related deficits in working memory, which may suggest that choline administration at this later developmental time affects functioning of the prefrontal cortex. Conclusions The results indicate that adolescent choline supplementation can attenuate some, but not all, of the behavioral deficits associated with early developmental alcohol exposure. The results of this study indicate that dietary intervention may reduce some fetal alcohol effects, even when administered later in life, findings with important implications for adolescents and young adults with fetal alcohol spectrum disorders. PMID:27038598

Phenobarbital and midazolam increase neonatal seizure-associated neuronal injury.

PubMed

Torolira, Daniel; Suchomelova, Lucie; Wasterlain, Claude G; Niquet, Jerome

2017-07-01

Status epilepticus is common in neonates and infants, and is associated with neuronal injury and adverse developmental outcomes. γ-Aminobutyric acidergic (GABAergic) drugs, the standard treatment for neonatal seizures, can have excitatory effects in the neonatal brain, which may worsen the seizures and their effects. Using a recently developed model of status epilepticus in postnatal day 7 rat pups that results in widespread neuronal injury, we found that the GABA A agonists phenobarbital and midazolam significantly increased status epilepticus-associated neuronal injury in various brain regions. Our results suggest that more research is needed into the possible deleterious effects of GABAergic drugs on neonatal seizures and on excitotoxic neuronal injury in the immature brain. Ann Neurol 2017;82:115-120. © 2017 American Neurological Association.

In vivo biocompatibility of boron nitride nanotubes: effects on stem cell biology and tissue regeneration in planarians.

PubMed

Salvetti, Alessandra; Rossi, Leonardo; Iacopetti, Paola; Li, Xia; Nitti, Simone; Pellegrino, Teresa; Mattoli, Virgilio; Golberg, Dmitri; Ciofani, Gianni

2015-07-01

Boron nitride nanotubes (BNNTs) represent an extremely interesting class of nanomaterials, and recent findings have suggested a number of applications in the biomedical field. Anyhow, extensive biocompatibility investigations are mandatory before any further advancement toward preclinical testing. Here, we report on the effects of multiwalled BNNTs in freshwater planarians, one of the best-characterized in vivo models for developmental biology and regeneration research. Obtained results indicate that BNNTs are biocompatible in the investigated model, since they do not induce oxidative DNA damage and apoptosis, and do not show adverse effects on planarian stem cell biology and on de novo tissue regeneration. In summary, collected findings represent another important step toward BNNT realistic applications in nanomedicine.

Multiscale modeling and simulation of embryogenesis for in silico predictive toxicology (WC9)

EPA Science Inventory

Translating big data from alternative and HTS platforms into hazard identification and risk assessment is an important need for predictive toxicology and for elucidating adverse outcome pathways (AOPs) in developmental toxicity. Understanding how chemical disruption of molecular ...

Adverse Outcome Pathway (AOP) framework for embryonic vascular disruption and developmental defects (SOT)

EPA Science Inventory

Vascular development commences with de novo assembly of a primary capillary plexus (vasculogenesis) followed by its expansion (angiogenesis) and maturation (angio-adaptation) into a hierarchical system of arteries and veins. These processes are tightly regulated by genetic signal...

Adverse Childhood Experiences and Psychosocial Well-Being of Women Who Were in Foster Care as Children

PubMed Central

Bruskas, Delilah; Tessin, Dale H

2013-01-01

Background and Objective: Research has shown that many children in foster care later have psychosocial problems as adults; this is often attributed to cumulative adversities and a lack of supportive caregivers. The risk factors associated with foster care, such as maternal separation and multiple placements, often counteract many protective factors that can ameliorate the effects of childhood adversities. This study assessed the relationship between adverse childhood experiences (ACEs) and psychosocial well-being in women who were in foster care as children. Methods: A total of 101 women aged 18–71 years (mean, 36.83 [12.95] years) completed an anonymous online survey based on the 10-item ACE Questionnaire, the Sense of Coherence questionnaire, and the General Health Questionnaire. Results: More than 56% of respondents were identified as experiencing current psychological distress. Sense of coherence scores (mean, 54.26 [15.35]) showed a significant inverse association with both General Health Questionnaire (mean, 14.83 [5.88]) and ACE (mean, 5.68 [2.90]) scores (r = −0.64 and −0.31, respectively) and 97% reported at least 1 ACE, 70% reported ≥ 5 and 33% reported ≥ 8. Linear regressions indicated that ACEs reported to occur before foster care were associated with lower levels of sense of coherence (8%) and higher levels of psychological distress (6%). Physical neglect and living in a dysfunctional household (parental loss, maternal abuse, or household member associated with substance abuse or prison) significantly decreased during foster care by 16 and 19 percentage points, respectively. Rates of emotional and physical abuse did not change. Conclusion: The number of ACEs was associated with the level of psychological distress. Our findings suggest that children entering the foster care system are already vulnerable and at risk of experiencing ACEs during foster care and psychological distress during adulthood. Measures implemented to protect children must not cause more harm than good. Social services that preserve and strengthen the family unit and reduce the number of ACEs both before and during foster care are recommended. Social workers and clinicians who are trained to address and manage the unique developmental needs of children in foster care may help reduce the effects of ACEs and optimize developmental health. PMID:24355905

Public health impact of plastics: An overview

PubMed Central

Rustagi, Neeti; Pradhan, S. K.; Singh, Ritesh

2011-01-01

Plastic, one of the most preferred materials in today's industrial world is posing serious threat to environment and consumer's health in many direct and indirect ways. Exposure to harmful chemicals during manufacturing, leaching in the stored food items while using plastic packages or chewing of plastic teethers and toys by children are linked with severe adverse health outcomes such as cancers, birth defects, impaired immunity, endocrine disruption, developmental and reproductive effects etc. Promotion of plastics substitutes and safe disposal of plastic waste requires urgent and definitive action to take care of this potential health hazard in future. PMID:22412286

Collagen in organ development

NASA Technical Reports Server (NTRS)

Hardman, P.; Spooner, B. S.

1992-01-01

It is important to know whether microgravity will adversely affect developmental processes. Collagens are macromolecular structural components of the extracellular matrix (ECM) which may be altered by perturbations in gravity. Interstitial collagens have been shown to be necessary for normal growth and morphogenesis in some embryonic organs, and in the mouse salivary gland, the biosynthetic pattern of these molecules changes during development. Determination of the effects of microgravity on epithelial organ development must be preceded by crucial ground-based studies. These will define control of normal synthesis, secretion, and deposition of ECM macromolecules and the relationship of these processes to morphogenesis.

Detrimental Psychological Outcomes Associated with Early Pubertal Timing in Adolescent Girls

PubMed Central

Mendle, Jane; Turkheimer, Eric; Emery, Robert E.

2010-01-01

Though often discussed as though it were a discrete event, puberty comprises one segment of a larger developmental continuum and is notable for rapid transformation across a multitude of domains. Research suggests that an earlier rate of pubertal maturation in girls correlates with a number of detrimental outcomes compared with on-time or later maturation. The present review synthesizes the research on negative psychological sequelae of early pubertal timing in adolescent girls. Emphasis is on three theoretical perspectives by which precocious development is believed to affect the emergence of adverse outcomes: biological, psychosocial, and selection effects. PMID:20740062

Translational toxicology: a developmental focus for integrated research strategies.

PubMed

Hughes, Claude; Waters, Michael; Allen, David; Obasanjo, Iyabo

2013-09-30

Given that toxicology studies the potential adverse effects of environmental exposures on various forms of life and that clinical toxicology typically focuses on human health effects, what can and should the relatively new term of "translational toxicology" be taken to mean? Our assertion is that the core concept of translational toxicology must incorporate existing principles of toxicology and epidemiology, but be driven by the aim of developing safe and effective interventions beyond simple reduction or avoidance of exposure to prevent, mitigate or reverse adverse human health effects of exposures.The field of toxicology has now reached a point where advances in multiple areas of biomedical research and information technologies empower us to make fundamental transitions in directly impacting human health. Translational toxicology must encompass four action elements as follows: 1) Assessing human exposures in critical windows across the lifespan; 2) Defining modes of action and relevance of data from animal models; 3) Use of mathematical models to develop plausible predictions as the basis for: 4) Protective and restorative human health interventions. The discussion focuses on the critical window of in-utero development. Exposure assessment, basic toxicology and development of certain categories of mathematical models are not new areas of research; however overtly integrating these in order to conceive, assess and validate effective interventions to mitigate or reverse adverse effects of environmental exposures is our novel opportunity. This is what we should do in translational toxicology so that we have a portfolio of interventional options to improve human health that include both minimizing exposures and specific preventative/restorative/mitigative therapeutics.

[Adverse events in patients from a pediatric hospital.

PubMed

Ornelas-Aguirre, José Manuel; Arriaga-Dávila, José de Jesús; Domínguez-Serrano, María Isabel; Guzmán-Bihouet, Beatriz Filomena; Navarrete-Navarro, Susana

2013-01-01

Background: detection of adverse events is part of the safety management in hospitalized patients. The objective of this study was to describe the incidence of adverse events that occurred in a pediatric hospital. Methods: cross-sectional study of the adverse events occurred in a pediatric hospital from 2007 to 2009. Factors associated with their developmental causes were identified. The statistical analysis was descriptive and bivariate, with contingency tables to estimate the relationship between those factors. A p value = 0.05 was considered significant. Results: a total of 177 adverse events were registered. When they began, human factor occurred in 23 cases (13 %, OR = 1.41, p = 0.001), organizational factor was present in 71 cases (40 %, OR = 1.91, p = 0.236) and technical factor in 46 cases (26 %, OR = 0.87, p = 0.01). Blows or bruises from falls as a result of adverse events occurred in 71 cases (40 %, 95 % CI = 64-78). Conclusions: we found 1.84 events per 100 hospital discharges during the study period. The fall of patients ranked first of the adverse events identified.

Developmentally dynamic genome: Evidence of genetic influences on increases and decreases in conduct problems from early childhood to adolescence

PubMed Central

Pingault, Jean-Baptiste; Rijsdijk, Frühling; Zheng, Yao; Plomin, Robert; Viding, Essi

2015-01-01

The development of conduct problems in childhood and adolescence is associated with adverse long-term outcomes, including psychiatric morbidity. Although genes constitute a proven factor of stability in conduct problems, less is known regarding their role in conduct problems’ developmental course (i.e. systematic age changes, for instance linear increases or decreases).Mothers rated conduct problems from age 4 to 16 years in 10,038 twin pairs from the Twins Early Development Study. Individual differences in the baseline level (.78; 95% CI: .68-.88) and the developmental course of conduct problems (.73; 95% CI: .60-.86) were under high and largely independent additive genetic influences. Shared environment made a small contribution to the baseline level but not to the developmental course of conduct problems. These results show that genetic influences not only contribute to behavioural stability but also explain systematic change in conduct problems. Different sets of genes may be associated with the developmental course versus the baseline level of conduct problems. The structure of genetic and environmental influences on the development of conduct problems suggests that repeated preventive interventions at different developmental stages might be necessary to achieve a long-term impact. PMID:25944445

Developmentally dynamic genome: Evidence of genetic influences on increases and decreases in conduct problems from early childhood to adolescence.

PubMed

Pingault, Jean-Baptiste; Rijsdijk, Frühling; Zheng, Yao; Plomin, Robert; Viding, Essi

2015-05-06

The development of conduct problems in childhood and adolescence is associated with adverse long-term outcomes, including psychiatric morbidity. Although genes constitute a proven factor of stability in conduct problems, less is known regarding their role in conduct problems' developmental course (i.e. systematic age changes, for instance linear increases or decreases).Mothers rated conduct problems from age 4 to 16 years in 10,038 twin pairs from the Twins Early Development Study. Individual differences in the baseline level (.78; 95% CI: .68-.88) and the developmental course of conduct problems (.73; 95% CI: .60-.86) were under high and largely independent additive genetic influences. Shared environment made a small contribution to the baseline level but not to the developmental course of conduct problems. These results show that genetic influences not only contribute to behavioural stability but also explain systematic change in conduct problems. Different sets of genes may be associated with the developmental course versus the baseline level of conduct problems. The structure of genetic and environmental influences on the development of conduct problems suggests that repeated preventive interventions at different developmental stages might be necessary to achieve a long-term impact.

Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity

PubMed Central

Bal-Price, Anna; Lein, Pamela J.; Keil, Kimberly P.; Sethi, Sunjay; Shafer, Timothy; Barenys, Marta; Fritsche, Ellen; Sachana, Magdalini; Meek, M.E. (Bette)

2016-01-01

The Adverse Outcome Pathway (AOP) concept has recently been proposed to support a paradigm shift in regulatory toxicology testing and risk assessment. This concept is similar to the Mode of Action (MOA), in that it describes a sequence of measurable key events triggered by a molecular initiating event in which a stressor interacts with a biological target. The resulting cascade of key events includes molecular, cellular, structural and functional changes in biological systems, resulting in a measurable adverse outcome. Thereby, an AOP ideally provides information relevant to chemical structure-activity relationships as a basis for predicting effects of structurally similar compounds. AOPs could potentially also form the basis for qualitative and quantitative predictive modeling of the human adverse outcome resulting from molecular initiating or other key events for which higher-throughput testing methods are available or can be developed. A variety of cellular and molecular processes are known to be critical for normal function of the central (CNS) and peripheral nervous systems (PNS). Because of the biological and functional complexity of the CNS and PNS, it has been challenging to establish causative links and quantitative relationships between key events that comprise the pathways leading from chemical exposure to an adverse outcome in the nervous system. Following introduction of the principles of MOA and AOPs, examples of potential or putative adverse outcome pathways specific for developmental or adult neurotoxicity are summarized and aspects of their assessment considered. Their possible application in developing mechanistically informed Integrated Approaches to Testing and Assessment (IATA) is also discussed. PMID:27212452

BDE 49 and developmental toxicity in zebrafish

PubMed Central

McClain, Valerie; Stapleton, Heather M.; Gallagher, Evan

2011-01-01

The polybrominated diphenyl ethers (PBDEs) are a group of brominated flame retardants. Human health concerns of these agents have largely centered upon their potential to elicit reproductive and developmental effects. Of the various congeners, BDE 49 (2,2’,4,5’-tetrabromodiphenyl ether) has been poorly studied, despite the fact that it is often detected in the tissues of fish and wildlife species. Furthermore, we have previously shown that BDE 49 is a metabolic debromination product of BDE 99 hepatic metabolism in salmon, carp and trout, underscoring the need for a better understanding of biological effects. In the current study, we investigated the developmental toxicity of BDE 49 using the zebrafish (Danio rerio) embryo larval model. Embryo and larval zebrafish were exposed to BDE 49 at either 5 hours post fertilization (hpf) or 24 hpf and monitored for developmental and neurotoxicity. Exposure to BDE 49 at concentrations of 4 µM- 32 µM caused a dose-dependent loss in survivorship at 6 days post fertilization (dpf). Morphological impairments were observed prior to the onset of mortality, the most striking of which included severe dorsal curvatures of the tail. The incidence of dorsal tail curvatures was dose and time dependent. Exposure to BDE 49 caused cardiac toxicity as evidenced by a significant reduction in zebrafish heart rates at 6 dpf but not earlier, suggesting that cardiac toxicity was non-specific and associated with physiological stress. Neurobehavioral injury from BDE 49 was evidenced by an impairment of touch-escape responses observed at 5 dpf. Our results indicate that BDE 49 is a developmental toxicant in larval zebrafish that can cause morphological abnormalities and adversely affect neurobehavior. The observed toxicities from BDE 49 were similar in scope to those previously reported for the more common tetrabrominated congener, BDE 47, and also for other lower brominated PBDEs, suggest that these compounds may share similarities in risk to aquatic species. PMID:21951712

IMPROVING EXPOSURE ASSESSMENT IN DISINFECTION BYPRODUCTS (DBP) EPIDEMIOLOGIC STUDIES

EPA Science Inventory

In 1997, an EPA expert panel was convened to evaluate epidemiologic studies of adverse reproductive or developmental outcomes that may be associated with drinking water DBPs. The panel recommended that further efforts be made in an existing cohort study, headed by Dr. Waller and ...

Developmental Exposure to Organophosphate Flame Retardants Elicits Overt Toxicity and Alters Behavior in Zebrafish (Danio rerio)

EPA Science Inventory

Organophosphate flame retardants (OPFRs) are common replacements for the phased-out polybrominated diphenyl ethers (PBDEs) and have been detected at high concentrations in environmental samples. OPFRs are structurally similar to organophosphate pesticides and may adversely affect...

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

EPA Science Inventory

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...

LIFE-STAGE DEPENDENT DOSIMETRY AND POTENTIAL IMPACTS ON RISK ASSESSMENT APPROACHES

EPA Science Inventory

Increasingly reproductive and developmental toxicity studies are utilized in assessing the potential for adverse affects in pregnant women, nursing infants, and children. These studies largely have been utilized based upon the dose to the mother due to the complexity of describi...

Novel adverse outcome pathways revealed by chemical genetics in a developing marine fish

PubMed Central

Sørhus, Elin; Incardona, John P; Furmanek, Tomasz; Goetz, Giles W; Scholz, Nathaniel L; Meier, Sonnich; Edvardsen, Rolf B; Jentoft, Sissel

2017-01-01

Crude oil spills are a worldwide ocean conservation threat. Fish are particularly vulnerable to the oiling of spawning habitats, and crude oil causes severe abnormalities in embryos and larvae. However, the underlying mechanisms for these developmental defects are not well understood. Here, we explore the transcriptional basis for four discrete crude oil injury phenotypes in the early life stages of the commercially important Atlantic haddock (Melanogrammus aeglefinus). These include defects in (1) cardiac form and function, (2) craniofacial development, (3) ionoregulation and fluid balance, and (4) cholesterol synthesis and homeostasis. Our findings suggest a key role for intracellular calcium cycling and excitation-transcription coupling in the dysregulation of heart and jaw morphogenesis. Moreover, the disruption of ionoregulatory pathways sheds new light on buoyancy control in marine fish embryos. Overall, our chemical-genetic approach identifies initiating events for distinct adverse outcome pathways and novel roles for individual genes in fundamental developmental processes. DOI: http://dx.doi.org/10.7554/eLife.20707.001 PMID:28117666

Prenatal nicotine alters the developmental neurotoxicity of postnatal chlorpyrifos directed toward cholinergic systems: better, worse, or just "different?".

PubMed

Slotkin, Theodore A; Seidler, Frederic J

2015-01-01

This study examines whether prenatal nicotine exposure sensitizes the developing brain to subsequent developmental neurotoxicity evoked by chlorpyrifos, a commonly-used insecticide. We gave nicotine to pregnant rats throughout gestation at a dose (3mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1mg/kg) that produces minimally-detectable inhibition of brain cholinesterase activity. We evaluated indices for acetylcholine (ACh) synaptic function throughout adolescence, young adulthood and later adulthood, in brain regions possessing the majority of ACh projections and cell bodies; we measured nicotinic ACh receptor binding, hemicholinium-3 binding to the presynaptic choline transporter and choline acetyltransferase activity, all known targets for the adverse developmental effects of nicotine and chlorpyrifos given individually. By itself nicotine elicited overall upregulation of the ACh markers, albeit with selective differences by sex, region and age. Likewise, chlorpyrifos alone had highly sex-selective effects. Importantly, all the effects showed temporal progression between adolescence and adulthood, pointing to ongoing synaptic changes rather than just persistence after an initial injury. Prenatal nicotine administration altered the responses to chlorpyrifos in a consistent pattern for all three markers, lowering values relative to those of the individual treatments or to those expected from simple additive effects of nicotine and chlorpyrifos. The combination produced global interference with emergence of the ACh phenotype, an effect not seen with nicotine or chlorpyrifos alone. Given that human exposures to nicotine and chlorpyrifos are widespread, our results point to the creation of a subpopulation with heightened vulnerability. Copyright © 2014 Elsevier Inc. All rights reserved.

Prenatal Nicotine Alters the Developmental Neurotoxicity of Postnatal Chlorpyrifos Directed Toward Cholinergic Systems: Better, Worse, or Just “Different?”

PubMed Central

Slotkin, Theodore A.; Seidler, Frederic J.

