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

Developmental vitamin D deficiency alters MK 801-induced hyperlocomotion in the adult rat: An animal model of schizophrenia.

PubMed

Kesby, James P; Burne, Thomas H J; McGrath, John J; Eyles, Darryl W

2006-09-15

Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. The behavioral phenotype of adult rats subjected to transient low prenatal vitamin D is characterized by spontaneous hyperlocomotion but normal prepulse inhibition of acoustic startle (PPI). The aim of this study was to examine the impact of selected psychotropic agents and one well-known antipsychotic agent on the behavioral phenotype of DVD deplete rats. Control versus DVD deplete adult rats were assessed on holeboard, open field and PPI. In the open field, animals were given MK-801 and/or haloperidol. For PPI, the animals were given apomorphine or MK-801. DVD deplete rats had increased baseline locomotion on the holeboard task and increased locomotion in response to MK-801 compared to control rats. At low doses, haloperidol antagonized the MK-801 hyperactivity of DVD deplete rats preferentially and, at a high dose, resulted in a more pronounced reduction in spontaneous locomotion in DVD deplete rats. DVD depletion did not affect either baseline or drug-mediated PPI response. These results suggest that DVD deficiency is associated with a persistent alteration in neuronal systems associated with motor function but not those associated with sensory motor gating. In light of the putative association between low prenatal vitamin D and schizophrenia, the discrete behavioral differences associated with the DVD model may help elucidate the neurobiological correlates of schizophrenia.

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

Comparing rat and rabbit embryo-fetal developmental toxicity studies for 379 pharmaceuticals: On systemic dose and developmental effects (Critical Reviews in Toxicology)

EPA Science Inventory

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 ef...

Computer Simulation of Embryonic Systems: What can a virtual embryo teach us about developmental toxicity? Microcephaly: Computational and organotypic modeling of a complex human birth defect (seminar and lecture - Thomas Jefferson University, Philadelphia, PA)

EPA Science Inventory

(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 pro...

Model of excitation-contraction coupling of rat neonatal ventricular myocytes.

PubMed

Korhonen, Topi; Hänninen, Sandra L; Tavi, Pasi

2009-02-01

The neonatal rat ventricular myocyte culture is one of the most popular experimental cardiac cell models. To our knowledge, the excitation-contraction coupling (ECC) of these cells, i.e., the process linking the electrical activity to the cytosolic Ca2+ transient and contraction, has not been previously analyzed, nor has it been presented as a complete system in detail. Neonatal cardiomyocytes are in the postnatal developmental stage, and therefore, the features of their ECC differ vastly from those of adult ventricular myocytes. We present the first complete analysis of ECC in these cells by characterizing experimentally the action potential and calcium signaling and developing the first mathematical model of ECC in neonatal cardiomyocytes that we know of. We show that in comparison to adult cardiomyocytes, neonatal cardiomyocytes have long action potentials, heterogeneous cytosolic Ca2+ signals, weaker sarcoplasmic reticulum Ca2+ handling, and stronger sarcolemmal Ca2+ handling, with a significant contribution by the Na+/Ca2+ exchanger. The developed model reproduces faithfully the ECC of rat neonatal cardiomyocytes with a novel description of spatial cytosolic [Ca2+] signals. Simulations also demonstrate how an increase in the cell size (hypertrophy) affects the ECC in neonatal cardiomyocytes. This model of ECC in developing cardiomyocytes provides a platform for developing future models of cardiomyocytes at different developmental stages.

Developmental toxicity evaluation of unleaded gasoline vapor in the rat.

PubMed

Roberts, L; White, R; Bui, Q; Daughtrey, W; Koschier, F; Rodney, S; Schreiner, C; Steup, D; Breglia, R; Rhoden, R; Schroeder, R; Newton, P

2001-01-01

To evaluate the potential of unleaded gasoline vapor for developmental toxicity, a sample was prepared by slowly heating API 94-02 (1990 industry average gasoline) and condensing the vapor. The composition of this vapor condensate, which comprises 10.4% by volume of the starting gasoline, is representative of real-world exposure to gasoline vapor encountered at service stations and other occupational settings and consists primarily of volatile short chain (C4-C6) aliphatic hydrocarbons (i.e. paraffins) with small amounts of cycloparaffins and aromatic hydrocarbons. A preliminary study in rats and mice resulted in no developmental toxicity in either species. However, a slight reduction in maternal body weight gain in rats led to the selection of rats for this guideline study. Groups of pregnant rats (n = 24/group) were exposed to unleaded gasoline vapor at concentrations of 0, 1000, 3000, or 9000 (75% lower explosive limit) ppm equivalent to 0, 2653, 7960, or 23,900 mg/m3, for 6 h/day on gestation days 6-19. All rats were sacrificed on gestation day 20. No maternal toxicity was observed. Developmentally, there were no differences between treated and control groups in malformations, total variations, resorptions, fetal body weight, or viability. The maternal and developmental NOAEL is 9000 ppm. Under conditions of this study, unleaded gasoline vapors did not produce evidence of developmental toxicity.

A quantitative magnetic resonance histology atlas of postnatal rat brain development with regional estimates of growth and variability.

PubMed

Calabrese, Evan; Badea, Alexandra; Watson, Charles; Johnson, G Allan

2013-05-01

There has been growing interest in the role of postnatal brain development in the etiology of several neurologic diseases. The rat has long been recognized as a powerful model system for studying neuropathology and the safety of pharmacologic treatments. However, the complex spatiotemporal changes that occur during rat neurodevelopment remain to be elucidated. This work establishes the first magnetic resonance histology (MRH) atlas of the developing rat brain, with an emphasis on quantitation. The atlas comprises five specimens at each of nine time points, imaged with eight distinct MR contrasts and segmented into 26 developmentally defined brain regions. The atlas was used to establish a timeline of morphometric changes and variability throughout neurodevelopment and represents a quantitative database of rat neurodevelopment for characterizing rat models of human neurologic disease. Published by Elsevier Inc.

Prenatal ethanol exposure-induced adrenal developmental abnormality of male offspring rats and its possible intrauterine programming mechanisms

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

Huang, Hegui; He, Zheng; Zhu, Chunyan

Fetal adrenal developmental status is the major determinant of fetal tissue maturation and offspring growth. We have previously proposed that prenatal ethanol exposure (PEE) suppresses fetal adrenal corticosterone (CORT) synthesis. Here, we focused on PEE-induced adrenal developmental abnormalities of male offspring rats before and after birth, and aimed to explore its intrauterine programming mechanisms. A rat model of intrauterine growth retardation (IUGR) was established by PEE (4 g/kg·d). In PEE fetus, increased serum CORT concentration and decreased insulin-like growth factor 1 (IGF1) concentration, with lower bodyweight and structural abnormalities as well as a decreased Ki67 expression (proliferative marker), were observedmore » in the male fetal adrenal cortex. Adrenal glucocorticoid (GC)-metabolic activation system was enhanced while gene expression of IGF1 signaling pathway with steroidogenic acute regulatory protein (StAR), 3β-hydroxysteroid dehydrogenase (3β-HSD) was decreased. Furthermore, in the male adult offspring of PEE, serum CORT level was decreased but IGF1 was increased with partial catch-up growth, and Ki67 expression demonstrated no obvious change. Adrenal GC-metabolic activation system was inhibited, while IGF1 signaling pathway and 3β-HSD was enhanced with the steroidogenic factor 1 (SF1), and StAR was down-regulated in the adult adrenal. Based on these findings, we propose a “two-programming” mechanism for PEE-induced adrenal developmental toxicity: “the first programming” is a lower functional programming of adrenal steroidogenesis, and “the second programming” is GC-metabolic activation system-related GC-IGF1 axis programming. - Highlights: • Prenatal ethanol exposure induces adrenal developmental abnormality in offspring rats. • Prenatal ethanol exposure induces intrauterine programming of adrenal steroidogenesis. • Intrauterine GC-IGF1 axis programming might mediate adrenal developmental abnormality.« less

Effects of Pubertal Cannabinoid Administration on Attentional Set-Shifting and Dopaminergic Hyper-Responsivity in a Developmental Disruption Model of Schizophrenia

PubMed Central

Guimarães, Francisco S.; Grace, Anthony A.

2015-01-01

Background: Adolescent exposure to cannabinoids in vulnerable individuals is proposed to be a risk factor for psychiatric conditions later in life, particularly schizophrenia. Evidence from studies in animals has indicated that a combination of repeated pubertal cannabinoid administration with either neonatal prefrontocortical lesion, isolation rearing, or chronic NMDA receptor antagonism administration induces enhanced schizophrenia-like behavioral disruptions. The effects of adolescent exposure to CB1 receptor agonists, however, have not been tested in a developmental disruption model of schizophrenia. Methods: This was tested in the methylazoxymethanol (MAM) model, in which repeated treatment with the synthetic cannabinoid agonist WIN 55,212-2 (WIN; 1.2mg/kg) was extended over 25 days throughout puberty (postnatal days 40–65) in control and MAM rats. The rats received 20 injections, which were delivered irregularly to mimic the human condition. Adult rats were tested for attentional set-shifting task and locomotor response to amphetamine, which was compared with in vivo recording from ventral tegmental area (VTA) dopamine (DA) neurons. Results: MAM-treated rats showed impairment in the attentional set-shifting task, augmented locomotor response to amphetamine administration, and an increased number of spontaneously active DA neurons in the VTA. Interestingly, pubertal WIN treatment in normal animals induced similar changes at adulthood as those observed in MAM-treated rats, supporting the notion that adolescence exposure to cannabinoids may represent a risk factor for developing schizophrenia-like signs at adulthood. However, contrary to expectations, pubertal WIN administration did not exacerbate the behavioral and electrophysiological changes in MAM-treated rats beyond that observed in WIN-treated saline rats (Sal). Indeed, WIN treatment actually attenuated the locomotor response to amphetamine in MAM rats without impacting DA neuron activity states. Conclusions: Taken together, the present results indicate that the impact of cannabinoids during puberty/adolescence on schizophrenia models is more complex than may be predicted. PMID:25522381

Developmental Effects of the ToxCast™ Phase I and Phase II Chemicals in Caenorhabditis elegans and Corresponding Responses in Zebrafish, Rats, and Rabbits

PubMed Central

Boyd, Windy A.; Smith, Marjolein V.; Co, Caroll A.; Pirone, Jason R.; Rice, Julie R.; Shockley, Keith R.; Freedman, Jonathan H.

2015-01-01

Background: Modern toxicology is shifting from an observational to a mechanistic science. As part of this shift, high-throughput toxicity assays are being developed using alternative, nonmammalian species to prioritize chemicals and develop prediction models of human toxicity. Methods: The nematode Caenorhabditis elegans (C. elegans) was used to screen the U.S. Environmental Protection Agency’s (EPA’s) ToxCast™ Phase I and Phase II libraries, which contain 292 and 676 chemicals, respectively, for chemicals leading to decreased larval development and growth. Chemical toxicity was evaluated using three parameters: a biologically defined effect size threshold, half-maximal activity concentration (AC50), and lowest effective concentration (LEC). Results: Across both the Phase I and Phase II libraries, 62% of the chemicals were classified as active ≤ 200 μM in the C. elegans assay. Chemical activities and potencies in C. elegans were compared with those from two zebrafish embryonic development toxicity studies and developmental toxicity data for rats and rabbits. Concordance of chemical activity was higher between C. elegans and one zebrafish assay across Phase I chemicals (79%) than with a second zebrafish assay (59%). Using C. elegans or zebrafish to predict rat or rabbit developmental toxicity resulted in balanced accuracies (the average value of the sensitivity and specificity for an assay) ranging from 45% to 53%, slightly lower than the concordance between rat and rabbit (58%). Conclusions: Here, we present an assay that quantitatively and reliably describes the effects of chemical toxicants on C. elegans growth and development. We found significant overlap in the activity of chemicals in the ToxCast™ libraries between C. elegans and zebrafish developmental screens. Incorporating C. elegans toxicological assays as part of a battery of in vitro and in vivo assays provides additional information for the development of models to predict a chemical’s potential toxicity to humans. Citation: Boyd WA, Smith MV, Co CA, Pirone JR, Rice JR, Shockley KR, Freedman JH. 2016. Developmental effects of the ToxCast™ Phase I and II chemicals in Caenorhabditis elegans and corresponding responses in zebrafish, rats, and rabbits. Environ Health Perspect 124:586–593; http://dx.doi.org/10.1289/ehp.1409645 PMID:26496690

Gene expression during blow fly development: improving the precision of age estimates in forensic entomology.

PubMed

Tarone, Aaron M; Foran, David R

2011-01-01

Forensic entomologists use size and developmental stage to estimate blow fly age, and from those, a postmortem interval. Since such estimates are generally accurate but often lack precision, particularly in the older developmental stages, alternative aging methods would be advantageous. Presented here is a means of incorporating developmentally regulated gene expression levels into traditional stage and size data, with a goal of more precisely estimating developmental age of immature Lucilia sericata. Generalized additive models of development showed improved statistical support compared to models that did not include gene expression data, resulting in an increase in estimate precision, especially for postfeeding third instars and pupae. The models were then used to make blind estimates of development for 86 immature L. sericata raised on rat carcasses. Overall, inclusion of gene expression data resulted in increased precision in aging blow flies. © 2010 American Academy of Forensic Sciences.

Triclosan Decreases Rat Thyroxine: Mode-of-Action, Developmental Susceptibility and Human Relevance

EPA Science Inventory

Triclosan (TCS) decreases serum thyroxine (T4) in the rat. In vivo and in vitro approaches were used to address three uncertainties: by what mode-of-action (MOA) does TCS decrease T4; does TCS decrease T4 developmentally; and, are effects observed in rats relevant to humans? To t...

Neurodevelopmental Reflex Testing in Neonatal Rat Pups.

PubMed

Nguyen, Antoinette T; Armstrong, Edward A; Yager, Jerome Y

2017-04-24

Neurodevelopmental reflex testing is commonly used in clinical practice to assess the maturation of the nervous system. Neurodevelopmental reflexes are also referred to as primitive reflexes. They are sensitive and consistent with later outcomes. Abnormal reflexes are described as an absence, persistence, reappearance, or latency of reflexes, which are predictive indices of infants that are at high risk for neurodevelopmental disorders. Animal models of neurodevelopmental disabilities, such as cerebral palsy, often display aberrant developmental reflexes, as would be observed in human infants. The techniques described assess a variety of neurodevelopmental reflexes in neonatal rats. Neurodevelopmental reflex testing offers the investigator a testing method that is not otherwise available in such young animals. The methodology presented here aims to assist investigators in examining developmental milestones in neonatal rats as a method of detecting early-onset brain injury and/or determining the effectiveness of therapeutic interventions. The methodology presented here aims to provide a general guideline for investigators.

Comparison of rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on the nature and severity of developmental effects (Critical Reviews in Toxicology)

EPA Science Inventory

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 conditio...

The Threshold of Toxicological Concern for prenatal developmental toxicity in rats and rabbits

PubMed Central

van Ravenzwaay, B.; Jiang, X.; Luechtefeld, T.; Hartung, T.

2018-01-01

The Threshold Toxicological Concern (TTC) is based on the concept that in absence of experimental data reasonable assurance of safety can be given if exposure is sufficiently low. Using the REACH database the low 5th percentile of the NO(A)EL distribution, for prenatal developmental toxicity (OECD guideline 414) was determined. For rats, (434 NO(A)ELs values) for maternal toxicity, this value was 10 mg/kg-bw/day. For developmental toxicity (469 NO(A)ELs): 13 mg/kg-bw/day. For rabbits, (100 NO(A)ELs), the value for maternal toxicity was 4 mg/kg-bw/day, for developmental toxicity, (112 NO(A)EL values): 10 mg/kg-bw/day. The maternal organism may thus be slightly more sensitive than the fetus. Combining REACH- (industrial chemicals) and published BASF-data (mostly agrochemicals), 537 unique compounds with NO(A)EL values for developmental toxicity in rats and 150 in rabbits were evaluated. The low 5th percentile NO(A)EL for developmental toxicity in rats was 10 mg/kg-bw/day and 9.5 mg/kg-bw/day for rabbits. Using an assessment factor of 100, a TTC value for developmental toxicity of 100 µg/kg-bw/day for rats and 95 µg/kg-bw/day for rabbits is calculated. These values could serve as guidance whether or not to perform an animal experiment, if exposure is sufficiently low. In emergency situations this value may be useful for a first tier risk assessment. PMID:28645885

Development of PBPK Models for Gasoline in Adult and Pregnant Rats and their Fetuses

EPA Science Inventory

Concern for potential developmental effects of exposure to gasoline-ethanol blends has grown along with their increased use in the US fuel supply. Physiologically-based pharmacokinetic (PBPK) models for these complex mixtures were developed to address dosimetric issues related to...

LONG-LASTING NEUROSTRUCTURAL CONSEQUENCES IN THE RAT HIPPOCAMPUS BY DEVELOPMENTAL EXPOSURE TO A MIXTURE OF POLYCHLORINATED BIPHENYLS (PCBS).

EPA Science Inventory

The objective of the study was to assess the effects of developmental exposure to a commercial mixture of PCBs (Aroclor 1254) on neuronal dendritic morphology of hippocampal CA1 pyramidal neurons in postnatal day (PND) 22 and PND 60 male Long-Evans rats. Rat pups were born to mot...

Development of brain-wide connectivity architecture in awake rats.

PubMed

Ma, Zilu; Ma, Yuncong; Zhang, Nanyin

2018-08-01

Childhood and adolescence are both critical developmental periods, evidenced by complex neurophysiological changes the brain undergoes and high occurrence rates of neuropsychiatric disorders during these periods. Despite substantial progress in elucidating the developmental trajectories of individual neural circuits, our knowledge of developmental changes of whole-brain connectivity architecture in animals is sparse. To fill this gap, here we longitudinally acquired rsfMRI data in awake rats during five developmental stages from juvenile to adulthood. We found that the maturation timelines of brain circuits were heterogeneous and system specific. Functional connectivity (FC) tended to decrease in subcortical circuits, but increase in cortical circuits during development. In addition, the developing brain exhibited hemispheric functional specialization, evidenced by reduced inter-hemispheric FC between homotopic regions, and lower similarity of region-to-region FC patterns between the two hemispheres. Finally, we showed that whole-brain network development was characterized by reduced clustering (i.e. local communication) but increased integration (distant communication). Taken together, the present study has systematically characterized the development of brain-wide connectivity architecture from juvenile to adulthood in awake rats. It also serves as a critical reference point for understanding circuit- and network-level changes in animal models of brain development-related disorders. Furthermore, FC data during brain development in awake rodents contain high translational value and can shed light onto comparative neuroanatomy. Copyright © 2018 Elsevier Inc. All rights reserved.

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.

Gene targeting technologies in rats: zinc finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeats.

PubMed

Mashimo, Tomoji

2014-01-01

The laboratory rat has been widely used as an animal model in biomedical science for more than 150 years. Applying zinc-finger nucleases or transcription activator-like effector nucleases to rat embryos via microinjection is an efficient genome editing tool for generating targeted knockout rats. Recently, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated endonucleases have been used as an effective tool for precise and multiplex genome editing in mice and rats. In this review, the advantages and disadvantages of these site-specific nuclease technologies for genetic analysis and manipulation in rats are discussed. © 2013 The Author Development, Growth & Differentiation © 2013 Japanese Society of Developmental Biologists.

Validation of a Candida albicans delayed-type hypersensitivity (DTH) model in female juvenile rats for use in immunotoxicity assessments.

PubMed

Collinge, Mark; Thorn, Mitchell; Peachee, Vanessa; White, Kimber

2013-01-01

Establishing an in vivo cell-mediated immunity (CMI) assay, such as the delayed-type hypersensitivity (DTH) assay, has been identified as an important gap and recommended to receive highest priority for new model development in several workshops on developmental immunotoxicity. A Candida albicans DTH model has recently been developed that has the advantage over other DTH models, which use alternative sensitizing antigens, in that antigen-specific antibodies, which may interfere with the assay, are not produced. In addition, the in vivo C. albicans DTH model was demonstrated to be more sensitive in detecting immunosuppression than DTH models using keyhole limpet hemocyanin (KLH) or sheep red blood cells as antigens, as well as some ex vivo CMI assays. While KLH and sheep red blood cells are non-physiological immunogens, C. albicans is an important human pathogen. The present studies were conducted in order to optimize and validate the C. albicans DTH model for use in developmental immunotoxicity studies using juvenile rats. Three known immunosuppressive compounds with different mechanisms of action were tested in this model, cyclosprorin A (CsA), cyclophosphamide (CPS), and dexamethasone (DEX). Animals were sensitized with formalin-fixed C. albicans on postnatal day (PND) 28 and challenged with chitosan on PND 38. Drug was administered beginning on PND 23 and continued until PND 37. Exposure to each of the three immunotoxicants resulted in statistically significant decreases in the DTH response to C. albicans-derived chitosan. Decreases in footpad swelling were observed at ≥10 mg CsA/kg/day, ≥5 mg CPS/kg/day, and ≥0.03 mg DEX/kg/day. These results demonstrate that the C. albicans DTH model, optimized for use in juvenile rats, can be used to identify immunotoxic compounds, and fills the need for a sensitive in vivo CMI model for assessments of developmental immunotoxicity. Abbreviations Ab, antibody APC, antigen presenting cell BSA, bovine serum albumin C. albicans, Candida albicans CI, challenge interval CMI, cell-mediated immunity CO, challenge only CPS, cyclophosphamide CsA, cyclosporin A CTL, cytotoxic T lymphocyte DEX, dexamethasone DIT, developmental immunotoxicity DTH, delayed-type hypersensitivity ip, intraperitoneal KLH, keyhole limpet hemocyanin MLR, mixed lymphocyte reaction OVA, ovalbumin PBS, phosphate-buffered saline PND, postnatal day sc, subcutaneous SEM, standard error of the mean SRBC, sheep red blood cells.

Identification of secretaglobin Scgb2a1 as a target for developmental reprogramming by BPA in the rat prostate.

PubMed

Wong, Rebecca Lee Yean; Wang, Quan; Treviño, Lindsey S; Bosland, Maarten C; Chen, Jing; Medvedovic, Mario; Prins, Gail S; Kannan, Kurunthachalam; Ho, Shuk-Mei; Walker, Cheryl Lyn

2015-01-01

Secretoglobins are a superfamily of secreted proteins thought to participate in inflammation, tissue repair, and tumorigenesis. Secretoglobin family 2A member 1 (Scgb2a1) is a component of prostatein, a major androgen-binding protein secreted by the rat prostate. Using a rat model for developmental reprogramming of susceptibility to prostate carcinogenesis, we identified, by RNA-seq, that Scgb2a1 is significantly upregulated (>100-fold) in the prostate of adult rats neonatally exposed to bisphenol A (BPA), with increased gene expression confirmed by quantitative RT-PCR and chromatin immunoprecipitation for histone H3 lysine 9 acetylation. Bisulfite analysis of both CpG islands located within 10 kb of the Scgb2a1 promoter identified significant hypomethylation of the CpG island upstream of the transcription start site of this gene in the reprogrammed prostate. These data suggest that expression of Scgb2a1 in the adult prostate could be epigenetically reprogrammed by BPA exposure during prostate development, with potential implications for cancer risk and response to chemotherapeutics associated with prostatein binding.

MATERNAL AND DEVELOPMENTAL TOXICITY OF PERFLUOROOCTANE SULFONATE IN THE RAT

EPA Science Inventory

MATERNAL AND DEVELOPMENTAL TOXICITY OF PERFLUOROOCTANE SULFONATE IN THE RAT.
C. Lau and J.M. Rogers, Reproductive Toxicology Division, NHEERL, ORD, USEPA, Research Triangle Park, NC, USA

Perfluorooctane sulfonate (PFOS), an environmentally persistent compound used ...

The developmental potential of parthenogenetic and somatic cell nuclear-transferred rat oocytes in vitro.

PubMed

Mizumoto, Shigetoshi; Kato, Yoko; Tsunoda, Yukio

2008-12-01

We examined the optimal conditions for somatic cell nuclear transfer (SCNT) in rat oocytes. First, we compared the effects of two types of inhibitors of spontaneous activation, MG132 and demecolcine, on the developmental potential of parthenogenetic oocytes. The potential of activated oocytes to develop into blastocysts significantly decreased 2 h after oocyte recovery (77% vs. 7%). The developmental potential of oocytes preserved in MG132-supplemented medium for 1 to 4 h was high (62% to 77%), but the potential of those preserved in demecolcine-supplemented medium for 3 and 4 h was low (77% vs. 41% and 37%, respectively). Second, the effect of the duration of parthenogenetic activation on the developmental potential was examined. When oocytes preserved in MG132 for 4 h were treated with 10 mM strontium for 5 or 6 h, the potential of activated oocytes to develop into blastocysts was high (78% and 70%, respectively). Using the optimal conditions for parthenogenetic activation, we examined the potential of rat enucleated oocytes receiving cumulus cells to develop into blastocysts. In contrast to parthenogenotes, the potential of SCNT rat oocytes to develop into blastocysts was low (2%) even if then oocytes were treated with the histone deacetylation inhibitor trichostatin A. The reason for the low developmental potential of rat SCNT oocytes is discussed.

Environmental Enrichment Decreases Asphyxia-Induced Neurobehavioral Developmental Delay in Neonatal Rats

PubMed Central

Kiss, Peter; Vadasz, Gyongyver; Kiss-Illes, Blanka; Horvath, Gabor; Tamas, Andrea; Reglodi, Dora; Koppan, Miklos

2013-01-01

Perinatal asphyxia during delivery produces long-term disability and represents a major problem in neonatal and pediatric care. Numerous neuroprotective approaches have been described to decrease the effects of perinatal asphyxia. Enriched environment is a popular strategy to counteract nervous system injuries. The aim of the present study was to investigate whether enriched environment is able to decrease the asphyxia-induced neurobehavioral developmental delay in neonatal rats. Asphyxia was induced in ready-to-deliver mothers by removing the pups by caesarian section after 15 min of asphyxia. Somatic and neurobehavioral development was tested daily and motor coordination weekly. Our results show that rats undergoing perinatal asphyxia had a marked developmental delay and worse performance in motor coordination tests. However, pups kept in enriched environment showed a decrease in the developmental delay observed in control asphyctic pups. Rats growing up in enriched environment did not show decrease in weight gain after the first week and the delay in reflex appearance was not as marked as in control rats. In addition, the development of motor coordination was not as strikingly delayed as in the control group. Short-term neurofunctional outcome are known to correlate with long-term deficits. Our results thus show that enriched environment could be a powerful strategy to decrease the deleterious developmental effects of perinatal asphyxia. PMID:24232451

Environmental enrichment decreases asphyxia-induced neurobehavioral developmental delay in neonatal rats.