2014-01-01

This study examines whether prenatal nicotine exposure sensitizes the developing brain to subsequent developmental neurotoxicity evoked by chlorpyrifos, a commonly-used insecticide. We gave nicotine to pregnant rats throughout gestation at a dose (3 mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1–4, at a dose (1 mg/kg) that produces minimally-detectable inhibition of brain cholinesterase activity. We evaluated indices for acetylcholine (ACh) synaptic function throughout adolescence, young adulthood and later adulthood, in brain regions possessing the majority of ACh projections and cell bodies; we measured nicotinic ACh receptor binding, hemicholinium-3 binding to the presynaptic choline transporter and choline acetyltransferase activity, all known targets for the adverse developmental effects of nicotine and chlorpyrifos given individually. By itself nicotine elicited overall upregulation of the ACh markers, albeit with selective differences by sex, region and age. Likewise, chlorpyrifos alone had highly sex-selective effects. Importantly, all the effects showed temporal progression between adolescence and adulthood, pointing to ongoing synaptic changes rather than just persistence after an initial injury. Prenatal nicotine administration altered the responses to chlorpyrifos in a consistent pattern for all three markers, lowering values relative to those of the individual treatments or to those expected from simple additive effects of nicotine and chlorpyrifos. The combination produced global interference with emergence of the ACh phenotype, an effect not seen with nicotine or chlorpyrifos alone. Given that human exposures to nicotine and chlorpyrifos are widespread, our results point to the creation of a subpopulation with heightened vulnerability. PMID:25510202

Hydroxylated PBDEs induce developmental arrest in zebrafish

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

Usenko, Crystal Y., E-mail: Crystal_usenko@baylor.edu; Hopkins, David C.; Trumble, Stephen J., E-mail: Stephen_trumble@baylor.edu

The ubiquitous spread of polybrominated diphenyl ethers (PBDEs) has led to concerns regarding the metabolites of these congeners, in particular hydroxylated PBDEs. There are limited studies regarding the biological interactions of these chemicals, yet there is some concern they may be more toxic than their parent compounds. In this study three hydroxylated PBDEs were assessed for toxicity in embryonic zebrafish: 3-OH-BDE 47, 5-OH-BDE 47, and 6-OH-BDE 47. All three congeners induced developmental arrest in a concentration-dependent manner; however, 6-OH-BDE 47 induced adverse effects at lower concentrations than the other congeners. Furthermore, all three induced cell death; however apoptosis was notmore » observed. In short-term exposures (24–28 hours post fertilization), all hydroxylated PBDEs generated oxidative stress in the region corresponding to the cell death at 5 and 10 ppm. To further investigate the short-term effects that may be responsible for the developmental arrest observed in this study, gene regulation was assessed for embryos exposed to 0.625 ppm 6-OH-BDE 47 from 24 to 28 hpf. Genes involved in stress response, thyroid hormone regulation, and neurodevelopment were significantly upregulated compared to controls; however, genes related to oxidative stress were either unaffected or downregulated. This study suggests that hydroxylated PBDEs disrupt development, and may induce oxidative stress and potentially disrupt the cholinergic system and thyroid hormone homeostasis. -- Highlights: ► OH-PBDEs induce developmental arrest in a concentration-dependent manner. ► Hydroxyl group location influences biological interaction. ► OH-PBDEs induce oxidative stress. ► Thyroid hormone gene regulation was disrupted following exposure. ► To our knowledge, this is the first whole organism study of OH-PBDE toxicity.« less

[Prospective study of ketogenic diet in treatment of children with global developmental delay].

PubMed

Zhu, Deng-Na; Li, Ping; Wang, Jun; Yuan, Jun-Ying; Zhang, Guang-Yu; Liang, Jiang-Fang; Wang, Ming-Mei; Zhao, Yun-Xia; An, Shuang; Ma, Na; Ma, Dan-Dan

2017-10-01

To study the effect of ketogenic diet (KD) on neurobehavioral development, emotional and social behaviors, and life ability in children with global developmental delay (GDD). A prospective case-control study was performed for hospitalized children with GDD, who were randomly divided into KD treatment group (n=40) and conventional treatment group (n=37). The children in both groups were given comprehensive rehabilitation training, and those in the KD treatment group were given modified Atkins diet in addition to the comprehensive rehabilitation training. The children in both groups were assessed with the Gesell Developmental Scale, Chinese version of Urban Infant-Toddler Social and Emotional Assessment (CITSEA)/Achenbach Child Behavior Checklist (CBCL), and Infants-Junior High School Students' Social Life Abilities Scale (S-M scale) before treatment and after 3, 6, and 9 months of treatment. The two groups were compared in terms of the improvements in neurobehavioral development, emotional and social behaviors, and social life ability. After 3, 6, and 9 months of treatment, the KD treatment group had significantly greater improvements in the scores of the adaptive, fine motor, and language quotients of the Gesell Developmental Scale compared with the conventional treatment group (P<0.05); the KD treatment group had significantly greater improvements in CITSEA/CBCL scores than the conventional treatment group (P<0.05). The KD treatment group had a greater improvement in the score of the S-M scale after 9 months of treatment (P<0.05). During the KD treatment, 6 children experienced diarrhea and 1 experienced mild urinary stones. KD can improve the neurobehavioral development and behavioral and emotional behaviors in children with GDD, and it has few adverse effects.

DEVELOPMENTAL NEUROTOXICITY OF POLYBROMINATED DIPHENYL ETHER (PBDE) FLAME RETARDANTS

PubMed Central

Costa, Lucio G.; Giordano, Gennaro

2007-01-01

Polybrominated diphenyl ethers (PBDEs) are a class of flame retardants used in a variety of consumer products. In the past 25 years, PBDEs have become ubiquitous environmental contaminants. They have been detected in soil, air, sediments, birds, marine species, fish, house dust, and human tissues, blood and breast milk. Diet and house dust appear to be the major sources of PBDE exposure in the general population, though occupational exposure can also occur. Levels of PBDEs in human tissues are particularly high in North America, compared to Asian and European countries, and have been increasing in the past 30 years. Concentrations of PBDEs are particularly high in breast milk, resulting in high exposure of infants. In addition, for toddlers, dust has been estimated to account for a large percentage of exposure. PBDEs can also cross the placenta, as they have been detected in fetal blood and liver. Tetra-, penta- and hexa BDEs are most commonly present in human tissues. The current greatest concern for potential adverse effects of PBDEs relates to their developmental neurotoxicity. Pre- or postnatal exposure of mice or rats to various PBDEs has been shown to cause long-lasting changes in spontaneous motor activity, mostly characterized as hyperactivity or decreased habituation, and to disrupt performance in learning and memory tests. While a reduction in circulating thyroid hormone (T4) may contribute to the developmental neurotoxicity of PBDEs, direct effects on the developing brain have also been reported. Among these, PBDEs have been shown to affect signal transduction pathways and to cause oxidative stress. Levels of PBDEs causing developmental neurotoxicity in animals are not much dissimilar from levels found in highly exposed infants and toddlers. PMID:17904639

The sea urchin embryo as a model for mammalian developmental neurotoxicity: ontogenesis of the high-affinity choline transporter and its role in cholinergic trophic activity.

PubMed Central

Qiao, Dan; Nikitina, Lyudmila A; Buznikov, Gennady A; Lauder, Jean M; Seidler, Frederic J; Slotkin, Theodore A

2003-01-01

Embryonic development in the sea urchin requires trophic actions of the same neurotransmitters that participate in mammalian brain assembly. We evaluated the development of the high-affinity choline transporter, which controls acetylcholine synthesis. A variety of developmental neurotoxicants affect this transporter in mammalian brain. [3H]Hemicholinium-3 binding to the transporter was found in the cell membrane fraction at stages from the unfertilized egg to pluteus, with a binding affinity comparable with that seen in mammalian brain. Over the course of development, the concentration of transporter sites rose more than 3-fold, achieving concentrations comparable with those of cholinergically enriched mammalian brain regions. Dimethylaminoethanol (DMAE), a competitive inhibitor of choline transport, elicited dysmorphology beginning at the mid-blastula stage, with anomalies beginning progressively later as the concentration of DMAE was lowered. Pretreatment, cotreatment, or delayed treatment with acetylcholine or choline prevented the adverse effects of DMAE. Because acetylcholine was protective at a lower threshold, the DMAE-induced defects were most likely mediated by its effects on acetylcholine synthesis. Transient removal of the hyaline layer enabled a charged transport inhibitor, hemicholinium-3, to penetrate sufficiently to elicit similar anomalies, which were again prevented by acetylcholine or choline. These results indicate that the developing sea urchin possesses a high-affinity choline transporter analogous to that found in the mammalian brain, and, as in mammals, the functioning of this transporter plays a key role in the developmental, trophic activity of acetylcholine. The sea urchin model may thus be useful in high-throughput screening of suspected developmental neurotoxicants. PMID:14594623

The sea urchin embryo as a model for mammalian developmental neurotoxicity: ontogenesis of the high-affinity choline transporter and its role in cholinergic trophic activity.

PubMed

Qiao, Dan; Nikitina, Lyudmila A; Buznikov, Gennady A; Lauder, Jean M; Seidler, Frederic J; Slotkin, Theodore A

2003-11-01

Embryonic development in the sea urchin requires trophic actions of the same neurotransmitters that participate in mammalian brain assembly. We evaluated the development of the high-affinity choline transporter, which controls acetylcholine synthesis. A variety of developmental neurotoxicants affect this transporter in mammalian brain. [3H]Hemicholinium-3 binding to the transporter was found in the cell membrane fraction at stages from the unfertilized egg to pluteus, with a binding affinity comparable with that seen in mammalian brain. Over the course of development, the concentration of transporter sites rose more than 3-fold, achieving concentrations comparable with those of cholinergically enriched mammalian brain regions. Dimethylaminoethanol (DMAE), a competitive inhibitor of choline transport, elicited dysmorphology beginning at the mid-blastula stage, with anomalies beginning progressively later as the concentration of DMAE was lowered. Pretreatment, cotreatment, or delayed treatment with acetylcholine or choline prevented the adverse effects of DMAE. Because acetylcholine was protective at a lower threshold, the DMAE-induced defects were most likely mediated by its effects on acetylcholine synthesis. Transient removal of the hyaline layer enabled a charged transport inhibitor, hemicholinium-3, to penetrate sufficiently to elicit similar anomalies, which were again prevented by acetylcholine or choline. These results indicate that the developing sea urchin possesses a high-affinity choline transporter analogous to that found in the mammalian brain, and, as in mammals, the functioning of this transporter plays a key role in the developmental, trophic activity of acetylcholine. The sea urchin model may thus be useful in high-throughput screening of suspected developmental neurotoxicants.

DNA Damage Response Is Involved in the Developmental Toxicity of Mebendazole in Zebrafish Retina

PubMed Central

Sasagawa, Shota; Nishimura, Yuhei; Kon, Tetsuo; Yamanaka, Yukiko; Murakami, Soichiro; Ashikawa, Yoshifumi; Yuge, Mizuki; Okabe, Shiko; Kawaguchi, Koki; Kawase, Reiko; Tanaka, Toshio

2016-01-01

Intestinal helminths cause iron-deficiency anemia in pregnant women, associated with premature delivery, low birth weight, maternal ill health, and maternal death. Although benzimidazole compounds such as mebendazole (MBZ) are highly efficacious against helminths, there are limited data on its use during pregnancy. In this study, we performed in vivo imaging of the retinas of zebrafish larvae exposed to MBZ, and found that exposure to MBZ during 2 and 3 days post-fertilization caused malformation of the retinal layers. To identify the molecular mechanism underlying the developmental toxicity of MBZ, we performed transcriptome analysis of zebrafish eyes. The analysis revealed that the DNA damage response was involved in the developmental toxicity of MBZ. We were also able to demonstrate that inhibition of ATM significantly attenuated the apoptosis induced by MBZ in the zebrafish retina. These results suggest that MBZ causes developmental toxicity in the zebrafish retina at least partly by activating the DNA damage response, including ATM signaling, providing a potential adverse outcome pathway in the developmental toxicity of MBZ in mammals. PMID:27014071

Prenatal drug exposure effects on subsequent vulnerability to drug abuse.

PubMed

Glantz, Meyer D; Chambers, Jessica Campbell

2006-01-01

Research has shown that both prenatal alcohol and tobacco exposure are associated with increased risk of significant adverse medical, developmental, and behavioral outcomes including substance abuse. Research on the outcomes of prenatal exposure to illicit drugs (PNDE) has also found increased physical and behavioral problems for gestationally drug-exposed children. However, a clear picture has not emerged on whether the consequences of PNDE are independent from those associated with having a substance abusing parent and whether PNDE increases vulnerability to drug abuse. Because of its typical co-occurrence with factors inherent in having a drug-abusing parent, PNDE is at least a marker of significant increased risk for a range of negative outcomes including greater vulnerability to substance abuse. Although a review of the relevant research literatures indicates that the direct consequences of PNDE appear to be generally both subtle and nonglobal, PNDE does appear to have negative developmental and behavioral outcomes, and there is evidence that it is a modest direct contributor to increased substance abuse vulnerability.

Zebrafish embryo developmental toxicology assay.

PubMed

Panzica-Kelly, Julieta M; Zhang, Cindy X; Augustine-Rauch, Karen

2012-01-01

A promising in vitro zebrafish developmental toxicology assay was generated to test compounds for their teratogenic potential. The assay's predictivity is approximately 87% in AB strain fish (Brannen KC et al., Birth Defects Res B Dev Reprod Toxicol 89:66-77, 2010). The procedure entails exposing dechorionated gastrulation-stage embryos to a range of compound concentrations for 5 days throughout embryonic and larva development. The larvae are evaluated for viability in order to identify an LC25 (the compound concentration in which 25% lethality is observed) and morphological anomalies using a numerical score system to identify the NOAEL (no observed adverse effect level). These values are used to calculate the teratogenic index (LC25/NOAEL ratio) of each compound. If the teratogenic index is equal to or greater than 10 then the compound is classified as a teratogen, and if the ratio is less than 10 then the compound is classified as a nonteratogen (Brannen KC et al., Birth Defects Res B Dev Reprod Toxicol 89:66-77, 2010).

Matching mice to malignancy: molecular subgroups and models of medulloblastoma

PubMed Central

Lau, Jasmine; Schmidt, Christin; Markant, Shirley L.; Taylor, Michael D.; Wechsler-Reya, Robert J.

2012-01-01

Introduction Medulloblastoma, the largest group of embryonal brain tumors, has historically been classified into five variants based on histopathology. More recently, epigenetic and transcriptional analyses of primary tumors have sub-classified medulloblastoma into four to six subgroups, most of which are incongruous with histopathological classification. Discussion Improved stratification is required for prognosis and development of targeted treatment strategies, to maximize cure and minimize adverse effects. Several mouse models of medulloblastoma have contributed both to an improved understanding of progression and to developmental therapeutics. In this review, we summarize the classification of human medulloblastoma subtypes based on histopathology and molecular features. We describe existing genetically engineered mouse models, compare these to human disease, and discuss the utility of mouse models for developmental therapeutics. Just as accurate knowledge of the correct molecular subtype of medulloblastoma is critical to the development of targeted therapy in patients, we propose that accurate modeling of each subtype of medulloblastoma in mice will be necessary for preclinical evaluation and optimization of those targeted therapies. PMID:22315164

A systematic evaluation of the potential effects of trichloroethylene exposure on cardiac development.

PubMed

Makris, Susan L; Scott, Cheryl Siegel; Fox, John; Knudsen, Thomas B; Hotchkiss, Andrew K; Arzuaga, Xabier; Euling, Susan Y; Powers, Christina M; Jinot, Jennifer; Hogan, Karen A; Abbott, Barbara D; Hunter, E Sidney; Narotsky, Michael G

2016-10-01

The 2011 EPA trichloroethylene (TCE) IRIS assessment, used developmental cardiac defects from a controversial drinking water study in rats (Johnson et al. [51]), along with several other studies/endpoints to derive reference values. An updated literature search of TCE-related developmental cardiac defects was conducted. Study quality, strengths, and limitations were assessed. A putative adverse outcome pathway (AOP) construct was developed to explore key events for the most commonly observed cardiac dysmorphologies, particularly those involved with epithelial-mesenchymal transition (EMT) of endothelial origin (EndMT); several candidate pathways were identified. A hypothesis-driven weight-of-evidence analysis of epidemiological, toxicological, in vitro, in ovo, and mechanistic/AOP data concluded that TCE has the potential to cause cardiac defects in humans when exposure occurs at sufficient doses during a sensitive window of fetal development. The study by Johnson et al. [51] was reaffirmed as suitable for hazard characterization and reference value derivation, though acknowledging study limitations and uncertainties. Published by Elsevier Inc.

Prevention of postpartum traumatic stress in mothers with preterm infants: manual development and evaluation.

PubMed

Shaw, Richard J; Sweester, Carrie J; St John, Nicholas; Lilo, Emily; Corcoran, Julia B; Jo, Booil; Howell, Shelley H K; Benitz, William E; Feinstein, Nancy; Melnyk, Bernadette; Horwitz, Sarah M

2013-08-01

Premature birth has been associated with multiple adverse maternal psychological outcomes that include depression, anxiety, and trauma as well as adverse effects on maternal coping ability and parenting style. Infants who are premature are more likely to have poorer cognitive and developmental functioning and, thus, may be harder to parent, both as infants and as they get older. In response to these findings, a number of educational and behavioral interventions have been developed that target maternal psychological functioning, parenting, and aspects of the parent-infant relationship. The current study aimed to both develop and evaluate a treatment that integrates, for the first time, effective interventions for reducing symptoms of posttraumatic stress disorder (PTSD) and enhancing maternal-infant interactions. Conclusions from the study indicate that the intervention is feasible, able to be implemented with a high level of fidelity, and is rated as highly satisfactory by participants. Though encouraging, these findings are preliminary, and future studies should strive to reproduce these findings with a larger sample size and a comparison group.

PREVENTION OF POSTPARTUM TRAUMATIC STRESS IN MOTHERS WITH PRETERM INFANTS: MANUAL DEVELOPMENT AND EVALUATION

PubMed Central

Shaw, Richard J.; Brecht, Carrie Jean; St. John, Nick; Lilo, Emily; Corcoran, Julia; Jo, Booil; Howell, Shelley; Benitz, William; Feinstein, Nancy F.; Melnyk, Bernadette; Horwitz, Sarah M.

2014-01-01

Premature birth has been associated with multiple adverse maternal psychological outcomes that include depression, anxiety, and trauma as well as adverse effects on maternal coping ability and parenting style. Infants and children who are premature are more likely to have poorer cognitive and developmental functioning and, thus, may be harder to parent. In response to these findings, there have been a number of educational and behavioral interventions developed that target maternal psychological functioning, parenting and aspects of the parent-infant relationship. The current study aimed to both develop and evaluate a treatment that integrates, for the first time, effective interventions for both reducing symptoms of posttraumatic stress disorder (PTSD) as well as enhancing maternal-infant interactions. Conclusions from the study indicate that the intervention is feasible, able to be implemented with a high level of fidelity, and is rated as highly satisfactory by participants. Though encouraging, these findings are preliminary, and future studies should strive to reproduce these findings with a larger sample size and a comparison group. PMID:23909669

The impact of general anesthesia on child development and school performance: a population-based study.

PubMed

Schneuer, Francisco J; Bentley, Jason P; Davidson, Andrew J; Holland, Andrew Ja; Badawi, Nadia; Martin, Andrew J; Skowno, Justin; Lain, Samantha J; Nassar, Natasha

2018-04-27

There has been considerable interest in the possible adverse neurocognitive effects of exposure to general anesthesia and surgery in early childhood. The aim of this data linkage study was to investigate developmental and school performance outcomes of children undergoing procedures requiring general anesthesia in early childhood. We included children born in New South Wales, Australia of 37+ weeks' gestation without major congenital anomalies or neurodevelopmental disability with either a school entry developmental assessment in 2009, 2012, or Grade-3 school test results in 2008-2014. We compared children exposed to general anesthesia aged <48 months to those without any hospitalization. Children with only 1 hospitalization with general anesthesia and no other hospitalization were assessed separately. Outcomes included being classified developmentally high risk at school entry and scoring below national minimum standard in school numeracy and reading tests. Of 211 978 children included, 82 156 had developmental assessment and 153 025 had school test results, with 12 848 (15.7%) and 25 032 (16.4%) exposed to general anesthesia, respectively. Children exposed to general anesthesia had 17%, 34%, and 23% increased odds of being developmentally high risk (adjusted odds ratio [aOR]: 1.17; 95% CI: 1.07-1.29); or scoring below the national minimum standard in numeracy (aOR: 1.34; 95% CI: 1.21-1.48) and reading (aOR: 1.23; 95% CI: 1.12-1.36), respectively. Although the risk for being developmentally high risk and poor reading attenuated for children with only 1 hospitalization and exposure to general anesthesia, the association with poor numeracy results remained. Children exposed to general anesthesia before 4 years have poorer development at school entry and school performance. While the association among children with 1 hospitalization with 1 general anesthesia and no other hospitalization was attenuated, poor numeracy outcome remained. Further investigation of the specific effects of general anesthesia and the impact of the underlying health conditions that prompt the need for surgery or diagnostic procedures is required, particularly among children exposed to long duration of general anesthesia or with repeated hospitalizations. © 2018 John Wiley & Sons Ltd.

The 2014 FDA assessment of commercial fish: practical considerations for improved dietary guidance.

PubMed

McGuire, Jennifer; Kaplan, Jason; Lapolla, John; Kleiner, Rima

2016-07-13

The U.S. Food and Drug Administration (FDA) recently released its report: A Quantitative Assessment of the Net Effects on Fetal Neurodevelopment from Eating Commercial Fish (As Measured by IQ and also by Early Age Verbal Development in Children). By evaluating the benefits and potential concerns of eating fish during pregnancy and breastfeeding, the analysis suggests that pregnant women consuming two seafood meals (8-12 oz) per week could provide their child with an additional 3.3 IQ points by age 9. Recent insights from behavioral economics research indicate that other factors, such as concerns about price and methylmercury (MeHg) exposure, appear to reduce fish consumption in many individuals.To assess the net effects of eating commercial fish during pregnancy, we compared the consumption of select fish species necessary to achieve IQ benefits with the amount necessary to have adverse developmental effects due to MeHg exposure. For the species or market types evaluated, the number of servings necessary to reach MeHg exposure to observe an adverse effect was at least twice that the amount estimated to achieve peak developmental benefit. We then reported average costs of fresh and canned or pouched fish, and calculated the cost per week for pregnant women to achieve maximum IQ benefits for their gestating child. Canned light tuna was the least expensive option at $1.83 per week to achieve maximum IQ benefit.Due to their relatively low cost, canned and pouched fish products eaten with enough regularity are likely to provide peak cognitive benefits. Because of its popularity, canned and pouched tuna could provide some of the largest cognitive benefits from fish consumption in the U.S. Future FDA consumer advice and related educational initiatives could benefit from a broader perspective that highlights the importance of affordable and accessible fish choices. These observations underscore the importance of clear public health messaging that address both health benefits and such real-world considerations as cost and convenience.

Prenatal exposure to bisphenol a at environmentally relevant doses adversely affects the murine female reproductive tract later in life.

PubMed

Newbold, Retha R; Jefferson, Wendy N; Padilla-Banks, Elizabeth

2009-06-01

Exposure to endocrine-disrupting chemicals during critical developmental periods causes adverse consequences later in life; an example is prenatal exposure to the pharmaceutical diethylstilbestrol (DES). Bisphenol A (BPA), an environmental estrogen used in the synthesis of plastics, is of concern because its chemical structure resembles that of DES, and it is a "high-volume production" chemical with widespread human exposure. In this study we investigated whether prenatal BPA causes long-term adverse effects in female reproductive tissues in an experimental animal model previously shown useful in studying effects of prenatal DES. Timed pregnant CD-1 mice were treated on days 9-16 of gestation with BPA (0.1, 1, 10, 100, or 1,000 mug/kg/day). After delivery, pups were held for 18 months; reproductive tissues were then evaluated. Ovarian cysts were significantly increased in the 1-mug/kg BPA group; ovarian cyst-adenomas were seen in the other three BPA-treated groups but not in corn-oil controls. We observed increased progressive proliferative lesions of the oviduct after BPA treatment, similar to those described in response to DES. Further, although not statistically different from the controls, prominent mesonephric (Wolffian) remnants and squamous metaplasia of the uterus, as well as vaginal adenosis, were present in BPA-treated mice, similar to lesions reported following DES treatment. More severe pathologies observed in some BPA-treated animals included atypical hyperplasia and stromal polyps of the uterus; sarcoma of the uterine cervix; and mammary adenocarcinoma. We did not observe these lesions in controls. These data suggest that BPA causes long-term adverse reproductive and carcinogenic effects if exposure occurs during critical periods of differentiation.

Prenatal Exposure to Bisphenol A at Environmentally Relevant Doses Adversely Affects the Murine Female Reproductive Tract Later in Life

PubMed Central

Newbold, Retha R.; Jefferson, Wendy N.; Padilla-Banks, Elizabeth

2009-01-01

Background Exposure to endocrine-disrupting chemicals during critical developmental periods causes adverse consequences later in life; an example is prenatal exposure to the pharmaceutical diethylstilbestrol (DES). Bisphenol A (BPA), an environmental estrogen used in the synthesis of plastics, is of concern because its chemical structure resembles that of DES, and it is a “high-volume production” chemical with widespread human exposure. Objectives In this study we investigated whether prenatal BPA causes long-term adverse effects in female reproductive tissues in an experimental animal model previously shown useful in studying effects of prenatal DES. Methods Timed pregnant CD-1 mice were treated on days 9–16 of gestation with BPA (0.1, 1, 10, 100, or 1,000 μg/kg/day). After delivery, pups were held for 18 months; reproductive tissues were then evaluated. Results Ovarian cysts were significantly increased in the 1-μg/kg BPA group; ovarian cyst-adenomas were seen in the other three BPA-treated groups but not in corn-oil controls. We observed increased progressive proliferative lesions of the oviduct after BPA treatment, similar to those described in response to DES. Further, although not statistically different from the controls, prominent mesonephric (Wolffian) remnants and squamous metaplasia of the uterus, as well as vaginal adenosis, were present in BPA-treated mice, similar to lesions reported following DES treatment. More severe pathologies observed in some BPA-treated animals included atypical hyperplasia and stromal polyps of the uterus; sarcoma of the uterine cervix; and mammary adenocarcinoma. We did not observe these lesions in controls. Conclusions These data suggest that BPA causes long-term adverse reproductive and carcinogenic effects if exposure occurs during critical periods of differentiation. PMID:19590677

DEVELOPMENTAL THYROID HORMONE INSUFFICIENCY ALTERS THE AMPLITUDE OF THE ACOUSTIC STARTLE RESPONSE IN RATS

EPA Science Inventory

Purpose: The thyroid hormone (TH) system is one of the targets of endocrine disrupting chemicals. Since TH is essential for proper brain development, disruption by exposure to chemicals during development can result in adverse neurological outcomes. Previous studies revealed th...

The International Resilience Research Project.

ERIC Educational Resources Information Center

Grotberg, Edith H.

Resilience is defined as "the human capacity to face, overcome, and be strengthened by experiences of adversity." This study used an Eriksonian developmental model to examine parents', caregivers', and children's resilience-promotion in children up to 12 years of age. Age and gender differences and cultural/ethnic similarities and…

Childhood exposure to violence and lifelong health: Clinical intervention science and stress biology research join forces

PubMed Central

Moffitt, Terrie E.

2013-01-01

Many young people who are mistreated by an adult, victimized by bullies, criminally assaulted, or who witness domestic violence react to this violence exposure by developing behavioral, emotional, or learning problems. What is less well known is that adverse experiences like violence exposure can lead to hidden physical alterations inside a child’s body, alterations which may have adverse effects on life-long health. We discuss why this is important for the field of developmental psychopathology and for society, and we recommend that stress-biology research and intervention science join forces to tackle the problem. We examine the evidence base in relation to stress-sensitive measures for the body (inflammatory reactions, telomere erosion, epigenetic methylation, and gene expression) and brain (mental disorders, neuroimaging, and neuropsychological testing). We also review promising interventions for families, couples, and children that have been designed to reduce the effects of childhood violence exposure. We invite intervention scientists and stress-biology researchers to collaborate in adding stress-biology measures to randomized clinical trials of interventions intended to reduce effects of violence exposure and other traumas on young people. PMID:24342859

EXTRAHEPATIC TOXICITY OF ACETAMINOPHEN: CRITICAL EVALUATION OF THE EVIDENCE AND PROPOSED MECHANISMS

PubMed Central

Kennon-McGill, Stefanie; McGill, Mitchell R.

2017-01-01

Research on acetaminophen (APAP) toxicity over the last several decades has focused on the pathophysiology of liver injury, but increasing attention is being paid to other known and possible adverse effects. It has been known for decades that APAP causes acute kidney injury, but confusion exists regarding prevalence, and the mechanisms have not been well investigated. More recently, a number of experimental, clinical and epidemiological studies have reported evidence for pulmonary, endocrine, neurological and neurodevelopmental toxicity, but the quality of evidence from those studies varies. It is important to consider these data due to implications for regulation and clinical practice. Here, we review the evidence and proposed mechanisms for extrahepatic adverse effects of APAP and weigh weaknesses and strengths in the data. We consider results from clinical, epidemiological and experimental research. Our goal is to determine the strength of claims regarding extrahepatic toxicity of APAP and to identify areas of need for future research. It is especially important to view claims of developmental effects of antenatal APAP exposure with a critical eye because APAP is currently the only over-the-counter medication recommended for pregnant women to self-treat pain and fever. PMID:29457141

Stage-dependent teratogenic and lethal effects exerted by ultraviolet B radiation on Rhinella (Bufo) arenarum embryos.

PubMed

Castañaga, Luis A; Asorey, Cynthia M; Sandoval, María T; Pérez-Coll, Cristina S; Argibay, Teresa I; Herkovits, Jorge

2009-02-01

The adverse effects of ultraviolet B radiation from 547.2 to 30,096 J/m2 on morphogenesis, cell differentiation, and lethality of amphibian embryos at six developmental stages were evaluated from 24 up to 168 h postexposure. The ultraviolet B radiation lethal dose 10, 50, and 90 values were obtained for all developmental stages evaluated. The lethal dose 50 values, considered as the dose causing lethality in the 50% of the organisms exposed, in J/m2 at 168 h postexposure, ranged from 2,307 to 18,930; gill circulation and blastula were the most susceptible and resistant stages, respectively. Ultraviolet B radiation caused malformations in all developmental stages but was significantly more teratogenic at the gill circulation and complete operculum stages. Moreover, at the gill circulation stage, even the lowest dose (547.2 J/m2) resulted in malformations to 100% of embryos. The most common malformations were persistent yolk plug, bifid spine, reduced body size, delayed development, asymmetry, microcephaly and anencephaly, tail and body flexures toward the irradiated side, agenesia or partial gill development, abnormal pigment distribution, and hypermotility. The stage-dependent susceptibility to ultraviolet B radiation during amphibian embryogenesis could be explained in the framework of evoecotoxicology, considering ontogenic features as biomarkers of environmental signatures of living forms ancestors during the evolutionary process. The stage-dependent susceptibility to ultraviolet B radiation on Rhinella (Bufo) arenarum embryos for both lethal and teratogenic effects could contribute to a better understanding of the role of the increased ultraviolet B radiation on worldwide amphibian populations decline.

Chronic Stress Modulates Regional Cerebral Glucose Transporter Expression in an Age-Specific and Sexually-Dimorphic Manner

PubMed Central

Kelly, Sean D.; Harrell, Constance S.; Neigh, Gretchen N.

2014-01-01

Facilitative glucose transporters (GLUT) mediate glucose uptake across the blood-brain-barrier into neurons and glia. Deficits in specific cerebral GLUT isoforms are linked to developmental and neurological dysfunction, but less is known about the range of variation in cerebral GLUT expression in normal conditions and the effects of environmental influences on cerebral GLUT expression. Knowing that puberty is a time of increased cerebral plasticity, metabolic demand, and shifts in hormonal balance for males and females, we first assessed gene expression of five GLUT subtypes in four brain regions in male and female adolescent and adult Wistar rats. The data indicated that sex differences in GLUT expression were most profound in the hypothalamus, and the transition from adolescence to adulthood had the most profound effect on GLUT expression in the hippocampus. Next, given the substantial energetic demands during adolescence and prior demonstrations of the adverse effects of adolescent stress, we determined the extent to which chronic stress altered GLUT expression in males and females in both adolescence and adulthood. Chronic stress significantly altered cerebral GLUT expression in males and females throughout both developmental stages but in a sexually dimorphic and brain region-specific manner. Collectively, our data demonstrate that cerebral GLUTs are expressed differentially based on brain region, sex, age, and stress exposure. These results suggest that developmental and environmental factors influence GLUT expression in multiple brain regions. Given the importance of appropriate metabolic balance within the brain, further assessment of the functional implications of life stage and environmentally-induced changes in GLUTs are warranted. PMID:24382486

Early-Life Toxic Insults and Onset of Sporadic Neurodegenerative Diseases-an Overview of Experimental Studies.

PubMed

Tartaglione, Anna Maria; Venerosi, Aldina; Calamandrei, Gemma

2016-01-01

The developmental origin of health and disease hypothesis states that adverse fetal and early childhood exposures can predispose to obesity, cardiovascular, and neurodegenerative diseases (NDDs) in adult life. Early exposure to environmental chemicals interferes with developmental programming and induces subclinical alterations that may hesitate in pathophysiology and behavioral deficits at a later life stage. The mechanisms by which perinatal insults lead to altered programming and to disease later in life are still undefined. The long latency between exposure and onset of disease, the difficulty of reconstructing early exposures, and the wealth of factors which the individual is exposed to during the life course make extremely difficult to prove the developmental origin of NDDs in clinical and epidemiological studies. An overview of animal studies assessing the long-term effects of perinatal exposure to different chemicals (heavy metals and pesticides) supports the link between exposure and hallmarks of neurodegeneration at the adult stage. Furthermore, models of maternal immune activation show that brain inflammation in early life may enhance adult vulnerability to environmental toxins, thus supporting the multiple hit hypothesis for NDDs' etiology. The study of prospective animal cohorts may help to unraveling the complex pathophysiology of sporadic NDDs. In vivo models could be a powerful tool to clarify the mechanisms through which different kinds of insults predispose to cell loss in the adult age, to establish a cause-effect relationship between "omic" signatures and disease/dysfunction later in life, and to identify peripheral biomarkers of exposure, effects, and susceptibility, for translation to prospective epidemiological studies.

Developmental effects of exposures to environmental factors: the Polish Mother and Child Cohort Study.

PubMed

Polanska, Kinga; Hanke, Wojciech; Sobala, Wojciech; Trzcinka-Ochocka, Malgorzata; Ligocka, Danuta; Brzeznicki, Slawomir; Strugala-Stawik, Halina; Magnus, Per

2013-01-01

This paper estimates the effects of exposure to environmental factors, including lead, mercury, environmental tobacco smoke (ETS), and polycyclic aromatic hydrocarbons (PAH), on child psychomotor development. The study population consists of mother-child pairs in the Polish Mother and Child Cohort Study. Prenatal and postnatal exposure to environmental factors was determined from biomarker measurements as follows: for lead exposure--cord blood lead level, for mercury--maternal hair mercury level, for ETS--cotinine level in saliva and urine, and for PAH--1-hydroxypyrene (1-HP) in urine. At the age of 12 (406 subjects) and 24 months (198 subjects) children were assessed using Bayley Scales of Infant and Toddler Development. There were no statistically significant effects of prenatal exposure to mercury or 1-HP on child psychomotor development. After adjusting for potential confounders, adverse effects of prenatal exposure to ETS on motor development ( β = -2.6; P = 0.02) and postnatal exposure to ETS on cognitive ( β = -0.2; P = 0.05) and motor functions ( β = -0.5; P = 0.01) were found. The adverse effect of prenatal lead exposure on cognitive score was of borderline significance ( β = -6.2; P = 0.06). The study underscores the importance of policies and public health interventions that aim to reduce prenatal and postnatal exposure to lead and ETS.

WAFs lead molting retardation of naupliar stages with down-regulated expression profiles of chitin metabolic pathway and related genes in the copepod Tigriopus japonicus.

PubMed

Hwang, Dae-Sik; Lee, Min-Chul; Kyung, Do-Hyun; Kim, Hui-Su; Han, Jeonghoon; Kim, Il-Chan; Puthumana, Jayesh; Lee, Jae-Seong

2017-03-01

Oil pollution is considered being disastrous to marine organisms and ecosystems. As molting is critical in the developmental process of arthropods in general and copepods, in particular, the impact will be adverse if the target of spilled oil is on molting. Thus, we investigated the harmful effects of water accommodated fractions (WAFs) of crude oil with an emphasis on inhibition of chitin metabolic pathways related genes and developmental retardation in the copepod Tigriopus japonicus. Also, we analysed the ontology and domain of chitin metabolic pathway genes and mRNA expression patterns of developmental stage-specific genes. Further, the developmental retardation followed by transcriptional modulations in nuclear receptor genes (NR) and chitin metabolic pathway-related genes were observed in the WAFs-exposed T. japonicus. As a result, the developmental time was found significantly (P<0.05) delayed in response to 40% WAFs in comparison with that of control. Moreover, the NR gene, HR3 and chitinases (CHT9 and CHT10) were up-regulated in N4-5 stages, while chitin synthase genes (CHS-1, CHS-2-1, and CHS-2-2) down-regulated in response to WAFs. In brief, a high concentration of WAFs repressed nuclear receptor genes but elicited activation of some of the transcription factors at low concentration of WAFs, resulting in suppression of chitin synthesis. Thus, we suggest that WAF can lead molting retardation of naupliar stages in T. japonicus through down-regulations of chitin metabolism. These findings will provide a better understanding of the mode of action of chitin biosynthesis associated with molting mechanism in WAF-exposed T. japonicus. Copyright © 2016 Elsevier Inc. All rights reserved.

The science of early adversity: is there a role for large institutions in the care of vulnerable children?

PubMed

Berens, Anne E; Nelson, Charles A

2015-07-25

It has been more than 80 years since researchers in child psychiatry first documented developmental delays among children separated from family environments and placed in orphanages or other institutions. Informed by such findings, global conventions, including the 1989 UN Convention on the Rights of the Child, assert a child's right to care within a family-like environment that offers individualised support. Nevertheless, an estimated 8 million children are presently growing up in congregate care institutions. Common reasons for institutionalisation include orphaning, abandonment due to poverty, abuse in families of origin, disability, and mental illness. Although the practice remains widespread, a robust body of scientific work suggests that institutionalisation in early childhood can incur developmental damage across diverse domains. Specific deficits have been documented in areas including physical growth, cognitive function, neurodevelopment, and social-psychological health. Effects seem most pronounced when children have least access to individualised caregiving, and when deprivation coincides with early developmental sensitive periods. Offering hope, early interventions that place institutionalised children into families have afforded substantial recovery. The strength of scientific evidence imparts urgency to efforts to achieve deinstitutionalisation in global child protection sectors, and to intervene early for individual children experiencing deprivation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pre-implantation alcohol exposure and developmental programming of FASD: an epigenetic perspective.

PubMed

Legault, Lisa-Marie; Bertrand-Lehouillier, Virginie; McGraw, Serge

2018-04-01

Exposure to alcohol during in-utero development can permanently change the developmental programming of physiological responses, thereby increasing the risk of neurological illnesses during childhood and later adverse health outcomes associated with fetal alcohol spectrum disorder (FASD). There is an increasing body of evidence indicating that exposure to alcohol during gestation triggers lasting epigenetic alterations in offspring, long after the initial insult; together, these studies support the role of epigenetics in FASD etiology. However, we still have little information about how ethanol interferes with the fundamental epigenetic reprogramming wave (e.g., erasure and re-establishment of DNA methylation marks) that characterizes pre-implantation embryo development. This review examines key epigenetic processes that occur during pre-implantation development and especially focus on the current knowledge regarding how prenatal exposure to alcohol during this period could affect the developmental programming of the early stage pre-implantation embryo. We will also outline the current limitations of studies examining the in-vivo and in-vitro effects of alcohol exposure on embryos and underline the next critical steps to be taken if we want to better understand the implicated mechanisms to strengthen the translational potential for epigenetic markers for non-invasive early detection, and the treatment of newborns that have higher risk of developing FASD.

Developmental toxicity study of sodium molybdate dihydrate administered in the diet to Sprague Dawley rats.

PubMed

Jay Murray, F; Tyl, Rochelle W; Sullivan, Frank M; Tiwary, Asheesh K; Carey, Sandra

2014-11-01

Molybdenum is an essential nutrient for humans and animals and is a constituent of several important oxidase enzymes. It is normally absorbed from the diet and to a lesser extent from drinking water and the typical human intake is around 2μg/kg bodyweight per day. No developmental toxicity studies to contemporary standards have been published and regulatory decisions have been based primarily on older studies where the nature of the test material, or the actual dose levels consumed is uncertain. In the current study the developmental toxicity of sodium molybdate dihydrate as a representative of a broad class of soluble molybdenum(VI) compounds, was given in the diet to Sprague Dawley rats in accordance with OECD Test Guideline 414. Dose levels of 0, 3, 10, 20 and 40mgMo/kgbw/day were administered from GD6 to GD20. No adverse effects were observed at any dose level on the dams, or on embryofetal survival, fetal bodyweight, or development, with no increase in malformations or variations. Significant increases in serum and tissue copper levels were observed but no toxicity related to these was observed. The NOAEL observed in this study was 40mgMo/kgbw/day, the highest dose tested. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Annual Research Review: Resilient functioning in maltreated children: Past, present, and future perspectives

PubMed Central

Cicchetti, Dante

2012-01-01

Through a process of probabilistic epigenesis, child maltreatment progressively contributes to compromised adaptation on a variety of developmental domains central to successful adjustment. These developmental failures pose significant risk for the emergence of psychopathology across the life course. In addition to the psychological consequences of maltreatment, a growing body of research has documented the deleterious effects of abuse and neglect on biological processes. Nonetheless, not all maltreated children develop maladaptively. Indeed, some percentage of maltreated children develop in a resilient fashion despite the significant adversity and stress they experience. The literature on the determinants of resilience in maltreated children is selectively reviewed and criteria for the inclusion of the studies are delineated. The majority of the research on the contributors to resilient functioning has focused on a single level of analysis and on psychosocial processes. Multilevel investigations have begun to appear, resulting in several studies on the processes to resilient functioning that integrate biological/genetic and psychological domains. Much additional research on the determinants of resilient functioning must be completed before we possess adequate knowledge based on a multiple levels of analysis approach that is commensurate with the complexity inherent in this dynamic developmental process. Suggestions for future research on the development of resilient functioning in maltreated children are proffered and intervention implications are discussed. PMID:22928717

Rethinking evidence-based practice and two-generation programs to create the future of early childhood policy

PubMed Central

Shonkoff, Jack P.; Fisher, Philip A.