PubMed

Kiss, Peter; Vadasz, Gyongyver; Kiss-Illes, Blanka; Horvath, Gabor; Tamas, Andrea; Reglodi, Dora; Koppan, Miklos

2013-11-13

Perinatal asphyxia during delivery produces long-term disability and represents a major problem in neonatal and pediatric care. Numerous neuroprotective approaches have been described to decrease the effects of perinatal asphyxia. Enriched environment is a popular strategy to counteract nervous system injuries. The aim of the present study was to investigate whether enriched environment is able to decrease the asphyxia-induced neurobehavioral developmental delay in neonatal rats. Asphyxia was induced in ready-to-deliver mothers by removing the pups by caesarian section after 15 min of asphyxia. Somatic and neurobehavioral development was tested daily and motor coordination weekly. Our results show that rats undergoing perinatal asphyxia had a marked developmental delay and worse performance in motor coordination tests. However, pups kept in enriched environment showed a decrease in the developmental delay observed in control asphyctic pups. Rats growing up in enriched environment did not show decrease in weight gain after the first week and the delay in reflex appearance was not as marked as in control rats. In addition, the development of motor coordination was not as strikingly delayed as in the control group. Short-term neurofunctional outcome are known to correlate with long-term deficits. Our results thus show that enriched environment could be a powerful strategy to decrease the deleterious developmental effects of perinatal asphyxia.

Reproductive and developmental toxicity of hydrofluorocarbons used as refrigerants.

PubMed

Ema, Makoto; Naya, Masato; Yoshida, Kikuo; Nagaosa, Ryuichi

2010-04-01

The present paper summarizes data on the reproductive and developmental toxicity of hydrofluorocarbons (HFCs), including pentafluoroethane (HFC-125), 1,1,1,2-tetrafluoroethane (HFC-134a), 1,1,1-trifluoroethane (HFC-143a), 1,1-difluoroethane (HFC-152a), difluoromethane (HFC-32) and 1,1,1,3,3-pentafluoropropane (HFC-245fa), used as refrigerants, published in openly available scientific literature. No developmental toxicity of HFC-125 was found even at 50,000 ppm in rats or rabbits. Although HFC-134a exhibited no dominant lethal effect or reproductive toxicity in rats, it caused low body weight in pre- and postnatal offspring and slightly retarded skeletal ossification in fetuses at 50,000 ppm in rats. No maternal or developmental toxicity was noted after exposure to HFC-143a even at 40,000 ppm in rats or rabbits or HFC-152a even at 50,000 ppm in rats. HFC-32 is slightly maternally and developmentally toxic at 50,000 ppm in rats, but not in rabbits. HFC-245fa caused decreases in maternal body weight and food consumption at 10,000 and 50,000 ppm and fetal weight at 50 000ppm. No evidence of teratogenicity for these HFCs was noted in rats or rabbits. There is limited information about the reproductive toxicity of these HFCs. Animal studies remain necessary for risk assessments of chemicals because it is difficult to find alternative methods to determine the toxic effects of chemicals. It is required to reduce emissions of organic vapors containing HFCs to reduce the risk of exposure. Copyright 2009 Elsevier Inc. All rights reserved.

A physiologically based pharmacokinetic model for developmental exposure to BDE-47 in rats

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

Emond, Claude, E-mail: claude.emond@umontreal.c; BioSimulation Consulting Inc., Newark, DE 19711; Raymer, James H.

2010-02-01

Polybrominated diphenyl ethers (PBDEs) are used commercially as additive flame retardants and have been shown to transfer into environmental compartments, where they have the potential to bioaccumulate in wildlife and humans. Of the 209 possible PBDEs, 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is usually the dominant congener found in human blood and milk samples. BDE-47 has been shown to have endocrine activity and produce developmental, reproductive, and neurotoxic effects. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for BDE-47 in male and female (pregnant and non-pregnant) adult rats to facilitate investigations of developmental exposure. This model consistsmore » of eight compartments: liver, brain, adipose tissue, kidney, placenta, fetus, blood, and the rest of the body. Concentrations of BDE-47 from the literature and from maternal-fetal pharmacokinetic studies conducted at RTI International were used to parameterize and evaluate the model. The results showed that the model simulated BDE-47 tissue concentrations in adult male, maternal, and fetal compartments within the standard deviations of the experimental data. The model's ability to estimate BDE-47 concentrations in the fetus after maternal exposure will be useful to design in utero exposure/effect studies. This PBPK model is the first one designed for any PBDE pharmaco/toxicokinetic description. The next steps will be to expand this model to simulate BDE-47 pharmacokinetics and distributions across species (mice), and then extrapolate it to humans. After mouse and human model development, additional PBDE congeners will be incorporated into the model and simulated as a mixture.« less

Oral supplements of inulin during gestation offsets rotenone-induced oxidative impairments and neurotoxicity in maternal and prenatal rat brain.

PubMed

Krishna, Gokul; Muralidhara

2018-05-25

Environmental insults including pesticide exposure and their entry into the immature brain are of increased concern due to their developmental neurotoxicity. Several lines of evidence suggest that maternal gut microbiota influences in utero fetal development via modulation of host's microbial composition with prebiotics. Hence we examined the hypothesis if inulin (IN) supplements during pregnancy in rats possess the potential to alleviate brain oxidative response and mitochondrial deficits employing a developmental model of rotenone (ROT) neurotoxicity. Initially, pregnant Sprague-Dawley rats were gavaged during gestational days (GDs) 6-19 with 0 (control), 10 (low), 30 (mid) or 50 (high) mg/kg bw/day of ROT to recapitulate developmental effects on general fetotoxicity (assessed by the number of fetuses, fetal body and placental weights), markers of oxidative stress and cholinergic activities in maternal brain regions and whole fetal-brain. Secondly, dams orally supplemented with inulin (2×/day, 2 g/kg/bw) on GD 0-21 were administered ROT (50 mg/kg, GD 6-19). IN supplements increased maternal cecal bacterial numbers that significantly corresponded with improved exploratory-related behavior among ROT administered rats. In addition, IN supplements improved fetal and placental weight on GD 19. IN diminished gestational ROT-induced increased reactive oxygen species levels, protein and lipid peroxidation biomarkers, and cholinesterase activity in maternal brain regions (cortex, cerebellum, and striatum) and fetal brain. Moreover, in the maternal cortex, mitochondrial assessment revealed IN protected against ROT-induced reduction in NADH cytochrome c oxidoreductase and ATPase activities. These data suggest a potential role for indigestible oligosaccharides in reducing oxidative stress-mediated developmental origins of neurodegenerative disorders. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Utility of Small Animal Models of Developmental Programming.

PubMed

Reynolds, Clare M; Vickers, Mark H

2018-01-01

Any effective strategy to tackle the global obesity and rising noncommunicable disease epidemic requires an in-depth understanding of the mechanisms that underlie these conditions that manifest as a consequence of complex gene-environment interactions. In this context, it is now well established that alterations in the early life environment, including suboptimal nutrition, can result in an increased risk for a range of metabolic, cardiovascular, and behavioral disorders in later life, a process preferentially termed developmental programming. To date, most of the mechanistic knowledge around the processes underpinning development programming has been derived from preclinical research performed mostly, but not exclusively, in laboratory mouse and rat strains. This review will cover the utility of small animal models in developmental programming, the limitations of such models, and potential future directions that are required to fully maximize information derived from preclinical models in order to effectively translate to clinical use.

A dysmorphology score system for assessing embryo abnormalities in rat whole embryo culture.

PubMed

Zhang, Cindy X; Danberry, Tracy; Jacobs, Mary Ann; Augustine-Rauch, Karen

2010-12-01

The rodent whole embryo culture (WEC) system is a well-established model for characterizing developmental toxicity of test compounds and conducting mechanistic studies. Laboratories have taken various approaches in describing type and severity of developmental findings of organogenesis-stage rodent embryos, but the Brown and Fabro morphological score system is commonly used as a quantitative approach. The associated score criteria is based upon developmental stage and growth parameters, where a series of embryonic structures are assessed and assigned respective scores relative to their gestational stage, with a Total Morphological Score (TMS) assigned to the embryo. This score system is beneficial because it assesses a series of stage-specific anatomical landmarks, facilitating harmonized evaluation across laboratories. Although the TMS provides a quantitative approach to assess growth and determine developmental delay, it is limited to its ability to identify and/or delineate subtle or structure-specific abnormalities. Because of this, the TMS may not be sufficiently sensitive for identifying compounds that induce structure or organ-selective effects. This study describes a distinct morphological score system called the "Dysmorphology Score System (DMS system)" that has been developed for assessing gestation day 11 (approximately 20-26 somite stage) rat embryos using numerical scores to differentiate normal from abnormal morphology and define the respective severity of dysmorphology of specific embryonic structures and organ systems. This method can also be used in scoring mouse embryos of the equivalent developmental stage. The DMS system enhances capabilities to rank-order compounds based upon teratogenic potency, conduct structure- relationships of chemicals, and develop statistical prediction models to support abbreviated developmental toxicity screens. © 2010 Wiley-Liss, Inc.

BEHAVIORAL AND NEUROCHEMICAL CONSEQUENCES OF DEVELOPMENTAL ORGANOTIN EXPOSURE IN RATS.

EPA Science Inventory

Behavioral and Neurochemical Consequences of Developmental Organotin Exposure in Rats.
Ehman, K.,1 Jenkins, S.,2 Barone Jr., S.2 and Moser, V.2 1Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC, 2Neurotoxicology Division, U.S. Environmental Protection ...

DEVELOPMENTAL TOXICITY OF ATRAZINE METABOLITES IN FISCHER 344 RATS

EPA Science Inventory

Previously we have shown that atrazine, a commonly used herbicide, causes full-litter resorption (FLR) in Fischer 344 rats at 50 mg/kg. In this study, we tested four atrazine metabolites for their potential to cause FLR and developmental toxicity. Desethylatrazine (DEA), desis...

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

Developmental rodent models of fear and anxiety: from neurobiology to pharmacology.

PubMed

Ganella, Despina E; Kim, Jee Hyun

2014-10-01

Anxiety disorders pose one of the biggest threats to mental health in the world, and they predominantly emerge early in life. However, research of anxiety disorders and fear-related memories during development has been largely neglected, and existing treatments have been developed based on adult models of anxiety. The present review describes animal models of anxiety disorders across development and what is currently known of their pharmacology. To summarize, the underlying mechanisms of intrinsic 'unlearned' fear are poorly understood, especially beyond the period of infancy. Models using 'learned' fear reveal that through development, rats exhibit a stress hyporesponsive period before postnatal day 10, where they paradoxically form odour-shock preferences, and then switch to more adult-like conditioned fear responses. Juvenile rats appear to forget these aversive associations more easily, as is observed with the phenomenon of infantile amnesia. Juvenile rats also undergo more robust extinction, until adolescence where they display increased resistance to extinction. Maturation of brain structures, such as the amygdala, prefrontal cortex and hippocampus, along with the different temporal recruitment and involvement of various neurotransmitter systems (including NMDA, GABA, corticosterone and opioids) are responsible for these developmental changes. Taken together, the studies described in this review highlight that there is a period early in development where rats appear to be more robust in overcoming adverse early life experience. We need to understand the fundamental pharmacological processes underlying anxiety early in life in order to take advantage of this period for the treatment of anxiety disorders. © 2014 The British Pharmacological Society.

DEVELOPMENTAL ATRAZINE EXPOSURE SUPPRESSES IMMUNE FUNCTION IN MALE, BUT NOT FEMALE SPRAGUE-DAWLEY RATS

EPA Science Inventory

Developmental Atrazine Exposure Suppresses Immune Function in Male, but not Female Sprague-Dawley Rats

Andrew A. Rooney,*,1 Raymond A. Matulka,? and Robert Luebke?

*College of Veterinary Medicine, Anatomy, Physiological Sciences and Radiology, NCSU, Raleigh, North...

PBPK Models for Gasoline-Ethanol Biofuels in Adult and Pregnant Rats**

EPA Science Inventory

As utilization of biofuels (BF) in the commercial marketplace has increased in recent years, so has the need for evaluation of exposure-related health effects, such as developmental neurotoxicity. This research describes the development of inhalation life-stage physiologically-ba...

PBPK Models for Gasoline-Ethanol Biofuels in Adult and Pregnant Rats

EPA Science Inventory

As utilization of biofuels (BF) in the commercial marketplace has increased in recent years, so has the need for evaluation of exposure-related health effects, such as developmental neurotoxicity. This research describes the development of inhalation life-stage physiologically-ba...

PBPK Models for Gasoline-Ethanol Biofuels in Adult and Pregnant Rats####

EPA Science Inventory

As utilization of biofuels (BF) in the commercial marketplace has increased in recent years, so has the need for evaluation of exposure-related health effects, such as developmental neurotoxicity. This research describes the development of inhalation life-stage physiologically-ba...

PBPK Models for Gasoline-Ethanol Biofuels in Adult and Pregnant Rats###

EPA Science Inventory

As utilization of biofuels (BF) in the commercial marketplace has increased in recent years, so has the need for evaluation of exposure-related health effects, such as developmental neurotoxicity. This research describes the development of inhalation life-stage physiologically-ba...

PBPK Models for Gasoline-Ethanol Biofuels in Adult and Pregnant Rats@@@@

EPA Science Inventory

As utilization of biofuels (BF) in the commercial marketplace has increased in recent years, so has the need for evaluation of exposure-related health effects, such as developmental neurotoxicity. This research describes the development of inhalation life-stage physiologically-ba...

The MAM rodent model of schizophrenia

PubMed Central

Lodge, Daniel J.

2013-01-01

Rodent models of human disease are essential to obtain a better understanding of disease pathology, the mechanism of action underlying conventional treatments, as well as for the generation of novel therapeutic approaches. There are a number of rodent models of schizophrenia based on either genetic manipulations, acute or sub-chronic drug administration, or developmental disturbances. The prenatal methylazoxymethanol acetate (MAM) rodent model is a developmental disruption model gaining increased attention because it displays a number of histological, neurophysiological and behavioral deficits analogous to those observed in schizophrenia patients. This unit describes the procedures required to safely induce the MAM phenotype in rats. In addition, we describe a simple behavioral procedure, amphetamine-induced hyper-locomotion, which can be utilized to verify the MAM phenotype. PMID:23559309

Two-hit model of schizophrenia induced by neonatal immune activation and peripubertal stress in rats: Study of sex differences and brain oxidative alterations.

PubMed

Monte, Aline Santos; Mello, Bruna Stefânia Ferreira; Borella, Vládia Célia Moreira; da Silva Araujo, Tatiane; da Silva, Francisco Eliclécio Rodrigues; Sousa, Francisca Cléa F de; de Oliveira, Antônio Carlos Pinheiro; Gama, Clarissa Severino; Seeman, Mary V; Vasconcelos, Silvânia Maria Mendes; Lucena, David Freitas De; Macêdo, Danielle

2017-07-28

Schizophrenia is considered to be a developmental disorder with distinctive sex differences. Aiming to simulate the vulnerability of the third trimester of human pregnancy to the developmental course of schizophrenia, an animal model was developed, using neonatal poly(I:C) as a first-hit, and peripubertal stress as a second-hit, i.e. a two-hit model. Since, to date, there have been no references to sex differences in the two-hit model, our study sought to determine sex influences on the development of behavior and brain oxidative change in adult rats submitted to neonatal exposure to poly(I:C) on postnatal days 5-7 as well as peripubertal unpredictable stress (PUS). Our results showed that adult two-hit rats present sex-specific behavioral alterations, with females showing more pronounced deficits in prepulse inhibition of the startle reflex and hyperlocomotion, while males showing more deficits in social interaction. Male and female animals exhibited similar working memory deficits. The levels of the endogenous antioxidant, reduced glutathione, were decreased in the prefrontal cortex (PFC) of both male and female animals exposed to both poly(I:C) and poly(I:C)+PUS. Only females presented decrements in GSH levels in the striatum. Nitrite levels were increased in the PFC of male and in the striatum of female poly(I:C)+PUS rats. Increased lipid peroxidation was observed in the PFC of females and in the striatum of males and females exposed to poly(I:C) and poly(I:C)+PUS. Thus, the present study presents evidence for sex differences in behavior and oxidative brain change induced by a two-hit model of schizophrenia. Copyright © 2017 Elsevier B.V. All rights reserved.

Developmental rodent models of fear and anxiety: from neurobiology to pharmacology

PubMed Central

Ganella, Despina E; Kim, Jee Hyun

2014-01-01

Anxiety disorders pose one of the biggest threats to mental health in the world, and they predominantly emerge early in life. However, research of anxiety disorders and fear-related memories during development has been largely neglected, and existing treatments have been developed based on adult models of anxiety. The present review describes animal models of anxiety disorders across development and what is currently known of their pharmacology. To summarize, the underlying mechanisms of intrinsic ‘unlearned’ fear are poorly understood, especially beyond the period of infancy. Models using ‘learned’ fear reveal that through development, rats exhibit a stress hyporesponsive period before postnatal day 10, where they paradoxically form odour-shock preferences, and then switch to more adult-like conditioned fear responses. Juvenile rats appear to forget these aversive associations more easily, as is observed with the phenomenon of infantile amnesia. Juvenile rats also undergo more robust extinction, until adolescence where they display increased resistance to extinction. Maturation of brain structures, such as the amygdala, prefrontal cortex and hippocampus, along with the different temporal recruitment and involvement of various neurotransmitter systems (including NMDA, GABA, corticosterone and opioids) are responsible for these developmental changes. Taken together, the studies described in this review highlight that there is a period early in development where rats appear to be more robust in overcoming adverse early life experience. We need to understand the fundamental pharmacological processes underlying anxiety early in life in order to take advantage of this period for the treatment of anxiety disorders. Linked Articles This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-20 PMID:24527726

The teratology testing of food additives.

PubMed

Barrow, Paul C; Spézia, François

2013-01-01

The developmental and reproductive toxicity testing (including teratogenicity) of new foods and food additives is performed worldwide according to the guidelines given in the FDA Redbook. These studies are not required for substances that are generally recognized as safe, according to the FDA inventory. The anticipated cumulated human exposure level above which developmental or reproduction studies are required depends on the structure-alert category. For food additives of concern, both developmental (prenatal) and reproduction (multigeneration) studies are required. The developmental studies are performed in two species, usually the rat and the rabbit. The reproduction study is generally performed in the rat. The two rat studies are preferably combined into a single experimental design, if possible. The test methods described in the FDA Redbook are similar to those specified by the OECD for the reproductive toxicity testing of chemicals.

DEVELOPMENTAL EXPOSURE TO A THYROID DISRUPTING CHEMICAL STIMULATES PHAGOCYTOSIS IN JUVENILE SPRAGUE-DAWLEY RATS

EPA Science Inventory

Developmental Exposure to a Thyroid Disrupting Chemical Stimulates Phagocytosis in Juvenile Sprague-Dawley Rats.
AA Rooney1, R Matulka2, and R Luebke3. 1NCSU/US EPA CVM, Department of Anatomy, Physiological Sciences and Radiology, Raleigh, NC;2UNC Department of Toxicology, Cha...

GLUCOCORTICOID RECEPTOR REGULATION IN THE RAT EMBRYO: A POTENTIAL SITE FOR DEVELOPMENTAL TOXICITY?

EPA Science Inventory

Glucocorticoid receptor regulation in the rat embryo: a potential site for developmental toxicity?

Ghosh B, Wood CR, Held GA, Abbott BD, Lau C.

National Research Council, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.

The maternal immune activation (MIA) model of schizophrenia produces pre-pulse inhibition (PPI) deficits in both juvenile and adult rats but these effects are not associated with maternal weight loss.

PubMed

Wolff, Amy R; Bilkey, David K

2010-12-01

The developmental onset of deficits in sensorimotor-gating was examined in the maternal immune activation (MIA) animal model of schizophrenia. Pre-pulse inhibition (PPI) deficits were evident in juvenile MIA rats. This parallels the sensorimotor-gating deficits observed in groups at high-risk of schizophrenia. PPI deficits were independent of maternal weight loss following the MIA manipulation, suggesting that this measure may not be a useful marker of treatment efficacy. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Developmental exposure to an environmental PCB mixture delays the propagation of electrical kindling from the amygdala.

PubMed

Bandara, Suren B; Sadowski, Renee N; Schantz, Susan L; Gilbert, Mary E

2017-01-01

Developmental PCB exposure impairs hearing and induces brainstem audiogenic seizures in adult offspring. The degree to which this enhanced susceptibility to seizure is manifest in other brain regions has not been examined. Thus, electrical kindling of the amygdala was used to evaluate the effect of developmental exposure to an environmentally relevant PCB mixture on seizure susceptibility in the rat. Female Long-Evans rats were dosed orally with 0 or 6mg/kg/day of the PCB mixture dissolved in corn oil vehicle 4 weeks prior to mating and continued through gestation and up until postnatal day (PND) 21. On PND 21, pups were weaned, and two males from each litter were randomly selected for the kindling study. As adults, the male rats were implanted bilaterally with electrodes in the basolateral amygdala. For each animal, afterdischarge (AD) thresholds in the amygdala were determined on the first day of testing followed by once daily stimulation at a standard 200μA stimulus intensity until three stage 5 generalized seizures (GS) ensued. Developmental PCB exposure did not affect the AD threshold or total cumulative AD duration, but PCB exposure did increase the latency to behavioral manifestations of seizure propagation. PCB exposed animals required significantly more stimulations to reach stage 2 seizures compared to control animals, indicating attenuated focal (amygdala) excitability. A delay in kindling progression in the amygdala stands in contrast to our previous finding of increased susceptibility to brainstem-mediated audiogenic seizures in PCB-exposed animals in response to a an intense auditory stimulus. These seemingly divergent results are not unexpected given the distinct source, type, and mechanistic underpinnings of these different seizure models. A delay in epileptogenesis following focal amygdala stimulation may reflect a decrease in neuroplasticity following developmental PCB exposure consistent with reductions in use-dependent synaptic plasticity that have been reported in the hippocampus of developmentally PCB exposed animals. Copyright © 2016 Elsevier B.V. All rights reserved.

Prenatal exposure to a novel antipsychotic quetiapine: impact on neuro-architecture, apoptotic neurodegeneration in fetal hippocampus and cognitive impairment in young rats.

PubMed

Singh, K P; Tripathi, Nidhi

2015-05-01

Reports on prenatal exposure to some of the first generation antipsychotic drugs like, haloperidol, their effects on fetal neurotoxicity and functional impairments in the offspring, are well documented. But studies on in utero exposure to second generation antipsychotics, especially quetiapine, and its effects on fetal neurotoxicity, apoptotic neurodegeneration, postnatal developmental delay and neurobehavioral consequences are lacking. Therefore, the present study was undertaken to evaluate the effect of prenatal administration to equivalent therapeutic doses of quetiapine on neuro-architectural abnormalities, neurohistopathological changes, apoptotic neurodegeneration in fetal hippocampus, and postnatal development and growth as well as its long-lasting imprint on cognitive impairment in young-adult offspring. Pregnant Wistar rats (n=24) were exposed to selected doses (55 mg, 80 mg and 100mg/kg) of quetiapine, equivalent to human therapeutic doses, from gestation day 6 to 21 orally with control subjects. Half of the pregnant subjects of each group were sacrificed at gestation day 21 for histopathological, confocal and electron microscopic studies and rest of the dams were allowed to deliver naturally. Their pups were reared postnatally up to 10 weeks of age for neurobehavioral observations. In quetiapine treated groups, there was significant alterations in total and differential thickness of three typical layers of hippocampus associated with neuronal cells deficit and enhanced apoptotic neurodegeneration in the CA1 area of fetal hippocampus. Prenatally drug treated rat offspring displayed post-natal developmental delay till postnatal day 70, and these young-adult rats displayed cognitive impairment in Morris water maze and passive avoidance regimes as long-lasting impact of the drug. Therefore, quetiapine should be used with cautions considering its developmental neurotoxicological and neurobehavioral potential in animal model, rat. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

Reduced motivation in the BACHD rat model of Huntington disease is dependent on the choice of food deprivation strategy.

PubMed

Jansson, Erik Karl Håkan; Clemens, Laura Emily; Riess, Olaf; Nguyen, Huu Phuc

2014-01-01

Huntington disease (HD) is an inherited neurodegenerative disease characterized by motor, cognitive, psychiatric and metabolic symptoms. Animal models of HD show phenotypes that can be divided into similar categories, with the metabolic phenotype of certain models being characterized by obesity. Although interesting in terms of modeling metabolic symptoms of HD, the obesity phenotype can be problematic as it might confound the results of certain behavioral tests. This concerns the assessment of cognitive function in particular, as tests for such phenotypes are often based on food depriving the animals and having them perform tasks for food rewards. The BACHD rat is a recently established animal model of HD, and in order to ensure that behavioral characterization of these rats is done in a reliable way, a basic understanding of their physiology is needed. Here, we show that BACHD rats are obese and suffer from discrete developmental deficits. When assessing the motivation to lever push for a food reward, BACHD rats were found to be less motivated than wild type rats, although this phenotype was dependent on the food deprivation strategy. Specifically, the phenotype was present when rats of both genotypes were deprived to 85% of their respective free-feeding body weight, but not when deprivation levels were adjusted in order to match the rats' apparent hunger levels. The study emphasizes the importance of considering metabolic abnormalities as a confounding factor when performing behavioral characterization of HD animal models.

Reduced Motivation in the BACHD Rat Model of Huntington Disease Is Dependent on the Choice of Food Deprivation Strategy

PubMed Central

Riess, Olaf; Nguyen, Huu Phuc

2014-01-01

Huntington disease (HD) is an inherited neurodegenerative disease characterized by motor, cognitive, psychiatric and metabolic symptoms. Animal models of HD show phenotypes that can be divided into similar categories, with the metabolic phenotype of certain models being characterized by obesity. Although interesting in terms of modeling metabolic symptoms of HD, the obesity phenotype can be problematic as it might confound the results of certain behavioral tests. This concerns the assessment of cognitive function in particular, as tests for such phenotypes are often based on food depriving the animals and having them perform tasks for food rewards. The BACHD rat is a recently established animal model of HD, and in order to ensure that behavioral characterization of these rats is done in a reliable way, a basic understanding of their physiology is needed. Here, we show that BACHD rats are obese and suffer from discrete developmental deficits. When assessing the motivation to lever push for a food reward, BACHD rats were found to be less motivated than wild type rats, although this phenotype was dependent on the food deprivation strategy. Specifically, the phenotype was present when rats of both genotypes were deprived to 85% of their respective free-feeding body weight, but not when deprivation levels were adjusted in order to match the rats' apparent hunger levels. The study emphasizes the importance of considering metabolic abnormalities as a confounding factor when performing behavioral characterization of HD animal models. PMID:25144554

The anatomy of the rat eye with oxygen-induced retinopathy.

PubMed

Akula, James D; Favazza, Tara L; Mocko, Julie A; Benador, Ilan Y; Asturias, Ana L; Kleinman, Michael S; Hansen, Ronald M; Fulton, Anne B

2010-02-01

Prior studies have documented the intertwined developmental courses of retinal blood vessel tortuosity (in fundus photographs) and retinal dysfunction (in electroretinographs) in Sprague-Dawley rat models of retinopathy of prematurity (ROP). Two such models, the "50/10 model" and the "75 model," are named after the oxygen regimens used to induce retinopathy and are characterized by distinct neurovascular courses that span a range of disease severity. In this study of 50/10 and 75 model rats, retinal flatmounts were used to study the full vasculature at postnatal day (P) 15, P19 and P30. In addition, the layers of the neural retina were measured in toluidine blue-stained cross sections. Finally, gross anatomic features of the eye, including axial length, retinal surface area, and the ratio of anterior to posterior axial-lengths were evaluated. Both clock hours of neovascularization (NV) and percent avascular retina (AR) peaked at P19 and resolved by P30. Through P19, NV was found in every 50/10 model rat, but in only 60% of 75 model rats. AR was positively related to NV. All inner layers of the retina (outer plexiform layer through ganglion cell layer) were attenuated in 50/10 model rats but, in the 75 model, no layer differed significantly from that in controls. The eyes in both ROP models were smaller than those of age-matched controls. The ratio of anterior to posterior axial-lengths ranged from 0.45 in controls through 0.37 in the 75 model to 0.32 in the 50/10 model. Thus, eye growth is altered in these rat models of ROP.