2016-01-01

Half a century of research and program evaluation has fueled a diverse landscape of early childhood policies and practices that produce a range of positive effects on the life prospects of children who face the burdens of significant adversity. Drawing on advances in neurobiology, developmental psychology, developmental psychopathology, and prevention science, this paper presents a framework for elucidating underlying causal mechanisms that explain differences in outcomes, formulating enhanced theories of change about how to shift developmental trajectories, designing creative interventions and rethinking the concept of a two-generation strategy to produce breakthrough impacts, and launching a new era of investment in young children and their families that will achieve greater reductions in intergenerational disparities in learning, behavior, and health than those produced by current best practices. Particular attention is focused on the hypothesis that substantially better outcomes for vulnerable, young children could be achieved by greater attention to strengthening the resources and capabilities of the adults who care for them rather than by continuing to focus primarily on the provision of child-focused enrichment, parenting education, and informal support. Central to achieving this goal is the need to establish an innovation-friendly environment that embraces fast-cycle sharing, supports risk taking, and celebrates learning from failure. PMID:24342860

Rejected by peers-attracted to antisocial media content: rejection-based anger impairs moral judgment among adolescents.

PubMed

Plaisier, Xanthe S; Konijn, Elly A

2013-06-01

Adolescence is an important developmental stage during which both peers and the media have a strong influence. Both peer rejection and the use of morally adverse media are associated with negative developmental outcomes. This study examines processes by which peer rejection might drive adolescents to select antisocial media content by tying together developmental research on peer rejection and research on media effects. Assumed underlying mechanisms are rejection-based anger and frustration and the adolescent's moral judgment. A between-participants experimental design manipulated peer rejection versus acceptance in adolescents (Mage = 13.88 years; N = 74) and young adults (Mage = 21.37 years; N = 75), applying the Cyberball paradigm. Measures included the State Anger Inventory (STAXI) to assess feelings of rejection and the newly devised Media, Morals, and Youth Questionnaire (MMaYQue) to assess media preferences and moral judgment of media content. Using bootstrapping analyses, a double mediation was established: Higher levels of state anger in peer-rejected adolescents induced more tolerable moral judgments of antisocial media content, subsequently instigating a preference for antisocial media content. In contrast, the young adult sample showed no relations between peer rejection and antisocial media preference. Results are discussed within a downward spiral framework of combined peer and media influences. PsycINFO Database Record (c) 2013 APA, all rights reserved

BISPHENOL A EXPOSURE DURING EARLY DEVELOPMENT INDUCES SEX-SPECIFIC CHANGES IN ADULT ZEBRAFISH SOCIAL INTERACTIONS

PubMed Central

Weber, Daniel N.; Hoffmann, Raymond G.; Hoke, Elizabeth S.; Tanguay, Robert L.

2014-01-01

Developmental bisphenol A (BPA) exposure is associated with adverse behavioral effects, although underlying modes of action remain unclear. Because BPA is a suspected xenoestrogen, the objective was to identify sex-based changes in adult zebrafish social behavior developmentally exposed to BPA (0.0, 0.1 or 1 μM) or one of two control compounds (0.1μM 17β-estradiol [E2], and 0.1 μM GSK4716, a synthetic estrogen-related receptor γ ligand). A test chamber was divided lengthwise so each arena held one fish unable to detect the presence of the other fish. A mirror was inserted at one end of each arena; baseline activity levels were determined without mirror. Arenas were divided into 3, computer-generated zones to represent different distances from mirror image. Circadian rhythm patterns were evaluated at 1–3 (= AM) and 5–8 (= PM) hr postprandial. Adult zebrafish were placed into arenas and monitored by digital camera for 5 min. Total distance traveled, % time spent at mirror image, and number of attacks on mirror image were quantified. E2, GSK4716, and all BPA treatments dampened male activity and altered male circadian activity patterns; there was no marked effect on female activity. BPA induced non-monotonic effects (response curve changes direction within range of concentrations examined) on male % time at mirror only in AM. All treatments produced increased % time at the mirror during PM. Male attacks on the mirror were reduced by BPA exposure only during AM. There were sex-specific effects of developmental BPA on social interactions and time-of-day of observation affected results. PMID:25424546

Infertility, Pregnancy Loss and Adverse Birth Outcomes in Relation to Maternal Secondhand Tobacco Smoke Exposure

PubMed Central

Meeker, John D.; Benedict, Merle D.

2013-01-01

A substantial proportion of the etiology involved in female infertility and adverse pregnancy outcomes remains idiopathic. Recent scientific research has suggested a role for environmental factors in these conditions. Secondhand tobacco smoke (STS) contains a number of known or suspected reproductive toxins, and human exposure to STS is prevalent worldwide. Robust evidence exists for the toxic effects of active smoking on fertility and pregnancy, but studies of passive exposure are much more limited in number. While the association between maternal STS exposure and declined birth weight has been fairly well-documented, only recently have epidemiologic studies begun to provide suggestive evidence for delayed conception, altered menstrual cycling, early pregnancy loss (e.g. spontaneous abortion), preterm delivery, and congenital malformations in relation to STS exposure. There is also new evidence that developmental exposures to tobacco smoke may be associated with reproductive effects in adulthood. To date, most studies have estimated maternal STS exposure through self-report even though exposure biomarkers are less prone to error and recall bias. In addition to utilizing biomarkers of STS exposure, future studies should aim to identify vital windows of STS exposure, important environmental co-exposures, individual susceptibility factors, and specific STS constituents associated with female infertility and adverse pregnancy outcomes. The role of paternal exposures/factors should also be investigated. PMID:23888128

Developmental Changes in the Whole Number Bias

ERIC Educational Resources Information Center

Braithwaite, David W.; Siegler, Robert S.

2017-01-01

Many students' knowledge of fractions is adversely affected by whole number bias, the tendency to focus on the separate whole number components (numerator and denominator) of a fraction rather than on the fraction's integrated magnitude (ratio of numerator to denominator). Although whole number bias appears early in the fraction learning process…

REDOX DISRUPTING POTENTIAL OF TOXCAST CHEMICALS RANKED BY ACTIVITY IN MOUSE EMBRYONIC STEM CELLS

EPA Science Inventory

To gain insight regarding the adverse outcome pathways leading to developmental toxicity following exposure to chemicals, we evaluated ToxCast™ Phase I chemicals in an adherent mouse embryonic stem cell (mESC) assay and identified a redox sensitive pathway that correlated with al...

Redox Disrupting Potential of ToxCast™Chemicals Ranked by Activity in Mouse Embryonic Stem Cells

EPA Science Inventory

Little is known regarding the adverse outcome pathways responsible for developmental toxicity following exposure to chemicals. An evaluation of Toxoast™ Phase I chemicals in an adherent mouse embryonic stem cell (mESC) assay revealed a redox sensitive pathway that correlated with...

Current Status of Chemical Public Health Risks and Testing Guidelines for Chemical Cardiovascular Safety Assessments

EPA Science Inventory

The cardiovascular system, at all its various developmental and life stages, represents a critical target organ system that can be adversely affected by a variety of chemicals and routes of exposure. A World Health Organization report estimated the impact of environmental chemica...

CHANGES IN PROTEOMIC PROFILES OF CEREBELLUM AND HIPPOCAMPUS FOLLOWING EXPOSURE TO A DEVELOPMENTAL NEUROTOXICANT.

EPA Science Inventory

The vast literature on the group of chemicals known as polychlorinated biphenyls (PCBs) makes it a unique model to understand major issues related to environmental mixtures of persistent chemicals. At background levels of exposure, PCBs have been shown to adversely affect human h...

Lessons Learned from Our Elders: How to Study Polypharmacy in Populations with Intellectual and Developmental Disabilities

ERIC Educational Resources Information Center

Stortz, Jessica N.; Lake, Johanna K.; Cobigo, Virginie; Ouellette-Kuntz, Hélène M. J.; Lunsky, Yona

2014-01-01

"Polypharmacy" is the concurrent use of multiple medications, including both psychotropic and non-psychotropic drugs. Although it may sometimes be clinically indicated, polypharmacy can have a number of negative consequences, including medication nonadherence, adverse drug reactions, and undesirable drug--drug interactions. The objective…

Trauma in Early Childhood: A Neglected Population

ERIC Educational Resources Information Center

De Young, Alexandra C.; Kenardy, Justin A.; Cobham, Vanessa E.

2011-01-01

Infants, toddlers and preschoolers are a high risk group for exposure to trauma. Young children are also vulnerable to experiencing adverse outcomes as they are undergoing a rapid developmental period, have limited coping skills and are strongly dependent on their primary caregiver to protect them physically and emotionally. However, although…

Obstetrical Complications and Violent Delinquency: Testing Two Developmental Pathways.

ERIC Educational Resources Information Center

Arseneault, Louise; Tremblay, Richard E.; Boulerice, Bernard; Saucier, Jean-Francois

2002-01-01

Assessed interaction between obstetrical complications and early family adversity in predicting violent behavior during childhood and adolescence among 849 boys from low SES areas. Found that elevated scores on scale of obstetrical complications (preeclampsia, umbilical cord prolapse, induced labor) increased risk of being violent at 6 and 17…

Developmental Changes in the Whole Number Bias

ERIC Educational Resources Information Center

Braithwaite, David W.; Siegler, Robert S.

2018-01-01

Many students' knowledge of fractions is adversely affected by whole number bias, the tendency to focus on the separate whole number components (numerator and denominator) of a fraction rather than on the fraction's magnitude (ratio of numerator to denominator). Although whole number bias appears early in the fraction learning process and under…

Educational Resilience in Inner Cities. Publication Series #93-5d.

ERIC Educational Resources Information Center

Wang, M. C.; And Others

Educational resilience is defined as the heightened likelihood of success in school and in other life accomplishments, despite environmental adversities. This paper summarizes the concept of resilience as it has been advanced in developmental psychopathology and discusses educationally relevant research that is consonant with the definition of…

Clinical Use of Aromatase Inhibitors in Adult Males.

PubMed

Tan, Ronny B W; Guay, Andre T; Hellstrom, Wayne J G

2014-04-01

There is a growing interest in the treatment of late-onset hypogonadism, another name for the study of testosterone deficiency in an older age group. Initial attempts at testosterone replacement have also brought attention to the possible adverse effects on the patients' cardiovascular risk factors and their prostate health. The "female" hormone estradiol is no longer considered as the feminizing hormone, as it has been identified to have an effect on the sexual and general well-being of adult males. Urologists and endocrinologists alike have started to pay attention to the serum T/E 2 (testosterone : estradiol) ratio that appears to be more important than the respective individual hormonal levels. Therein lies the possible role of aromatase inhibitors (AIs) in restoring the normal balance of serum testosterone and estradiol levels for the adequate treatment of late-onset hypogonadism, while limiting the potential adverse effects. Currently, other established clinical indications of AIs include the treatment of breast cancer in female patients and developmental growth problems in pediatric patients. This review evaluates the role of AIs as a treatment option for late-onset hypogonadism and the evidence for its other clinical uses in men, including its possible adverse effects. A literature review was performed with regards to the use of aromatase inhibitors in adult males, the role of estrogens in adult males, as well as adverse effect of AIs on bone health in adult males. To evaluate the evidence for the use of AIs in adult males to treat late-onset hypogonadism, obesity-related hypogonadotropic hypogonadism, gynecomastia, and male subfertility. To evaluate the evidence for the possible adverse effects on the bone health of adult males with the use of AIs. Currently there is no literature to recommend the use of AIs in adult males to treat late-onset hypogonadism, obesity-related hypogonadotropic hypogonadism, gynecomastia, or male subfertility, although some positive effects have been reported. The adverse effects on bone health seen in females treated with AIs are not seen in males. With the better understanding of the T/E 2 ratio in adult males, the lack of scientific data to show that bone health is adversely affected by AI usage in adult males, the positive effects of AIs on the treatment of conditions like late-onset hypogonadism and male subfertility encourages conducting large-scale, multicenter, randomized controlled trials for the clinical use of AIs in adult males. Tan RBW, Guay AT, and Hellstrom WJG. Clinical use of aromatase inhibitors in adult males. Sex Med Rev 2014;2:79-90. Copyright © 2014 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

NTP-CERHR monograph on the potential human reproductive and developmental effects of di (2-ethylhexyl) phthalate (DEHP).

PubMed

Shelby, Michael D

2006-11-01

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an updated evaluation of the potential for DEHP to cause adverse effects on reproduction and development in humans. The first CERHR expert panel evaluation of DEHP was completed in 2000 by the Phthalates Expert Panel. CERHR selected DEHP for an updated evaluation because of: (1) widespread human exposure, (2) public and government interest in adverse health effects, (3) recently available human exposure studies, and (4) the large number of relevant toxicity papers published since the earlier evaluation. DEHP (CAS RN: 117-81-7) is a high production volume chemical used as a plasticizer of polyvinyl chloride in the manufacture of a wide variety of consumer goods, such as building products, car products, clothing, food packaging, children's products (but not in toys intended for mouthing), and in medical devices made of polyvinyl chloride. The public can be exposed to DEHP by ingesting food, drink or dust that has been in contact with DEHP-containing materials, by inhaling contaminated air or dust, or by undergoing a medical procedure that uses polyvinyl chloride medical tubing or storage bags. It is estimated that the general population of the United States is exposed to DEHP levels ranging from 1 to 30 microg/kg bw/day (micrograms per kilogram body weight per day). The results of this DEHP update evaluation are published in an NTP-CERHR monograph that includes: (1) the NTP Brief, (2) the Expert Panel Update on the Reproductive and Developmental Toxicity of DEHP, and (3) public comments on the expert panel report. The NTP reached the following conclusions on the possible effects of exposure to DEHP on human development and reproduction. Note that the possible levels of concern, from lowest to highest, are negligible concern, minimal concern, some concern, concern, and serious concern. There is serious concern that certain intensive medical treatments of male infants may result in DEHP exposure levels that adversely affect development of the male reproductive tract. DEHP exposure from medical procedures in infants was estimated to be as high as 6000 microg/kg bw/day. There is concern for adverse effects on development of the reproductive tract in male offspring of pregnant and breast feeding women undergoing certain medical procedures that may result in exposure to high levels of DEHP. There is concern for effects of DEHP exposure on development of the male reproductive tract for infants less than one year old. Diet, mouthing of DEHP-containing objects, and certain medical treatments may lead to DEHP exposures that are higher than those experienced by the general population. There is some concern for effects of DEHP exposure on development of the reproductive tract of male children older than one year. As in infants, exposures of children to DEHP may be higher than in the general population. There is some concern for adverse effects of DEHP exposure on development of the male reproductive tract in male offspring of pregnant women not medically exposed to DEHP. Although DEHP exposures are assumed to be the same as for the general population, the developing male reproductive tract is sensitive to the adverse effects of DEHP. There is minimal concern for reproductive toxicity in adults exposed to DEHP at 1 - 30 microg/kg bw/day. This level of concern is not altered for adults medically exposed to DEHP. NTP will transmit the NTP-CERHR Monograph on DEHP to federal and state agencies, interested parties, and the public and it will be available in electronic PDF format on the CERHR web site http://cerhr.niehs.nih.gov and in printed text or CD-ROM from the CERHR.

Multiple Endocrine Disrupting Effects in Rats Perinatally Exposed to Butylparaben.

PubMed

Boberg, J; Axelstad, M; Svingen, T; Mandrup, K; Christiansen, S; Vinggaard, A M; Hass, U

2016-07-01

Parabens comprise a group of preservatives commonly added to cosmetics, lotions, and other consumer products. Butylparaben has estrogenic and antiandrogenic properties and is known to reduce sperm counts in rats following perinatal exposure. Whether butylparaben exposure can affect other endocrine sensitive endpoints, however, remains largely unknown. In this study, time-mated Wistar rats (n = 18) were orally exposed to 0, 10, 100, or 500 mg/kg bw/d of butylparaben from gestation day 7 to pup day 22. Several endocrine-sensitive endpoints were adversely affected. In the 2 highest dose groups, the anogenital distance of newborn male and female offspring was significantly reduced, and in prepubertal females, ovary weights were reduced and mammary gland outgrowth was increased. In male offspring, sperm count was significantly reduced at all doses from 10 mg/kg bw/d. Testicular CYP19a1 (aromatase) expression was reduced in prepubertal, but not adult animals exposed to butylparaben. In adult testes, Nr5a1 expression was reduced at all doses, indicating persistent disruption of steroidogenesis. Prostate histology was altered at prepuberty and adult prostate weights were reduced in the high dose group. Thus, butylparaben exerted endocrine disrupting effects on both male and female offspring. The observed adverse developmental effect on sperm count at the lowest dose is highly relevant to risk assessment, as this is the lowest observed adverse effect level in a study on perinatal exposure to butylparaben. © 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.

Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics

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

Kleinstreuer, N.C., E-mail: kleinstreuer.nicole@epa.gov; Smith, A.M.; West, P.R.

2011-11-15

Metabolomics analysis was performed on the supernatant of human embryonic stem (hES) cell cultures exposed to a blinded subset of 11 chemicals selected from the chemical library of EPA's ToxCast Trade-Mark-Sign chemical screening and prioritization research project. Metabolites from hES cultures were evaluated for known and novel signatures that may be indicative of developmental toxicity. Significant fold changes in endogenous metabolites were detected for 83 putatively annotated mass features in response to the subset of ToxCast chemicals. The annotations were mapped to specific human metabolic pathways. This revealed strong effects on pathways for nicotinate and nicotinamide metabolism, pantothenate and CoAmore » biosynthesis, glutathione metabolism, and arginine and proline metabolism pathways. Predictivity for adverse outcomes in mammalian prenatal developmental toxicity studies used ToxRefDB and other sources of information, including Stemina Biomarker Discovery's predictive DevTox Registered-Sign model trained on 23 pharmaceutical agents of known developmental toxicity and differing potency. The model initially predicted developmental toxicity from the blinded ToxCast compounds in concordance with animal data with 73% accuracy. Retraining the model with data from the unblinded test compounds at one concentration level increased the predictive accuracy for the remaining concentrations to 83%. These preliminary results on a 11-chemical subset of the ToxCast chemical library indicate that metabolomics analysis of the hES secretome provides information valuable for predictive modeling and mechanistic understanding of mammalian developmental toxicity. -- Highlights: Black-Right-Pointing-Pointer We tested 11 environmental compounds in a hESC metabolomics platform. Black-Right-Pointing-Pointer Significant changes in secreted small molecule metabolites were observed. Black-Right-Pointing-Pointer Perturbed mass features map to pathways critical for normal development and pregnancy. Black-Right-Pointing-Pointer Arginine, proline, nicotinate, nicotinamide and glutathione pathways were affected.« less

Developmental toxicity study in Sprague-Dawley rats by whole-body exposure to N,N-diethylethanolamine vapor.

PubMed

Leung, H W; Murphy, S R

1998-01-01

Timed-pregnant Sprague-Dawley rats were exposed whole body to N,N-diethylethanolamine vapor for 6 h per day on gestational days (GD) 6-15 at targeted concentrations of 33, 66 or 100 ppm. Dams were sacrificed on GD 21. There was no maternal mortality in any exposed groups. Maternal toxicity observed in the 100 ppm group included dry rales, reduced body weight (9.5%) on GD 15 and reduced weight gain (48%) during exposure. Suppression of body weight gain was also noted in the 66 ppm group during GD 12-15. There were no effects of treatment on gestational parameters, including pre- and post-implantation loss or sex ratio. Mean fetal body weights in treated groups were comparable to controls. There was no increase in the incidence of total malformations (external, visceral or skeletal) or individually by category. The incidence of a single developmental variation (hypoplastic bones of the forepaw) in the 100 ppm groups was statistically significantly decreased relative to that of controls. The no-observed-adverse-effect level was 33 ppm for maternal toxicity but greater than 100 ppm for embryofetal toxicity and teratogenicity.

Developmental conditioning of endothelium-derived hyperpolarizing factor-mediated vasorelaxation

PubMed Central

Stead, Rebecca; Musa, Moji G.; Bryant, Claire L.; Lanham, Stuart A.; Johnston, David A.; Reynolds, Richard; Torrens, Christopher; Fraser, Paul A.; Clough, Geraldine F.

2016-01-01

Objectives: The endothelium maintains vascular homeostasis through the release of endothelium-derived relaxing factors (EDRF) and endothelium-derived hyperpolarization (EDH). The balance in EDH : EDRF is disturbed in cardiovascular disease and may also be susceptible to developmental conditioning through exposure to an adverse uterine environment to predispose to later risk of hypertension and vascular disease. Methods: Developmentally conditioned changes in EDH : EDRF signalling pathways were investigated in cremaster arterioles (18–32 μm diameter) and third-order mesenteric arteries of adult male mice offspring of dams fed either a fat-rich (high fat, HF, 45% energy from fat) or control (C, 10% energy from fat) diet. After weaning, offspring either continued on high fat or were placed on control diets to give four dietary groups (C/C, HF/C, C/HF, and HF/HF) and studied at 15 weeks of age. Results: EDH via intermediate (IKCa) and small (SKca) conductance calcium-activated potassium channels contributed less than 10% to arteriolar acetylcholine-induced relaxation in in-situ conditioned HF/C offspring compared with ∼60% in C/C (P < 0.01). The conditioned reduction in EDH signalling in HF/C offspring was reversed in offspring exposed to a high-fat diet both before and after weaning (HF/HF, 55%, P < 0.01 vs. HF/C). EDH signalling was unaffected in arterioles from C/HF offspring. The changes in EDH : EDRF were associated with altered endothelial cell expression and localization of IKCa channels. Conclusion: This is the first evidence that EDH-mediated microvascular relaxation is susceptible to an adverse developmental environment through down-regulation of the IKCa signalling pathway. Conditioned offspring exposed to a ‘second hit’ (HF/HF) exhibit adaptive vascular mechanisms to preserve dilator function. PMID:26682783

Developmental conditioning of endothelium-derived hyperpolarizing factor-mediated vasorelaxation.

PubMed

Stead, Rebecca; Musa, Moji G; Bryant, Claire L; Lanham, Stuart A; Johnston, David A; Reynolds, Richard; Torrens, Christopher; Fraser, Paul A; Clough, Geraldine F

2016-03-01

The endothelium maintains vascular homeostasis through the release of endothelium-derived relaxing factors (EDRF) and endothelium-derived hyperpolarization (EDH). The balance in EDH : EDRF is disturbed in cardiovascular disease and may also be susceptible to developmental conditioning through exposure to an adverse uterine environment to predispose to later risk of hypertension and vascular disease. Developmentally conditioned changes in EDH : EDRF signalling pathways were investigated in cremaster arterioles (18-32  μm diameter) and third-order mesenteric arteries of adult male mice offspring of dams fed either a fat-rich (high fat, HF, 45% energy from fat) or control (C, 10% energy from fat) diet. After weaning, offspring either continued on high fat or were placed on control diets to give four dietary groups (C/C, HF/C, C/HF, and HF/HF) and studied at 15 weeks of age. EDH via intermediate (IKCa) and small (SKca) conductance calcium-activated potassium channels contributed less than 10% to arteriolar acetylcholine-induced relaxation in in-situ conditioned HF/C offspring compared with ∼60% in C/C (P < 0.01). The conditioned reduction in EDH signalling in HF/C offspring was reversed in offspring exposed to a high-fat diet both before and after weaning (HF/HF, 55%, P < 0.01 vs. HF/C). EDH signalling was unaffected in arterioles from C/HF offspring. The changes in EDH : EDRF were associated with altered endothelial cell expression and localization of IKCa channels. This is the first evidence that EDH-mediated microvascular relaxation is susceptible to an adverse developmental environment through down-regulation of the IKCa signalling pathway. Conditioned offspring exposed to a 'second hit' (HF/HF) exhibit adaptive vascular mechanisms to preserve dilator function.

Intravenous Exposure of Pregnant Mice to Silver Nanoparticles: Silver Tissue Distribution and Effects in Maternal and Extra-Embryonic Tissues and Embryos

NASA Astrophysics Data System (ADS)

Austin, Carlye Anne

This research explores the tissue distribution of silver, as well as adverse effects in pregnant mice and embryos, following prenatal silver nanoparticle (AgNP) exposure. Chapter one of this dissertation is a survey of the published literature on the reproductive and/or developmental toxicity of AgNPs. The available data indicate that AgNPs adversely affect sperm count, viability, and/or motility both in vivo and in vitro, and cause apoptosis and necrosis in spermatogonial stem cells and testicular cells. Additionally, AgNP exposure results in mortality and morphological deformities in fish embryos, but produces no adverse effects in chicken embryos. The current published research on in vivo AgNP exposure to mammals during gestation consists of only three studies, one of which is described in chapter two of this dissertation. These studies report results that may suggest a potential for adverse effects on fetal development (e.g. , decreased viability and fetal and placental weights, increased incidence of developmentally young embryos), but additional research is needed. Chapter two of this dissertation investigates the distribution of silver in tissues of pregnant mice and gestation day (GD) 10 embryos following intravenous maternal exposure to 50 nm AgNPs during early organogenesis (GDs 7-9). Examinations of embryo morphology and histology were also performed. Results demonstrated the presence of silver in all organs and tissues examined. Silver concentrations were highest in liver, spleen, and visceral yolk sac, and lowest in embryos. Groups of mice were also treated with soluble silver nitrate, and the pattern of silver tissue distribution following silver nitrate exposure was similar to that which followed AgNP treatment. Transmission electron microscopy-energy dispersive x-ray spectroscopy (TEM-EDS) confirmed the presence of vesicle-bound nanoparticulate silver in visceral yolk sac endoderm, but not mesoderm. This finding, along with the high silver concentration in visceral yolk sac and low silver concentration in embryos, suggests that visceral yolk sac tissue mitigates AgNP transfer to embryos. No significant treatment-related effects on embryo morphology or tissue histology were detected. Chapter three constitutes an expanded study of silver distribution in pregnant mice and developing embryos, with the addition of 10 nm AgNP treatment groups and examination of fetuses at GD16. Very low concentrations of silver were measured in GD10 embryos and GD16 fetuses following 10 nm AgNP treatment or in GD16 fetuses following 50 nm AgNP treatment. Highest silver concentrations were measured in maternal liver, spleen, and visceral yolk sac. AgNP particle size (10 or 50 nm) did not consistently affect silver tissue distribution. At GD10, 50 nm AgNP treatment resulted in significantly higher silver concentrations than 10 nm AgNP treatment for liver, spleen, and visceral yolk sac only; at GD16, in visceral yolk sac only, 10 nm AgNP treatment resulted in a significantly higher silver concentration than 50 nm AgNP treatment. In liver, spleen, visceral yolk sac, and uterus, absolute silver concentrations following 10 nm AgNP treatment were significantly lower at GD16 compared to GD10; the patterns of silver tissue distribution were similar at both time points. Silver nitrate and 10 nm AgNP treatments resulted in similar tissue concentrations in GD10 tissues with the exception of visceral yolk sac, for which the silver concentration was significantly higher after silver nitrate treatment. Silver distribution patterns were generally similar between 10 nm AgNP and silver nitrate treatments. No histological abnormalities were noted in maternal tissues, extra-embryonic tissues, or embryos. A significantly increased incidence of developmentally young (for gestational age) GD10 embryos was seen following 10 nm AgNP treatment; no significant morphological effects were observed in embryos or maternal tissues. Further research will be needed to fully evaluate potential effects of prenatal AgNP exposure on embryos. (Abstract shortened by UMI.)

Transitioning to Adulthood from Foster Care.

PubMed

Lee, Terry; Morgan, Wynne

2017-04-01

Transitional age foster youth do not typically receive the types of family supports their nonfoster peers enjoy. Many foster youth experience multiple adversities and often fare worse than nonfoster peers on long-term functional outcomes. Governments increasingly recognize their responsibility to act as parents for state dependents transitioning to adulthood and the need to provide services to address social/emotional supports, living skills, finances, housing, education, employment, and physical and mental health. More research is needed to inform the development of effective programs. Transitional age foster youth benefit from policies promoting a developmentally appropriate, comprehensive, and integrated transition system of care. Copyright © 2016 Elsevier Inc. All rights reserved.

Applying Evolutionary Genetics to Developmental Toxicology and Risk Assessment

PubMed Central

Leung, Maxwell C. K.; Procter, Andrew C.; Goldstone, Jared V.; Foox, Jonathan; DeSalle, Robert; Mattingly, Carolyn J.; Siddall, Mark E.; Timme-Laragy, Alicia R.

2018-01-01

Evolutionary thinking continues to challenge our views on health and disease. Yet, there is a communication gap between evolutionary biologists and toxicologists in recognizing the connections among developmental pathways, high-throughput screening, and birth defects in humans. To increase our capability in identifying potential developmental toxicants in humans, we propose to apply evolutionary genetics to improve the experimental design and data interpretation with various in vitro and whole-organism models. We review five molecular systems of stress response and update 18 consensual cell-cell signaling pathways that are the hallmark for early development, organogenesis, and differentiation; and revisit the principles of teratology in light of recent advances in high-throughput screening, big data techniques, and systems toxicology. Multiscale systems modeling plays an integral role in the evolutionary approach to cross-species extrapolation. Phylogenetic analysis and comparative bioinformatics are both valuable tools in identifying and validating the molecular initiating events that account for adverse developmental outcomes in humans. The discordance of susceptibility between test species and humans (ontogeny) reflects their differences in evolutionary history (phylogeny). This synthesis not only can lead to novel applications in developmental toxicity and risk assessment, but also can pave the way for applying an evo-devo perspective to the study of developmental origins of health and disease. PMID:28267574

Derivation of an occupational exposure limit for inorganic borates using a weight of evidence approach.

PubMed

Maier, A; Vincent, M; Hack, E; Nance, P; Ball, W

2014-04-01

Inorganic borates are encountered in many settings worldwide, spurring international efforts to develop exposure guidance (US EPA, 2004; WHO, 2009; ATSDR, 2010) and occupational exposure limits (OEL) (ACGIH, 2005; MAK, 2011). We derived an updated OEL to reflect new data and current international risk assessment frameworks. We assessed toxicity and epidemiology data on inorganic borates to identify relevant adverse effects. International risk assessment frameworks (IPCS, 2005, 2007) were used to evaluate endpoint candidates: reproductive toxicity, developmental toxicity, and sensory irritation. For each endpoint, a preliminary OEL was derived and adjusted based on consideration of toxicokinetics, toxicodynamics, and other uncertainties. Selection of the endpoint point of departures (PODs) is supported by dose-response modeling. Developmental toxicity was the most sensitive systemic effect. An OEL of 1.6mgB/m(3) was estimated for this effect based on a POD of 63mgB/m(3) with an uncertainty factor (UF) of 40. Sensory irritation was considered to be the most sensitive effect for the portal of entry. An OEL of 1.4mgB/m(3) was estimated for this effect based on the identified POD and an UF of 1. An OEL of 1.4mgB/m(3) as an 8-h time-weighted average (TWA) is recommended. Copyright © 2014 Elsevier Inc. All rights reserved.

A Review of Atomoxetine Effects in Young People with Developmental Disabilities

PubMed Central

Aman, Michael G.; Smith, Tristram; Arnold, L. Eugene; Corbett-Dick, Patricia; Rameshwari.Tumuluru; Hollway, Jill A.; Hyman, Susan L.; Mendoza-Burchamm, Marissa; Pan, Xueliang; Mruzek, Daniel W.; Lecavalier, Luc; Levato, Lynne; Silverman, Laura B.; Handen, Benjamin

2014-01-01

This review summarizes the pharmacokinetic characteristics, pharmacodynamic properties, common side effects, and clinical advantages and disadvantages associated with atomoxetine (ATX) treatment in typically developing children and adults with ADHD. Then the clinical research to date in developmental disabilities (DD), including autism spectrum disorders (ASD), is summarized and reviewed. Of the 11 relevant reports available, only two were placebo-controlled randomized clinical trials, and both focused on a single DD population (ASD). All trials but one indicated clinical improvement in ADHD symptoms with ATX, although it was difficult to judge the magnitude and validity of reported improvement in the absence of placebo controls. Effects of ATX on co-occurring behavioral and cognitive symptoms were much less consistent. Appetite decrease, nausea, and irritability were the most common adverse events reported among children with DD; clinicians should be aware that, as with stimulants, irritability appears to occur much more commonly in persons with DD than in typically developing individuals. Splitting the dose initially, starting below the recommended starting dose, and titrating slowly may prevent or ameliorate side effects. Patience is needed for the slow build-up of benefit. Conclusions: ATX holds promise for managing ADHD symptoms in DD, but properly controlled, randomized clinical trials of atomoxetine in intellectual disability and ASD are sorely needed. Clinicians and researchers should be vigilant for emergence of irritability with ATX treatment. Effects of ATX on cognition in DD are virtually unstudied. PMID:24732041

Adversity, Adaptive Calibration, and Health: The Case of Disadvantaged Families.

PubMed

de Baca, Tomás Cabeza; Wahl, Richard A; Barnett, Melissa A; Figueredo, Aurelio José; Ellis, Bruce J

2016-06-01

Epidemiologists and medical researchers often employ an allostatic load model that focuses on environmental and lifestyle factors, together with biological vulnerabilities, to explain the deterioration of human physiological systems and chronic degenerative disease. Although this perspective has informed medicine and public health, it is agnostic toward the functional significance of pathophysiology and health deterioration. Drawing on Life History (LH) theory, the current paper reviews the literature on disadvantaged families to serve as a conceptual model of stress-health relationships in which the allocation of reproductive effort is instantiated in the LH strategies of individuals and reflects the bioenergetic and material resource tradeoffs . We propose that researchers interested in health disparities reframe chronic degenerative diseases as outcomes resulting from strategic calibration of physiological systems to best adapt, survive, and reproduce in response to demands of specific developmental contexts. These effects of adversity on later-age degenerative disease are mediated, in part, by socioemotional and cognitive mechanisms expressed in different life history strategies.

Adversity, Adaptive Calibration, and Health: The Case of Disadvantaged Families

PubMed Central

de Baca, Tomás Cabeza; Wahl, Richard A.; Barnett, Melissa A.; Figueredo, Aurelio José; Ellis, Bruce J.

2016-01-01

Epidemiologists and medical researchers often employ an allostatic load model that focuses on environmental and lifestyle factors, together with biological vulnerabilities, to explain the deterioration of human physiological systems and chronic degenerative disease. Although this perspective has informed medicine and public health, it is agnostic toward the functional significance of pathophysiology and health deterioration. Drawing on Life History (LH) theory, the current paper reviews the literature on disadvantaged families to serve as a conceptual model of stress-health relationships in which the allocation of reproductive effort is instantiated in the LH strategies of individuals and reflects the bioenergetic and material resource tradeoffs. We propose that researchers interested in health disparities reframe chronic degenerative diseases as outcomes resulting from strategic calibration of physiological systems to best adapt, survive, and reproduce in response to demands of specific developmental contexts. These effects of adversity on later-age degenerative disease are mediated, in part, by socioemotional and cognitive mechanisms expressed in different life history strategies. PMID:27175327

Vitamin B-12 and Cognition in Children.

PubMed

Venkatramanan, Sudha; Armata, Ilianna E; Strupp, Barbara J; Finkelstein, Julia L

2016-09-01

Vitamin B-12 is essential for brain development, neural myelination, and cognitive function. Inadequate vitamin B-12 status during pregnancy and early childhood has been associated with adverse child health outcomes, including impaired cognitive development. However, the underlying mechanisms have not been elucidated. This review was conducted to examine the evidence that links vitamin B-12 and cognition in children. The search strategy resulted in 17 studies: 3 cross-sectional, 1 case-control, and 12 cohort studies, and 1 randomized trial. Cognitive processes assessed included attention, memory, and perception. Developmental outcomes, academic performance, and intelligence quotient were also considered. Despite the high prevalence of vitamin B-12 insufficiency and associated risk of adverse cognitive outcomes in children, to our knowledge, no studies to date have been conducted to examine the effects of vitamin B-12 supplementation on cognition in children. The role of vitamin B-12 in the etiology of child cognitive outcomes needs to be elucidated to inform public health interventions. © 2016 American Society for Nutrition.

Translational Neuroscience as a Tool for Intervention Development in the Context of High-Adversity Families

PubMed Central

Fisher, Philip A.

2017-01-01

The use of theory-driven models to develop and evaluate family-based intervention programs has a long history in psychology. Some of the first evidence-based parenting programs to address child problem behavior, developed in the 1970s, were grounded in causal models derived from longitudinal developmental research. The same translational strategies can also be applied to designing programs that leverage emerging scientific knowledge about the effects of early adverse experiences on neurobiological systems to reduce risk and promote well-being. By specifying not only behavioral targets but also affected underlying neural systems, interventions can become more precise and efficient. This chapter describes the development of a program of research focusing on an intervention for young children in foster care. The intervention emerged from social learning theory research and employs a translational neuroscience approach. The conceptual model guiding the research, which incorporates behavioral domains as well as stress-regulatory neural systems, is described. Finally, future directions for translational neuroscience in family-based intervention research are considered. PMID:27589501

Current Status of Chemical Public Health Risks and Testing ...

EPA Pesticide Factsheets

The cardiovascular system, at all its various developmental and life stages, represents a critical target organ system that can be adversely affected by a variety of chemicals and routes of exposure. A World Health Organization report estimated the impact of environmental chemical exposures on health to be 16% (range: 7—23%) of the total global burden of cardiovascular disease, corresponding to ~2.5 million deaths per year. Currently, the overall impact of environmental chemical exposures on all causes of cardiovascular disease and the number one cause of morbidity and mortality in the United States is unknown. Evidence from epidemiology, clinical, and toxicological studies will be presented documenting adverse cardiovascular effects associated with environmental exposure to chemicals. The presentation will cover US EPA’s ability to regulate and test chemicals as well as current challenges faced by the Agency to assess chemical cardiovascular risk and public health safety. (This abstract does not necessarily reflect US EPA Policy) Will be presented at the Workshop titled

Training the Brain: Practical Applications of Neural Plasticity From the Intersection of Cognitive Neuroscience, Developmental Psychology, and Prevention Science

PubMed Central

Bryck, Richard L.; Fisher, Philip A.

2012-01-01

Prior researchers have shown that the brain has a remarkable ability for adapting to environmental changes. The positive effects of such neural plasticity include enhanced functioning in specific cognitive domains and shifts in cortical representation following naturally occurring cases of sensory deprivation; however, maladaptive changes in brain function and development owing to early developmental adversity and stress have also been well documented. Researchers examining enriched rearing environments in animals have revealed the potential for inducing positive brain plasticity effects and have helped to popularize methods for training the brain to reverse early brain deficits or to boost normal cognitive functioning. In this paper, two classes of empirically based methods of brain training in children are reviewed and critiqued: laboratory-based, mental process training paradigms and ecological interventions based upon neurocognitive conceptual models. Given the susceptibility of executive function disruption, special attention is paid to training programs that emphasize executive function enhancement. In addition, a third approach to brain training, aimed at tapping into compensatory processes, is postulated. Study results showing the effectiveness of this strategy in the field of neurorehabilitation and in terms of naturally occurring compensatory processing in human aging lend credence to the potential of this approach. PMID:21787037

Training the brain: practical applications of neural plasticity from the intersection of cognitive neuroscience, developmental psychology, and prevention science.

PubMed

Bryck, Richard L; Fisher, Philip A

2012-01-01

Prior researchers have shown that the brain has a remarkable ability for adapting to environmental changes. The positive effects of such neural plasticity include enhanced functioning in specific cognitive domains and shifts in cortical representation following naturally occurring cases of sensory deprivation; however, maladaptive changes in brain function and development owing to early developmental adversity and stress have also been well documented. Researchers examining enriched rearing environments in animals have revealed the potential for inducing positive brain plasticity effects and have helped to popularize methods for training the brain to reverse early brain deficits or to boost normal cognitive functioning. In this article, two classes of empirically based methods of brain training in children are reviewed and critiqued: laboratory-based, mental process training paradigms and ecological interventions based upon neurocognitive conceptual models. Given the susceptibility of executive function disruption, special attention is paid to training programs that emphasize executive function enhancement. In addition, a third approach to brain training, aimed at tapping into compensatory processes, is postulated. Study results showing the effectiveness of this strategy in the field of neurorehabilitation and in terms of naturally occurring compensatory processing in human aging lend credence to the potential of this approach. (PsycINFO Database Record (c) 2012 APA, all rights reserved).