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.

Low glucose utilization and neurodegenerative changes caused by sodium fluoride exposure in rat's developmental brain.

PubMed

Jiang, Chunyang; Zhang, Shun; Liu, Hongliang; Guan, Zhizhong; Zeng, Qiang; Zhang, Cheng; Lei, Rongrong; Xia, Tao; Wang, Zhenglun; Yang, Lu; Chen, Yihu; Wu, Xue; Zhang, Xiaofei; Cui, Yushan; Yu, Linyu; Wang, Aiguo

2014-03-01

Fluorine, a toxic and reactive element, is widely prevalent throughout the environment and can induce toxicity when absorbed into the body. This study was to explore the possible mechanisms of developmental neurotoxicity in rats treated with different levels of sodium fluoride (NaF). The rats' intelligence, as well as changes in neuronal morphology, glucose absorption, and functional gene expression within the brain were determined using the Morris water maze test, transmission electron microscopy, small-animal magnetic resonance imaging and Positron emission tomography and computed tomography, and Western blotting techniques. We found that NaF treatment-impaired learning and memory in these rats. Furthermore, NaF caused neuronal degeneration, decreased brain glucose utilization, decreased the protein expression of glucose transporter 1 and glial fibrillary acidic protein, and increased levels of brain-derived neurotrophic factor in the rat brains. The developmental neurotoxicity of fluoride may be closely associated with low glucose utilization and neurodegenerative changes.

Effects of developmental exposure to a Commercial PBDE mixture (DE-71) on protein networks in the rat Cerebellum and Hippocampus

EPA Science Inventory

Title (20 words): Effects of developmental exposure to a Commercial PBDE mixture (DE-71) on protein networks in the rat Cerebellum and Hippocampus. Introduction (120 words): Polybrominated diphenyl ethers (PBDE5) possess neurotoxic effects similar to those of PCBs. The cellular a...

EFFECTS OF PERFLUOROOCTANE SULFONATE (PFOS) ON MATERNAL AND DEVELOPMENTAL THYROID STATUS IN THE RAT

EPA Science Inventory

EFFECTS OF PERFLUOROOCTANE SULFONATE (PFOS) ON MATERNAL AND DEVELOPMENTAL THYROID STATUS IN THE RAT. JR Thibodeaux1, R Hanson1, B Grey1, JM Rogers1, ME Stanton2, and C Lau1. 1Reproductive Toxicology Division; 2Neurotoxicology Division, NHEERL, ORD, US EPA, Research Triangle P...

DEVELOPMENTAL NEUOTOXICITY EVALUATION OF MIXTURES OF MONO- AND DIMETHYL TIN IN DRINKING WATER OF RATS.

EPA Science Inventory

Developmental Neurotoxicity Evaluation of Mixtures of Mono- and Dimethyl Tin in Drinking Water of Rats

V.C. Moser, K.L. McDaniel, P.M. Phillips

Neurotoxicology Division, NHEERL, ORD, US EPA, RTP, NC, USA

Organotins, especially monomethyl (MMT) and dimethyl (D...

Animal Models for Testing the DOHaD Hypothesis

EPA Science Inventory

Since the seminal work in human populations by David Barker and colleagues, several species of animals have been used in the laboratory to test the Developmental Origins of Health and Disease (DOHaD) hypothesis. Rats, mice, guinea pigs, sheep, pigs and non-human primates have bee...

ASSESSMENT OF SYNAPSE FORMATION IN RAT PRIMARY NEURAL CELL CULTURE USING HIGH CONTENT MICROSCOPY.

EPA Science Inventory

Cell-based assays can model neurodevelopmental processes including neurite growth and synaptogenesis, and may be useful for screening and evaluation of large numbers of chemicals for developmental neurotoxicity. This work describes the use of high content screening (HCS) to dete...

Sex-specific disruptions in spatial memory and anhedonia in a "two hit" rat model correspond with alterations in hippocampal brain-derived neurotrophic factor expression and signaling.

PubMed

Hill, Rachel A; Klug, Maren; Kiss Von Soly, Szerenke; Binder, Michele D; Hannan, Anthony J; van den Buuse, Maarten

2014-10-01

Post-mortem studies have demonstrated reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of schizophrenia and major depression patients. The "two hit" hypothesis proposes that two or more major disruptions at specific time points during development are involved in the pathophysiology of these mental illnesses. However, the role of BDNF in these "two hit" effects is unclear. Our aim was to behaviorally characterize a "two hit" rat model of developmental stress accompanied by an in-depth assessment of BDNF expression and signalling. Wistar rats were exposed to neonatal maternal separation (MS) stress and/or adolescent/young-adult corticosterone (CORT) treatment. In adulthood, models of cognitive and negative symptoms of mental illness were analyzed. The hippocampus was then dissected into dorsal (DHP) and ventral (VHP) regions and analyzed by qPCR for exon-specific BDNF gene expression or by Western blot for BDNF protein expression and downstream signaling. Male "two hit" rats showed marked disruptions in short-term spatial memory (Y-maze) which were absent in females. However, female "two hit" rats showed signs of anhedonia (sucrose preference test), which were absent in males. Novel object recognition and anxiety (elevated plus maze) were unchanged by either of the two "hits". In the DHP, MS caused a male-specific increase in BDNF Exons I, II, IV, VII, and IX mRNA but a decrease in mature BDNF and phosphorylated TrkB (pTrkB) protein expression in adulthood. In the VHP, BDNF transcript expression was unchanged; however, in female rats only, MS significantly decreased mature BDNF and pTrkB protein expression in adulthood. These data demonstrate that MS causes region-specific and sex-specific long-term effects on BDNF expression and signaling and, importantly, mRNA expression does not always infer protein expression. Alterations to BDNF signaling may mediate the sex-specific effects of developmental stress on anhedonic behaviors. © 2014 Wiley Periodicals, Inc.

Prenatal ethanol exposure-induced adrenal developmental abnormality of male offspring rats and its possible intrauterine programming mechanisms.

PubMed

Huang, Hegui; He, Zheng; Zhu, Chunyan; Liu, Lian; Kou, Hao; Shen, Lang; Wang, Hui

2015-10-01

Fetal adrenal developmental status is the major determinant of fetal tissue maturation and offspring growth. We have previously proposed that prenatal ethanol exposure (PEE) suppresses fetal adrenal corticosterone (CORT) synthesis. Here, we focused on PEE-induced adrenal developmental abnormalities of male offspring rats before and after birth, and aimed to explore its intrauterine programming mechanisms. A rat model of intrauterine growth retardation (IUGR) was established by PEE (4g/kg·d). In PEE fetus, increased serum CORT concentration and decreased insulin-like growth factor 1 (IGF1) concentration, with lower bodyweight and structural abnormalities as well as a decreased Ki67 expression (proliferative marker), were observed in the male fetal adrenal cortex. Adrenal glucocorticoid (GC)-metabolic activation system was enhanced while gene expression of IGF1 signaling pathway with steroidogenic acute regulatory protein (StAR), 3β-hydroxysteroid dehydrogenase (3β-HSD) was decreased. Furthermore, in the male adult offspring of PEE, serum CORT level was decreased but IGF1 was increased with partial catch-up growth, and Ki67 expression demonstrated no obvious change. Adrenal GC-metabolic activation system was inhibited, while IGF1 signaling pathway and 3β-HSD was enhanced with the steroidogenic factor 1 (SF1), and StAR was down-regulated in the adult adrenal. Based on these findings, we propose a "two-programming" mechanism for PEE-induced adrenal developmental toxicity: "the first programming" is a lower functional programming of adrenal steroidogenesis, and "the second programming" is GC-metabolic activation system-related GC-IGF1 axis programming. Copyright © 2015 Elsevier Inc. All rights reserved.

Developmental fluoxetine and prenatal stress effects on serotonin, dopamine, and synaptophysin density in the PFC and hippocampus of offspring at weaning.

PubMed

Gemmel, Mary; Rayen, Ine; Lotus, Tiffany; van Donkelaar, Eva; Steinbusch, Harry W; De Lacalle, Sonsoles; Kokras, Nikolaos; Dalla, Christina; Pawluski, Jodi L

2016-04-01

Selective serotonin reuptake inhibitor medication exposure during the perinatal period can have a long term impact in adult offspring on neuroplasticity and the serotonergic system, but the impact of these medications during early development is poorly understood. The aim of this study was to determine the effects of developmental exposure to the SSRI, fluoxetine, on the serotonergic system, dopaminergic system, and synaptophysin density in the prefrontal cortex and hippocampus, as well as number of immature neurons in the dentate gyrus, in juvenile rat offspring at weaning. To model aspects of maternal depression, prenatal restraint stress was used. Sprague-Dawley rat offspring were exposed to either prenatal stress and/or fluoxetine. Main findings show that developmental fluoxetine exposure to prenatally stressed offspring decreased 5-HT and 5-HIAA levels and altered the dopaminergic system in the hippocampus. Prenatal stress, regardless of fluoxetine, increased synaptophysin density in the PFC. This work indicates that early exposure to maternal stress and SSRI medication can alter brain monoamine levels and synaptophysin density in offspring at weaning. © 2015 Wiley Periodicals, Inc.

Maternal Style Selectively Shapes Amygdalar Development and Social Behavior in Rats Genetically Prone to High Anxiety.

PubMed

Cohen, Joshua L; Glover, Matthew E; Pugh, Phyllis C; Fant, Andrew D; Simmons, Rebecca K; Akil, Huda; Kerman, Ilan A; Clinton, Sarah M

2015-01-01

The early-life environment critically influences neurodevelopment and later psychological health. To elucidate neural and environmental elements that shape emotional behavior, we developed a rat model of individual differences in temperament and environmental reactivity. We selectively bred rats for high versus low behavioral response to novelty and found that high-reactive (bred high-responder, bHR) rats displayed greater risk-taking, impulsivity and aggression relative to low-reactive (bred low-responder, bLR) rats, which showed high levels of anxiety/depression-like behavior and certain stress vulnerability. The bHR/bLR traits are heritable, but prior work revealed bHR/bLR maternal style differences, with bLR dams showing more maternal attention than bHRs. The present study implemented a cross-fostering paradigm to examine the contribution of maternal behavior to the brain development and emotional behavior of bLR offspring. bLR offspring were reared by biological bLR mothers or fostered to a bLR or bHR mother and then evaluated to determine the effects on the following: (1) developmental gene expression in the hippocampus and amygdala and (2) adult anxiety/depression-like behavior. Genome-wide expression profiling showed that cross-fostering bLR rats to bHR mothers shifted developmental gene expression in the amygdala (but not hippocampus), reduced adult anxiety and enhanced social interaction. Our findings illustrate how an early-life manipulation such as cross-fostering changes the brain's developmental trajectory and ultimately impacts adult behavior. Moreover, while earlier studies highlighted hippocampal differences contributing to the bHR/bLR phenotypes, our results point to a role of the amygdala as well. Future work will pursue genetic and cellular mechanisms within the amygdala that contribute to bHR/bLR behavior either at baseline or following environmental manipulations. © 2015 S. Karger AG, Basel.

Effect of Gestational Intake of Fisetin (3,3',4',7-Tetrahydroxyflavone) on Developmental Methyl Mercury Neurotoxicity in F1 Generation Rats.

PubMed

Jacob, Sherin; Thangarajan, Sumathi

2017-06-01

Methyl mercury (MeHg) is a developmental neurotoxin that causes irreversible cognitive damage in offspring of gestationally exposed mothers. Currently, no preventive drugs are established against MeHg developmental neurotoxicity. The neuroprotective effect of gestational administration of a flavanoid against in utero toxicity of MeHg is not explored much. Hence, the present study validated the effect of a bioactive flavanoid, fisetin, on MeHg developmental neurotoxicity outcomes in rat offspring at postnatal weaning age. Pregnant Wistar rats were simultaneously given MeHg (1.5 mg/kg b.w.) and two doses of fisetin (10 and 50 mg/kg b.w. in two separate groups) orally from gestational day (GD) 5 till parturition. Accordingly, after parturition, on postnatal day (PND) 24, weaning F 1 generation rats were studied for motor and cognitive behavioural changes. Biochemical and histopathological changes were also studied in the cerebral cortex, cerebellum and hippocampus on PND 25. Administration of fisetin during pregnancy prevented behavioural impairment due to transplacental MeHg exposure in weaning rats. Fisetin decreased the levels of oxidative stress markers, increased enzymatic and non-enzymatic antioxidant levels and increased the activity of membrane-bound ATPases and cholinergic function in F 1 generation rats. In light microscopic studies, fisetin treatment protected the specific offspring brain regions from significant morphological aberrations. Between the two doses of fisetin studied, 10 mg/kg b.w. was found to be more satisfactory and effective than 50 mg/kg b.w. The present study shows that intake of fisetin during pregnancy in rats ameliorated in utero MeHg exposure-induced neurotoxicity outcomes in postnatal weaning F 1 generation rats.

75 FR 14082 - Ammonium Salts of Fatty Acids (C8

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-24

... study did not see any significant systemic toxicity from nonanoic acid (C 9 saturated) given to rats at... approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding... systemic toxicity or developmental toxicity in rats at doses up to 1,500 mg/kg/day in a developmental...

CHANGES IN NUCLEAR TRANSCRIPTION FACTORS IN RAT HIPPOCAMPUS AND CEREBELLUM FOLLOWING DEVELOPMENTAL EXPOSURE TO A COMMERCIAL PCB MIXTURE.

EPA Science Inventory

Polychlorinated biphenyls (PCBs) offer a unique model to understand the major issues related to complex environmental mixtures. These pollutants are ubiquitous and exist as mixtures of several congeners in the environment. Human exposures to PCBs are associated with a variety of ...

EYEBLINK CONDITIONING IN THE INFANT RAT: AN ANIMAL MODEL OF LEARNING IN DEVELOPMENTAL NEUROTOXICOLOGY

EPA Science Inventory

Classical conditioning of the eyeblink reflex is a relatively simple procedure for studying associative learning that was first developed for use with human subjects more than half a century ago. The use of this procedure in laboratory animals by psychologists and neuro-scientist...

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...

Comparative sensitivity of human and rat neural cultures to chemical-induced inhibition of neurite outgrowth

EPA Science Inventory

There is a need for rapid, efficient and cost effective alternatives to traditional in vivo developmental neurotoxicity testing. In vitro cell culture models can recapitulate many of the key cellular processes of nervous system development, including neurite outgrowth, and may be...

ASSESSMENT OF CHEMICAL EFFECTS ON NEURITE OUTGROWTH, NEURONAL POLARIZATION AND SYNAPTOGENESIS IN RAT CORTICAL NEURONS USING HIGH CONTENT IMAGE ANALYSIS

EPA Science Inventory

There is a need for efficient, cost-effective methods for screening and prioritization of potential developmental neurotoxicants. One approach uses in vitro cell culture models that can recapitulate the critical processes of nervous system development. In vitro, primary cultures ...

Identification of Metabolism and Excretion Differences of Procymidone between Rats and Humans Using Chimeric Mice: Implications for Differential Developmental Toxicity.

PubMed

Abe, Jun; Tomigahara, Yoshitaka; Tarui, Hirokazu; Omori, Rie; Kawamura, Satoshi

2018-02-28

A metabolite of procymidone, hydroxylated-PCM, causes rat-specific developmental toxicity due to higher exposure to it in rats than in rabbits or monkeys. When procymidone was administered to chimeric mice with rat or human hepatocytes, the plasma level of hydroxylated-PCM was higher than that of procymidone in rat chimeric mice, and the metabolic profile of procymidone in intact rats was well reproduced in rat chimeric mice. In human chimeric mice, the plasma level of hydroxylated-PCM was less, resulting in a much lower exposure. The main excretion route of hydroxylated-PCM-glucuronide was bile (the point that hydroxylated-PCM enters the enterohepatic circulation) in rat chimeric mice, and urine in human chimeric mice. These data suggest that humans, in contrast to rats, extensively form the glucuronide and excrete it in urine, as do rabbits and monkeys. Overall, procymidone's potential for causing teratogenicity in humans must be low compared to that in rats.

The effects of a probiotic formulation (Lactobacillus rhamnosus and L. helveticus) on developmental trajectories of emotional learning in stressed infant rats.

PubMed

Cowan, C S M; Callaghan, B L; Richardson, R

2016-05-31

Recently, scientific interest in the brain-gut axis has grown dramatically, particularly with respect to the link between gastrointestinal and psychiatric dysfunction. However, the role of gut function in early emotional dysregulation is yet to be examined, despite the prevalence and treatment resistance of early-onset psychiatric disorders. The present studies utilized a developmental rodent model of early-life stress (ELS) to explore this gap. Rats were exposed to maternal separation (MS) on postnatal days 2-14. Throughout MS, dams received either vehicle or a probiotic formulation (previously shown to reduce gastrointestinal dysfunction) in their drinking water. Replicating past research, untreated MS infants exhibited an adult-like profile of long-lasting fear memories and fear relapse following extinction. In contrast, probiotic-exposed MS infants exhibited age-appropriate infantile amnesia and resistance to relapse. These effects were not mediated by changes in pups' or dams' anxiety at the time of training, nor by maternal responsiveness. Overall, probiotics acted as an effective and non-invasive treatment to restore normal developmental trajectories of emotion-related behaviors in infant rats exposed to ELS. These results provide promising initial evidence for this novel approach to reduce the risk of mental health problems in vulnerable individuals. Future studies are needed to test this treatment in humans exposed to ELS and to elucidate mechanisms for the observed behavioral changes.

The effects of a probiotic formulation (Lactobacillus rhamnosus and L. helveticus) on developmental trajectories of emotional learning in stressed infant rats

PubMed Central

Cowan, C S M; Callaghan, B L; Richardson, R

2016-01-01

Recently, scientific interest in the brain–gut axis has grown dramatically, particularly with respect to the link between gastrointestinal and psychiatric dysfunction. However, the role of gut function in early emotional dysregulation is yet to be examined, despite the prevalence and treatment resistance of early-onset psychiatric disorders. The present studies utilized a developmental rodent model of early-life stress (ELS) to explore this gap. Rats were exposed to maternal separation (MS) on postnatal days 2–14. Throughout MS, dams received either vehicle or a probiotic formulation (previously shown to reduce gastrointestinal dysfunction) in their drinking water. Replicating past research, untreated MS infants exhibited an adult-like profile of long-lasting fear memories and fear relapse following extinction. In contrast, probiotic-exposed MS infants exhibited age-appropriate infantile amnesia and resistance to relapse. These effects were not mediated by changes in pups’ or dams’ anxiety at the time of training, nor by maternal responsiveness. Overall, probiotics acted as an effective and non-invasive treatment to restore normal developmental trajectories of emotion-related behaviors in infant rats exposed to ELS. These results provide promising initial evidence for this novel approach to reduce the risk of mental health problems in vulnerable individuals. Future studies are needed to test this treatment in humans exposed to ELS and to elucidate mechanisms for the observed behavioral changes. PMID:27244232

Early neural disruption and auditory processing outcomes in rodent models: implications for developmental language disability

PubMed Central

Fitch, R. Holly; Alexander, Michelle L.; Threlkeld, Steven W.

2013-01-01

Most researchers in the field of neural plasticity are familiar with the “Kennard Principle,” which purports a positive relationship between age at brain injury and severity of subsequent deficits (plateauing in adulthood). As an example, a child with left hemispherectomy can recover seemingly normal language, while an adult with focal injury to sub-regions of left temporal and/or frontal cortex can suffer dramatic and permanent language loss. Here we present data regarding the impact of early brain injury in rat models as a function of type and timing, measuring long-term behavioral outcomes via auditory discrimination tasks varying in temporal demand. These tasks were created to model (in rodents) aspects of human sensory processing that may correlate—both developmentally and functionally—with typical and atypical language. We found that bilateral focal lesions to the cortical plate in rats during active neuronal migration led to worse auditory outcomes than comparable lesions induced after cortical migration was complete. Conversely, unilateral hypoxic-ischemic (HI) injuries (similar to those seen in premature infants and term infants with birth complications) led to permanent auditory processing deficits when induced at a neurodevelopmental point comparable to human “term,” but only transient deficits (undetectable in adulthood) when induced in a “preterm” window. Convergent evidence suggests that regardless of when or how disruption of early neural development occurs, the consequences may be particularly deleterious to rapid auditory processing (RAP) outcomes when they trigger developmental alterations that extend into subcortical structures (i.e., lower sensory processing stations). Collective findings hold implications for the study of behavioral outcomes following early brain injury as well as genetic/environmental disruption, and are relevant to our understanding of the neurologic risk factors underlying developmental language disability in human populations. PMID:24155699

Postnatal choline levels mediate cognitive deficits in a rat model of schizophrenia.

PubMed

Corriveau, Jennifer A; Glenn, Melissa J

2012-11-01

In the present study, we investigated whether the essential nutrient choline may protect against schizophrenic-like cognitive deficits in a rat model. Theories regarding the etiology of schizophrenia suggest that early life events render an individual more vulnerable to adult challenges, and the combination may precipitate disease onset. To model this, the adult male offspring of dams who either experienced stress during late gestation or did not were given a 5 mg/kg dose of the NMDA antagonist,MK-801. The presence of both the prenatal challenge of stress and the adult challenge of MK-801 was expected to impair memory in these offspring. Memory was not expected to be impaired in rats that did not experience prenatal stress, but did receive MK-801 as adults. To study whether choline levels altered outcomes in these groups, rats were fed a choline-supplemented, -deficient, or standard diet during the period between the two challenges: beginning at weaning and continuing for 25 days. All rats consumed regular rat chow thereafter. The efficacy of the model was confirmed in the standard fed rats in that only those that were prenatally stressed and received MK-801 as adults displayed impaired memory on a novelty preference test of object recognition. Contrary to this finding and consistent with our hypothesis, choline-supplemented rats that were also both prenatally stressed and given MK-801 as adults showed intact memory. Choline deficiency impaired memory in rats that were just prenatally stressed, just given MK-801 as adults, and subjected to both. Thus, a choline deficient diet may render rats vulnerable to either challenge. Taken together, we offer evidence that developmental choline levels modulate the effects of prenatal stress and/or MK-801 and thereby alter the cognitive outcome in a rat model of schizophrenia.

Postnatal choline levels mediate cognitive deficits in a rat model of schizophrenia

PubMed Central

Corriveau, Jennifer A.; Glenn, Melissa J.

2012-01-01

In the present study, we investigated whether the essential nutrient choline may protect against schizophrenic-like cognitive deficits in a rat model. Theories regarding the etiology of schizophrenia suggest that early life events render an individual more vulnerable to adult challenges, and the combination may precipitate disease onset. To model this, the adult male offspring of dams who either experienced stress during late gestation or did not were given a 5 mg/kg dose of the NMDA antagonist, MK-801. The presence of both the prenatal challenge of stress and the adult challenge of MK-801 was expected to impair memory in these offspring. Memory was not expected to be impaired in rats that did not experience prenatal stress, but did receive MK-801 as adults. To study whether choline levels altered outcomes in these groups, rats were fed a choline-supplemented, -deficient, or standard diet during the period between the two challenges: beginning at weaning and continuing for 25 days. All rats consumed regular rat chow thereafter. The efficacy of the model was confirmed in the standard fed rats in that only those that were prenatally stressed and received MK-801 as adults displayed impaired memory on a novelty preference test of object recognition. Contrary to this finding and consistent with our hypothesis, choline-supplemented rats that were also both prenatally stressed and given MK-801 as adults showed intact memory. Choline deficiency impaired memory in rats that were just prenatally stressed, just given MK-801 as adults, and subjected to both. Thus, a choline deficient diet may render rats vulnerable to either challenge. Taken together, we offer evidence that developmental choline levels modulate the effects of prenatal stress and/or MK-801 and thereby alter the cognitive outcome in a rat model of schizophrenia. PMID:22917834

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

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

Motivational responses to natural and drug rewards in rats with neonatal ventral hippocampal lesions: an animal model of dual diagnosis schizophrenia.

PubMed

Chambers, R Andrew; Self, David W

2002-12-01

The high prevalence of substance use disorders in schizophrenia relative to the general population and other psychiatric diagnoses could result from developmental neuropathology in hippocampal and cortical structures that underlie schizophrenia. In this study, we tested the effects of neonatal ventral hippocampal lesions on instrumental behavior reinforced by sucrose pellets and intravenous cocaine injections. Lesioned rats acquired sucrose self-administration faster than sham-lesioned rats, but rates of extinction were not altered. Lesioned rats also responded at higher rates during acquisition of cocaine self-administration, and tended to acquire self-administration faster. Higher response rates reflected perseveration of responding during the post-injection "time-out" periods, and a greater incidence of binge-like cocaine intake, which persisted even after cocaine self-administration stabilized. In contrast to sucrose, extinction from cocaine self-administration was prolonged in lesioned rats, and reinstatement of cocaine seeking induced by cocaine priming increased compared with shams. These results suggest that neonatal ventral hippocampal lesions facilitate instrumental learning for both natural and drug rewards, and reduce inhibitory control over cocaine taking while promoting cocaine seeking and relapse after withdrawal. The findings are discussed in terms of possible developmental or direct effects of the lesions, and both positive reinforcement (substance use vulnerability as a primary disease symptom) and negative reinforcement (self-medication) theories of substance use comorbidity in schizophrenia.

MATERNAL AND DEVELOPMENTAL TOXICITY OF PERFLUOROOCATANE SULFONATE (PFOS) IN THE RAT

EPA Science Inventory

MATERNAL AND DEVELOPMENTAL TOXICITY OF PERFLUOROOCTANE SULFONATE (PFOS) IN THE RAT. C. Lau1, J.M. Rogers1, J.R. Thibodeaux1, R.G. Hanson1, B.E. Grey1, B.D. Barbee1, J.H. Richards2, J.L. Butenoff3. 1Reprod. Tox. Div., 2Exp. Tox. Div., NHEERL, USEPA, Research Triangle Park, NC, 3...

DEVELOPMENTAL TOXICITY OF 2-CHLORO-2'-DEOXYADENOSINE IN THE RAT: INDUCTION OF LUMBAR HERNIA

EPA Science Inventory

DEVELOPMENTAL TOXICITY OF 2-CHLORO-2'DEOXYADENOSINE IN THE RAT: INDUCTION OF LUMBAR HERNIA. C. Lau1, M.G. Narotsky1, D. Lui1, D. Best1, R.W. Setzer2, T.B. Knudsen3. 1Reprod. Tox. Div., 2Exp. Tox. Div., NHEERL, US EPA, Research Triangle Park, NC, USA, 3Dept. Path. Anat. Cell Bio...

Self-organized huddles of rat pups modeled by simple rules of individual behavior.

PubMed

Schank, J C; Alberts, J R

1997-11-07

Starting at infancy and continuing throughout adult life, huddling is a major component of the behavioral repertoire of Norway rats (Rattus norvegicus). Huddling behavior maintains the cohesion of litters throughout early life, and in adulthood, it remains a consistent feature of social behavior of R. norvegicus. During infancy, rats have severely limited sensorimotor capabilities, and yet they are capable of aggregating and display a form of group regulatory behavior that conserves metabolic effort and augments body temperature regulation. The functions of huddling are generally understood as group adaptations, which are beyond the capabilities of the individual infant rat. We show, however, that huddling as aggregative or cohesive behavior can emerge as a self-organizing process from autonomous individuals following simple sensorimotor rules. In our model, two sets of sensorimotor parameters characterize the topotaxic responses and the dynamics of contact in 7-day-old rats. The first set of parameters are conditional probabilities of activity and inactivity given prior activity or inactivity and the second set are preferences for objects in the infant rat's environment. We found that the behavior of the model and of actual rat pups compare very favorably, demonstrating that the aggregative feature of huddling can emerge from the local sensorimotor interactions of individuals, and that complex group regulatory behaviors in infant rats may also emerge from self-organizing processes. We discuss the model and the underlying approach as a paradigm for investigating the dynamics of social interactions, group behavior, and developmental change.

The effects of perinatal choline supplementation on hippocampal cholinergic development in rats exposed to alcohol during the brain growth spurt.

PubMed

Monk, Bradley R; Leslie, Frances M; Thomas, Jennifer D

2012-08-01

Prenatal alcohol exposure leads to long-lasting cognitive and attention deficits, as well as hyperactivity. Using a rat model, we have previously shown that perinatal supplementation with the essential nutrient, choline, can reduce the severity of some fetal alcohol effects, including hyperactivity and deficits in learning and memory. In fact, choline can mitigate alcohol-related learning deficits even when administered after developmental alcohol exposure, during the postnatal period. However, it is not yet known how choline is able to mitigate alcohol-related behavioral alterations. Choline may act by altering cholinergic signaling in the hippocampus. This study examined the effects of developmental alcohol exposure and perinatal choline supplementation on hippocampal M(1) and M(2/4) muscarinic receptors. Sprague-Dawley rat pups were orally intubated with ethanol (5.25 mg/kg/day) from postnatal days (PD) 4-9, a period of brain development equivalent to the human third trimester; control subjects received sham intubations. From PD 4-30, subjects were injected s.c. with choline chloride (100 mg/kg/day) or saline vehicle. Open field activity was assessed from PD 30 through 33, and brain tissue was collected on PD 35 for autoradiographic analysis. Ethanol-exposed subjects were more active compared to controls during the first 2 days of testing, an effect attenuated with choline supplementation. Developmental alcohol exposure significantly decreased the density of muscarinic M(1) receptors in the dorsal hippocampus, an effect that was not altered by choline supplementation. In contrast, developmental alcohol exposure significantly increased M(2/4) receptor density, an effect mitigated by choline supplementation. In fact, M(2/4) receptor density of subjects exposed to alcohol and treated with choline did not differ significantly from that of controls. These data suggest that developmental alcohol exposure can cause long-lasting changes in the hippocampal cholinergic system and that perinatal choline supplementation may attenuate alcohol-related behavioral changes by influencing cholinergic systems. Copyright © 2012 Wiley Periodicals, Inc.

The Effects of Perinatal Choline Supplementation on Hippocampal Cholinergic Development in Rats Exposed to Alcohol During the Brain Growth Spurt

PubMed Central

Monk, Bradley R.; Leslie, Frances M.; Thomas, Jennifer D.

2012-01-01

Prenatal alcohol exposure leads to long-lasting cognitive and attention deficits, as well as hyperactivity. Using a rat model, we have previously shown that perinatal supplementation with the essential nutrient, choline, can reduce the severity of some fetal alcohol effects, including hyperactivity and deficits in learning and memory. In fact, choline can mitigate alcohol-related learning deficits even when administered after developmental alcohol exposure, during the postnatal period. However, it is not yet known how choline is able to mitigate alcohol-related behavioral alterations. Choline may act by altering cholinergic signaling in the hippocampus. This study examined the effects of developmental alcohol exposure and perinatal choline supplementation on hippocampal M1 and M2/4 muscarinic receptors. Sprague-Dawley rat pups were orally intubated with ethanol (5.25 mg/kg/day) from postnatal days (PD) 4-9, a period of brain development equivalent to the human 3rd trimester; control subjects received sham intubations. From PD 4-30, subjects were injected s.c. with choline chloride (100 mg/kg/day) or saline vehicle. Open field activity was assessed from PD 30-33 and brain tissue was collected on PD 35 for autoradiographic analysis. Ethanol-exposed subjects were more active compared to controls during the first two days of testing, an effect attenuated with choline supplementation. Developmental alcohol exposure significantly decreased the density of muscarinic M1 receptors in the dorsal hippocampus, an effect that was not altered by choline supplementation. In contrast, developmental alcohol exposure significantly increased M2/4 receptor density, an effect mitigated by choline supplementation. In fact, M2/4 receptor density of subjects exposed to alcohol and treated with choline did not differ significantly from that of controls. These data suggest that developmental alcohol exposure can cause long-lasting changes in the hippocampal cholinergic system and that perinatal choline supplementation may attenuate alcohol-related behavioral changes by influencing cholinergic systems. PMID:22431326

Relative sensitivity of developmental and immune parameters in juvenile versus adult male rats after exposure to di(2-ethylhexyl) phthalate

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

Tonk, Elisa C.M., E-mail: ilse.tonk@rivm.nl; Laboratory for Health Protection Research, National Institute for Public Health and the Environment; Verhoef, Aart

The developing immune system displays a relatively high sensitivity as compared to both general toxicity parameters and to the adult immune system. In this study we have performed such comparisons using di(2-ethylhexyl) phthalate (DEHP) as a model compound. DEHP is the most abundant phthalate in the environment and perinatal exposure to DEHP has been shown to disrupt male sexual differentiation. In addition, phthalate exposure has been associated with immune dysfunction as evidenced by effects on the expression of allergy. Male wistar rats were dosed with corn oil or DEHP by gavage from postnatal day (PND) 10–50 or PND 50–90 atmore » doses between 1 and 1000 mg/kg/day. Androgen-dependent organ weights showed effects at lower dose levels in juvenile versus adult animals. Immune parameters affected included TDAR parameters in both age groups, NK activity in juvenile animals and TNF-α production by adherent splenocytes in adult animals. Immune parameters were affected at lower dose levels compared to developmental parameters. Overall, more immune parameters were affected in juvenile animals compared to adult animals and effects were observed at lower dose levels. The results of this study show a relatively higher sensitivity of juvenile versus adult rats. Furthermore, they illustrate the relative sensitivity of the developing immune system in juvenile animals as compared to general toxicity and developmental parameters. This study therefore provides further argumentation for performing dedicated developmental immune toxicity testing as a default in regulatory toxicology. -- Highlights: ► In this study we evaluate the relative sensitivities for DEHP induced effects. ► Results of this study demonstrate the age-dependency of DEHP toxicity. ► Functional immune parameters were more sensitive than structural immune parameters. ► Immune parameters were affected at lower dose levels than developmental parameters. ► Findings demonstrate the susceptibility of the developing immune system for DEHP.« less

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...

USE OF HIGH CONTENT IMAGE ANALYSES TO DETECT CHEMICAL-MEDIATED EFFECTS ON NEURITE SUB-POPULATIONS IN PRIMARY RAT CORTICAL NEURONS

EPA Science Inventory

Traditional developmental neurotoxicity tests performed in vivo are costly, time-consuming and utilize a large number of animals. In order to address these inefficiencies, in vitro models of neuronal development have been used in a first tier screening approach for developmenta...

Effect of Culture Conditions on Viability of Mouse and Rat Embryos Developed in Vitro

PubMed Central

Popova, Elena; Bader, Michael; Krivokharchenko, Alexander

2011-01-01

Currently in vitro culture of mouse preimplantation embryos has become a very important technique to investigate different mechanisms of early embryogenesis. However, there is a big difference in the preimplantation development between mammalian species. Despite close relatedness to mice, in vitro cultivation of rat preimplantation embryos is still delicate and needs further investigation and optimizations. In this study we have compared the in vitro developmental potential of mouse and rat embryos cultured at different culture conditions in parallel experiments. Interestingly, mouse zygotes developed in vitro until blastocyst stage even in inadequate medium without any phosphates and with low osmolarity which was formulated especially for cultivation of rat embryos. Rat parthenotes and zygotes developed in M16 medium formulated for mouse embryos only till 2-cell stage and further development is blocked completely at this stage. Moreover, developmental ability of rat embryos in vitro was significantly lower in comparison with mouse even in special rat mR1ECM medium. Mouse and rat embryos at 2-cell stage obtained in vivo developed until blastocyst stages significantly more efficiently compared to zygotes. Culture of mouse zygotes in glass capillaries resulted in a significantly higher rate of morula and blastocyst development compared with dishes. The Well-of-the-Well system resulted in a significant improvement when compared with dishes for the culture of rat zygotes only until morula stage. Reduced oxygen tension increased the developmental rate of rat but not mouse zygotes until blastocyst stage. This study demonstrates that development of early preimplantation embryos is altered by different culture conditions and show strong differences even between two related species such as mice and rats. Therefore, for understanding the fundamental mechanisms of early mammalian development it is very important to use embryos of various species. PMID:24710194

The neonatal ventral hippocampal lesion model of schizophrenia: effects on dopamine and GABA mRNA markers in the rat midbrain.

PubMed

Lipska, Barbara K; Lerman, Daniel N; Khaing, Zin Z; Weinberger, Daniel R

2003-12-01

The neonatal ventral hippocampal lesion in the rat has been used as a model of schizophrenia, a human disorder associated with changes in markers of dopamine and gamma-aminobutyric acid (GABA) circuits in various regions of the brain. We investigated whether alterations in mRNA markers related to the activity of midbrain dopaminergic and GABAergic neurons are associated with this model. We used in situ hybridization histochemistry to assess expression of mRNAs for dopamine transporter (DAT), tyrosine hydroxylase (TH) and glutamate decarboxylase-67 (GAD67) in the midbrain of adult rats with neonatal and adult ibotenic acid lesions of the ventral hippocampus. Neonatally lesioned rats showed in adulthood significantly reduced expression of DAT mRNA in the substantia nigra and the ventral tegmental area but no changes in the expression of TH and GAD67 mRNAs in these midbrain regions. Adult lesioned rats showed no changes in the expression of any of these genes. As the neonatal ventral hippocampal lesion reproduces many aspects of schizophrenia and is used as an animal model of this disorder, these results suggest that the reduction in DAT mRNA could result from developmental neuropathology in the ventral hippocampus and may thus represent a molecular substrate of the disease process.

Developmental vitamin D deficiency alters MK-801-induced behaviours in adult offspring.

PubMed

Kesby, James P; O'Loan, Jonathan C; Alexander, Suzanne; Deng, Chao; Huang, Xu-Feng; McGrath, John J; Eyles, Darryl W; Burne, Thomas H J

2012-04-01

Developmental vitamin D (DVD) deficiency is a candidate risk factor for developing schizophrenia in humans. In rodents DVD deficiency induces subtle changes in the way the brain develops. This early developmental insult leads to select behavioural changes in the adult, such as an enhanced response to amphetamine-induced locomotion in female DVD-deficient rats but not in male DVD-deficient rats and an enhanced locomotor response to the N-methyl-D: -aspartate (NMDA) receptor antagonist, MK-801, in male DVD-deficient rats. However, the response to MK-801-induced locomotion in female DVD-deficient rats is unknown. Therefore, the aim of the current study was to further examine this behavioural finding in male and female rats and assess NMDA receptor density. DVD-deficient Sprague Dawley rats were assessed for locomotion, ataxia, acoustic startle response (ASR) and prepulse inhibition (PPI) of the ASR to multiple doses of MK-801. The NMDA receptor density in relevant brain regions was assessed in a drug-naive cohort. DVD deficiency increased locomotion in response to MK-801 in both sexes. DVD-deficient rats also showed an enhanced ASR compared with control rats, but PPI was normal. Moreover, DVD deficiency decreased NMDA receptor density in the caudate putamen of both sexes. These results suggest that a transient prenatal vitamin D deficiency has a long-lasting effect on NMDA-mediated signalling in the rodent brain and may be a plausible candidate risk factor for schizophrenia and other neuropsychiatric disorders.

Deconstructing the function of maternal stimulation in offspring development: Insights from the artificial rearing model in rats.

PubMed

Lomanowska, Anna M; Melo, Angel I

2016-01-01

This article is part of a Special Issue on "Parental Care". Maternal behavior has an important function in stimulating adequate growth and development of the young. Several approaches have been used in primates and rodents to deconstruct and examine the influence of specific components of maternal stimulation on offspring development. These approaches include observational studies of typical mother-infant interactions and studies of the effects of intermittent or complete deprivation of maternal contact. In this review, we focus on one unique approach using rats that enables the complete control of maternal variables by means of rearing rat pups artificially without contact with the mother or litter, while maintaining stable nutrition, temperature and exposure to stressful stimuli. This artificial rearing model permits the removal and controlled replacement of relevant maternal and litter stimuli and has contributed valuable insights regarding the influence of these stimuli on various developmental outcomes. It also enables the analysis of factors implicated in social isolation itself and their long-term influence. We provide an overview of the effects of artificial rearing on behavior, physiology, and neurobiology, including the influence of replacing maternal tactile stimulation and littermate contact on these outcomes. We then discuss the relevance of these effects in terms of the maternal role in regulating different aspects of offspring development and implications for human research. We emphasize that artificial rearing of rats does not lead to a global insult of nervous system development, making this paradigm useful in investigating specific developmental effects associated with maternal stimulation. Copyright © 2015 Elsevier Inc. All rights reserved.

Deep brain stimulation of the ventral hippocampus restores deficits in processing of auditory evoked potentials in a rodent developmental disruption model of schizophrenia.

PubMed

Ewing, Samuel G; Grace, Anthony A

2013-02-01

Existing antipsychotic drugs are most effective at treating the positive symptoms of schizophrenia but their relative efficacy is low and they are associated with considerable side effects. In this study deep brain stimulation of the ventral hippocampus was performed in a rodent model of schizophrenia (MAM-E17) in an attempt to alleviate one set of neurophysiological alterations observed in this disorder. Bipolar stimulating electrodes were fabricated and implanted, bilaterally, into the ventral hippocampus of rats. High frequency stimulation was delivered bilaterally via a custom-made stimulation device and both spectral analysis (power and coherence) of resting state local field potentials and amplitude of auditory evoked potential components during a standard inhibitory gating paradigm were examined. MAM rats exhibited alterations in specific components of the auditory evoked potential in the infralimbic cortex, the core of the nucleus accumbens, mediodorsal thalamic nucleus, and ventral hippocampus in the left hemisphere only. DBS was effective in reversing these evoked deficits in the infralimbic cortex and the mediodorsal thalamic nucleus of MAM-treated rats to levels similar to those observed in control animals. In contrast stimulation did not alter evoked potentials in control rats. No deficits or stimulation-induced alterations were observed in the prelimbic and orbitofrontal cortices, the shell of the nucleus accumbens or ventral tegmental area. These data indicate a normalization of deficits in generating auditory evoked potentials induced by a developmental disruption by acute high frequency, electrical stimulation of the ventral hippocampus. Copyright © 2012 Elsevier B.V. All rights reserved.

Deep brain stimulation of the ventral hippocampus restores deficits in processing of auditory evoked potentials in a rodent developmental disruption model of schizophrenia

PubMed Central

Ewing, Samuel G.; Grace, Anthony A.

2012-01-01

Existing antipsychotic drugs are most effective at treating the positive symptoms of schizophrenia, but their relative efficacy is low and they are associated with considerable side effects. In this study deep brain stimulation of the ventral hippocampus was performed in a rodent model of schizophrenia (MAM-E17) in an attempt to alleviate one set of neurophysiological alterations observed in this disorder. Bipolar stimulating electrodes were fabricated and implanted, bilaterally, into the ventral hippocampus of rats. High frequency stimulation was delivered bilaterally via a custom-made stimulation device and both spectral analysis (power and coherence) of resting state local field potentials and amplitude of auditory evoked potential components during a standard inhibitory gating paradigm were examined. MAM rats exhibited alterations in specific components of the auditory evoked potential in the infralimbic cortex, the core of the nucleus accumbens, mediodorsal thalamic nucleus, and ventral hippocampus in the left hemisphere only. DBS was effective in reversing these evoked deficits in the infralimbic cortex and the mediodorsal thalamic nucleus of MAM-treated rats to levels similar to those observed in control animals. In contrast stimulation did not alter evoked potentials in control rats. No deficits or stimulation-induced alterations were observed in the prelimbic and orbitofrontal cortices, the shell of the nucleus accumbens or ventral tegmental area. These data indicate a normalization of deficits in generating auditory evoked potentials induced by a developmental disruption by acute high frequency, electrical stimulation of the ventral hippocampus. PMID:23269227

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.

DEVELOPMENTAL DISRUPTION OF THYROID HORMONE: CORRELATIONS WITH HEARING DYSFUNCTION IN RATS.

EPA Science Inventory

A manuscript presents evidence that thyroxine (T4) is a good biomarker-of-effect for developmental neurotoxicity associated with exposure to environmental thyrotoxicants. A major uncertainty in assessing the risks of developmental exposure to thyrotoxicants is the lack of a clear...

STRUCTURE-ACTIVITY RELATIONSHIP AMONG ORGANOTINS IN AN IN VITRO MODEL OF NEURONAL DIFFERENTIATION AND PROGRAMMED CELL DEATH.

EPA Science Inventory

The organotins are used as heat stabilizers in PVC pipes and as marine biocides. Human exposure to monomethyltin (MMT) and dimethyltin (DMT) can occur in the water supply as a result of leaching from PVC pipes. Developmental exposure of rats to MMT and the known neurotoxicant t...

Developmental co-expression of small molecular weight apolipoprotein B synthesis and triacylglycerol secretion

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

Coleman, R.A.; Haynes, E.B.; Sand, T.M.

1987-05-01

The development of the liver's ability to coordinately express the synthesis and secretion of the two major components of very low density lipoproteins (VLDL): triacylglycerol (TG) and apolipoprotein B (apo B) was examined in cultured hepatocytes obtained from fetal, suckling and adult rats. Hepatocytes from fetal and suckling rats synthesized and secreted TG at rates lower than that displayed by adult cells. When TG synthesis was equalized by adding oleic acid to the culture medium, fetal cells still secreted only 39% as much TG as did adult cells. To determine the basis for the apparent defect in VLDL assembly/secretion displayedmore » by fetal cells, the synthesis and secretion of (TVS)methionine-labeled apo B was quantified by immunoprecipitation. Although adult and fetal cells synthesized and secreted large molecular weight apo B at similar rates, the synthesis and secretion of small molecular weight apo B was 2-fold greater in adult cells. These data suggest that the ability to assemble/secrete VLDL triacylglycerol varies in parallel with the developmental expression of small molecular weight apo B. Furthermore, these studies show the usefulness of the cultured rat hepatocyte model for examining the ontogeny and regulation of VLDL assembly/secretion.« less

The rat whole embryo culture assay using the Dysmorphology Score system.

PubMed

Zhang, Cindy; Panzica-Kelly, Julie; Augustine-Rauch, Karen

2013-01-01

The rat whole embryo culture (WEC) system has been used extensively for characterizing teratogenic properties of test chemicals. In this chapter, we describe the methodology for culturing rat embryos as well as a new morphological score system, the Dysmorphology Score (DMS) system for assessing morphology of mid gestation (gestational day 11) rat embryos. In contrast to the developmental stage focused scoring associated with the Brown and Fabro score system, this new score system assesses the respective degree of severity of dysmorphology, which delineates normal from abnormal morphology of specific embryonic structures and organ systems. This score system generates an approach that allows rapid identification and quantification of adverse developmental findings, making it conducive for characterization of compounds for teratogenic properties and screening activities.

Maternal and developmental toxicity of ayahuasca in Wistar rats.

PubMed

Oliveira, Carolina Dizioli Rodrigues; Moreira, Camila Queiroz; de Sá, Lilian Rose Marques; Spinosa, Helenice de Souza; Yonamine, Mauricio

2010-06-01

Ayahuasca is a psychotropic plant beverage initially used by shamans throughout the Amazon region during traditional religious cult. In recent years, ayahuasca has also been used in ceremonies of a number of modern syncretic religious groups, including pregnant women. However, no documented study has been performed to evaluate the risk of developmental toxicity of ayahuasca. In the present work, maternal and developmental toxicity was evaluated in Wistar rats. Ayahuasca was administered to pregnant rats in three different doses [the equivalent typical dose (TD) administered to humans, five-fold TD and 10-fold TD] during the gestational period (6-20 days). Dams treated with the highest ayahuasca dose showed maternal toxicity with decrease of weight gain and food intake. Visceral fetal findings were observed in all treatment groups. Skeletal findings were observed in the intermediate- and high-dose groups. The fetuses deriving from the highest dose group also presented a decrease in body weight. From these results, it is possible to conclude that there is a risk of maternal and developmental toxicity following ayahuasca exposure and that the level of toxicity appears to be dose-dependent.

Soy but not bisphenol A (BPA) induces hallmarks of polycystic ovary syndrome (PCOS) and related metabolic co-morbidities in rats.

PubMed

Patisaul, Heather B; Mabrey, Natalie; Adewale, Heather B; Sullivan, Alana W

2014-11-01

Polycystic ovarian syndrome (PCOS) is the most common female endocrine disorder with a prevalence as high as 8-15% depending on ethnicity and the diagnostic criteria employed. The basic pathophysiology and mode of inheritance remain unclear, but environmental factors such as diet, stress and chemical exposures are thought to be contributory. Developmental exposure to endocrine disrupting compounds (EDCs) have been hypothesized to exacerbate risk, in part because PCOS hallmarks and associated metabolic co-morbidities can be reliably induced in animal models by perinatal androgen exposure. Here we show that lifetime exposure to a soy diet, containing endocrine active phytoestrogens, but not developmental exposure (gestational day 6-lactational day 40) to the endocrine disrupting monomer bisphenol A (BPA), can induce key features of PCOS in the rat; results which support the hypothesis that hormonally active diets may contribute to risk when consumed throughout gestation and post-natal life. Copyright © 2014 Elsevier Inc. All rights reserved.

Abnormal stress responsivity in a rodent developmental disruption model of schizophrenia.

PubMed

Zimmerman, Eric C; Bellaire, Mark; Ewing, Samuel G; Grace, Anthony A

2013-10-01

Although numerous studies have implicated stress in the pathophysiology of schizophrenia, less is known about how the effects of stress interact with genetic, developmental, and/or environmental determinants to promote disease progression. In particular, it has been proposed that in humans, stress exposure in adolescence could combine with a predisposition towards increased stress sensitivity, leading to prodromal symptoms and eventually psychosis. However, the neurobiological substrates for this interaction are not fully characterized. Previous work in our lab has demonstrated that rats born to dams administered with the DNA-methylating agent methylazoxymethanol acetate (MAM) at gestational day 17 exhibit as adults behavioral and anatomical abnormalities consistent with those observed in patients with schizophrenia. Here, we examined behavioral and neuroendocrine responses to stress in the MAM model of schizophrenia. MAM-treated male rats were exposed to acute and repeated footshock stress at prepubertal, peripubteral, and adult ages. Ultrasonic vocalizations (USVs), freezing, and corticosterone responses were quantified. We found that juvenile MAM-treated rats emitted significantly more calls, spent more time vocalizing, emitted calls at a higher rate, and showed more freezing in response to acute footshock stress when compared with their saline (SAL) treated counterparts, and that this difference is not present in older animals. In addition, adolescent MAM-treated animals displayed a blunted HPA axis corticosterone response to acute footshock that did not adapt after 10 days of stress exposure. These data demonstrate abnormal stress responsivity in the MAM model of schizophrenia and suggest that these animals are more sensitive to the effects of stress in youth.

Genetic Diversity Influences the Response of the Brain to Developmental Lead Exposure

PubMed Central

Schneider, Jay S.; Talsania, Keyur; Mettil, William; Anderson, David W.

2014-01-01

Although extrinsic factors, such as nutritional status, and some intrinsic genetic factors may modify susceptibility to developmental lead (Pb) poisoning, no studies have specifically examined the influence of genetic background on outcomes from Pb exposure. In this study, we used gene microarray profiling to identify Pb-responsive genes in rats of different genetic backgrounds, including inbred (Fischer 344 (F344)) and outbred (Long Evans (LE), Sprague Dawley (SD)) strains, to investigate the role that genetic variation may play in influencing outcomes from developmental Pb exposure. Male and female animals received either perinatal (gestation through lactation) or postnatal (birth through weaning) exposure to Pb in food (0, 250, or 750 ppm). RNA was extracted from the hippocampus at day 55 and hybridized to Affymetrix Rat Gene 1.0 ST Arrays. There were significant strain-specific effects of Pb on the hippocampal transcriptome with 978 transcripts differentially expressed in LE rats across all experimental groups, 269 transcripts differentially expressed in F344 rats, and only 179 transcripts differentially expressed in SD rats. These results were not due to strain-related differences in brain accumulation of Pb. Further, no genes were consistently differentially regulated in all experimental conditions. There was no set of “Pb toxicity” genes that are a molecular signature for Pb neurotoxicity that transcended sex, exposure condition, and strain. These results demonstrate the influence that strain and genetic background play in modifying the brain's response to developmental Pb exposure and may have relevance for better understanding the molecular underpinnings of the lack of a neurobehavioral signature in childhood Pb poisoning. PMID:24913800

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.

Inhalation developmental toxicology studies: Acetonitrile in rats. Final report

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

Mast, T.J.; Weigel, R.J.; Westerberg, R.B.

1994-02-01

The potential for acetonitrile to cause developmental toxicity was assessed in Sprague-Dawley rats exposed to 0, 100, 400, or 1200 ppM acetonitrile, 6 hours/day, 7 days/week. Exposure of rats to these concentrations of acetonitrile resulted in mortality in the 1200 ppM group (2/33 pregnant females; 1/10 non-pregnant females). However, there were no treatment-related effects upon body weights or reproduction indices at any exposure level, nor was there a significant increase in the incidence of fetal malformations or variations. The only effect observed in the fetuses was a slight, but not statiscally significant, exposure-correlated increase in the incidence of supernumerary ribs.more » Determination of acetonitrile and cyanide concentrations in maternal rat blood showed that acetonitrile concentration in the blood increased with exposure concentration for all exposed maternal rats. Detectable amounts of cyanide in the blood were found only in the rats exposed to 1200 ppM acetonitrile ({approximately}2 {mu}g cyanide/g of blood).« less

EPO improved neurologic outcome in rat pups late after traumatic brain injury.