Neonatal (+)-methamphetamine exposure in rats alters adult locomotor responses to dopamine D1 and D2 agonists and to a glutamate NMDA receptor antagonist, but not to serotonin agonists

PubMed Central

Graham, Devon L.; Amos-Kroohs, Robyn M.; Braun, Amanda A.; Grace, Curtis E.; Schaefer, Tori L.; Skelton, Matthew R.; Williams, Michael T.; Vorhees, Charles V.

2015-01-01

Neonatal exposure to (+)-methamphetamine (Meth) results in long-term behavioural abnormalities but its developmental mechanisms are unknown. In a series of experiments, rats were treated from post-natal days (PD) 11–20 (stage that approximates human development from the second to third trimester) with Meth or saline and assessed using locomotor activity as the readout following pharmacological challenge doses with dopamine, serotonin and glutamate agonists or antagonists during adulthood. Exposure to Meth early in life resulted in an exaggerated adult locomotor hyperactivity response to the dopamine D1 agonist SKF-82958 at multiple doses, a high dose only under-response activating effect of the D2 agonist quinpirole, and an exaggerated under-response to the activating effect of the N-methyl-D-aspartic acid (NMDA) receptor antagonist, MK-801. No change in locomotor response was seen following challenge with the 5-HT releaser p-chloroamphetamine or the 5-HT2/3 receptor agonist, quipazine. These are the first data to show that PD 11-20 Meth exposure induces long-lasting alterations to dopamine D1, D2 and glutamate NMDA receptor function and may suggest how developmental Meth exposure leads to many of its long-term adverse effects. PMID:22391043

An occupational reproductive research agenda for the third millennium.

PubMed Central

Lawson, Christina C; Schnorr, Teresa M; Daston, George P; Grajewski, Barbara; Marcus, Michele; McDiarmid, Melissa; Murono, Eisuke; Perreault, Sally D; Schrader, Steven M; Shelby, Michael

2003-01-01

There is a significant public health concern about the potential effects of occupational exposure to toxic substances on reproductive outcomes. Several toxicants with reported reproductive and developmental effects are still in regular commercial or therapeutic use and thus present potential exposure to workers. Examples of these include heavy metals, organic solvents, pesticides and herbicides, and sterilants, anesthetic gases, and anticancer drugs used in health care. Many other substances are suspected of producing reproductive or developmental toxicity but lack sufficient data. Progress has been limited in identifying hazards and quantifying their potencies and in separating the contribution of these hazards from other etiologic factors. Identifying the causative agents, mechanisms by which they act, and any potential target populations, present the opportunity to intervene and protect the reproductive health of workers. The pace of laboratory studies to identify hazards and to underpin the biologic plausibility of effects in humans has not matched the pace at which new chemicals are introduced into commerce. Though many research challenges exist today, recent technologic and methodologic advances have been made that allow researchers to overcome some of these obstacles. The objective of this article is to recommend future directions in occupational reproductive health research. By bridging interdisciplinary gaps, the scientific community can work together to improve health and reduce adverse outcomes. PMID:12676620

Review shows that early foetal alcohol exposure may cause adverse effects even when the mother consumes low levels.

PubMed

Sarman, Ihsan

2018-06-01

Studies are increasingly focusing on the effects of prenatal alcohol exposure (PAE) on child health. The aim of this review was to provide paediatricians with new insights to help them communicate key messages about avoiding alcohol during pregnancy. Inspired by the 7th International Conference on Fetal Alcohol Spectrum Disorder, which focused on integrating research, policy and practice, we studied English language papers published since 2010 on how early PAE triggered epigenetic mechanisms that had an impact on the development of some chronic diseases. We also report the findings of a human study using three-dimensional photography of the face to explore associations between PAE and craniofacial phenotyping. Animal models with different alcohol exposure patterns show that early PAE may lead to long-term chronic effects, due to developmental programming for some adult diseases in cardiovascular, metabolic and renal systems. The study with three-dimensional photographing is very promising in helping paediatricians to understand how even small amounts of PAE can affect craniofacial phenotyping. Even low levels of PAE can cause adverse foetal effects and not just in the brain. It is not currently possible to determine a safe period and level when alcohol consumption would not affect the foetus. ©2018 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

External-environmental and internal-health early life predictors of adolescent development.

PubMed

Hartman, Sarah; Li, Zhi; Nettle, Daniel; Belsky, Jay

2017-12-01

A wealth of evidence documents associations between various aspects of the rearing environment and later development. Two evolutionary-inspired models advance explanations for why and how such early experiences shape later functioning: (a) the external-prediction model, which highlights the role of the early environment (e.g., parenting) in regulating children's development, and (b) the internal-prediction model, which emphasizes internal state (i.e., health) as the critical regulator. Thus, by using data from the NICHD Study of Early Child Care and Youth Development, the current project draws from both models by investigating whether the effect of the early environment on later adolescent functioning is subject to an indirect effect by internal-health variables. Results showed a significant indirect effect of internal health on the relation between the early environment and adolescent behavior. Specifically, early environmental adversity during the first 5 years of life predicted lower quality health during childhood, which then led to problematic adolescent functioning and earlier age of menarche for girls. In addition, for girls, early adversity predicted lower quality health that forecasted earlier age of menarche leading to increased adolescent risk taking. The discussion highlights the importance of integrating both internal and external models to further understand the developmental processes that effect adolescent behavior.

Heparin and cAMP modulators interact during pre-in vitro maturation to affect mouse and human oocyte meiosis and developmental competence.

PubMed

Zeng, Hai-tao; Ren, Zi; Guzman, Luis; Wang, Xiaoqian; Sutton-McDowall, Melanie L; Ritter, Lesley J; De Vos, Michel; Smitz, Johan; Thompson, Jeremy G; Gilchrist, Robert B

2013-06-01

Does heparin ablate the advantageous effects of cyclic adenosine mono-phosphate (cAMP) modulators during pre-in vitro maturation (IVM) and have a deleterious effect in standard oocyte IVM? Heparin interrupts energy metabolism and meiotic progression and adversely affects subsequent development of oocytes under conditions of elevated cAMP levels in cumulus-oocyte complexes (COCs) after pre-IVM treatment with forskolin. In animal IVM studies, artificial regulation of meiotic resumption by cAMP-elevating agents improves subsequent oocyte developmental competence. Heparin has no effect on spontaneous, FSH- or epidermal growth factor (EGF)-stimulated meiotic maturation. An in vitro cross-sectional study was conducted using immature mouse and human COCs. Depending on individual experimental design, COCs were treated during pre-IVM with or without heparin, in the presence or absence of forskolin and/or 3-isobutyl-1-methylxanthine (IBMX), and then COC function was assessed by various means. Forty-two women with polycystic ovaries (PCOs) or polycystic ovarian syndrome (PCOS) donated COCs after oocyte retrieval in a non-hCG-triggered IVM cycle. COCs were collected in pre-IVM treatments and then cultured for 40 h and meiotic progression was assessed. COCs from 21- to 24-day-old female CBA F1 mice were collected 46 h after stimulation with equine chorionic gonadotrophin. Following treatments, COCs were checked for meiotic progression. Effects on mouse oocyte metabolism were measured by assessing oocyte mitochondrial membrane potential using JC-1 staining and oocyte ATP content. Post-IVM mouse oocyte developmental competence was assessed by in vitro fertilization and embryo production. Blastocyst quality was evaluated by differential staining of inner cell mass (ICM) and trophectoderm (TE) layers. In the absence of heparin in pre-IVM culture, the addition of cAMP modulators did not affect human oocyte MII competence after 40 h. In standard IVM, heparin supplementation in pre-IVM did not affect MII competence; however, when heparin was combined with cAMP modulators, MII competence was significantly reduced from 65 to 15% (P < 0.05). In mouse experiments, heparin alone in pre-IVM significantly delayed germinal vesicle breakdown (GVBD) so that fewer GVBDs were observed at 0 and 1 h of IVM (P < 0.05), but not by 2 or 3 h of IVM. Combined treatment with IBMX and forskolin in the pre-IVM medium produced a large delay in GVBD such that no COCs exhibited GVBD in the first 1 h of IVM, and the addition of heparin in pre-IVM further significantly delayed the progression of GVBD (P < 0.05), in a dose-dependent manner (P < 0.01). Combined IBMX and forskolin treatment of mouse COCs during pre-IVM significantly increased mitochondrial membrane potential and ATP production in the oocyte at the end of pre-IVM (P < 0.05), and significantly improved fertilization, embryo development and quality (P < 0.05). However, heparin abolished the IBMX + forskolin-stimulated increase in mitochondrial membrane potential and ATP production (P < 0.05), and adversely affected embryonic cleavage, development rates and embryo quality (P < 0.05). This latter adverse combinational effect was negated when mouse COCs were collected in heparin and IBMX for 15 min, washed and then cultured for 45 min in IBMX and forskolin without heparin. Experiments in mice found that heparin ablation of the advantageous effects of cAMP modulators during pre-IVM was associated with altered oocyte metabolism, but the mechanism by which heparin affects metabolism remains unclear. This study has revealed a novel and unexpected interaction between heparin and cAMP modulators in pre-IVM in immature mouse and human oocytes, and established a means to collect oocytes using heparin while modulating oocyte cAMP to improve developmental potential.

Associations between prenatal, childhood, and adolescent stress and variations in white-matter properties in young men.

PubMed

Jensen, Sarah K G; Pangelinan, Melissa; Björnholm, Lassi; Klasnja, Anja; Leemans, Alexander; Drakesmith, Mark; Evans, C J; Barker, Edward D; Paus, Tomáš

2017-10-21

Previous studies have shown that both pre- and post-natal adversities, the latter including exposures to stress during childhood and adolescence, explain variation in structural properties of white matter (WM) in the brain. While previous studies have examined effects of independent stress exposures within one developmental period, such as childhood, we examine effects of stress across development using data from a prospective longitudinal study. More specifically, we ask how stressful events during prenatal development, childhood, and adolescence relate to variation in WM properties in early adulthood in young men recruited from a birth cohort. Using data from 393 mother-son pairs from a community-based birth cohort from England (Avon Longitudinal Study of Parents and Children), we examined how stressful life events relate to variation in different structural properties of WM in the corpus callosum and across the whole brain in early adulthood in men aged 18-21 years. We distinguish between stress occurring during three developmental periods: a) prenatal maternal stress, b) postnatal stress within the first four years of life, c) stress during adolescence (age 12-16 years). To obtain a comprehensive quantification of variation in WM, we assess structural properties of WM using four different measures, namely fractional anisotropy (FA), mean diffusivity (MD), magnetization transfer ratio (MTR) and myelin water fraction (MWF). The developmental model shows that prenatal stress is associated with lower MTR and MWF in the genu and/or splenium of the corpus callosum, and with lower MTR in global (lobar) WM. Stress during early childhood is associated with higher MTR in the splenium, and stress during adolescence is associated with higher MTR in the genu and lower MD in the splenium. We see no associations between postnatal stress and variation in global (lobar) WM. The current study found evidence for independent effects of stress on WM properties during distinct neurodevelopmental periods. We speculate that these independent effects are due to differences in the developmental processes unfolding at different developmental time points. We suggest that associations between prenatal stress and WM properties may relate to abnormalities in neurogenesis, affecting the number and density of axons, while postnatal stress may interfere with processes related to myelination or radial growth of axons. Potential consequences of prenatal glucocorticoid exposure should be considered in obstetric care. Copyright © 2017 Elsevier Inc. All rights reserved.

Sublethal effects of atrazine on embryo-larval development of Rhinella arenarum (Anura: Bufonidae).

PubMed

Svartz, Gabriela V; Herkovits, Jorge; Pérez-Coll, Cristina S

2012-05-01

Atrazine (ATR), one of the most widely used herbicides in the world, affects not only target organisms but also the biota in general. Here, the teratogenic and neurotoxic effects of ATR on Rhinella arenarum (South American toad) embryos, and larvae were evaluated by means of standardized bioassays during acute and chronic exposures. The herbicide had a significant incidence of malformations, with a Teratogenic Index (TI) of 3.28. The main effects were delayed development, reduced body size, microcephaly, axial flexures, wavy tail and edema. In addition, delayed development, reduced development of forelimbs, and edema were recorded at metamorphosis stages. Scanning electron microscopy allowed observing different degrees of cellular dissociation and persistent cilliar cells in specific regions like the adhesive structure and tail fin. Results obtained by ATR 24 h pulse exposures at six developmental stages pointed out blastula as the most susceptible developmental stage both for immediate and delayed adverse effects. A noteworthy recovery capacity from acute toxic effects was recorded from the neural plate stage onwards. Regarding neurotoxic effects, abnormal, and erratic swimming and spasmodic contractions were recorded. Both the teratogenic and neurotoxic effects reported in this study demonstrate the importance of evaluating sublethal effects in non-target organisms as they could imply reduced fitness of individuals and eventually a population decline. The Hazard Quotients (HQ) for ATR ranged from 0.14 to 10.80, and the fact that some of these values are above USEPA's level of concern indicate that ATR is likely a risk to R. arenarum.

Gender differences in developmental programming of cardiovascular diseases

PubMed Central

Dasinger, John Henry; Alexander, Barbara T.

2016-01-01

Hypertension is a risk factor for cardiovascular disease, the leading cause of death worldwide. Although multiple factors contribute to the pathogenesis of hypertension, studies by Dr. David Barker reporting an inverse relationship between birth weight and blood pressure led to the hypothesis that slow growth during fetal life increases blood pressure and the risk for cardiovascular disease in later life. It is now recognized that growth during infancy and childhood in addition to exposure to adverse influences during fetal life contribute to the developmental programming of increased cardiovascular risk. Numerous epidemiological studies support the link between influences during early life with later cardiovascular health; experimental models provide proof of principle and indicate that numerous mechanisms contribute to the developmental origins of chronic disease. Sex impacts the severity of cardiovascular risk in experimental models of developmental insult. Yet, few studies examine the influence of sex on blood pressure and cardiovascular health in low birth weight men and women. Fewer still assess how aging impacts sex differences in programmed cardiovascular risk. Thus, the aim of this review is to highlight current data regarding sex differences in the developmental programming of blood pressure and cardiovascular disease. PMID:26814204

Hazards to Early Development: The Biological Embedding of Early Life Adversity.

PubMed

Nelson, Charles A

2017-10-11

The number of children under 18 years of age has increased worldwide over the past decade. This growth spurt is due, in part, to remarkable progress in child survival. Alas, surviving early hazards, like prematurity or infectious disease, does not guarantee that children's development will not be compromised by other hazards as they grow older. Throughout the world, children continue to be confronted with a large number of biological and psychosocial challenges that greatly limit their developmental potential. The focus of this article is how such adverse experiences impact the developing brain. Copyright © 2017 Elsevier Inc. All rights reserved.

Neurological Effects of Bisphenol A and its Analogues

PubMed Central

Inadera, Hidekuni

2015-01-01

The endocrine disrupting chemical bisphenol A (BPA) is widely used in the production of polycarbonate plastics and epoxy resins. The use of BPA-containing products in daily life makes exposure ubiquitous, and the potential human health risks of this chemical are a major public health concern. Although numerous in vitro and in vivo studies have been published on the effects of BPA on biological systems, there is controversy as to whether ordinary levels of exposure can have adverse effects in humans. However, the increasing incidence of developmental disorders is of concern, and accumulating evidence indicates that BPA has detrimental effects on neurological development. Other bisphenol analogues, used as substitutes for BPA, are also suspected of having a broad range of biological actions. The objective of this review is to summarize our current understanding of the neurobiological effects of BPA and its analogues, and to discuss preventive strategies from a public health perspective. PMID:26664253

Can assisted reproductive technologies cause adult-onset disease? Evidence from human and mouse

PubMed Central

Vrooman, Lisa A.; Bartolomei, Marisa S.

2016-01-01

Millions of children have been born worldwide though assisted reproductive technologies (ART). Consistent with the Developmental Origins of Health and Disease hypothesis, there is concern that ART can induce adverse effects, especially because procedures coincide with epigenetic reprogramming events. Although the majority of studies investigating the effects of ART have focused on perinatal outcomes, more recent studies demonstrate that ART-conceived children may be at increased risk for postnatal effects. Here, we present the current epidemiological evidence that ART-conceived children have detectable differences in blood pressure, body composition, and glucose homeostasis. Similar effects are observed in the ART mouse model, which have no underlying infertility, suggesting that cardiometabolic effects are likely caused by ART procedures and not due to reasons related to infertility. We propose that the mouse system can, consequently, be used to adequately study, modify, and improve outcomes for ART children. PMID:27474254

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

EPA Science Inventory

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 l...

Research Note: Are Life-Course-Persistent Offenders at Risk for Adverse Health Outcomes?

ERIC Educational Resources Information Center

Piquero, Alex R.; Daigle, Leah E.; Gibson, Chris; Piquero, Nicole Leeper; Tibbetts, Stephen G.

2007-01-01

Moffitt's developmental taxonomy of adolescence-limited and life-course-persistent offenders has received much empirical attention, with researchers focusing on the etiology and trajectory of offending between the two groups. Recently, Moffitt articulated a new hypothesis that has yet to be empirically assessed--that life-course-persistent…

Teaching and Leading for Human Flourishing: Creating a Liberal Arts Framework for Teacher Preparation

ERIC Educational Resources Information Center

Lederhouse, Jillian N.

2014-01-01

To satisfy the ongoing demands of external communities, education faculty at liberal arts colleges often make curricular and instructional compromises within their programs which can adversely affect the developmental goals of liberal education. This article highlights several of the complex tensions faculty members face in offering their…

Adolescent Pregnancy in an Urban Environment: Issues, Programs, and Evaluation.

ERIC Educational Resources Information Center

Hardy, Janet B.; Zabin, Laurie Schwab

An in-depth discussion of national and local statistics regarding teenage and adolescent pregnancy and the developmental issues involved opens this analysis. Problems and adverse consequences of adolescent pregnancy in an urban setting are explored using a city-wide random sample of adolescent births. A model pregnancy and parenting program and…

Parental Substance Abuse and Child Well-Being: A Consideration of Parents' Gender and Coresidence

ERIC Educational Resources Information Center

Osborne, Cynthia; Berger, Lawrence M.

2009-01-01

Parental substance abuse is associated with adverse health and developmental outcomes for children. Existing research, however, has not fully explored the relative magnitude of the associations between maternal, paternal, and both parents' substance abuse and child outcomes, nor has it examined these associations in regard to substance abuse among…

Using an Adoption Design to Separate Genetic, Prenatal, and Temperament Influences on Toddler Executive Function

ERIC Educational Resources Information Center

Leve, Leslie D.; DeGarmo, David S.; Bridgett, David J.; Neiderhiser, Jenae M.; Shaw, Daniel S.; Harold, Gordon T.; Natsuaki, Misaki N.; Reiss, David

2013-01-01

Poor executive functioning has been implicated in children's concurrent and future behavioral difficulties, making work aimed at understanding processes related to the development of early executive function (EF) critical for models of developmental psychopathology. Deficits in EF have been associated with adverse prenatal experiences, genetic…

Overeating and Binge Eating in Emerging Adulthood: 10-Year Stability and Risk Factors

ERIC Educational Resources Information Center

Goldschmidt, Andrea B.; Wall, Melanie M.; Zhang, Jun; Loth, Katie A.; Neumark-Sztainer, Dianne

2016-01-01

Overeating (eating an unusually large amount of food) and binge eating (overeating with loss of control [LOC]) predict adverse health consequences in adolescence. We aimed to characterize the stability of and risk factors for these distinct but interrelated constructs during critical developmental transitions. We used a population-based sample (n…

Resiliency Profiles of Children with Intellectual Disability and Their Typically Developing Peers

ERIC Educational Resources Information Center

Gilmore, Linda; Campbell, Marilyn; Shochet, Ian; Roberts, Clare

2013-01-01

Intellectual disability (ID) is associated with a range of risk factors that make children more vulnerable to adverse developmental outcomes, including mental health problems. Nevertheless, some children with ID do much better than others, presumably because of the presence of protective factors that increase their resilience. The current study…

African American Millennials: "A Profile of Promise"

ERIC Educational Resources Information Center

Burley, Hansel; Barnard-Brak, Lucy; Marbley, Aretha Faye; Deason, Christopher

2010-01-01

Resilience refers to positive adaptation in the face of present or past adversity. It is the "ordinary magic" that rises from the minds of children and their families as they interact with their communities. Gonzales (2003) defined three major components of Resiliency Theory: (1) risk factors; (2) protective factors; and (3) developmental assets.…

Reproductive and Developmental Toxicity of Orally Administered Botanical Composition, UP446-Part III: Effects on Fertility and Early Embryonic Development to Implantation in Sprague Dawley Rats.