PubMed

Schober, Michelle E; Requena, Daniela F; Rodesch, Christopher K

2018-05-01

In adult rats, erythropoietin improved outcomes early and late after traumatic brain injury, associated with increased levels of Brain Derived Neurotrophic Factor. Using our model of pediatric traumatic brain injury, controlled cortical impact in 17-day old rats, we previously showed that erythropoietin increased hippocampal neuronal fraction in the first two days after injury. Erythropoietin also decreased activation of caspase3, an apoptotic enzyme modulated by Brain Derived Neurotrophic Factor, and improved Novel Object Recognition testing 14 days after injury. Data on long-term effects of erythropoietin on Brain Derived Neurotrophic Factor expression, histology and cognitive function after developmental traumatic brain injury are lacking. We hypothesized that erythropoietin would increase Brain Derived Neurotrophic Factor and improve long-term object recognition in rat pups after controlled cortical impact, associated with increased neuronal fraction in the hippocampus. Rats pups received erythropoietin or vehicle at 1, 24, and 48 h and 7 days after injury or sham surgery followed by histology at 35 days, Novel Object Recognition testing at adulthood, and Brain Derived Neurotrophic Factor measurements early and late after injury. Erythropoietin improved Novel Object Recognition performance and preserved hippocampal volume, but not neuronal fraction, late after injury. Improved object recognition in erythropoietin treated rats was associated with preserved hippocampal volume late after traumatic brain injury. Erythropoietin is approved to treat various pediatric conditions. Coupled with exciting experimental and clinical studies suggesting it is beneficial after neonatal hypoxic ischemic brain injury, our preliminary findings support further study of erythropoietin use after developmental traumatic brain injury. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Developmental manganese neurotoxicity in rats: Cognitive deficits in allocentric and egocentric learning and memory.

PubMed

Amos-Kroohs, Robyn M; Davenport, Laurie L; Atanasova, Nina; Abdulla, Zuhair I; Skelton, Matthew R; Vorhees, Charles V; Williams, Michael T

Manganese (Mn) is an essential element but neurotoxic at higher exposure levels. The effects of Mn overexposure (MnOE) on hippocampal and striatal-dependent learning and memory in rats were tested in combination with iron deficiency (FeD) and developmental stress that often co-occur with MnOE. Moderate FeD affects up to 15% of U.S. children and developmental stress is common in lower socio-economic areas where MnOE occurs. Pregnant Sprague-Dawley rats and their litters were housed in cages with or without (barren cage (BAR)) standard bedding from embryonic day (E)7 to postnatal day (P)28. Dams were fed a 90% FeD or iron sufficient (FeS) diet from E15-P28. Within each litter, separate offspring were treated with 100mg/kg Mn (MnOE) or vehicle (VEH) by gavage on alternate days from P4-28. Offspring were tested as adults in the Morris and Cincinnati water mazes. FeD and developmental stress interactively impaired spatial learning in the Morris water maze. Developmental stress and MnOE impaired learning and memory in both mazes. MnOE resulted in reduced CA1 hippocampal long-term potentiation (LTP) and increased levels of α-synuclein. Preweaning MnOE resulted in cognitive deficits on multiple domains of learning and memory accompanied by impaired LTP and α-synuclein changes, effects worsened by developmental stress. Copyright © 2016 Elsevier Inc. All rights reserved.

Developmental Hypothyroxinemia and Hypothyroidism Reduce Parallel Fiber-Purkinje Cell Synapses in Rat Offspring by Downregulation of Neurexin1/Cbln1/GluD2 Tripartite Complex.

PubMed

Wang, Yuan; Dong, Jing; Wang, Yi; Wei, Wei; Song, Binbin; Shan, Zhongyan; Teng, Weiping; Chen, Jie

2016-10-01

Iodine is a significant micronutrient. Iodine deficiency (ID)-induced hypothyroxinemia and hypothyroidism during developmental period can cause cerebellar dysfunction. However, mechanisms are still unclear. Therefore, the present research aims to study effects of developmental hypothyroxinemia caused by mild ID and hypothyroidism caused by severe ID or methimazole (MMZ) on parallel fiber-Purkinje cell (PF-PC) synapses in filial cerebellum. Maternal hypothyroxinemia and hypothyroidism models were established in Wistar rats using ID diet and deionized water supplemented with different concentrations of potassium iodide or MMZ water. Birth weight and cerebellum weight were measured. We also examined PF-PC synapses using immunofluorescence, and western blot analysis was conducted to investigate the activity of Neurexin1/cerebellin1 (Cbln1)/glutamate receptor d2 (GluD2) tripartite complex. Our results showed that hypothyroxinemia and hypothyroidism decreased birth weight and cerebellum weight and reduced the PF-PC synapses on postnatal day (PN) 14 and PN21. Accordingly, the mean intensity of vesicular glutamate transporter (VGluT1) and Calbindin immunofluorescence was reduced in mild ID, severe ID, and MMZ groups. Moreover, maternal hypothyroxinemia and hypothyroidism reduced expression of Neurexin1/Cbln1/GluD2 tripartite complex. Our study supports the hypothesis that developmental hypothyroxinemia and hypothyroidism reduce PF-PC synapses, which may be attributed to the downregulation of Neurexin1/Cbln1/GluD2 tripartite complex.

Genetic threshold hypothesis of neocortical spike-and-wave discharges in the rat: An animal model of petit mal epilepsy

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

Vadasz, C.; Fleischer, A.; Carpi, D.

1995-02-27

Neocortical high-voltage spike-and-wave discharges (HVS) in the rat are an animal model of petit mal epilepsy. Genetic analysis of total duration of HVS (s/12 hr) in reciprocal F1 and F2 hybrids of F344 and BN rats indicated that the phenotypic variability of HVS cannot be explained by simple, monogenic Mendelian model. Biometrical analysis suggested the presence of additive, dominance, and sex-linked-epistatic effects, buffering maternal influence, and heterosis. High correlation was observed between average duration (s/episode) and frequency of occurrence of spike-and-wave episodes (n/12 hr) in parental and segregating generations, indicating that common genes affect both duration and frequency of themore » spike-and-wave pattern. We propose that both genetic and developmental - environmental factors control an underlying quantitative variable, which, above a certain threshold level, precipitates HVS discharges. These findings, together with the recent availability of rat DNA markers for total genome mapping, pave the way to the identification of genes that control the susceptibility of the brain to spike-and-wave discharges. 67 refs., 3 figs., 5 tabs.« less

Ontogeny of sensorimotor gating and short-term memory processing throughout the adolescent period in rats.

PubMed

Goepfrich, Anja A; Friemel, Chris M; Pauen, Sabina; Schneider, Miriam

2017-06-01

Adolescence and puberty are highly susceptible developmental periods during which the neuronal organization and maturation of the brain is completed. The endocannabinoid (eCB) system, which is well known to modulate cognitive processing, undergoes profound and transient developmental changes during adolescence. With the present study we were aiming to examine the ontogeny of cognitive skills throughout adolescence in male rats and clarify the potential modulatory role of CB1 receptor signalling. Cognitive skills were assessed repeatedly every 10th day in rats throughout adolescence. All animals were tested for object recognition memory and prepulse inhibition of the acoustic startle reflex. Although cognitive performance in short-term memory as well as sensorimotor gating abilities were decreased during puberty compared to adulthood, both tasks were found to show different developmental trajectories throughout adolescence. A low dose of the CB1 receptor antagonist/inverse agonist SR141716 was found to improve recognition memory specifically in pubertal animals while not affecting behavioral performance at other ages tested. The present findings demonstrate that the developmental trajectory of cognitive abilities does not occur linearly for all cognitive processes and is strongly influenced by pubertal maturation. Developmental alterations within the eCB system at puberty onset may be involved in these changes in cognitive processing. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

The guinea pig as an animal model for developmental and reproductive toxicology studies.

PubMed

Rocca, Meredith S; Wehner, Nancy G

2009-04-01

Regulatory guidelines for developmental and reproductive toxicology (DART) studies require selection of "relevant" animal models as determined by kinetic, pharmacological, and toxicological data. Traditionally, rats, mice, and rabbits are the preferred animal models for these studies. However, for test articles that are pharmacologically inactive in the traditional animal models, the guinea pig may be a viable option. This choice should not be made lightly, as guinea pigs have many disadvantages compared to the traditional species, including limited historical control data, variability in pregnancy rates, small and variable litter size, long gestation, relative maturity at birth, and difficulty in dosing and breeding. This report describes methods for using guinea pigs in DART studies and provides results of positive and negative controls. Standard study designs and animal husbandry methods were modified to allow mating on the postpartum estrus in fertility studies and were used for producing cohorts of pregnant females for developmental studies. A positive control study with the pregnancy-disrupting agent mifepristone resulted in the anticipated failure of embryo implantation and supported the use of the guinea pig model. Control data for reproductive endpoints collected from 5 studies are presented. In cases where the traditional animal models are not relevant, the guinea pig can be used successfully for DART studies. (c) 2009 Wiley-Liss, Inc.

Comprehensive analysis of titin protein isoform and alternative splicing in normal and mutant rats.

PubMed

Li, Shijun; Guo, Wei; Schmitt, Benjamin M; Greaser, Marion L

2012-04-01

Titin is a giant protein with multiple functions in cardiac and skeletal muscles. Rat cardiac titin undergoes developmental isoform transition from the neonatal 3.7 MDa N2BA isoform to primarily the adult 2.97 MDa N2B isoform. An autosomal dominant mutation dramatically altered this transformation. Titins from eight skeletal muscles: Tibialis Anterior (TA), Longissimus Dorsi (LD) and Gastrocnemius (GA), Extensor Digitorum Longus (ED), Soleus (SO), Psoas (PS), Extensor Oblique (EO), and Diaphram (DI) were characterized in wild type and in homozygous mutant (Hm) rats with a titin splicing defect. Results showed that the developmental reduction in titin size is eliminated in the mutant rat so that the titins in all investigated skeletal muscles remain large in the adult. The alternative splicing of titin mRNA was found repressed by this mutation, a result consistent with the large titin isoform in the mutant. The developmental pattern of titin mRNA alternative splicing differs between heart and skeletal muscles. The retention of intron 49 reveals a possible mechanism for the absence of the N2B unique region in the expressed titin protein of skeletal muscle. © 2011 Wiley Periodicals, Inc.

Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome

PubMed Central

Veeraragavan, Surabi; Wan, Ying-Wooi; Connolly, Daniel R.; Hamilton, Shannon M.; Ward, Christopher S.; Soriano, Sirena; Pitcher, Meagan R.; McGraw, Christopher M.; Huang, Sharon G.; Green, Jennie R.; Yuva, Lisa A.; Liang, Agnes J.; Neul, Jeffrey L.; Yasui, Dag H.; LaSalle, Janine M.; Liu, Zhandong; Paylor, Richard; Samaco, Rodney C.

2016-01-01

Mouse models of the transcriptional modulator Methyl-CpG-Binding Protein 2 (MeCP2) have advanced our understanding of Rett syndrome (RTT). RTT is a ‘prototypical’ neurodevelopmental disorder with many clinical features overlapping with other intellectual and developmental disabilities (IDD). Therapeutic interventions for RTT may therefore have broader applications. However, the reliance on the laboratory mouse to identify viable therapies for the human condition may present challenges in translating findings from the bench to the clinic. In addition, the need to identify outcome measures in well-chosen animal models is critical for preclinical trials. Here, we report that a novel Mecp2 rat model displays high face validity for modelling psychomotor regression of a learned skill, a deficit that has not been shown in Mecp2 mice. Juvenile play, a behavioural feature that is uniquely present in rats and not mice, is also impaired in female Mecp2 rats. Finally, we demonstrate that evaluating the molecular consequences of the loss of MeCP2 in both mouse and rat may result in higher predictive validity with respect to transcriptional changes in the human RTT brain. These data underscore the similarities and differences caused by the loss of MeCP2 among divergent rodent species which may have important implications for the treatment of individuals with disease-causing MECP2 mutations. Taken together, these findings demonstrate that the Mecp2 rat model is a complementary tool with unique features for the study of RTT and highlight the potential benefit of cross-species analyses in identifying potential disease-relevant preclinical outcome measures. PMID:27365498

Assessment of an aqueous seed extract of Parkia clappertoniana on reproductive performance and toxicity in rodents.

PubMed

Boye, Alex; Boampong, Victor Addai; Takyi, Nutifafa; Martey, Orleans

2016-06-05

The seeds of Parkia clappertoniana Keay (Family: Fabaceae) are extensively used in food in the form of a local condiment called 'Dawadawa' in Ghana and consumed by all class of people including sensitive groups such as pregnant women and children. Also, crudely pounded preparations of P. clappertoniana seeds are used as labor inducing agent in farm animals by local farmers across northern Ghana where nomadism is the livelihood of most indigenes. Ecologically, P. clappertoniana is extensively distributed across the savannah ecological zone of many African countries where just like Ghana it enjoys ethnobotanical usage. Although, many studies have investigated some aspects of the pharmacological activity of P. clappertoniana, none of these studies focused on the reproductive system, particularly its effects on reproductive performance and toxicity. To contribute, this study assessed the effect of aqueous seed extract of P. clappertoniana (PCE) on reproductive performance and toxicity in Sprague-Dawley rats and ICR mice. After preparation of PCE, it was then tested on rodents at different gestational and developmental windows (1-7, 8-14, and 15-term gestational days) to assess the following: mating behavior, implantation rate, maternal and developmental toxicities. Generally, animals were randomly grouped into five and treated as follows: normal saline group (5ml/kg po), cytotec (misoprostol) group (200mg/kg po), folic acid group (5mg/kg po), and PCE groups (100, 200, and 500mg/kg po), however, these groupings were varied to suit the specific requirements of some parameters. For acute toxicity, animals were orally administered PCE (3 and 5g/kg for mice and rats respectively). PCE-treated rats showed improved mating behavior compared to control rats. PCE improved implantation rate compared to misoprostol-treated rats. On the average, PCE-treated rats delivered termed live pubs at 21 days compared to that of folic acid-treated rats at 23 days. Also, PCE-treated rats showed no observable maternal and developmental toxicities compared to folic acid and control rats. PCE (3-5g/kg po) was orally tolerated in rodents. Oral administration of Parkia clappertoniana seed extract improves reproductive performance in rodents with no observable maternal and developmental toxicity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Brain heparan sulphate proteoglycans are altered in developing foetus when exposed to in-utero hyperglycaemia.

PubMed

Sandeep, M S; Nandini, C D

2017-08-01

In-utero exposure of foetus to hyperglycaemic condition affects the growth and development of the organism. The brain is one of the first organs that start to develop during embryonic period and glycosaminoglycans (GAGs) and proteoglycans (PGs) are one of the key molecules involved in its development. But studies on the effect of hyperglycaemic conditions on brain GAGs/PGs are few and far between. We, therefore, looked into the changes in brain GAGs and PGs at various developmental stages of pre- and post-natal rats from non-diabetic and diabetic mothers as well as in adult rats induced with diabetes using a diabetogenic agent, Streptozotocin. Increased expression of GAGs especially that of heparan sulphate class in various developmental stages were observed in the brain as a result of in-utero hyperglycaemic condition but not in that of adult rats. Changes in disaccharides of heparan sulphate (HS) were observed in various developmental stages. Furthermore, various HSPGs namely, syndecans-1 and -3 and glypican-1 were overexpressed in offspring from diabetic mother. However, in adult diabetic rats, only glypican-1 was overexpressed. The offsprings from diabetic mothers became hyperphagic at the end of 8 weeks after birth which can have implications in the long run. Our results highlight the likely impact of the in-utero exposure of foetus to hyperglycaemic condition on brain GAGs/PGs compared to diabetic adult rats.

Developmental Triclosan Exposure Decreases Maternal and Offspring Thyroxine in Rats*

EPA Science Inventory

Epidemiological and laboratory data have demonstrated that disruption of maternal thyroid hormones during fetal developmental may result in irreversible neurological consequences in offspring. In a short-term exposure paradigm, triclosan decreased systemic thyroxine (T4) concentr...

CUMULATIVE DEVELOPMENTAL EFFECTS OF ENDOCRINE DISRUPTERS: SYNERGY OR ADDITIVITY?

EPA Science Inventory

Exposure to chemicals with hormonal activity during critical developmental periods can disrupt reproductive function and development. Within the last decade, several classes of pesticides and toxic substances have been shown to disrupt differentiation of the male rat reproductive...

Cocaine Self-Administration in Male and Female Rats Perinatally Exposed to PCBs: Evaluating Drug Use in an Animal Model of Environmental Contaminant Exposure

PubMed Central

Miller, Mellessa M.; Meyer, Abby E.; Sprowles, Jenna L. N.; Sable, Helen J. K.

2017-01-01

Polychlorinated biphenyls (PCBs) are ubiquitous environmental toxicants known to adversely impact human health. Ortho-substituted PCBs affect the nervous system, including the brain dopaminergic system. The reinforcing effects of psychostimulants are typically modulated via the dopaminergic system, so this study used a preclinical (i.e., rodent) model to evaluate whether developmental contaminant exposure altered intravenous self-administration (i.v. SA) for the psychostimulant cocaine. Long Evans rats were perinatally exposed to 6 or 3 mg/kg/day of PCBs throughout gestation and lactation and compared to non-exposed controls. Rats were trained to lever press for a food reinforcer in an operant chamber under a fixed-ratio 5 (FR5) schedule and later underwent jugular catheterization. Food reinforcers were switched for infusions of 250 μg of cocaine, but the response requirement to earn the reinforcer remained. Active lever presses and infusions were higher in males during response acquisition and maintenance. The same sex effect was observed during later sessions which evaluated responding for cocaine doses ranging from 31.25 – 500 μg. PCB-exposed males (not females) exhibited an increase in cocaine infusions (with a similar trend in active lever presses) during acquisition, but no PCB-related differences were observed during maintenance, examination of the cocaine dose-response relationship, or progressive ratio sessions. Overall, these results indicated perinatal PCB exposure enhanced early cocaine drug-seeking in this preclinical model of developmental contaminant exposure (particularly the males), but no differences were seen during later cocaine SA sessions. As such, additional questions regarding substance abuse proclivity may be warranted in epidemiological studies evaluating environmental contaminant exposures. PMID:28287790

Differences in cooperative behavior among Damaraland mole rats are consequences of an age-related polyethism

PubMed Central

Zöttl, Markus; Vullioud, Philippe; Mendonça, Rute; Torrents Ticó, Miquel; Gaynor, David; Mitchell, Adam; Clutton-Brock, Tim

2016-01-01

In many cooperative breeders, the contributions of helpers to cooperative activities change with age, resulting in age-related polyethisms. In contrast, some studies of social mole rats (including naked mole rats, Heterocephalus glaber, and Damaraland mole rats, Fukomys damarensis) suggest that individual differences in cooperative behavior are the result of divergent developmental pathways, leading to discrete and permanent functional categories of helpers that resemble the caste systems found in eusocial insects. Here we show that, in Damaraland mole rats, individual contributions to cooperative behavior increase with age and are higher in fast-growing individuals. Individual contributions to different cooperative tasks are intercorrelated and repeatability of cooperative behavior is similar to that found in other cooperatively breeding vertebrates. Our data provide no evidence that nonreproductive individuals show divergent developmental pathways or specialize in particular tasks. Instead of representing a caste system, variation in the behavior of nonreproductive individuals in Damaraland mole rats closely resembles that found in other cooperatively breeding mammals and appears to be a consequence of age-related polyethism. PMID:27588902

Preclinical Screening for Treatments for Infantile Spasms in the Multiple Hit Rat Model of Infantile Spasms: An Update.

PubMed

Galanopoulou, Aristea S; Mowrey, Wenzhu B; Liu, Wei; Li, Qianyun; Shandra, Oleksii; Moshé, Solomon L

2017-07-01

Infantile spasms are the typical seizures of West syndrome, an infantile epileptic encephalopathy with poor outcomes. There is an increasing need to identify more effective and better tolerated treatments for infantile spasms. We have optimized the rat model of infantile spasms due to structural etiology, the multiple-hit rat model, for therapy discovery. Here, we test three compounds administered after spasms induction in the multiple hit model for efficacy and tolerability. Specifically, postnatal day 3 (PN3) male Sprague-Dawley rats were induced by right intracerebral injections of doxorubicin and lipopolysaccharide. On PN5 p-chlorophenylalanine was given intraperitoneally (i.p.). Daily monitoring of weights and developmental milestones was done and rats were intermittently video monitored. A blinded, randomized, vehicle-controlled study design was followed. The caspase 1 inhibitor VX-765 (50-200 mg/kg i.p.) and the GABA B receptor inhibitor CGP35348 (12.5-100 mg/kg i.p.) each was administered in different cohorts as single intraperitoneal injections on PN4, using a dose- and time-response design with intermittent monitoring till PN5. 17β-estradiol (40 ng/g/day subcutaneously) was given daily between PN3-10 and intermittent monitoring was done till PN12. None of the treatments demonstrated acute or delayed effects on spasms, yet all were well tolerated. We discuss the implications for therapy discovery and challenges of replication trials.

Early Postnatal Manganese Exposure Causes Lasting Impairment of Selective and Focused Attention and Arousal Regulation in Adult Rats.

PubMed

Beaudin, Stephane A; Strupp, Barbara J; Strawderman, Myla; Smith, Donald R

2017-02-01

Studies in children and adolescents have associated early developmental manganese (Mn) exposure with inattention, impulsivity, hyperactivity, and oppositional behaviors, but causal inferences are precluded by the correlational nature of the data and generally limited control for potential confounders. To determine whether early postnatal oral Mn exposure causes lasting attentional and impulse control deficits in adulthood, and whether continued lifelong Mn exposure exacerbates these effects, using a rat model of environmental Mn exposure. Neonates were exposed orally to 0, 25 or 50 mg Mn/kg/day during early postnatal life (PND 1-21) or throughout life from PND 1 until the end of the study. In adulthood, the animals were tested on a series of learning and attention tasks using the five-choice serial reaction time task. Early postnatal Mn exposure caused lasting attentional dysfunction due to impairments in attentional preparedness, selective attention, and arousal regulation, whereas associative ability (learning) and impulse control were spared. The presence and severity of these deficits varied with the dose and duration of Mn exposure. This study is the first to show that developmental Mn exposure can cause lasting impairments in focused and selective attention and arousal regulation, and to identify the specific nature of the impairments. Given the importance of attention and arousal regulation in cognitive functioning, these findings substantiate concerns about the adverse effects of developmental Mn exposure in humans. Citation: Beaudin SA, Strupp BJ, Strawderman M, Smith DR. 2017. Early postnatal manganese exposure causes lasting impairment of selective and focused attention and arousal regulation in adult rats. Environ Health Perspect 125:230-237; http://dx.doi.org/10.1289/EHP258.

Early Postnatal Manganese Exposure Causes Lasting Impairment of Selective and Focused Attention and Arousal Regulation in Adult Rats

PubMed Central

Beaudin, Stephane A.; Strupp, Barbara J.; Strawderman, Myla; Smith, Donald R.

2016-01-01

Background: Studies in children and adolescents have associated early developmental manganese (Mn) exposure with inattention, impulsivity, hyperactivity, and oppositional behaviors, but causal inferences are precluded by the correlational nature of the data and generally limited control for potential confounders. Objectives: To determine whether early postnatal oral Mn exposure causes lasting attentional and impulse control deficits in adulthood, and whether continued lifelong Mn exposure exacerbates these effects, using a rat model of environmental Mn exposure. Methods: Neonates were exposed orally to 0, 25 or 50 mg Mn/kg/day during early postnatal life (PND 1–21) or throughout life from PND 1 until the end of the study. In adulthood, the animals were tested on a series of learning and attention tasks using the five-choice serial reaction time task. Results: Early postnatal Mn exposure caused lasting attentional dysfunction due to impairments in attentional preparedness, selective attention, and arousal regulation, whereas associative ability (learning) and impulse control were spared. The presence and severity of these deficits varied with the dose and duration of Mn exposure. Conclusions: This study is the first to show that developmental Mn exposure can cause lasting impairments in focused and selective attention and arousal regulation, and to identify the specific nature of the impairments. Given the importance of attention and arousal regulation in cognitive functioning, these findings substantiate concerns about the adverse effects of developmental Mn exposure in humans. Citation: Beaudin SA, Strupp BJ, Strawderman M, Smith DR. 2017. Early postnatal manganese exposure causes lasting impairment of selective and focused attention and arousal regulation in adult rats. Environ Health Perspect 125:230–237; http://dx.doi.org/10.1289/EHP258 PMID:27384154

DEVELOPMENTAL NEUROTOXICITY FOLLOWING NEONATAL EXPOSURE TO 3,3'-IMINODIPROPIONITRILE IN THE RAT

EPA Science Inventory

Adult exposure to the neurotoxicant 3,3'-iminodipropionitrile (IDPN) induces a hyperkinetic syndrome consisting of spontaneous head movements, abnormal circling, backwards locomotion, and sensory disruption. e report here the behavioral effects of developmental exposure to IDPN i...

MULTIDISCIPLINARY APPROACH TO TOXICOLOGICAL SCREENING: II. DEVELOPMENTAL TOXICITY

EPA Science Inventory

As part of the validation of an integrated bioassay for systemic, neuro-, and developmental toxicity, we evaluated the responses of Fischer-344 rats to four pesticides, four chlorinated solvents, and two other industrial chemicals. he pesticides included carbaryl, triadimefon, ch...

78 FR 53039 - Pyraclostrobin; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-28

... behavior changes were not observed. In the rat developmental toxicity study, developmental toxicity... requires EPA to give special consideration to exposure of infants and children to the pesticide chemical... result to infants and children from aggregate exposure to the pesticide chemical residue...

CHANGES IN APICAL DENDRITIC STRUCTURE CORRELATE WITH SUSTAINED ERK1/2 PHOSPHORYLATION IN MEDIAL PREFRONTAL CORTEX OF A RAT MODEL OF DOPAMINE D1 RECEPTOR AGONIST SENSITIZATION

PubMed Central

Papadeas, Sophia T.; Halloran, Christopher; McCown, Thomas J.; Breese, George R.; Blake, Bonita L.

2008-01-01

Rats lesioned with 6-hydroxydopamine (6-OHDA) as neonates exhibit behavioral and neurochemical abnormalities in adulthood that mimic Lesch-Nyhan disease, schizophrenia and other developmental disorders of frontostriatal circuit dysfunction. In these animals, a latent sensitivity to D1 agonists is maximally exposed by repeated administration of dopamine agonists in the post-pubertal period (D1 priming). In neonate-lesioned, adult rats primed with SKF-38393, we found selective, persistent alterations in the morphology of pyramidal neuron apical dendrites in the prelimbic area of the medial prefrontal cortex (mPFC). In these animals, dendrite bundling patterns and the typically straight trajectories of primary dendritic shafts were disrupted, whereas the diameter of higher-order oblique branches was increased. Although not present in neonate-lesioned rats treated with saline, these morphological changes persisted at least 21 days after repeated dosing with SKF-38393, and were not accompanied by markers of neurodegenerative change. A sustained increase in phospho-ERK immunoreactivity in wavy dendritic shafts over the same period suggested a relationship between prolonged ERK phosphorylation and dendritic remodeling in D1-primed rats. In support of this hypothesis, pretreatment with the MEK1/2-ERK1/2 pathway inhibitors PD98059 or SL327, prior to each priming dose of SKF-38393, prevented the morphological changes associated with D1 priming. Together, these findings demonstrate that repeated stimulation of D1 receptors in adulthood interacts with the developmental loss of dopamine to profoundly and persistently modify neuronal signaling and dendrite morphology in the mature prefrontal cortex. Furthermore, sustained elevation of ERK activity in mPFC pyramidal neurons may play a role in guiding these morphological changes in vivo. PMID:18785628

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

Developmental changes in somatostatin-positive interneurons in a freeze-lesion model of epilepsy.