PubMed

Yimam, Mesfin; Lee, Young-Chul; Hyun, Eu-Jin; Jia, Qi

2015-08-01

In recent years, high prevalence of adverse effects associated to the use of traditional medicines during pregnancy is becoming alarming due to the self-medication of oral supplements by expecting mothers without supervision. Many expectant mothers use alternative and complementary medicines as a supplement to conventional pregnancy management with an inherent belief of considering herbal remedies as harmless. To the contrary, herbal remedies could incur a potential teratogenic risk both to the child bearing mother and the developing fetuses when consumed before or at the time of gestation. Here, we describe the potential adverse effects of orally administered UP446, a standardized bioflavonoid composition from the roots of Scutellaria baicalensis and the heartwoods of Acacia catechu, on fertility and early embryonic development to implantation in Sprague Dawley rats at doses of 250, 500, and 1000 mg/kg. Besides body weight and food consumption, reproductive functions, sperm motility and morphology, estrus cycle, and fertility rate were monitored. There were no statistically significant differences in reproductive function in all UP446 treated groups in both genders. Test substance impacts on reproductive parameters were very minimal. Neither sperm motility nor morphology was affected as a result of oral UP446 administrations in males. There were no treatment-related effects on estrus cycle stages in females. No significant changes in necropsy or histopathology were observed for all the groups. Therefore, the no observed adverse effect level (NOAEL) of UP446 was considered to be 1000 mg/kg, the highest dose tested, in both genders. © 2015 Wiley Periodicals, Inc.

Epigenetic Vestiges of Early Developmental Adversity: Childhood Stress Exposure and DNA Methylation in Adolescence

PubMed Central

Essex, Marilyn J.; Boyce, W. Thomas; Hertzman, Clyde; Lam, Lucia L.; Armstrong, Jeffrey M.; Neumann, Sarah M.A.; Kobor, Michael S.

2011-01-01

Fifteen-year-old adolescents (N=109) in a longitudinal study of child development were recruited to examine differences in DNA methylation in relation to parent reports of adversity during the adolescents’ infancy and preschool periods. Microarray technology applied to 28,000 cytosine-guanine dinucleotide (CpG) sites within DNA derived from buccal epithelial cells showed differential methylation among adolescents whose parents reported high levels of stress during their children’s early lives. Maternal stressors in infancy and paternal stressors in the preschool years were most strongly predictive of differential methylation, and the patterning of such epigenetic marks varied by children’s gender. To the authors’ knowledge, this is the first report of prospective associations between adversities in early childhood and the epigenetic conformation of adolescents’ genomic DNA. PMID:21883162

Numeric Estimates of Teratogenic Severity from Embryo-Fetal Developmental Toxicity Studies.

PubMed

Wise, L David

2016-02-01

A developing organism exposed to a toxicant will have a response that ranges from none to severe (i.e., death or malformation). The response at a given dosage may be termed teratogenic (or developmental toxic) severity and is dependent on exposure conditions. Prenatal/embryo-fetal developmental (EFD) toxicity studies in rodents and rabbits are the most consistent and definitive assessments of teratogenic severity, and teratogenesis screening assays are best validated against their results. A formula is presented that estimates teratogenic severity for each group, including control, within an EFD study. The developmental components include embryonic/fetal death, malformations, variations, and mean fetal weight. The contribution of maternal toxicity is included with multiplication factors to adjust for the extent of mortality, maternal body weight change, and other parameters deemed important. The derivation of the formula to calculate teratogenic severity is described. Various EFD data sets from the literature are presented to highlight considerations to the calculation of the various components of the formula. Each score is compared to the concurrent control group to obtain a relative teratogenic severity. The limited studies presented suggest relative scores of two- to

Gestational lead exposure induces developmental abnormalities and up-regulates apoptosis of fetal cerebellar cells in rats.

PubMed

Mousa, Alyaa M; Al-Fadhli, Ameera S; Rao, Muddanna S; Kilarkaje, Narayana

2015-01-01

Lead (Pb), a known environmental toxicant, adversely affects almost all organ systems. In this study, we investigated the effects of maternal lead exposure on fetal rat cerebellum. Female Sprague-Dawley rats were given lead nitrate in drinking water (0, 0.5, and 1%) for two weeks before conception, and during pregnancy. Fetuses were collected by caesarian section on gestational day 21 and observed for developmental abnormalities. The fetal cerebellar sections from control and 1% lead group were stained with cresyl violet. Immunohistochemical expressions of p53, Bax, Bcl-2, and caspase 3 were quantified by AnalySIS image analyzer (Life Science, Germany). Lead exposure induced developmental abnormalities of eyes, ear, limbs, neck and ventral abdominal wall; however, these abnormalities were commonly seen in the 1% lead-treated group. In addition, lead also caused fetal mortality and reduced body growth in both dose groups and reduced brain weight in the 1% lead-treated group. The fetal cerebella from the 1% lead-treated group showed unorganized cerebellar cortical layers, and degenerative changes in granule and Purkinje cells such as the formation of clumps of Nissl granules. An increase in Bax and caspase 3, and a decrease in Bcl-2 (p < 0.05), but not in p53, showed apoptosis of the neurons. In conclusion, gestational lead exposure in rats induces fetal toxicity and developmental abnormalities. The lead exposure also impairs development of cerebellar layers, induces structural changes, and apoptosis in the fetal cerebellar cortex. These results suggest that lead exposure during gestation is extremely toxic to developing cerebellum in rats.

Ketamine-induced apoptosis in the mouse cerebral cortex follows similar characteristic of physiological apoptosis and can be regulated by neuronal activity.

PubMed

Wang, Qi; Shen, Feng-Yan; Zou, Rong; Zheng, Jing-Jing; Yu, Xiang; Wang, Ying-Wei

2017-06-17

The effects of general anesthetics on inducing neuronal apoptosis during early brain development are well-documented. However, since physiological apoptosis also occurs during this developmental window, it is important to determine whether anesthesia-induced apoptosis targets the same cell population as physiological apoptosis or different cell types altogether. To provide an adequate plane of surgery, ketamine was co-administered with dexmedetomidine. The apoptotic neurons in the mouse primary somatosensory cortex (S1) were quantitated by immunohistochemistry. To explore the effect of neural activity on ketamine-induced apoptosis, the approaches of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) and an environmental enrichment (EE) were performed. Ketamine-induced apoptosis in S1 is most prominent at postnatal days 5 and 7 (P5 - P7), and becomes insignificant by P12. Physiological and ketamine-induced apoptosis follow similar developmental patterns, mostly comprised of layer V pyramidal neurons at P5 and shifting to mostly layer II to IV GABAergic neurons by P9. Changes in neuronal activity induced by the DREADD system bidirectionally regulated the pattern of ketamine-induced apoptosis, with reduced activity inducing increased apoptosis and shifting the lamination pattern to a more immature form. Importantly, rearing mice in an EE significantly reduced the magnitude of ketamine-induced apoptosis and shifted its developmental pattern to a more mature form. Together, these results demonstrate that lamination pattern and cell-type dependent vulnerability to ketamine-induced apoptosis follow the physiological apoptosis pattern and are age- and activity-dependent. Naturally elevating neuronal activity is a possible method for reducing the adverse effects of general anesthesia.

Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice.

PubMed

Ansorge, Mark S; Morelli, Emanuela; Gingrich, Jay A

2008-01-02

Serotonin (5-HT) acts as a neurotransmitter, but also modulates brain maturation during early development. The demonstrated influence of genetic variants on brain function, personality traits, and susceptibility to neuropsychiatric disorders suggests a critical importance of developmental mechanisms. However, little is known about how and when developmentally perturbed 5-HT signaling affects circuitry and resulting behavior. The 5-HT transporter (5-HTT) is a key regulator of extracellular 5-HT levels and we used pharmacologic strategies to manipulate 5-HTT function during development and determine behavioral consequences. Transient exposure to the 5-HTT inhibitors fluoxetine, clomipramine, and citalopram from postnatal day 4 (P4) to P21 produced abnormal emotional behaviors in adult mice. Similar treatment with the norepinephrine transporter (NET) inhibitor, desipramine, did not adversely affect adult behavior, suggesting that 5-HT and norepinephrine (NE) do not share the same effects on brain development. Shifting our period of treatment/testing to P90/P185 failed to mimic the effect of earlier exposure, demonstrating that 5-HT effects on adult behavior are developmentally specific. We have hypothesized that early-life perturbations of 5-HT signaling affect corticolimbic circuits that do not reach maturity until the peri-adolescent period. In support of this idea, we found that abnormal behaviors resulting from postnatal fluoxetine exposure have a post-pubescent onset and persist long after reaching adult age. A better understanding of the underlying 5-HT sensitive circuits and how they are perturbed should lead to new insights into how various genetic polymorphisms confer their risk to carriers. Furthermore, these studies should help determine whether in utero exposure to 5-HTT blocking drugs poses a risk for behavioral abnormalities in later life.

Developmental toxicity of PAH mixtures in fish early life stages. Part I: adverse effects in rainbow trout.

PubMed

Le Bihanic, Florane; Morin, Bénédicte; Cousin, Xavier; Le Menach, Karyn; Budzinski, Hélène; Cachot, Jérôme

2014-12-01

A new gravel-contact assay using rainbow trout, Oncorhynchus mykiss, embryos was developed to assess the toxicity of polycyclic aromatic hydrocarbons (PAHs) and other hydrophobic compounds. Environmentally realistic exposure conditions were mimicked with a direct exposure of eyed rainbow trout embryos incubated onto chemical-spiked gravels until hatching at 10 °C. Several endpoints were recorded including survival, hatching delay, hatching success, biometry, developmental abnormalities, and DNA damage (comet and micronucleus assays). This bioassay was firstly tested with two model PAHs, fluoranthene and benzo[a]pyrene. Then, the method was applied to compare the toxicity of three PAH complex mixtures characterized by different PAH compositions: a pyrolytic extract from a PAH-contaminated sediment (Seine estuary, France) and two petrogenic extracts from Arabian Light and Erika oils, at two environmental concentrations, 3 and 10 μg g(-1) sum of PAHs. The degree and spectrum of toxicity were different according to the extract considered. Acute effects including embryo mortality and decreased hatching success were observed only for Erika oil extract. Arabian Light and pyrolytic extracts induced mainly sublethal effects including reduced larvae size and hemorrhages. Arabian Light and Erika extracts both induced repairable DNA damage as revealed by the comet assay versus the micronucleus assay. The concentration and proportion of methylphenanthrenes and methylanthracenes appeared to drive the toxicity of the three PAH fractions tested, featuring a toxic gradient as follows: pyrolytic < Arabian Light < Erika. The minimal concentration causing developmental defects was as low as 0.7 μg g(-1) sum of PAHs, indicating the high sensitivity of the assay and validating its use for toxicity assessment of particle-bound pollutants.

Adolescent cannabis use and brain systems supporting adult working memory encoding, maintenance, and retrieval.

PubMed

Tervo-Clemmens, Brenden; Simmonds, Daniel; Calabro, Finnegan J; Day, Nancy L; Richardson, Gale A; Luna, Beatriz

2018-04-01

Given prior reports of adverse effects of cannabis use on working memory, an executive function with a protracted developmental course during adolescence, we examined associations between developmental patterns of cannabis use and adult working memory (WM) processes. Seventy-five adults with longitudinal assessments of cannabis use (60 with reported use, 15 with no reported use) and prenatal drug exposure assessment completed a spatial WM task during fMRI at age 28. All subjects passed a multi-drug urine screen on the day of testing and denied recreational drug use in the past week. A fast event-related design with partial trials was used to separate the BOLD response associated with encoding, maintenance, and retrieval periods of the WM task. Behavioral results showed that subjects who began using cannabis earlier in adolescence had longer reaction times (RT) than those with later initiation. Cannabis age of onset was further associated with reduced posterior parietal cortex (PPC) encoding BOLD activation, which significantly mediated age of onset WM RT associations. However, cannabis age of onset brain-behavior associations did not differ between groups with a single reported use and those with repeated use, suggesting age of onset effects may reflect substance use risk characteristics rather than a developmentally-timed cannabis exposure effect. Within repeated cannabis users, greater levels of total cannabis use were associated with performance-related increases in dorsolateral prefrontal cortex (DLPFC) activation during maintenance. This pattern of significant results remained unchanged with inclusion of demographic and prenatal measures as covariates. Surprisingly, however, at the group level, cannabis users generally performed better than participants who reported never using cannabis (faster RT, higher accuracy). We extend previous investigations by identifying that WM associations with cannabis age of onset may be primary to PPC stimulus encoding activity, while the amount of cannabis use is associated with DLPFC maintenance processes. Poorer performance of participants who reported never using cannabis and the consistency of cannabis age of onset associations across single and repeated users limit interpretation of direct developmental effects of cannabis on WM in adulthood. Copyright © 2017 Elsevier Inc. All rights reserved.

Associations of Timing of Sexual Orientation Developmental Milestones and Other Sexual Minority Stressors with Internalizing Mental Health Symptoms Among Sexual Minority Young Adults.

PubMed

Katz-Wise, Sabra L; Rosario, Margaret; Calzo, Jerel P; Scherer, Emily A; Sarda, Vishnudas; Austin, S Bryn

2017-07-01

Sexual minorities (mostly heterosexual, bisexual, lesbian/gay) are more likely than heterosexuals to have adverse mental health, which may be related to minority stress. We used longitudinal data from 1461 sexual minority women and men, aged 22-30 years, from Wave 2010 of the Growing Up Today Study, to examine associations between sexual minority stressors and mental health. We hypothesized that sexual minority stressors (earlier timing of sexual orientation developmental milestones categorized into early adolescence, middle adolescence, late adolescence/young adulthood; greater sexual orientation mobility; more bullying victimization) would be positively associated with mental health outcomes (depressive and anxious symptoms). Linear regression models stratified by gender and sexual orientation were fit via generalized estimating equations and controlled for age and race/ethnicity. Models were fit for each stressor predicting each mental health outcome. Reaching sexual minority milestones in early versus middle adolescence was associated with greater depressive and anxious symptoms among lesbians and gay men. Reaching sexual minority milestones in late adolescence/young adulthood versus middle adolescence was associated with greater depressive symptoms among lesbians, but fewer depressive and anxious symptoms among gay men. Greater sexual orientation mobility was associated with greater depressive symptoms among mostly heterosexual women. More bullying victimization was associated with greater depressive symptoms among bisexual women and with greater anxious symptoms among mostly heterosexual women. Sexual minority stressors are associated with adverse mental health among some sexual minority young adults. More research is needed to understand what may be protecting some subgroups from the mental health effects of sexual minority stressors.

Adolescent Choline Supplementation Attenuates Working Memory Deficits in Rats Exposed to Alcohol During the Third Trimester Equivalent.

PubMed

Schneider, Ronald D; Thomas, Jennifer D

2016-04-01

Children exposed to alcohol prenatally may suffer from behavioral and cognitive alterations that adversely affect their quality of life. Animal studies have shown that perinatal supplementation with the nutrient choline can attenuate ethanol's adverse effects on development; however, it is not clear how late in development choline can be administered and still effectively reduce the consequences of prenatal alcohol exposure. Using a rodent model, this study examined whether choline supplementation is effective in mitigating alcohol's teratogenic effects when administered during adolescence/young adulthood. Sprague-Dawley rats were exposed to alcohol (5.25 g/kg/d) during the third trimester equivalent brain growth spurt, which occurs from postnatal day (PD) 4 to 9, via oral intubation. Sham-intubated and nontreated controls were included. Subjects were treated with 100 mg/kg/d choline chloride or vehicle from PD 40 to 60, a period equivalent to young adulthood in the rat. After the choline treatment had ceased, subjects were tested on a series of behavioral tasks: open field activity (PD 61 to 64), Morris water maze spatial learning (PD 65 to 73), and spatial working memory (PD 87 to 91). Ethanol-exposed subjects were overactive in the activity chambers and impaired on both the spatial and the working memory versions of the Morris water maze. Choline treatment failed to attenuate alcohol-related overactivity in the open field and deficits in Morris water maze performance. In contrast, choline supplementation significantly mitigated alcohol-related deficits in working memory, which may suggest that choline administration at this later developmental time affects functioning of the prefrontal cortex. The results indicate that adolescent choline supplementation can attenuate some, but not all, of the behavioral deficits associated with early developmental alcohol exposure. The results of this study indicate that dietary intervention may reduce some fetal alcohol effects, even when administered later in life, findings with important implications for adolescents and young adults with fetal alcohol spectrum disorders. Copyright © 2016 by the Research Society on Alcoholism.

Developmental Outcomes of Extremely Preterm Infants Born to Adolescent Mothers

PubMed Central

Bann, Carla; Higgins, Rosemary; Vohr, Betty

2015-01-01

BACKGROUND AND OBJECTIVES: Extremely preterm infants and infants born to adolescent mothers are at risk for adverse developmental. The objectives were to evaluate development and behavior outcomes of extremely low birth weight (ELBW) infants born to adolescent mothers <20 compared with adult mothers ≥20 years and to identify socioeconomic risk factors that affect outcomes. METHODS: Retrospective cohort analysis of 211 infants >27 weeks of adolescent mothers and 1723 infants of adult mothers at Neonatal Research Network centers from 2008 to 2011. Groups were compared and regression models were run to predict 18- to 22-month adverse outcomes. Primary outcomes were Bayley-III scores, neurodevelopmental impairment, and Brief Infant Toddler Social Emotional Assessment problem scores (BITSEA/P) ≥75th percentile. RESULTS: Adolescent mothers were more often single, Hispanic, less educated, and had public insurance. By 18 to 22 months, their children had significantly increased rates of having lived ≥3 places (21% vs 9%), state supervision (7% vs 3%), rehospitalization (56% vs 46%), and BITSEA/P ≥75th percentile (50% vs 32%) and nonsignificant Bayley-III language scores <85 (56% vs 49%, P = .07). In regression analysis, children of adolescent mothers were more likely to have BITSEA/P ≥75th percentile (relative risk 1.50, 95% confidence interval 1.08–2.07). Living ≥3 places and nonwhite race were predictors of adverse behavior. State supervision was an independent predictor of each Bayley-III composite <70 and neurodevelopmental impairment. CONCLUSIONS: ELBW infants of adolescent mothers experience high social and environmental risks that are associated with adverse behavior outcomes. These findings inform the need for comprehensive follow-up, coordinated care services, and behavior interventions for ELBW infants of adolescent mothers. PMID:25963007

Dynamic interaction between fetal adversity and a genetic score reflecting dopamine function on developmental outcomes at 36 months.

PubMed

Bischoff, Adrianne R; Pokhvisneva, Irina; Léger, Étienne; Gaudreau, Hélène; Steiner, Meir; Kennedy, James L; O'Donnell, Kieran J; Diorio, Josie; Meaney, Michael J; Silveira, Patrícia P

2017-01-01

Fetal adversity, evidenced by poor fetal growth for instance, is associated with increased risk for several diseases later in life. Classical cut-offs to characterize small (SGA) and large for gestational age (LGA) newborns are used to define long term vulnerability. We aimed at exploring the possible dynamism of different birth weight cut-offs in defining vulnerability in developmental outcomes (through the Bayley Scales of Infant and Toddler Development), using the example of a gene vs. fetal adversity interaction considering gene choices based on functional relevance to the studied outcome. 36-month-old children from an established prospective birth cohort (Maternal Adversity, Vulnerability, and Neurodevelopment) were classified according to birth weight ratio (BWR) (SGA ≤0.85, LGA >1.15, exploring a wide range of other cut-offs) and genotyped for polymorphisms associated with dopamine signaling (TaqIA-A1 allele, DRD2-141C Ins/Ins, DRD4 7-repeat, DAT1-10- repeat, Met/Met-COMT), composing a score based on the described function, in which hypofunctional variants received lower scores. There were 251 children (123 girls and 128 boys). Using the classic cut-offs (0.85 and 1.15), there were no statistically significant interactions between the neonatal groups and the dopamine genetic score. However, when changing the cut-offs, it is possible to see ranges of BWR that could be associated with vulnerability to poorer development according to the variation in the dopamine function. The classic birth weight cut-offs to define SGA and LGA newborns should be seen with caution, as depending on the outcome in question, the protocols for long-term follow up could be either too inclusive-therefore most costly, or unable to screen true vulnerabilities-and therefore ineffective to establish early interventions and primary prevention.

Human environmental and occupational exposures to boric acid: reconciliation with experimental reproductive toxicity data.

PubMed

Bolt, Hermann M; Başaran, Nurşen; Duydu, Yalçın

2012-01-01

The reproductive toxicity of boric acid and borates is a matter of current regulatory concern. Based on experimental studies in rats, no-observed-adverse-effect levels (NOAELs) were found to be 17.5 mg boron (B)/kg body weight (b.w.) for male fertility and 9.6 mg B/kg b.w. for developmental toxicity. Recently, occupational human field studies in highly exposed cohorts were reported from China and Turkey, with both studies showing negative results regarding male reproduction. A comparison of the conditions of these studies with the experimental NOAEL conditions are based on reported B blood levels, which is clearly superior to a scaling according to estimated B exposures. A comparison of estimated daily B exposure levels and measured B blood levels confirms the preference of biomonitoring data for a comparison of human field studies. In general, it appears that high environmental exposures to B are lower than possible high occupational exposures. The comparison reveals no contradiction between human and experimental reproductive toxicity data. It clearly appears that human B exposures, even in the highest exposed cohorts, are too low to reach the blood (and target tissue) concentrations that would be required to exert adverse effects on reproductive functions.

Nicotine and the Developing Human

PubMed Central

England, Lucinda J.; Bunnell, Rebecca E.; Pechacek, Terry F.; Tong, Van T.; McAfee, Tim A.

2015-01-01

The elimination of cigarettes and other combusted tobacco products in the U.S. would prevent tens of millions of tobacco-related deaths. It has been suggested that the introduction of less harmful nicotine delivery devices, such as electronic cigarettes or other electronic nicotine delivery systems, will accelerate progress toward ending combustible cigarette use. However, careful consideration of the potential adverse health effects from nicotine itself is often absent from public health debates. Human and animal data support that nicotine exposure during periods of developmental vulnerability (fetal through adolescent stages) has multiple adverse health consequences, including impaired fetal brain and lung development, and altered development of cerebral cortex and hippocampus in adolescents. Measures to protect the health of pregnant women and children are needed and could include (1) strong prohibitions on marketing that increase youth uptake; (2) youth access laws similar to those in effect for other tobacco products; (3) appropriate health warnings for vulnerable populations; (4) packaging to prevent accidental poisonings; (5) protection of non-users from exposure to secondhand electronic cigarette aerosol; (6) pricing that helps minimize youth initiation and use; (7) regulations to reduce product addiction potential and appeal for youth; and (8) the age of legal sale. PMID:25794473

Estrogenic and anti-estrogenic activity of off-the-shelf hair and skin care products

PubMed Central

Myers, Sharon L.; Yang, Chun Z.; Bittner, George D.; Witt, Kristine L.; Tice, Raymond R.; Baird, Donna D.

2014-01-01

Use of personal care products is widespread in the United States but tends to be greater among African Americans than whites. Of special concern is the possible hazard of absorption of chemicals with estrogenic activity (EA) or anti-EA (AEA) in these products. Such exposure may have adverse health effects, especially when it occurs during developmental windows (e.g., prepubertally) when estrogen levels are low. We assessed the ethanol extracts of eight commonly used hair and skin products popular among African Americans for EA and AEA using a cell proliferation assay with the estrogen sensitive MCF-7:WS8 cell line derived from a human breast cancer. Four of the eight personal care products tested (Oil Hair Lotion, Extra-dry Skin Lotion, Intensive Skin Lotion, Petroleum Jelly) demonstrated detectable EA, whereas three (Placenta Hair Conditioner, Tea-Tree Hair Conditioner, Cocoa Butter Skin Cream) exhibited AEA. Our data indicate that hair and skin care products can have EA or AEA, and suggest that laboratory studies are warranted to investigate the in vivo activity of such products under chronic exposure conditions as well as epidemiologic studies to investigate potential adverse health effects that might be associated with use of such products. PMID:24849798

Estrogenic and anti-estrogenic activity of off-the-shelf hair and skin care products.

PubMed

Myers, Sharon L; Yang, Chun Z; Bittner, George D; Witt, Kristine L; Tice, Raymond R; Baird, Donna D

2015-05-01

Use of personal care products is widespread in the United States but tends to be greater among African Americans than whites. Of special concern is the possible hazard of absorption of chemicals with estrogenic activity (EA) or anti-EA (AEA) in these products. Such exposure may have adverse health effects, especially when it occurs during developmental windows (e.g., prepubertally) when estrogen levels are low. We assessed the ethanol extracts of eight commonly used hair and skin products popular among African Americans for EA and AEA using a cell proliferation assay with the estrogen sensitive MCF-7:WS8 cell line derived from a human breast cancer. Four of the eight personal care products tested (Oil Hair Lotion, Extra-dry Skin Lotion, Intensive Skin Lotion, Petroleum Jelly) demonstrated detectable EA, whereas three (Placenta Hair Conditioner, Tea-Tree Hair Conditioner, Cocoa Butter Skin Cream) exhibited AEA. Our data indicate that hair and skin care products can have EA or AEA, and suggest that laboratory studies are warranted to investigate the in vivo activity of such products under chronic exposure conditions as well as epidemiologic studies to investigate potential adverse health effects that might be associated with use of such products.

Sex-specific differences in effect of prenatal exposure to dioxin-like compounds on neurodevelopment in Japanese children: Sapporo cohort study.

PubMed

Nakajima, Sonomi; Saijo, Yasuaki; Miyashita, Chihiro; Ikeno, Tamiko; Sasaki, Seiko; Kajiwara, Junboku; Kishi, Reiko

2017-11-01

Consistent reports are not available on the effects of dioxin-like polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins (PCDD)/ polychlorinated dibenzofurans (PCDF) (dioxin-like compounds [DLCs]) on child neurodevelopment. Further, the effect of background-level exposure to individual DLC isomers is not known. We carried out the Sapporo cohort study to evaluate the effect of prenatal exposure to each DLC isomer on child neurodevelopment at 6 and 18 months of age, and assessed sex-specific differences in these effects. The levels of all and each individual DLC isomers were estimated in maternal peripheral blood. Neurodevelopment was evaluated using the Bayley Scales of Infant Development-2nd Edition for 6-month-old infants (n = 190) and 18-month-old children (n = 121). In male children, levels of 10 DLC isomers were significantly negatively associated with the Psychomotor Developmental Index (PDI) at 6 months of age after adjustment for potential confounding variables. However, at 18 months of age, these associations were absent. In female children, the level of only one DLC isomer was significantly negatively associated with PDI at 6 months of age. However, in contrast to the male children, the levels of six DLC isomers in 18-month-old female children were significantly positively associated with the Mental Developmental Index. These findings indicate that adverse neurodevelopmental effects of prenatal background-level exposure to DLCs may be stronger in male children. Copyright © 2017 Elsevier Inc. All rights reserved.

Epigenetic Perspective on the Developmental Effects of Bisphenol A

PubMed Central

Kundakovic, Marija; Champagne, Frances A.

2013-01-01

Bisphenol A (BPA) is an estrogenic environmental toxin widely used in the production of plastics and ubiquitous human exposure to this chemical has been proposed to be a potential risk to public health. Animal studies suggest that in utero and early postnatal exposure to this compound may produce a broad range of adverse effects, including impaired brain development, sexual differentiation, behavior, and immune function, which could extend to future generations. Molecular mechanisms that underlie the long-lasting effects of BPA continue to be elucidated, and likely involve disruption of epigenetic programming of gene expression during development. Several studies have provided evidence that maternal exposure to BPA results in postnatal changes in DNA methylation status and altered expression of specific genes in offspring. However, further studies are needed to extend these initial findings to other genes in different tissues, and to examine the correlations between BPA-induced epigenetic alterations, changes in gene expression, and various phenotypic outcomes. It will be also important to explore whether the epigenetic effects of BPA are related to its estrogenic activity, and to determine which downstream effector proteins could mediate changes in DNA methylation. In this review, we will highlight research indicating a consequence of prenatal BPA exposure for brain, behavior, and immune outcomes and discuss evidence for the role of epigenetic pathways in shaping these developmental effects. Based on this evidence, we will suggest future directions in the study of BPA-induced epigenetic effects and discuss the transgenerational implications of exposure to endocrine disrupting chemicals. PMID:21333735

Risk for psychopathology in the children of depressed mothers: a developmental model for understanding mechanisms of transmission.

PubMed

Goodman, S H; Gotlib, I H

1999-07-01

A large body of literature documents the adverse effects of maternal depression on the functioning and development of offspring. Although investigators have identified factors associated with risk for abnormal development and psychopathology in the children, little attention has been paid to the mechanisms explaining the transmission of risk from the mothers to the children. Moreover, no existing model both guides understanding of the various processes' interrelatedness and considers the role of development in explicating the manifestation of risk in the children. This article proposes a developmentally sensitive, integrative model for understanding children's risk in relation to maternal depression. Four mechanisms through which risk might be transmitted are evaluated: (a) heritability of depression; (b) innate dysfunctional neuroregulatory mechanisms; (c) exposure to negative maternal cognitions, behaviors, and affect; and (d) the stressful context of the children's lives. Three factors that might moderate this risk are considered: (a) the father's health and involvement with the child, (b) the course and timing of the mother's depression, and (c) characteristics of the child. Relevant issues are discussed, and promising directions for future research are suggested.

Comparison of rat and rabbit embryo-fetal developmental ...

EPA Pesticide Factsheets

Regulatory non-clinical safety testing of human pharmaceutical compounds typically requires embryo fetal developmental toxicity (EFDT) testing in two species, (one rodent and one non-rodent, usually the rat and the rabbit). The question has been raised whether under some conditions EFDT testing could be limited to one species, or whether the need for testing in a second species could be decided on a case by case basis. As part of an RIVM/CBG-MEB/HESI/US EPA consortium initiative, we built and queried a database of 379 EFDT studies conducted for marketed and non-marketed pharmaceutical compounds. The animal models (rat and rabbit) were assessed for their potential for adverse developmental and maternal outcomes. The database was analyzed for the prevalence of EFDT incidence and the nature and severity of adverse findings in the two species. Some manifestation of EFDT in either one or both species (rat and rabbit) was demonstrated for 282 compounds (74%), and EFDT was detected in only one species (rat or rabbit) in almost a third (31%, 118 compounds), with approximately 58% rat and 42% rabbit studies identifying an EFDT signal among the 379 compounds tested. For 24 compounds (6%), fetal malformations were observed in one species (rat or rabbit) in the absence of any EFDT in the second species. In general, growth retardation, fetal variations, and malformations were more prominent in the rat, whereas embryo-fetal death was observed more often in the rabbit. Discor

Anaemia of pregnancy, perinatal outcomes and children's developmental vulnerability: a whole-of-population study.

PubMed

Smithers, Lisa G; Gialamas, Angela; Scheil, Wendy; Brinkman, Sally; Lynch, John W

2014-09-01

There is limited longitudinal data from high-income countries on the sequelae of anaemia during pregnancy. The aim of this study is to examine whether anaemia of pregnancy is associated with adverse perinatal outcomes and with children's developmental vulnerability. We conducted a population-based study to link routinely collected government administrative data that involved all live births in the state of South Australia 1999-2005 (n = 124 061) and a subset for whom developmental data were collected during a national census of children attending their first year of school in 2009 (n = 13 654). Perinatal outcomes were recorded by midwives using a validated, standardised form. Development was recorded by schoolteachers using the Australian Early Development Index (AEDI). Children in the lowest 10% of AEDI scores are indicative of developmental vulnerability. There were 8764/124 061 (7.1%) cases of anaemia. After adjustment for a range of potentially confounding factors, anaemia of pregnancy was associated with a higher risk of fetal distress [incident rate ratio (IRR) 1.20 [95% CI 1.13, 1.27

Health assessment of gasoline and fuel oxygenate vapors: developmental toxicity in mice.

PubMed

Roberts, L G; Gray, T M; Marr, M C; Tyl, R W; Trimmer, G W; Hoffman, G M; Murray, F J; Clark, C R; Schreiner, C A

2014-11-01

CD-1 mice were exposed to baseline gasoline vapor condensate (BGVC) alone or to vapors of gasoline blended with methyl tertiary butyl ether (G/MTBE). Inhalation exposures were 6h/d on GD 5-17 at levels of 0, 2000, 10,000, and 20,000mg/m(3). Dams were evaluated for evidence of maternal toxicity, and fetuses were weighed, sexed, and evaluated for external, visceral, and skeletal anomalies. Exposure to 20,000mg/m(3) of BGVC produced slight reductions in maternal body weight/gain and decreased fetal body weight. G/MTBE exposure did not produce statistically significant maternal or developmental effects; however, two uncommon ventral wall closure defects occurred: gastroschisis (1 fetus at 10,000mg/m(3)) and ectopia cordis (1 fetus at 2000mg/m(3); 2 fetuses/1 litter at 10,000mg/m(3)). A second study (G/MTBE-2) evaluated similar exposure levels on GD 5-16 and an additional group exposed to 30,000mg/m(3) from GD 5-10. An increased incidence of cleft palate was observed at 30,000mg/m(3) G/MTBE. No ectopia cordis occurred in the replicate study, but a single observation of gastroschisis was observed at 30,000mg/m(3). The no observed adverse effect levels for maternal/developmental toxicity in the BGVC study were 10,000/2000mg/m(3), 20,000/20,000 for the G/MTBE study, and 10,000/20,000 for the G/MTBE-2 study. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Comparison of national gestational weight gain guidelines and energy intake recommendations.

PubMed

Alavi, N; Haley, S; Chow, K; McDonald, S D

2013-01-01

Although data showing adverse effects with high and low gestational weight gain (GWG) come from a large number of countries, a variety of guidelines about the GWG exist. Our objectives were to compare existing GWG and energy recommendations across various countries, as well as the rationale or evidence on which they were based. We used the United Nations' Human Developmental Index to determine the ranking of the country to ensure broad sampling and then searched for guidelines. We first searched the national government websites, and if necessary searched Medline and EMBASE, Global Health databases, and bibliographies of published articles for both guidelines and the studies on which they were based. We found guidelines for 31% of the countries, and 59% of these had a GWG recommendation, 68% had an energy intake recommendation (EIR), and 36% had both. About half of the GWG guidelines are similar to the 2009 American Institutes of Medicine (IOM) and 73% of the EIRs are similar to the 2006 IOM. Despite the documented relationship between both high GWG and adverse outcomes for women and infants and low GWG and adverse outcomes in infants, there are a wide variety of guidelines for GWG and energy recommendations by different countries around the world. © 2012 The Authors. obesity reviews © 2012 International Association for the Study of Obesit.

The presence of MWCNTs reduces developmental toxicity of PFOS in early life stage of zebrafish.

PubMed

Wang, Shutao; Zhuang, Changlu; Du, Jia; Wu, Chuan; You, Hong

2017-03-01

Both carbon nanotubes (CNTs) and perfluorooctane sulfonate (PFOS) are used widely. There is considerable concern regarding their ecotoxicity. CNTs might interact with PFOS in water and result in different impacts compared with those after single exposures. To our knowledge, the developmental toxicity of PFOS in the presence of multi-walled carbon nanotubes (MWCNTs) in the early life stage of zebrafish (from 3 h post fertilization (hpf) to 96 hpf) was investigated for the first time in this study. The embryos and larvae were exposed to PFOS (0.2, 0.4, 0.8, and 1.6 mg/L), MWCNTs (50 mg/L), and a mixture of both. Compared with PFOS exposure, the adverse effects induced by PFOS on the hatching rate of zebrafish embryos and the heart rate and body length of zebrafish larvae were reduced in the presence of MWCNTs, and mortality and malformation were also alleviated. In addition, zebrafish larvae exposed to PFOS showed decreased activities of superoxide dismutase, catalase, and glutathione peroxidase, as well as decreased levels of reactive oxygen species and malondialdehyde, in the presence of MWCNTs, indicating that oxidative stress and lipid peroxidation was relieved. Thus, the presence of MWCNTs reduces the developmental toxicity of PFOS in the early life stage of zebrafish. Copyright © 2016 Elsevier Ltd. All rights reserved.

Assessment and evaluation of the high risk neonate: the NICU Network Neurobehavioral Scale.

PubMed

Lester, Barry M; Andreozzi-Fontaine, Lynne; Tronick, Edward; Bigsby, Rosemarie

2014-08-25

There has been a long-standing interest in the assessment of the neurobehavioral integrity of the newborn infant. The NICU Network Neurobehavioral Scale (NNNS) was developed as an assessment for the at-risk infant. These are infants who are at increased risk for poor developmental outcome because of insults during prenatal development, such as substance exposure or prematurity or factors such as poverty, poor nutrition or lack of prenatal care that can have adverse effects on the intrauterine environment and affect the developing fetus. The NNNS assesses the full range of infant neurobehavioral performance including neurological integrity, behavioral functioning, and signs of stress/abstinence. The NNNS is a noninvasive neonatal assessment tool with demonstrated validity as a predictor, not only of medical outcomes such as cerebral palsy diagnosis, neurological abnormalities, and diseases with risks to the brain, but also of developmental outcomes such as mental and motor functioning, behavior problems, school readiness, and IQ. The NNNS can identify infants at high risk for abnormal developmental outcome and is an important clinical tool that enables medical researchers and health practitioners to identify these infants and develop intervention programs to optimize the development of these infants as early as possible. The video shows the NNNS procedures, shows examples of normal and abnormal performance and the various clinical populations in which the exam can be used.

Oil Exposure Impairs In Situ Cardiac Function in Response to β-Adrenergic Stimulation in Cobia (Rachycentron canadum).

PubMed

Cox, Georgina K; Crossley, Dane A; Stieglitz, John D; Heuer, Rachael M; Benetti, Daniel D; Grosell, Martin

2017-12-19

Aqueous crude oil spills expose fish to varying concentrations of dissolved polycyclic aromatic hydrocarbons (PAHs), which can have lethal and sublethal effects. The heart is particularly vulnerable in early life stages, as PAH toxicity causes developmental cardiac abnormalities and impaired cardiovascular function. However, cardiac responses of juvenile and adult fish to acute oil exposure remain poorly understood. We sought to assess cardiac function in a pelagic fish species, the cobia (Rachycentron canadum), following acute (24 h) exposure to two ecologically relevant levels of dissolved PAHs. Cardiac power output (CPO) was used to quantify cardiovascular performance using an in situ heart preparation. Cardiovascular performance was varied using multiple concentrations of the β-adrenoceptor agonist isoproterenol (ISO) and by varying afterload pressures. Oil exposure adversely affected CPO with control fish achieving maximum CPO's (4 mW g -1 Mv) greater than that of oil-exposed fish (1 mW g -1 Mv) at ISO concentrations of 1 × 10 -6 M. However, the highest concentration of ISO (1 × 10 -5 M) rescued cardiac function. This indicates an interactive effect between oil-exposure and β-adrenergic stimulation and suggests if animals achieve very large increases in β-adrenergic stimulation it could play a compensatory role that may mitigate some adverse effects of oil-exposure in vivo.

Comprehensive assessment of a chlorinated drinking water concentrate in a rat multigenerational reproductive toxicity study.

PubMed

Narotsky, Michael G; Klinefelter, Gary R; Goldman, Jerome M; Best, Deborah S; McDonald, Anthony; Strader, Lillian F; Suarez, Juan D; Murr, Ashley S; Thillainadarajah, Inthirany; Hunter, E Sidney; Richardson, Susan D; Speth, Thomas F; Miltner, Richard J; Pressman, Jonathan G; Teuschler, Linda K; Rice, Glenn E; Moser, Virginia C; Luebke, Robert W; Simmons, Jane Ellen

2013-09-17

Some epidemiological studies report associations between drinking water disinfection byproducts (DBPs) and adverse reproductive/developmental effects, e.g., low birth weight, spontaneous abortion, stillbirth, and birth defects. Using a multigenerational rat bioassay, we evaluated an environmentally relevant "whole" mixture of DBPs representative of chlorinated drinking water, including unidentified DBPs as well as realistic proportions of known DBPs at low-toxicity concentrations. Source water from a water utility was concentrated 136-fold, chlorinated, and provided as drinking water to Sprague-Dawley rats. Timed-pregnant females (P0 generation) were exposed during gestation and lactation. Weanlings (F1 generation) continued exposures and were bred to produce an F2 generation. Large sample sizes enhanced statistical power, particularly for pup weight and prenatal loss. No adverse effects were observed for pup weight, prenatal loss, pregnancy rate, gestation length, puberty onset in males, growth, estrous cycles, hormone levels, immunological end points, and most neurobehavioral end points. Significant, albeit slight, effects included delayed puberty for F1 females, reduced caput epidydimal sperm counts in F1 adult males, and increased incidences of thyroid follicular cell hypertrophy in adult females. These results highlight areas for future research, while the largely negative findings, particularly for pup weight and prenatal loss, are notable.