PubMed

Patrick, Saundra L; Connors, Barry W; Landisman, Carole E

2006-08-01

Somatostatin-expressing (SS) cells are inhibitory interneurons critical to the regulation of excitability in the cerebral cortex. It has been suggested in several animal models of epilepsy that the activity of these neurons reduces the occurrence and strength of epileptiform activity. The physiological properties of SS cells further support these hypotheses. Freeze lesions of neonatal rats serve as a model of human polymicrogyria, which is often characterized by severe seizures. Here we investigate the effects of neonatal freeze lesions on SS-expressing neurons by measuring their densities in control and lesioned hemispheres at two ages. We found that in late juveniles (P30-P32), SS-expressing neurons were depleted by 20% in areas adjacent to the freeze lesion, but at an earlier developmental age (P14-15), there was no significant loss. Since the deficit in SS-expressing neurons occurs well after the onset of epileptiform activity (P12-P18), we conclude that the death of these interneurons does not initiate hyperexcitability in this model.

Sleep and Behavior in Cross-Fostering Rats: Developmental and Sex Aspects.

PubMed

Santangeli, Olena; Lehtikuja, Henna; Palomäki, Eeva; Wigren, Henna-Kaisa; Paunio, Tiina; Porkka-Heiskanen, Tarja

2016-12-01

Adverse early-life events induce behavioral psychopathologies and sleep changes in adulthood. In order to understand the molecular level mechanisms by which the maltreatment modifies sleep, valid animal models are needed. Changing pups between mothers at early age (cross-fostering) may satisfyingly model adverse events in human childhood. Cross-fostering (CF) was used to model mild early-life stress in male and female Wistar rats. Behavior and BDNF gene expression in the basal forebrain (BF), cortex, and hypothalamus were assessed during adolescence and adulthood. Spontaneous sleep, sleep homeostasis, and BF extracellular adenosine levels were assessed in adulthood. CF rats demonstrated increased number of REM sleep onsets in light and dark periods of the day. Total REM and NREM sleep duration was also increased during the light period. While sleep homeostasis was not severely affected, basal level of adenosine in the BF of both male and female CF rats was lower than in controls. CF did not lead to considerable changes in behavior. Even when the consequences of adverse early-life events are not observed in tests for anxiety and depression, they leave a molecular mark in the brain, which can act as a vulnerability factor for psychopathologies in later life. Sleep is a sensitive indicator for even mild early-life stress. © 2016 Associated Professional Sleep Societies, LLC.

Developmental Toxic Effects of Exposure to Chemical Warfare Nerve Agents in Rats: Effects on Brain and Behavior

DTIC Science & Technology

2015-03-01

Analysis of seizure activity and dendritic spine density following exposure to sarin during puberty Methods Female rats were surgically implanted...effects were observed in rats exposed to GB on PND 7 or 21. This study shows that nerve agent exposure during puberty results in severe and life

EVALUATION OF THE TERATOGENIC EFFECTS OF TRI-ORTHO-CRESYL PHOSPHATE IN THE LONG-EVANS HOODED RAT

EPA Science Inventory

The developmental toxicity of tri-ortho-cresyl phosphate (TOCP) was evaluated in Long-Evans rats. Pregnant rats were treated with 87.5, 175, and 350 mg/kg/day TOCP throughout organogenesis from gestation day 6 through 18 (day of sperm = day 0). The highest dose tested (350 mg/kg)...

DEVELOPMENTAL NEUROTOXICITY TESTING GUIDELINES: VARIABILITY IN MORPHOMETRIC ASSESSMENTS OF NEUROPATHOLOGY.

EPA Science Inventory

The USEPA Developmental Neurotoxicity (DNT) Study Test Guideline (OPPTS 870.6300) calls for neuropathological and morphometric assessments of rat pups on postnatal day (PND) 11 and at study termination (after PND 60). In recent discussions about conducting these studies on pesti...

Developmental Exposure to a Commercial PBDE mixture, DE·71: Neurobehavioral, Hormonal, and Reproductive Effects

EPA Science Inventory

Developmental effects of PBDEs have been suspected due to their structural similarities to polychlorinated biphenyls (PCBs). This study evaluated neurobehavioral, hormonal, and reproductive effects in rat offspring perinatally exposed to a widely used pentabrominated commercial m...

Neurobehavioral, Hormonal, and Reproductive Effects following Developmental Exposure to a Commercial PBDE Mixture, DE-71

EPA Science Inventory

Developmental effects caused by PBDEs have been suspected due to their chemically structural similarities to polychlorinated biphenyls (PCBs). This study evaluated neurobehavioral, hormonal, and reproductive effects in rat offspring perinatally exposed to a widely used pentabromi...

EFFECTS OF DEVELOPMENTAL EXPOSURE TO HEPTACHLOR ON THE CHOLINERGIC SYSTEM IN RATS.

EPA Science Inventory

Heptachlor is an environmentally persistent cyclodiene pesticide which is a known antagonist of the -aminobutyric acid (GABA)A receptor. Since GABA is a trophic factor for the development of other neurotransmitter systems (Lauder et al., Perspectives in Developmental Neurobiolog...

HIGH-CONTENT ANALYSIS OF PRIMARY RAT NEURAL CORTICALCULTURES FOR DEVELOPMENTAL NEUROTOXICITY SCREENING

EPA Science Inventory

Development of the vertebrate nervous system proceeds through a number of critical processes, ultimately concluding with the extension of neurites and establishment of synaptic networks. Early-life exposure to toxicants that perturb these critical developmental processes can po...

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...

Developmental PCB Exposure Increases Audiogenic Seizures and Decreases Glutamic Acid Decarboxylase in the Inferior Colliculus

PubMed Central

Bandara, Suren B.; Eubig, Paul A.; Sadowski, Renee N.; Schantz, Susan L.

2016-01-01

Previously, we observed that developmental polychlorinated biphenyl (PCB) exposure resulted in an increase in audiogenic seizures (AGSs) in rats. However, the rats were exposed to loud noise in adulthood, and were not tested for AGS until after 1 year of age, either of which could have interacted with early PCB exposure to increase AGS susceptibility. This study assessed susceptibility to AGS in young adult rats following developmental PCB exposure alone (without loud noise exposure) and investigated whether there was a decrease in GABA inhibitory neurotransmission in the inferior colliculus (IC) that could potentially explain this effect. Female Long-Evans rats were dosed orally with 0 or 6 mg/kg/day of an environmentally relevant PCB mixture from 28 days prior to breeding until the pups were weaned at postnatal day 21. One male-female pair from each litter was retained for the AGS study whilst another was retained for Western blot analysis of glutamic acid decarboxylase (GAD) and GABAAα1 receptor in the IC, the site in the auditory midbrain where AGS are initiated. There was a significant increase in the number and severity of AGSs in the PCB groups, with females somewhat more affected than males. GAD65 was decreased but there was no change in GAD67 or GABAAα1 in the IC indicating decreased inhibitory regulation in the PCB group. These results confirm that developmental PCB exposure alone is sufficient to increase susceptibility to AGS, and provide the first evidence for a possible mechanism of action at the level of the IC. PMID:26543103

Development of PBPK Models for Gasoline in Adult and ...

EPA Pesticide Factsheets

Concern for potential developmental effects of exposure to gasoline-ethanol blends has grown along with their increased use in the US fuel supply. Physiologically-based pharmacokinetic (PBPK) models for these complex mixtures were developed to address dosimetric issues related to selection of exposure concentrations for in vivo toxicity studies. Sub-models for individual hydrocarbon (HC) constituents were first developed and calibrated with published literature or QSAR-derived data where available. Successfully calibrated sub-models for individual HCs were combined, assuming competitive metabolic inhibition in the liver, and a priori simulations of mixture interactions were performed. Blood HC concentration data were collected from exposed adult non-pregnant (NP) rats (9K ppm total HC vapor, 6h/day) to evaluate performance of the NP mixture model. This model was then converted to a pregnant (PG) rat mixture model using gestational growth equations that enabled a priori estimation of life-stage specific kinetic differences. To address the impact of changing relevant physiological parameters from NP to PG, the PG mixture model was first calibrated against the NP data. The PG mixture model was then evaluated against data from PG rats that were subsequently exposed (9K ppm/6.33h gestation days (GD) 9-20). Overall, the mixture models adequately simulated concentrations of HCs in blood from single (NP) or repeated (PG) exposures (within ~2-3 fold of measured values of

Comparison of the lethal effects of chemical warfare nerve agents across multiple ages.

PubMed

Wright, Linnzi K M; Lee, Robyn B; Vincelli, Nicole M; Whalley, Christopher E; Lumley, Lucille A

2016-01-22

Children may be inherently more vulnerable than adults to the lethal effects associated with chemical warfare nerve agent (CWNA) exposure because of their closer proximity to the ground, smaller body mass, higher respiratory rate, increased skin permeability and immature metabolic systems. Unfortunately, there have only been a handful of studies on the effects of CWNA in pediatric animal models, and more research is needed to confirm this hypothesis. Using a stagewise, adaptive dose design, we estimated the 24h median lethal dose for subcutaneous exposure to seven CWNA in both male and female Sprague-Dawley rats at six different developmental times. Perinatal (postnatal day [PND] 7, 14 and 21) and adult (PND 70) rats were more susceptible than pubertal (PND 28 and 42) rats to the lethal effects associated with exposure to tabun, sarin, soman and cyclosarin. Age-related differences in susceptibility were not observed in rats exposed to VM, Russian VX or VX. Published by Elsevier Ireland Ltd.

77 FR 12207 - Pyroxasulfone; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-29

... and post- natal toxicity database for pyroxasulfone includes developmental toxicity studies in rats... study and developmental toxicity study in rabbits following in utero or post-natal exposure to... reliability as well as the relationship of the results of the studies to human risk. EPA has also considered...

Tissue-specific, nutritional, and developmental regulation of rat fatty acid elongases

PubMed Central

Wang, Yun; Botolin, Daniela; Christian, Barbara; Busik, Julia; Xu, Jinghua; Jump, Donald B.

2008-01-01

Of the six fatty acid elongase (Elovl) subtypes expressed in mammals, adult rat liver expresses four subtypes: Elovl-5 > Elovl-1 = Elovl-2 = Elovl-6. Overnight starvation and fish oil-enriched diets repressed hepatic elongase activity in livers of adult male rats. Diet-induced changes in elongase activity correlate with Elovl-5 and Elovl-6 mRNA abundance. Adult rats fed the peroxisome proliferator-activated receptor α (PPARα) agonist WY14,643 have increased hepatic elongase activity, Elovl-1, Elovl-5, Elovl-6, Δ5, Δ6, and Δ9 desaturase mRNA abundance, and mead acid (20:3,n-9) content. PPARα agonists affect both fatty acid elongation and desaturation pathways leading to changes in hepatic lipid composition. Elovl activity is low in fetal liver but increases significantly after birth. Developmental changes in hepatic elongase activity paralleled the postnatal induction of Elovl-5 mRNA and mRNAs encoding the PPARα-regulated transcripts, Δ5 and Δ6 desaturase, and cytochrome P450 4A. In contrast, Elovl-6, Δ9 desaturase, and FAS mRNA abundance paralleled changes in hepatic sterol regulatory element binding protein 1c (SREBP-1c) nuclear content. SREBP-1c is present in fetal liver nuclei, absent from nuclei immediately after birth, and reappears in nuclei at weaning, 21 days postpartum. In conclusion, changes in Elovl-5 expression may account for much of the nutritional and developmental control of fatty acid elongation activity in the rat liver. PMID:15654130

Developmental Toxicity Studies with Pregabalin in Rats: Significance of Alterations in Skull Bone Morphology.

PubMed

Morse, Dennis C; Henck, Judith W; Bailey, Steven A

2016-04-01

Pregabalin was administered to pregnant Wistar rats during organogenesis to evaluate potential developmental toxicity. In an embryo-fetal development study, compared with controls, fetuses from pregabalin-treated rats exhibited increased incidence of jugal fused to maxilla (pregabalin 1250 and 2500 mg/kg) and fusion of the nasal sutures (pregabalin 2500 mg/kg). The alterations in skull development occurred in the presence of maternal toxicity (reduced body weight gain) and developmental toxicity (reduced fetal body weight and increased skeletal variations), and were initially classified as malformations. Subsequent investigative studies in pregnant rats treated with pregabalin during organogenesis confirmed the advanced jugal fused to maxilla, and fusion of the nasal sutures at cesarean section (gestation day/postmating day [PMD] 21) in pregabalin-treated groups. In a study designed to evaluate progression of skull development, advanced jugal fused to maxilla and fusion of the nasal sutures was observed on PMD 20-25 and PMD 21-23, respectively (birth occurs approximately on PMD 22). On postnatal day (PND) 21, complete jugal fused to maxilla was observed in the majority of control and 2500 mg/kg offspring. No treatment-related differences in the incidence of skull bone fusions occurred on PND 21, indicating no permanent adverse outcome. Based on the results of the investigative studies, and a review of historical data and scientific literature, the advanced skull bone fusions were reclassified as anatomic variations. Pregabalin was not teratogenic in rats under the conditions of these studies. © 2016 Wiley Periodicals, Inc.

Dental peculiarities in the silvery mole-rat: an original model for studying the evolutionary and biological origins of continuous dental generation in mammals

PubMed Central

Šumbera, Radim

2015-01-01

Unravelling the evolutionary and developmental mechanisms that have impacted the mammalian dentition, since more than 200 Ma, is an intricate issue. Interestingly, a few mammal species, including the silvery mole-rat Heliophobius argenteocinereus, are able to replace their dentition by the addition of supernumerary molars at the back of jaw migrating then toward the front. The aim here was to demonstrate the potential interest of further studying this rodent in order to better understand the origins of continuous dental replacement in mammals, which could also provide interesting data concerning the evolution of limited dental generation occurring in first mammals. In the present study, we described the main stages of the dental eruptive sequence in the silvery mole-rat and the associated characteristics of horizontal replacement using X-ray microtomography. This was coupled to the investigation of other African mole-rats which have no dental replacement. This method permitted to establish evidence that the initial development of the dentition in Heliophobius is comparable to what it is observed in most of African mole-rats. This rodent first has premolars, but then identical additional molars, a mechanism convergent to manatees and the pygmy rock-wallaby. Evidence of continuous replacement and strong dental dynamics were also illustrated in Heliophobius, and stressed the need to deeply investigate these aspects for evolutionary, functional and developmental purposes. We also noticed that two groups of extinct non-mammalian synapsids convergently acquired this dental mechanism, but in a way differing from extant mammals. The discussion on the diverse evolutionary origins of horizontal dental replacement put emphasis on the necessity of focusing on biological parameters potentially involved in both continuous and limited developments of teeth in mammals. In that context, the silvery mole-rat could appear as the most appropriate candidate to do so. PMID:26401449

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.

Health assessment of gasoline and fuel oxygenate vapors: developmental toxicity in rats.

PubMed

Roberts, Linda G; Gray, Thomas M; Trimmer, Gary W; Parker, Robert M; Murray, F Jay; Schreiner, Ceinwen A; Clark, Charles R

2014-11-01

Gasoline-vapor condensate (BGVC) or condensed vapors from gasoline blended with methyl t-butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME) diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA) were evaluated for developmental toxicity in Sprague-Dawley rats exposed via inhalation on gestation days (GD) 5-20 for 6h/day at levels of 0 (control filtered air), 2000, 10,000, and 20,000mg/m(3). These exposure durations and levels substantially exceed typical consumer exposure during refueling (<1-7mg/m(3), 5min). Dose responsive maternal effects were reduced maternal body weight and/or weight change, and/or reduced food consumption. No significant malformations were seen in any study. Developmental effects occurred at 20,000mg/m(3) of G/TAME (reduced fetal body weight, increased incidence of stunted fetuses), G/TBA (reduced fetal body weight, increased skeletal variants) and G/DIPE (reduced fetal weight) resulting in developmental NOAEL of 10,000mg/m(3) for these materials. Developmental NOAELs for other materials were 20,000mg/m(3) as no developmental toxicity was induced in those studies. Developmental NOAELs were equal to or greater than the concurrent maternal NOAELs which ranged from 2000 to 20,000mg/m(3). There were no clear cut differences in developmental toxicity between vapors of gasoline and gasoline blended with the ether or alcohol oxygenates. Copyright © 2014 Elsevier Inc. All rights reserved.

Inhalation developmental toxicology studies: Teratology study of acetone in mice and rats: Final report

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

Mast, T.J.; Evanoff, J.J.; Rommereim, R.L.

1988-11-01

Acetone, an aliphatic ketone, is a ubiquitous industrial solvent and chemical intermediate; consequently, the opportunity for human exposure is high. The potential for acetone to cause developmental toxicity was assessed in Sprague-Dawley rats exposed to 0, 440, 2200, or 11000 ppm, and in Swiss (CD-1) mice exposed to 0, 440, 2200, and 6600 ppm acetone vapors, 6 h/day, 7 days/week. Each of the four treatment groups consisted of 10 virgin females (for comparison), and approx.32 positively mated rats or mice. Positively mated mice were exposed on days 6-17 of gestation (dg), and rats on 6-19 dg. The day of plugmore » or sperm detection was designated as 0 dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. 46 refs., 6 figs., 27 tabs.« less

Effects of hesperidin on formaldehyde-induced toxicity in pregnant rats

PubMed Central

Merzoug, Sameha; Toumi, Mohamed Lamine

2017-01-01

This experimental study aimed to investigate the protective effect of a bioflavonoid, hesperidin (HP), on formaldehyde (FA)-related pathophysiological and behavioral outcomes in pregnant rats and developmental aspects in their offspring. Female Wistar rats were subjected to perigestational exposure to FA (2 mg/kg/day per os) with a concomitant treatment with HP (50 mg/kg/day per os). Pregnant rats were weighed throughout gestation and tested in two behavioral paradigms (elevated plus-maze and open field) at gestational days (GD) 1, 10 and 19 to evaluate the anxiety-like behavior and locomotive alterations. Another subset of rats was decapitated at GD19 to determine the hematological profile along with cortisol, 17β-estradiol, and progesterone plasma levels. Reproductive and fetal measures and observations were also performed to check for developmental deformities. Significant body weight loss, hemato-immune decline, hormonal changes, anxiety and lethargy signs, locomotor disabilities, reproductive failure and fetal weight decrease were observed in FA-exposed rats. Treatment with HP alleviated the reproductive and fetal weight defects. Its behavioral benefits were only seen at GD1 and 10. This flavanone ameliorated some hematological parameters, decreased cortisol levels and increased 17β-estradiol rates. A potential preventive impact of HP was found against FA toxicity in pregnant rats. PMID:28507483

ToxCast Profiling in a Human Stem Cell Assay for Developmental Toxicity (CompTox CoP)

EPA Science Inventory

Standard practice for assessing disruptions in embryogenesis involves testing pregnant animals of two species, typically rats and rabbits, exposed during major organogenesis and evaluated just prior to term. Under this design the major manifestations of developmental toxicity are...

Developmental exposure to perchlorate alters synaptic transmission in hippocampus of the adult rat: in vivo studies.

EPA Science Inventory

Perchlorate, a contaminant found in food and water supplies throughout the USA, blocks iodine uptake into the thyroid gland to reduce circulating levels of thyroid hormone. Neurological function accompanying developmental exposure to perchlorate was evaluated in the present study...

Abnormal morphology of the penis in male rats exposed neonatally to diethylstilbestrol is associated with altered profile of estrogen receptor-alpha protein, but not of androgen receptor protein: a developmental and immunocytochemical study.

PubMed

Goyal, H O; Braden, T D; Williams, C S; Dalvi, P; Mansour, M M; Mansour, M; Williams, J W; Bartol, F F; Wiley, A A; Birch, L; Prins, G S

2004-05-01

Objectives of the study were to determine developmental changes in morphology and expression of androgen receptor (AR) and estrogen receptor (ER)alpha in the body of the rat penis exposed neonatally to diethylstilbestrol (DES). Male pups received DES at a dose of 10 microg per rat on alternate days from Postnatal Day 2 to Postnatal Day 12. Controls received olive oil vehicle only. Tissue samples were collected on Days 18 (prepuberty), 41 (puberty), and 120 (adult) of age. DES-induced abnormalities were evident at 18 days of age and included smaller, lighter, and thinner penis, loss of cavernous spaces and associated smooth muscle cells, and increased deposition of fat cells in the corpora cavernosa penis. Fat cells virtually filled the entire area of the corpora cavernosa at puberty and adulthood. Plasma testosterone (T) was reduced to an undetectable level, while LH was unaltered in all treated groups. AR-positive cells were ubiquitous and their profile (incidence and staining intensity) did not differ between control and treated rats of the respective age groups. Conversely, ERalpha-positive cells were limited to the stroma of corpus spongiosus in all age groups of both control and treated rats, but the expression in treated rats at 18 days was up-regulated in stromal cells of corpora cavernosa, coincident with the presence of morphological abnormalities. Hence, this study reports for the first time DES-induced developmental, morphological abnormalities in the body of the penis and suggests that these abnormalities may have resulted from decreased T and/or overexpression of ERalpha.

Inhibition of transforming growth factor-β attenuates brain injury and neurological deficits in a rat model of germinal matrix hemorrhage.

PubMed

Manaenko, Anatol; Lekic, Tim; Barnhart, Margaret; Hartman, Richard; Zhang, John H

2014-03-01

Transforming growth factor-β (TGF-β) overproduction and activation of the TGF-β pathway are associated with the development of brain injury following germinal matrix hemorrhage (GMH) in premature infants. We examined the effects of GMH on the level of TGF-β1 in a novel rat collagenase-induced GMH model and determined the effect of inhibition of the TGF receptor I. In total, 92 seven-day old (P7) rats were used. Time-dependent effects of GMH on the level of TGF-β1 and TGF receptor I were evaluated by Western blot. A TGF receptor I inhibitor (SD208) was administered daily for 3 days, starting either 1 hour or 3 days after GMH induction. The effects of GMH and SD208 on the TGF-β pathway were evaluated by Western blot at day 3. The effects of GMH and SD208 on cognitive and motor function were also assessed. The effects of TGF receptor I inhibition by SD208 on GMH-induced brain injury and underlying molecular pathways were investigated by Western blot, immunofluorescence, and morphology studies 24 days after GMH. GMH induced significant delay in development, caused impairment in both cognitive and motor functions, and resulted in brain atrophy in rat subjects. GMH also caused deposition of both vitronectin (an extracellular matrix protein) and glial fibrillary acidic protein in perilesion areas, associated with development of hydrocephalus. SD208 ameliorated GMH-induced developmental delay, improved cognitive and motor functions, and attenuated body weight loss. SD208 also decreased vitronectin and glial fibrillary acidic protein deposition and decreased GMH-induced brain injury. Increased level of TGF-β1 and activation of the TGF-β pathway associate with the development of brain injury after GMH. SD208 inhibits GMH-induced activation of the TGF-β pathway and leads to an improved developmental profile, partial recovery of cognitive and motor functions, and attenuation of GMH-induced brain atrophy and hydrocephalus.

Altered dopamine ontogeny in the developmentally vitamin D deficient rat and its relevance to schizophrenia.

PubMed

Kesby, James P; Cui, Xiaoying; Burne, Thomas H J; Eyles, Darryl W

2013-01-01

Schizophrenia is a heterogeneous group of disorders with unknown etiology. Although abnormalities in multiple neurotransmitter systems have been linked to schizophrenia, alterations in dopamine (DA) neurotransmission remain central to the treatment of this disorder. Given that schizophrenia is considered a neurodevelopmental disorder we have hypothesized that abnormal DA signaling in the adult patient may result from altered DA signaling during fetal brain development. Environmental and genetic risk factors can be modeled in rodents to allow for the investigation of early neurodevelopmental pathogenesis that may lead to clues into the etiology of schizophrenia. To address this we created an animal model of one such risk factor, developmental vitamin D (DVD) deficiency. DVD-deficient adult rats display an altered behavioral profile in response to DA releasing and blocking agents that are reminiscent of that seen in schizophrenia patients. Furthermore, developmental studies revealed that DVD deficiency also altered cell proliferation, apoptosis, and neurotransmission across the embryonic brain. In particular, DVD deficiency reduces the expression of crucial dopaminergic specification factors and alters DA metabolism in the developing brain. We speculate such alterations in fetal brain development may change the trajectory of DA neuron ontogeny to induce the behavioral abnormalities observed in adult offspring. The widespread evidence that both dopaminergic and structural changes are present in people who develop schizophrenia prior to onset also suggest that early alterations in development are central to the disease. Taken together, early alterations in DA ontogeny may represent a core feature in the pathology of schizophrenia. Such a mechanism could bring together evidence from multiple risk factors and genetic vulnerabilities to form a convergent pathway in disease pathophysiology.

Developmental Exposure to an Environmental PCB Mixture ...

EPA Pesticide Factsheets

Developmental PCB exposure impairs hearing and induces brainstem audiogenic seizures in adult offspring. The degree to which this enhanced susceptibility to seizure is manifest in other brain regions has not been examined. Thus, electrical kindling of the amygdala was used to evaluate the effect of developmental exposure to an environmentally relevant PCB mixture on seizure susceptibility in the rat. Female Long-Evans rats were dosed orally with 0 or 6 mg/kg/day of the PCB mixture dissolved in corn oil vehicle during the perinatal period. On postnatal day (PND) 21, pups were weaned, and two males from each litter were randomly selected for the kindling study. As adults, the male rats were implanted bilaterally with electrodes in the basolateral amygdala. For each animal, afterdischarge (AD) thresholds in the amygdala were determined on the first day of testing followed by once daily stimulation at a standard 200 µA stimulus intensity until three stage 5 generalized seizures (GS) ensued. Developmental PCB exposure did not affect the AD threshold or total cumulative AD duration, but PCB exposure did increase the latency to behavioral manifestations of seizure propagation. PCB exposed animals required significantly more stimulations to reach stage 2 seizures compared to control animals, indicating an attenuated focal (amygdala) excitability. A delay in kindling progression from a focally stimulated limbic site stands in contrast to our previous finding of increase

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

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

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

2011-11-15

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

Age dependence of pilocarpine-induced status epilepticus and inhibition of CaM kinase II activity in the rat.

PubMed

Singleton, Michael W; Holbert, William H; Ryan, Matthew L; Lee, Anh Tuyet; Kurz, Jonathan E; Churn, Severn B

2005-04-21

This study was conducted to characterize the post-pubertal developmental aspects on seizure susceptibility and severity as well as calcium/calmodulin protein kinase type II (CaM kinase II) activity in status epilepticus (SE). Thirty- to ninety-day-old rats, in 10-day increments, were studied. This corresponds to a developmental age group that has not received thorough attention. The pilocarpine model of SE was characterized both behaviorally and electrographically. Seven criteria were analyzed for electrographical characterization: seizure severity, SE susceptibility, the average number of discrete seizures, average time until first seizure, average time to SE, average time from first discrete seizure to SE, and death. After 1 h of SE, specific brain regions were isolated for biochemical study. Phosphate incorporation into a CaM kinase II-specific substrate, autocamtide III, was used to determine kinase activity. There was no developmental effect on the average number of discrete seizures, average time until first seizure, average time to SE, average time from first discrete seizure to SE, and death; however, there was a significant effect on SE probability and seizure severity. Once SE was expressed, all animals showed a decrease in both cortical and hippocampal CaM kinase II activities. Conversely, seizure activity in the absence of SE did not result in a decrease in CaM kinase II activity. The data suggest that there is a gradual age-dependent modulation of SE susceptibility and seizure severity within the developmental stages studied. Additionally, once status epilepticus is observed at any age, there is a corresponding SE-induced inhibition of CaM kinase II.

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...

Profiling the activity of environmental chemicals in prenatal developmental toxicity studies using the U.S. EPA’s ToxRefDB

EPA Science Inventory

As the primary source for regulatory developmental toxicity information, prenatal studies characterize maternal effects and fetal endpoints including malformations, resorptions, and fetal weight reduction. Results from 383 rat and 368 rabbit prenatal studies on 387 chemicals, mo...

IN VITRO SCREENING OF DEVELOPMENTAL NEUROTOXICANTS IN RAT PRIMARY CORTICAL NEURONS USING HIGH CONTENT IMAGE

EPA Science Inventory

There is a need for more efficient and cost-effective methods for identifying, characterizing and prioritizing chemicals which may result in developmental neurotoxicity. One approach is to utilize in vitro test systems which recapitulate the critical processes of nervous system d...

DEVELOPMENTAL NEUROTOXICITY OF INHALED METHANOL IN RATS

EPA Science Inventory

Dr. Weiss and his colleagues conducted a controlled series of experiments in which they exposed pregnant rats and their newborn offspring to 4,500 parts per million (ppm) methanol by inhalation, and then submitted them to tests of behavioral function.

Exposure to 4,500...

THE DEVELOPMENTAL IMMUNOTOXICITY OF DIBUTYLTIN DICHLORIDE IN SPRAGUE-DAWLEY RATS

EPA Science Inventory

Methyl- and butyltin compounds used as stabilizers in polyvinyl chloride (PVC) pipe production are of concern as they leach from supply pipes into drinking water and have been associated with multisystem toxicity. This study assessed immune function in Sprague-Dawley (CD) rats d...

Developmental Exposure to PCBs Differentially Alters Sensitivity to Audiogenic and Kindling-Induced Seizures in Rats

EPA Science Inventory

Previously we reported an increased incidence of audiogenic seizures in offspring of pregnant rats exposed to an environmental mixture of polychlorinated biphenyls (PCBs). This study compares the proconvulsant properties of PCB exposure in audiogenic and electrical kindling seizu...

Maternal and developmental toxicity of the hallucinogenic plant-based beverage ayahuasca in rats.

PubMed

da Motta, Luciana Gueiros; de Morais, Juliana Alves; Tavares, Ana Carolina A M; Vianna, Leonora Maciel Sousa; Mortari, Marcia Renata; Amorim, Rivadávio Fernandes Batista; Carvalho, Rosângela R; Paumgartten, Francisco José R; Pic-Taylor, Aline; Caldas, Eloisa Dutra

2018-04-01

Rats were treated orally with ayahuasca (AYA) on gestation days (GD) 6-20 at doses corresponding to one-(1X) to eight-fold (8X) the average dose taken by a human adult in a religious ritual, and the pregnancy outcome evaluated on GD21. Rats treated with 4X and 8X doses died during the treatment period (44 and 52%), and those that survived showed kidney injury. Rats surviving the 8X dose showed neuronal loss in hippocampal regions and in the raphe nuclei, and those from the 2X dose neuronal loss in CA1. Delayed intrauterine growth, induced embryo deaths and increased occurrence of foetal anomalies were observed at the 8X dose. At non-lethal doses, AYA enhanced embryolethality and the incidence of foetal soft-tissue and skeleton anomalies. This study suggested that AYA is developmentally toxic and that its daily use by pregnant women may pose risks for the conceptus. Copyright © 2018 Elsevier Inc. All rights reserved.

Developmental Exposure to Cocaine Dynamically Dysregulates Cortical Arc/Arg3.1 Modulation in Response to a Challenge.

PubMed

Caffino, Lucia; Giannotti, Giuseppe; Mottarlini, Francesca; Racagni, Giorgio; Fumagalli, Fabio

2017-02-01

During adolescence, the medial prefrontal cortex (mPFC) is still developing. We have previously shown that developmental cocaine exposure alters mPFC's ability to cope with challenging events. In this manuscript, we exposed rats developmentally treated with cocaine to a novelty task and analyzed the molecular changes of mPFC. Rats were exposed to cocaine from post-natal day (PND) 28 to PND 42 and sacrificed at PND 43, immediately after the novel object recognition (NOR) test. Cocaine-treated rats spent more time exploring the novel object than saline-treated counterparts, suggesting an increased response to novelty. The messenger RNA (mRNA) and protein levels of the immediate early gene Arc/Arg3.1 were reduced in both infralimbic (IL) and prelimbic (PL) cortices highlighting a baseline reduction of mPFC neuronal activity as a consequence of developmental exposure to cocaine. Intriguingly, significant molecular changes were observed in the IL, but not PL, cortex in response to the combination of cocaine exposure and test such as a marked upregulation of both Arc/Arg3.1 mRNA and protein levels only in cocaine-treated rats. As for proteins, such increase was observed only in the post-synaptic density and not in the whole homogenate, suggesting psychostimulant-induced changes in trafficking of Arc/Arg3.1 or an increased local translation. Notably, the same profile of Arc/Arg3.1 was observed for post-synaptic density (PSD)-95 leading to the possibility that Arc/Arg3.1 and PSD-95 bridge together to promote aberrant synaptic connectivity in IL cortex following repeated exposure to cocaine during brain development.

Developmental PCB Exposure Increases Audiogenic Seizures and Decreases Glutamic Acid Decarboxylase in the Inferior Colliculus.

PubMed

Bandara, Suren B; Eubig, Paul A; Sadowski, Renee N; Schantz, Susan L

2016-02-01

Previously, we observed that developmental polychlorinated biphenyl (PCB) exposure resulted in an increase in audiogenic seizures (AGSs) in rats. However, the rats were exposed to loud noise in adulthood, and were not tested for AGS until after 1 year of age, either of which could have interacted with early PCB exposure to increase AGS susceptibility. This study assessed susceptibility to AGS in young adult rats following developmental PCB exposure alone (without loud noise exposure) and investigated whether there was a decrease in GABA inhibitory neurotransmission in the inferior colliculus (IC) that could potentially explain this effect. Female Long-Evans rats were dosed orally with 0 or 6 mg/kg/day of an environmentally relevant PCB mixture from 28 days prior to breeding until the pups were weaned at postnatal day 21. One male-female pair from each litter was retained for the AGS study whilst another was retained for Western blot analysis of glutamic acid decarboxylase (GAD) and GABAAα1 receptor in the IC, the site in the auditory midbrain where AGS are initiated. There was a significant increase in the number and severity of AGSs in the PCB groups, with females somewhat more affected than males. GAD65 was decreased but there was no change in GAD67 or GABAAα1 in the IC indicating decreased inhibitory regulation in the PCB group. These results confirm that developmental PCB exposure alone is sufficient to increase susceptibility to AGS, and provide the first evidence for a possible mechanism of action at the level of the IC. © 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.

Late onset deficits in synaptic plasticity in the valproic acid rat model of autism.

PubMed

Martin, Henry G S; Manzoni, Olivier J

2014-01-01

Valproic acid (VPA) is a frequently used drug in the treatment of epilepsy, bipolar disorders and migraines; however it is also a potent teratogen. Prenatal exposure increases the risk of childhood malformations and can result in cognitive deficits. In rodents in utero exposure to VPA also causes neurodevelopmental abnormalities and is an important model of autism. In early postnatal life VPA exposed rat pups show changes in medial prefrontal cortex (mPFC) physiology and synaptic connectivity. Specifically, principal neurons show decreased excitability but increased local connectivity, coupled with an increase in long-term potentiation (LTP) due to an up-regulation of NMDA receptor (NMDAR) expression. However recent evidence suggests compensatory homeostatic mechanisms lead to normalization of synaptic NMDARs during later postnatal development. Here we have extended study of mPFC synaptic physiology into adulthood to better understand the longitudinal consequences of early developmental abnormalities in VPA exposed rats. Surprisingly in contrast to early postnatal life and adolescence, we find that adult VPA exposed rats show reduced synaptic function. Both NMDAR mediated currents and LTP are lower in adult VPA rats, although spontaneous activity and endocannabinoid dependent long-term depression are normal. We conclude that rather than correcting, synaptic abnormalities persist into adulthood in VPA exposed rats, although a quite different synaptic phenotype is present. This switch from hyper to hypo function in mPFC may be linked to some of the neurodevelopmental defects found in prenatal VPA exposure and autism spectrum disorders in general.

Investigation of the mechanism for phthalate-induced toxicity during male sexual differentiation in the rat

EPA Science Inventory

Male rats exposed to phthalate esters during sexual differentiation (GDI4-GDI8) display various developmental abnormalities of the reproductive tract that are manifested later in adult life. Induction of these malformations is associated with declines in fetal testicular testoste...

Investigation of the mechanism for phthalate-induced toxicity during male sexual differentiation in the rat.

EPA Science Inventory

Male rats exposed to phthalate esters during sexual differentiation (GDI4-GDI8) display various reproductive developmental abnormalities later in adult life which are associated with declines in fetal testicular testosterone (T) production and insulin-like three hormone (lnsl-3...

The Effects of In Vivo Acute Exposure to Polychlorinatedbiphenyls on Free and Total Thyroxine in Rats

EPA Science Inventory

Hypothyroxinemia in rats has been well documented as a result of either developmental or adult exposure to polychlorinated biphenyls (PCBs). Hypothetical mechanisms for this include induction of hepatic catabolic enzymes and cellular hormone transporters, and/or interference wit...

Chronic central serotonin depletion attenuates ventilation and body temperature in young but not adult Tph2 knockout rats.

PubMed

Kaplan, Kara; Echert, Ashley E; Massat, Ben; Puissant, Madeleine M; Palygin, Oleg; Geurts, Aron M; Hodges, Matthew R

2016-05-01

Genetic deletion of brain serotonin (5-HT) neurons in mice leads to ventilatory deficits and increased neonatal mortality during development. However, it is unclear if the loss of the 5-HT neurons or the loss of the neurochemical 5-HT led to the observed physiologic deficits. Herein, we generated a mutant rat model with constitutive central nervous system (CNS) 5-HT depletion by mutation of the tryptophan hydroxylase 2 (Tph2) gene in dark agouti (DA(Tph2-/-)) rats. DA(Tph2-/-) rats lacked TPH immunoreactivity and brain 5-HT but retain dopa decarboxylase-expressing raphe neurons. Mutant rats were also smaller, had relatively high mortality (∼50%), and compared with controls had reduced room air ventilation and body temperatures at specific postnatal ages. In adult rats, breathing at rest and hypoxic and hypercapnic chemoreflexes were unaltered in adult male and female DA(Tph2-/-) rats. Body temperature was also maintained in adult DA(Tph2-/-) rats exposed to 4°C, indicating unaltered ventilatory and/or thermoregulatory control mechanisms. Finally, DA(Tph2-/-) rats treated with the 5-HT precursor 5-hydroxytryptophan (5-HTP) partially restored CNS 5-HT and showed increased ventilation (P < 0.05) at a developmental age when it was otherwise attenuated in the mutants. We conclude that constitutive CNS production of 5-HT is critically important to fundamental homeostatic control systems for breathing and temperature during postnatal development in the rat. Copyright © 2016 the American Physiological Society.

Chronic central serotonin depletion attenuates ventilation and body temperature in young but not adult Tph2 knockout rats

PubMed Central

Kaplan, Kara; Echert, Ashley E.; Massat, Ben; Puissant, Madeleine M.; Palygin, Oleg; Geurts, Aron M.

2016-01-01

Genetic deletion of brain serotonin (5-HT) neurons in mice leads to ventilatory deficits and increased neonatal mortality during development. However, it is unclear if the loss of the 5-HT neurons or the loss of the neurochemical 5-HT led to the observed physiologic deficits. Herein, we generated a mutant rat model with constitutive central nervous system (CNS) 5-HT depletion by mutation of the tryptophan hydroxylase 2 (Tph2) gene in dark agouti (DATph2−/−) rats. DATph2−/− rats lacked TPH immunoreactivity and brain 5-HT but retain dopa decarboxylase-expressing raphe neurons. Mutant rats were also smaller, had relatively high mortality (∼50%), and compared with controls had reduced room air ventilation and body temperatures at specific postnatal ages. In adult rats, breathing at rest and hypoxic and hypercapnic chemoreflexes were unaltered in adult male and female DATph2−/− rats. Body temperature was also maintained in adult DATph2−/− rats exposed to 4°C, indicating unaltered ventilatory and/or thermoregulatory control mechanisms. Finally, DATph2−/− rats treated with the 5-HT precursor 5-hydroxytryptophan (5-HTP) partially restored CNS 5-HT and showed increased ventilation (P < 0.05) at a developmental age when it was otherwise attenuated in the mutants. We conclude that constitutive CNS production of 5-HT is critically important to fundamental homeostatic control systems for breathing and temperature during postnatal development in the rat. PMID:26869713

Converging on a core cognitive deficit: the impact of various neurodevelopmental insults on cognitive control

PubMed Central

O'Reilly, Kally C.; Kao, Hsin-Yi; Lee, Heekyung; Fenton, André A.

2014-01-01

Despite substantial effort and immense need, the treatment options for major neuropsychiatric illnesses like schizophrenia are limited and largely ineffective at improving the most debilitating cognitive symptoms that are central to mental illness. These symptoms include cognitive control deficits, the inability to selectively use information that is currently relevant and ignore what is currently irrelevant. Contemporary attempts to accelerate progress are in part founded on an effort to reconceptualize neuropsychiatric illness as a disorder of neural development. This neuro-developmental framework emphasizes abnormal neural circuits on the one hand, and on the other, it suggests there are therapeutic opportunities to exploit the developmental processes of excitatory neuron pruning, inhibitory neuron proliferation, elaboration of myelination, and other circuit refinements that extend through adolescence and into early adulthood. We have crafted a preclinical research program aimed at cognition failures that may be relevant to mental illness. By working with a variety of neurodevelopmental rodent models, we strive to identify a common pathophysiology that underlies cognitive control failure as well as a common strategy for improving cognition in the face of neural circuit abnormalities. Here we review our work to characterize cognitive control deficits in rats with a neonatal ventral hippocampus lesion and rats that were exposed to Methylazoxymethanol acetate (MAM) in utero. We review our findings as they pertain to early developmental processes, including neurogenesis, as well as the power of cognitive experience to refine neural circuit function within the mature and maturing brain's cognitive circuitry. PMID:24966811

A review of developmental and reproductive toxicity of CS2 and H2 S generated by the pesticide sodium tetrathiocarbonate.

PubMed

Silva, Marilyn

2013-04-01

Sodium tetrathiocarbonate (STTC) is an example of a pesticide that when prepared for use in aqueous solution releases two toxic products carbon disulfide (CS2 ) (active ingredient) and hydrogen sulfide (H2 S) in ambient air in equimolar concentrations resulting in potential exposure to workers and bystanders. CS2 and H2 S are pollutants that are generated from several pesticides as well as in industrial settings. Registrant submitted reports and open literature studies for STTC, CS2 and H2 S were reviewed. Previous reports suggest that CS2 was a concern as a developmental and reproductive toxicant. H2 S was also examined since it is a neurotoxicant and potentially harmful to developing fetuses. STTC did not induce developmental or reproductive effects in animal studies. CS2 was a developmental neurobehavioral toxin in rat pups (inhalation no observed effect level [NOEL]=0.01 ppm). Reproductive effects occurred in male and female factory workers after CS2 exposure (NOEL=1 ppm). H2 S had developmental effects in rats at doses at or above those observed for nasal pathology (NOEL=10 ppm) but was not a reproductive or developmental toxin in humans. The database for CS2 indicates a strong potential for developmental neurotoxicity in animals at low doses but it is lacking in acceptable, well-performed studies. There is also a lack of studies performed with CS2 and H2 S as a mixture. © 2013 Wiley Periodicals, Inc.

The `TTIME' Package: Performance Evaluation in a Cluster Computing Environment

NASA Astrophysics Data System (ADS)

Howe, Marico; Berleant, Daniel; Everett, Albert

2011-06-01

The objective of translating developmental event time across mammalian species is to gain an understanding of the timing of human developmental events based on known time of those events in animals. The potential benefits include improvements to diagnostic and intervention capabilities. The CRAN `ttime' package provides the functionality to infer unknown event timings and investigate phylogenetic proximity utilizing hierarchical clustering of both known and predicted event timings. The original generic mammalian model included nine eutherian mammals: Felis domestica (cat), Mustela putorius furo (ferret), Mesocricetus auratus (hamster), Macaca mulatta (monkey), Homo sapiens (humans), Mus musculus (mouse), Oryctolagus cuniculus (rabbit), Rattus norvegicus (rat), and Acomys cahirinus (spiny mouse). However, the data for this model is expected to grow as more data about developmental events is identified and incorporated into the analysis. Performance evaluation of the `ttime' package across a cluster computing environment versus a comparative analysis in a serial computing environment provides an important computational performance assessment. A theoretical analysis is the first stage of a process in which the second stage, if justified by the theoretical analysis, is to investigate an actual implementation of the `ttime' package in a cluster computing environment and to understand the parallelization process that underlies implementation.

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

PubMed

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

2016-05-01

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

The Neonatal Ventral Hippocampal Lesion (NVHL) Rodent Model of Schizophrenia

PubMed Central

Brady, Anne Marie

2016-01-01

Animal models are crucial to the study of the neurobiological bases of psychiatric disorders, but schizophrenia is a particularly challenging disorder to model given the complexity and heavily verbal nature of its symptoms. This article describes a developmental surgical rodent model of schizophrenia, the neonatal ventral hippocampal lesion (NVHL) model. This widely used model produces reliable behavioral abnormalities that are comparable to those observed in patients, as well as anatomical and neurophysiological disruptions in forebrain areas that are also implicated in schizophrenia. A brief background of the development and validity of the NVHL model is discussed here, along with detailed procedures for producing the model in rats. Critical issues particular to neonatal surgery are discussed, and representative histological and behavioral results are presented. PMID:27696361

Prediction of in vivo developmental toxicity by combination of Hand1-Luc embryonic stem cell test and metabolic stability test with clarification of metabolically inapplicable candidates.

PubMed

Nagahori, Hirohisa; Suzuki, Noriyuki; Le Coz, Florian; Omori, Takashi; Saito, Koichi

2016-09-30

Hand1-Luc Embryonic Stem Cell Test (Hand1-Luc EST) is a promising alternative method for evaluation of developmental toxicity. However, the problems of predictivity have remained due to appropriateness of the solubility, metabolic system, and prediction model. Therefore, we assessed the usefulness of rat liver S9 metabolic stability test using LC-MS/MS to develop new prediction model. A total of 71 chemicals were analyzed by measuring cytotoxicity and differentiation toxicity, and highly reproducible (CV=20%) results were obtained. The first prediction model was developed by discriminant analysis performed on a full dataset using Hand1-Luc EST, and 66.2% of the chemicals were correctly classified by the cross-validated classification. A second model was developed with additional descriptors obtained from the metabolic stability test to calculate hepatic availability, and an accuracy of 83.3% was obtained with applicability domain of 50.7% (=36/71) after exclusion of 22 metabolically inapplicable candidates, which potentially have a metabolic activation property. A step-wise prediction scheme with combination of Hand1-Luc EST and metabolic stability test was therefore proposed. The current results provide a promising in vitro test method for accurately predicting in vivo developmental toxicity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Predicting Developmental Toxicity of ToxCast Phase I Chemicals Using Human Embryonic Stem Cells and Metabolomics

EPA Science Inventory

EPA’s ToxRefDB contains prenatal guideline study data from rats and rabbits for over 240 chemicals that overlap with the ToxCast in vitro high throughput screening project. A subset of these compounds were tested in Stemina Biomarker Discovery's developmental toxicity platform, a...

Developmental Toxicity Evaluations of Whole Mixtures of Disinfection By-products using Concentrated Drinking Water in Rats: Gestational and Lactational Effects of Sulfate and Sodium

EPA Science Inventory

A developmental toxicity bioassay was used in three experiments to evaluate drinking water concentrates for suitability in multigenerational studies. First, chlorinated water was concentrated 135 fold by reverse osmosis; select lost disinfection by-products were spiked back. Co...

Developmental Toxicity Evaluations of Whole Mixtures of Disinfection By-products using Concentrated Drinking Water in Rats: Gestational and Lactational Effects of Sulfate and Sodium*

EPA Science Inventory

A developmental toxicity bioassay was used in three experiments to evaluate drinking water concentrates for suitability in multigenerational studies. First, chlorinated water was concentrated 135 fold by reverse osmosis; select lost disinfection by-products were spiked back. Conc...

DEVELOPMENTAL TOXICITY OF PERFLUOROOCATANE SULFONATE (PFOS) IN THE RAT AND MOUSE

EPA Science Inventory

1Lau, C., 1J.M. Rogers, 1R.G. Hanson*, 1B.D. Barbee*, 1M.G. Narotsky, 1J.E. Schmid* and 2J.H. Richards*. 1Reproductive Toxicology Division, and 2Environmental Toxicology Division, NHEERL, US EPA, Research Triangle Park, North Carolina. Developmental toxicity of Perfluorooctane ...

DEVELOPMENTAL HYPOTHYROIDISM INDUCES A NEURONAL HETEROTOPIA IN THE CORPUS CALLOSUM OF THE RAT.

EPA Science Inventory

It is well established that severe hypothyroidism leads to profound alterations in brain development and mental retardation. In this study we examined the effect of subtle decreases in maternal thyroid hormones (TH) on brain development in the rat. To induce TH insufficiency pr...

BRAIN, LIVER AND THYROID BIOMARKERS REFLECT ENHANCED SENSITIVITY OF THE DEVELOPING RAT TO THYROID HORMONE DEPLETION.

EPA Science Inventory

Many developmental events are regulated at least in part by thyroid hormones. It was hypothesized that tissue biomarkers of thyroid status would be more accurate predictors of neurotoxicity than serum biomarkers in rats treated with the goitrogen propylthiouracil (PTU). Over seve...

75 FR 29901 - Boscalid; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-28

... level of concern for boscalid is a MOE of 100 or below, these MOEs are not of concern. 4. Intermediate... dogs resulted in increases in alkaline phosphatase levels as well as hepatic weights. In subchronic and... in rats and in the rat developmental neurotoxicity (DNT) study at a level that did not induce...

Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. I: maternal and prenatal evaluations

EPA Science Inventory

Abstract: The maternal and developmental toxicities of perfluorooctane sulfonate (PFOS, C8F17SO3-) were evaluated in the rat and mouse. PFOS is an environmentally persistent compound used as a surfactant and occurs as a degradation product of both perfluorooctane sulfonyl fluorid...

Prenatal exposure to vapors of gasoline-ethanol blends causes few cognitive deficits in adult rats

EPA Science Inventory

Developmental exposure to inhaled ethanol-gasoline fuel blends is a potential public health concern. Here we assessed cognitive functions in adult offspring of pregnant rats that were exposed to vapors of gasoline blended with a range of ethanol concentrations, including gasoli...

DEVELOPMENTAL EFFECTS OF TRICHLOROACETONITRILE ADMINISTERED IN CORN OIL TO PREGNANT LONG-EVANS RATS

EPA Science Inventory

Trichloroacetonitrile (TCAN) is a by-product of the chlorine disinfection of water containing natural organic material. When administered by gavage to pregnant Long-Evans rats in a medium-chain triglyceride vehicle, tricaprylin oil (Tricap), at a volume of 10 ml/kg, TCAN induced ...

Ontogeny of NHE8 in the rat proximal tubule

PubMed Central

Becker, Amy M.; Zhang, Jianning; Goyal, Sunita; Dwarakanath, Vangipuram; Aronson, Peter S.; Moe, Orson W.; Baum, Michel

2014-01-01

Proximal tubule bicarbonate reabsorption is primarily mediated via the Na+/H+ exchanger, identified as NHE3 in adults. Previous studies have demonstrated a maturational increase in rat proximal tubule NHE3 expression, with a paucity of NHE3 expression in neonates, despite significant Na+-dependent proton secretion. Recently, a novel Na+/H+ antiporter (NHE8) was identified and found to be expressed on the apical membrane of the proximal tubule. To determine whether NHE8 may be the antiporter responsible for proton secretion in neonates, the present study characterized the developmental expression of NHE8 in rat proximal tubules. RNA blots and real-time RT-PCR demonstrated no developmental difference in the mRNA of renal NHE8. Immunoblots, however, demonstrated peak protein abundance of NHE8 in brush border membrane vesicles of 7- and 14-day-old compared with adult rats. In contrast, the level of NHE8 expression in total cortical membrane protein was higher in adults than in neonates. Immunohistochemistry confirmed the presence of NHE8 on the apical membrane of the proximal tubules of neonatal and adult rats. These data demonstrate that NHE8 does undergo maturational changes on the apical membrane of the rat proximal tubule and may account for the Na+-dependent proton flux in neonatal proximal tubules. PMID:17429030

Antiepileptic effects of levetiracetam in a rodent neonatal seizure model.

PubMed

Talos, Delia M; Chang, Meayoung; Kosaras, Bela; Fitzgerald, Erin; Murphy, Andrew; Folkerth, Rebecca Dunn; Jensen, Frances E

2013-01-01

Neonatal seizures can result in chronic epilepsy and long-term behavioral and cognitive deficits. Levetiracetam (LEV), an antiepileptic drug that binds to the synaptic vesicle protein 2A (SV2A), has been increasingly used off-label for the therapy of neonatal seizures. Preclinical data regarding the acute or long-term efficacy of LEV are lacking. We tested the anticonvulsant efficacy of LEV in a rat model of hypoxia-induced neonatal seizures. In addition, we evaluated the protective effects of postnatal day (P)10 LEV treatment on later-life kainic acid (KA)-induced seizure susceptibility and seizure-induced neuronal injury. Western blot and immunohistochemistry were used to assess the developmental regulation of SV2A in the rat and human brain. LEV pretreatment at P10 significantly decreased the cumulative duration of behavioral and electrographic seizures at both 25 and 50 mg/kg. At P40, KA-induced seizures and neuronal loss were significantly diminished in rats previously treated with LEV. LEV target SV2A is present in both neonatal rat and human brain and increases steadily to adulthood. LEV suppressed acute seizures induced by perinatal hypoxia and diminished later-life seizure susceptibility and seizure-induced neuronal injury, providing evidence for disease modification. These results support consideration of a clinical trial of LEV in neonatal seizures.

Oral methylphenidate alleviates the fine motor dysfunction caused by chronic postnatal manganese exposure in adult rats.

PubMed

Beaudin, Stéphane A; Strupp, Barbara J; Lasley, Stephen M; Fornal, Casimir A; Mandal, Shyamali; Smith, Donald R

2015-04-01

Developmental manganese (Mn) exposure is associated with motor dysfunction in children and animal models, but little is known about the underlying neurochemical mechanisms or the potential for amelioration by pharmacotherapy. We investigated whether methylphenidate (MPH) alleviates fine motor dysfunction due to chronic postnatal Mn exposure, and whether Mn exposure impairs brain extracellular dopamine (DA) and norepinephrine (NE) in the prefrontal cortex (PFC) and striatum in adult animals. Rats were orally exposed to 0 or 50 mg Mn/kg/day from postnatal day 1 until the end of the study (PND 145). The staircase test was used to assess skilled forelimb function. Oral MPH (2.5 mg/kg/day) was administered daily 1 h before staircase testing for 16 days. DA and NE levels were measured by dual probe microdialysis. Results show that Mn exposure impaired reaching and grasping skills and the evoked release of DA and NE in the PFC and striatum of adult rats. Importantly, oral MPH treatment fully alleviated the fine motor deficits in the Mn-exposed animals, but did not affect forelimb skills of control rats not exposed to Mn. These results suggest that catecholaminergic hypofunctioning in the PFC and striatum may underlie the Mn-induced fine motor dysfunction, and that oral MPH pharmacotherapy is an effective treatment approach for alleviating this dysfunction in adult animals. The therapeutic potential of MPH for the treatment of motor dysfunction in Mn-exposed children and adults appears promising pending further characterization of MPH efficacy in other functional areas (eg, attention) believed to be affected by developmental Mn exposure. © 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.

Sex-specific effects of developmental alcohol exposure on cocaine-induced place preference in adulthood.

PubMed

Macht, Victoria A; Kelly, Sandra J; Gass, Justin T

2017-08-14

Fetal Alcohol Syndrome (FAS) is associated with high rates of drug addiction in adulthood. One possible basis for increased drug use in this population is altered sensitivity to drug-associated contexts. This experiment utilized a rat model of FASD to examine behavioral and neural changes in the processing of drug cues in adulthood. Alcohol was given by intragastric intubation to pregnant rats throughout gestation and to rat pups during the early postnatal period (ET group). Controls consisted of a non-treated group (NC) and a pair-fed group given the intubation procedure without alcohol (IC). On postnatal day (PD) 90, rats from all treatment groups were given saline, 0.3mg/kg, 3.0mg/kg, or 10.0mg/kg cocaine pairings with a specific context in the conditioned place preference (CPP) paradigm. While control animals of both sexes showed cocaine CPP at the 3.0 and 10.0mg/kg doses, ET females also showed cocaine CPP at 0.3mg/kg. This was accompanied by a decrease in c-Fos/GAD 67 cells in the nucleus accumbens (NAc) shell and GAD 67 -only cells in the NAc shell and PFC at this 0.3mg/kg dose. ET males failed to show cocaine CPP at the 3.0mg/kg dose. This was associated with an increase in c-Fos only-labeled cells in the NAc core and PFC at this 3.0mg/kg dose. These results suggest that developmental alcohol exposure has a sexually-dimorphic effect on cocaine's conditioning effects in adulthood and the NAc. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of postnatal growth restriction and subsequent catch-up growth on neurodevelopment and glucose homeostasis in rats.

PubMed

Alexeev, Erica E; Lönnerdal, Bo; Griffin, Ian J

2015-06-05

There is increasing evidence that poor growth of preterm infants is a risk factor for poor long-term development, while the effects of early postnatal growth restriction are not well known. We utilized a rat model to examine the consequences of different patterns of postnatal growth and hypothesized that early growth failure leads to impaired development and insulin resistance. Rat pups were separated at birth into normal (N, n = 10) or restricted intake (R, n = 16) litters. At d11, R pups were re-randomized into litters of 6 (R-6), 10 (R-10) or 16 (R-16) pups/dam. N pups remained in litters of 10 pups/dam (N-10). Memory and learning were examined through T-maze test. Insulin sensitivity was measured by i.p. insulin tolerance test and glucose tolerance test. By d10, N pups weighed 20% more than R pups (p < 0.001). By d15, the R-6 group caught up to the N-10 group in weight, the R-10 group showed partial catch-up growth and the R-16 group showed no catch-up growth. All R groups showed poorer scores in developmental testing when compared with the N-10 group during T-Maze test (p < 0.05). Although R-16 were more insulin sensitive than R-6 and R-10, all R groups were more glucose tolerant than N-10. In rats, differences in postnatal growth restriction leads to changes in development and in insulin sensitivity. These results may contribute to better elucidating the causes of poor developmental outcomes in human preterm infants.

Evaluation of developmental toxicity studies of glyphosate with attention to cardiovascular development.

PubMed

Kimmel, Gary L; Kimmel, Carole A; Williams, Amy L; DeSesso, John M

2013-02-01

The herbicide glyphosate has undergone multiple safety tests for developmental toxicity in rats and rabbits. The European Commission's 2002 review of available glyphosate data discusses specific heart defects observed in several individual rabbit developmental toxicity studies, but describes the evidence for a potential causal relationship as equivocal. The present assessment was undertaken to analyze the current body of information generated from seven unpublished rabbit studies in order to determine if glyphosate poses a risk for cardiovascular malformations. In addition, the results of six unpublished developmental toxicity studies in rats were considered. Five of the seven rabbit studies (dose range: 10-500 mg/kg/day) were GLP- and testing guideline-compliant for the era in which the studies were performed; a sixth study predated testing and GLP guidelines, but generally adhered to these principles. The seventh study was judged inadequate. In each of the adequate studies, offspring effects occurred only at doses that also caused maternal toxicity. An integrated evaluation of the six adequate studies, using conservative assumptions, demonstrated that neither the overall malformation rate nor the incidence of cardiovascular malformations increased with dose up to the point where severe maternal toxicity was observed (generally ≥150 mg/kg/day). Random occurrences of cardiovascular malformations were observed across all dose groups (including controls) and did not exhibit a dose-response relationship. In the six rat studies (dose range: 30-3500 mg/kg/day), a low incidence of sporadic cardiovascular malformations was reported that was clearly not related to treatment. In summary, assessment of the entire body of the developmental toxicity data reviewed fails to support a potential risk for increased cardiovascular defects as a result of glyphosate exposure during pregnancy.

Sarcomeric Myosin Expression in the Tongue Body of Humans, Macaques and Rats

PubMed Central

Rahnert, Jill A.; Sokoloff, Alan J.; Burkholder, Thomas J.

2010-01-01

Expression of developmental and unconventional myosin heavy chain (MHC) isoforms in some adult head and neck muscles is thought to reflect specific contractile demands of muscle fibers active during kinematically complex movements. Mammalian tongue muscles are active during oromotor behaviors that encompass a wide range of tongue movement speeds and tongue shape changes (e.g. respiration, oral transport, swallowing, rejection), but the extent to which tongue muscles express developmental and unconventional MHC is not known. Quantitative PCR was used to determine the mRNA content of conventional MHC-beta, MHC-2a, MHC-2b and MHC-2x, the developmental isoforms embryonic MHC and neonatal MHC and the unconventional isoforms atrial/cardiac-α MHC (MHC-alpha), extraocular MHC, masseter MHC and slow tonic MHC in tongue body muscles of the rat, macaque and human. In all species, conventional MHC isoforms predominate. MHC-2b and MHC-2x account for 98% of total MHC mRNA in the rat. MHC-2a, MHC-2x and MHC-beta account for 94% of total MHC mRNA in humans and 96% of total MHC mRNA in macaque. With the exception of MHC-alpha in humans (5%), developmental and unconventional MHC mRNA represents less than 0.3% of total MHC mRNA. We conclude that in these species, there is limited expression of developmental and unconventional MHC and that diversity of tongue body muscle fiber contractile properties is achieved primarily by MHC-beta, MHC-2a, MHC-2x and MHC-2b. Whether expression of MHC-alpha mRNA in tongue is unique to humans or present in other hominoids awaits further investigation. PMID:19907142

Evaluation of developmental toxicity studies of glyphosate with attention to cardiovascular development

PubMed Central

Kimmel, Gary L.; Kimmel, Carole A.; Williams, Amy L.

2013-01-01

The herbicide glyphosate has undergone multiple safety tests for developmental toxicity in rats and rabbits. The European Commission’s 2002 review of available glyphosate data discusses specific heart defects observed in several individual rabbit developmental toxicity studies, but describes the evidence for a potential causal relationship as equivocal. The present assessment was undertaken to analyze the current body of information generated from seven unpublished rabbit studies in order to determine if glyphosate poses a risk for cardiovascular malformations. In addition, the results of six unpublished developmental toxicity studies in rats were considered. Five of the seven rabbit studies (dose range: 10–500 mg/kg/day) were GLP- and testing guideline-compliant for the era in which the studies were performed; a sixth study predated testing and GLP guidelines, but generally adhered to these principles. The seventh study was judged inadequate. In each of the adequate studies, offspring effects occurred only at doses that also caused maternal toxicity. An integrated evaluation of the six adequate studies, using conservative assumptions, demonstrated that neither the overall malformation rate nor the incidence of cardiovascular malformations increased with dose up to the point where severe maternal toxicity was observed (generally ≥150 mg/kg/day). Random occurrences of cardiovascular malformations were observed across all dose groups (including controls) and did not exhibit a dose–response relationship. In the six rat studies (dose range: 30–3500 mg/kg/day), a low incidence of sporadic cardiovascular malformations was reported that was clearly not related to treatment. In summary, assessment of the entire body of the developmental toxicity data reviewed fails to support a potential risk for increased cardiovascular defects as a result of glyphosate exposure during pregnancy. PMID:23286529

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

Developmental differences in stress responding after repeated underwater trauma exposures in rats.

PubMed

Altman, Daniel E; Simmons, Laurence P; Vuong, Chau T; Taylor, Rachel M; Sousa, Jason C; Marcsisin, Sean R; Zottig, Victor E; Moore, Nicole L T

2018-05-01

Adolescence is a distinct developmental period characterized by behavioral and physiological maturation. Rapid ongoing changes during neurodevelopment in particular present potential opportunities for stress to have lasting effects on longitudinal outcomes of behavioral and neuroendocrine function. While adult stress effects on outcomes during adulthood have been characterized, little is known about the lasting effects of adolescent repeated stressor exposure on outcomes during adolescence. We have previously reported different stress responses in adolescent rats relative to adult rats, including a blunted fear response outcome in adulthood in rats stressed during adolescence. The present study characterized the ontogeny of behavioral and neuroendocrine responses to eight underwater trauma (UWT) exposures in rats over a two week poststress time period during adolescence (P34) or adulthood (P83) relative to age-matched control groups that underwent eight swimming episodes without UWT. Repeated UWT exposures starting in adolescence, but not adulthood, resulted in adverse behavioral responses on the elevated plus maze 1 day post-stress. Corticosterone responses did not differ between UWT-exposed and controls for either age group at 1 day or at 7 days poststress, although there was an effect of age on corticosterone levels. We conclude that repeated UWT stress events have a lasting, negative behavioral effect on adolescent rats that is not observed in adult rats after the two-week exposure window. These results suggest that neurophysiological mechanisms underlying recovery from a repeated stressor are immature in adolescence relative to adulthood in rats.

Early dietary sodium restriction disrupts the peripheral anatomical development of the gustatory system.

PubMed

Krimm, R F; Hill, D L

1999-05-01

Dietary sodium restriction has profound effects on the development of peripheral taste function and central taste system anatomy. This study examined whether early dietary sodium restriction also affects innervation of taste buds. The number of geniculate ganglion cells that innervate single fungiform taste buds were quantified for the midregion of the tongue in two groups of rats: those fed either a low-sodium diet and those fed a sodium replete diet (control rats) from early prenatal development through adulthood. The same mean number of ganglion cells in developmentally sodium-restricted and control adult rats innervated taste buds on the midregion of the tongue. However, the characteristic relationship of the larger the taste bud, the more neurons that innervate it did not develop in sodium-restricted rats. The failure to form such a relationship in experimental rats was likely due to a substantially smaller mean taste bud volume than controls and probably not to changes in innervation. Further experiments demonstrated that the altered association between number of innervating neurons and taste bud size in restricted rats was reversible. Feeding developmentally sodium-restricted rats a sodium replete diet at adulthood resulted in an increase in taste bud size. Accordingly, the high correlation between taste bud volume and innervation was established in sodium-replete rats. Findings from the current study reveal that early dietary manipulations influence neuron-target interactions; however, the effects of dietary sodium restriction on peripheral gustatory anatomy can be completely restored, even in adult animals.

Acute and developmental toxicity assessment of erincine A-enriched Hericium erinaceus mycelia in Sprague-Dawley rats.

PubMed

Li, I-Chen; Chen, Wan-Ping; Chen, Yen-Po; Lee, Li-Ya; Tsai, Yueh-Ting; Chen, Chin-Chu

2018-01-23

This study aimed to establish an in vitro model to confirm the efficacy of erinacine A-enriched Hericium erinaceus (EAHE) mycelia and investigate its potential adverse effects in a preclinical experimental setting, including an assessment on the oral administration of EAHE mycelia in acute and prenatal developmental toxicity tests. At a single dose of 5000 mg/kg body weight, EAHE mycelia elicited no death or treatment-related signs of toxicity in ten Sprague-Dawley rats of both sexes during the 14 days of the experimental period. After considering the recommended dose range of EAHE mycelia from the acute toxicity test as well as the therapeutic doses, EAHE mycelia was administered to 66 pregnant rats in the low, medium, and high-dose groups by gavage at 875, 1750, and 2625 mg/kg body weight, respectively. All dams were subjected to a Caesarean section on the 20th day of pregnancy, and the fetuses were examined for any morphological abnormalities. Results indicated that weight of uterus, fetal body weight, number of corpora lutea, implantation sites, pre-implantation loss, and post-implantation loss of the treatment groups and the control group exhibited no statistical difference. In addition, no significant differences were observed in the fetal external, organ, and skeletal examinations. Taken together, it can be concluded that EAHE mycelia is considered safe and practically nontoxic for consumption within the appropriate doses and investigation period in this study.

Post-injury stretch promotes recovery in a rat model of muscle damage induced by lengthening contractions.

PubMed

Mori, Tomohiro; Agata, Nobuhide; Itoh, Yuta; Inoue-Miyazu, Masumi; Mizumura, Kazue; Sokabe, Masahiro; Taguchi, Toru; Kawakami, Keisuke

2017-06-30

We investigated the cellular mechanisms and therapeutic effect of post-injury stretch on the recovery process from muscle injury induced by lengthening contractions (LC). One day after LC, a single 15-min bout of muscle stretch was applied at an intensity of 3 mNm. The maximal isometric torque was measured before and at 2-21 days after LC. The myofiber size was analyzed at 21 days after LC. Developmental myosin heavy chain-immunoreactive (dMHC-ir) cells, a marker of regenerating myofibers, were observed in the early recovery stage (2-5 days after LC). We observed that LC-induced injury markedly decreased isometric torque and myofiber size, which recovered faster in rats that underwent stretch than in rats that did not. Regenerating myofiber with dMHC-ir cells was observed earlier in rats that underwent stretch. These results indicate that post-injury stretch may facilitate the regeneration and early formation of new myofibers, thereby promoting structural and functional recovery from LC-induced muscle injury.

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.

The effect of developmental vitamin D deficiency in male and female Sprague-Dawley rats on decision-making using a rodent gambling task.

PubMed

Peak, J N; Turner, K M; Burne, T H J

2015-01-01

Developmental vitamin D (DVD) deficiency is a plausible risk factor for schizophrenia that has been associated with behavioural alterations including disruptions in latent inhibition and response inhibition. The rodent gambling task (rGT) assesses risk-based decision-making, which is a key cognitive deficit observed in schizophrenia patients. The primary aim of this study was to examine risk-based decision-making in DVD-deficient and control rats on the rGT. We also evaluated the performance of female Sprague-Dawley rats on the rGT for the first time. Adult male and female Sprague-Dawley rats from control and vitamin D deficient dams were trained to perform the rGT in standard operant chambers and their performance and choice-preferences were assessed. Female rats were significantly faster to reach rGT training criteria compared with male rats and DVD-deficient rats were faster to reach training criteria than control animals. After reaching stable performance on the rGT DVD-deficient and control rats showed a significant preference for the optimal choice-option in the rGT, but there were no significant effects of sex or diet on these responses. DVD deficiency did not alter the decision-making processes on the rGT because no significant changes in choice-preferences were evident. This is the first study to demonstrate that once established, the performance of females is comparable to male Sprague-Dawley rats on the rGT. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

Developmental cuprizone exposure impairs oligodendrocyte lineages differentially in cortical and white matter tissues and suppresses glutamatergic neurogenesis signals and synaptic plasticity in the hippocampal dentate gyrus of rats

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

Abe, Hajime; Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193; Saito, Fumiyo

2016-01-01

Developmental cuprizone (CPZ) exposure impairs rat hippocampal neurogenesis. Here, we captured the developmental neurotoxicity profile of CPZ using a region-specific expression microarray analysis in the hippocampal dentate gyrus, corpus callosum, cerebral cortex and cerebellar vermis of rat offspring exposed to 0, 0.1, or 0.4% CPZ in the maternal diet from gestation day 6 to postnatal day (PND) 21. Transcripts of those genes identified as altered were subjected to immunohistochemical analysis on PNDs 21 and 77. Our results showed that transcripts for myelinogenesis-related genes, including Cnp, were selectively downregulated in the cerebral cortex by CPZ at ≥ 0.1% or 0.4% onmore » PND 21. CPZ at 0.4% decreased immunostaining intensity for 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase) and CNPase{sup +} and OLIG2{sup +} oligodendrocyte densities in the cerebral cortex, whereas CNPase immunostaining intensity alone was decreased in the corpus callosum. By contrast, a striking transcript upregulation for Klotho gene and an increased density of Klotho{sup +} oligodendrocytes were detected in the corpus callosum at ≥ 0.1%. In the dentate gyrus, CPZ at ≥ 0.1% or 0.4% decreased the transcript levels for Gria1, Grin2a and Ptgs2, genes related to the synapse and synaptic transmission, and the number of GRIA1{sup +} and GRIN2A{sup +} hilar γ-aminobutyric acid (GABA)-ergic interneurons and cyclooxygenase-2{sup +} granule cells. All changes were reversed at PND 77. Thus, developmental CPZ exposure reversibly decreased mature oligodendrocytes in both cortical and white matter tissues, and Klotho protected white matter oligodendrocyte growth. CPZ also reversibly targeted glutamatergic signals of GABAergic interneuron to affect dentate gyrus neurogenesis and synaptic plasticity in granule cells. - Highlights: • We examined developmental cuprizone (CPZ) neurotoxicity in maternally exposed rats. • Multiple brain region-specific global gene expression profiling was performed. • CPZ decreased mature oligodendrocytes in both cortical and white matter tissues. • Klotho protected oligodendrocyte growth specifically in white matter. • CPZ also impaired glutamatergic signals and synaptic plasticity in the hippocampus.« less

Endosulfan and Cypermethrin Pesticide Mixture Induces Synergistic or Antagonistic Effects on Developmental Exposed Rats Depending on the Analyzed Behavioral or Neurochemical End Points.

PubMed

Gómez-Giménez, Belén; Llansola, Marta; Cabrera-Pastor, Andrea; Hernández-Rabaza, Vicente; Agustí, Ana; Felipo, Vicente

2018-02-21

Exposure to pesticides has been associated with neurodevelopmental toxicity. Usually people are exposed to mixtures of pesticides. However, most studies analyze the effects of individual pesticides. Developmental exposure to mixtures of pesticides may result in additive effects or in antagonistic or synergistic effects. The aim of this work was to compare the effects of developmental exposure of rats to cypermethrin or endosulfan with the effects of its mixture on cognitive and motor function and on some underlying mechanisms. Exposure to individual pesticides or the mixture was from gestational day 7 to postnatal day 21. We analyzed the effects, in males and females, on spatial learning and memory, associative learning, anxiety, motor coordination, and spontaneous motor activity. We also analyzed neuroinflammation and NMDA receptor subunits in hippocampus and extracellular GABA in cerebellum. Exposure to the mixture, but not to individual pesticides, impaired spatial memory in males, associative learning in females, and increased motor activity in males and females. This indicates a synergistic effect of cypermethrin and endolsufan exposure on these end points. In contrast, motor coordination was impaired by individual exposure to endosulfan or cypermethrin, associated with increased extracellular GABA in cerebellum, but these effects were prevented in rats exposed to the mixture, indicating an antagonistic effect of cypermethrin and endolsufan exposure on these end points. The results show different interaction modes (synergism or antagonism) of the pesticides, depending on the end point analyzed and the sex of the rats.

Elabela/Toddler Is an Endogenous Agonist of the Apelin APJ Receptor in the Adult Cardiovascular System, and Exogenous Administration of the Peptide Compensates for the Downregulation of Its Expression in Pulmonary Arterial Hypertension

PubMed Central

Yang, Peiran; Read, Cai; Kuc, Rhoda E.; Buonincontri, Guido; Southwood, Mark; Torella, Rubben; Upton, Paul D.; Crosby, Alexi; Sawiak, Stephen J.; Carpenter, T. Adrian; Glen, Robert C.; Morrell, Nicholas W.; Maguire, Janet J.

2017-01-01

Background: Elabela/toddler (ELA) is a critical cardiac developmental peptide that acts through the G-protein–coupled apelin receptor, despite lack of sequence similarity to the established ligand apelin. Our aim was to investigate the receptor pharmacology, expression pattern, and in vivo function of ELA peptides in the adult cardiovascular system, to seek evidence for alteration in pulmonary arterial hypertension (PAH) in which apelin signaling is downregulated, and to demonstrate attenuation of PAH severity with exogenous administration of ELA in a rat model. Methods: In silico docking analysis, competition binding experiments, and downstream assays were used to characterize ELA receptor binding in human heart and signaling in cells expressing the apelin receptor. ELA expression in human cardiovascular tissues and plasma was determined using real-time quantitative polymerase chain reaction, dual-labeling immunofluorescent staining, and immunoassays. Acute cardiac effects of ELA-32 and [Pyr1]apelin-13 were assessed by MRI and cardiac catheterization in anesthetized rats. Cardiopulmonary human and rat tissues from PAH patients and monocrotaline- and Sugen/hypoxia-exposed rats were used to show changes in ELA expression in PAH. The effect of ELA treatment on cardiopulmonary remodeling in PAH was investigated in the monocrotaline rat model. Results: ELA competed for binding of apelin in human heart with overlap for the 2 peptides indicated by in silico modeling. ELA activated G-protein– and β-arrestin–dependent pathways. We detected ELA expression in human vascular endothelium and plasma. Comparable to apelin, ELA increased cardiac contractility, ejection fraction, and cardiac output and elicited vasodilatation in rat in vivo. ELA expression was reduced in cardiopulmonary tissues from PAH patients and PAH rat models, respectively. ELA treatment significantly attenuated elevation of right ventricular systolic pressure and right ventricular hypertrophy and pulmonary vascular remodeling in monocrotaline-exposed rats. Conclusions: These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin, and is downregulated in human disease and rodent PAH models, and exogenous peptide can reduce the severity of cardiopulmonary remodeling and function in PAH in rats. This study provides additional proof of principle that an apelin receptor agonist may be of therapeutic use in PAH in humans. PMID:28137936

Elabela/Toddler Is an Endogenous Agonist of the Apelin APJ Receptor in the Adult Cardiovascular System, and Exogenous Administration of the Peptide Compensates for the Downregulation of Its Expression in Pulmonary Arterial Hypertension.

PubMed

Yang, Peiran; Read, Cai; Kuc, Rhoda E; Buonincontri, Guido; Southwood, Mark; Torella, Rubben; Upton, Paul D; Crosby, Alexi; Sawiak, Stephen J; Carpenter, T Adrian; Glen, Robert C; Morrell, Nicholas W; Maguire, Janet J; Davenport, Anthony P

2017-03-21

Elabela/toddler (ELA) is a critical cardiac developmental peptide that acts through the G-protein-coupled apelin receptor, despite lack of sequence similarity to the established ligand apelin. Our aim was to investigate the receptor pharmacology, expression pattern, and in vivo function of ELA peptides in the adult cardiovascular system, to seek evidence for alteration in pulmonary arterial hypertension (PAH) in which apelin signaling is downregulated, and to demonstrate attenuation of PAH severity with exogenous administration of ELA in a rat model. In silico docking analysis, competition binding experiments, and downstream assays were used to characterize ELA receptor binding in human heart and signaling in cells expressing the apelin receptor. ELA expression in human cardiovascular tissues and plasma was determined using real-time quantitative polymerase chain reaction, dual-labeling immunofluorescent staining, and immunoassays. Acute cardiac effects of ELA-32 and [Pyr 1 ]apelin-13 were assessed by MRI and cardiac catheterization in anesthetized rats. Cardiopulmonary human and rat tissues from PAH patients and monocrotaline- and Sugen/hypoxia-exposed rats were used to show changes in ELA expression in PAH. The effect of ELA treatment on cardiopulmonary remodeling in PAH was investigated in the monocrotaline rat model. ELA competed for binding of apelin in human heart with overlap for the 2 peptides indicated by in silico modeling. ELA activated G-protein- and β-arrestin-dependent pathways. We detected ELA expression in human vascular endothelium and plasma. Comparable to apelin, ELA increased cardiac contractility, ejection fraction, and cardiac output and elicited vasodilatation in rat in vivo. ELA expression was reduced in cardiopulmonary tissues from PAH patients and PAH rat models, respectively. ELA treatment significantly attenuated elevation of right ventricular systolic pressure and right ventricular hypertrophy and pulmonary vascular remodeling in monocrotaline-exposed rats. These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin, and is downregulated in human disease and rodent PAH models, and exogenous peptide can reduce the severity of cardiopulmonary remodeling and function in PAH in rats. This study provides additional proof of principle that an apelin receptor agonist may be of therapeutic use in PAH in humans. © 2017 The Authors.

A Barnes Maze for Juvenile Rats Delineates the Emergence of Spatial Navigation Ability

ERIC Educational Resources Information Center

McHail, Daniel G.; Valibeigi, Nazanin; Dumas, Theodore C.

2018-01-01

The neural bases of cognition may be greatly informed by relating temporally defined developmental changes in behavior with concurrent alterations in neural function. A robust improvement in performance in spatial learning and memory tasks occurs at 3 wk of age in rodents. We reported that the developmental increase of spontaneous alternation in a…

78 FR 78731 - Indoxacarb; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-27

.../kg/day Chronic RfD = 0.02 Weight of evidence approach was UFA = 10x mg/kg/day. used from four studies..... Weight of evidence approach was 30 days), intermediate-term (1 UFA = 10x used from four studies: to 6..., one developmental toxicity study in rats with DPX-MP062 and DPX-KN128, one developmental toxicity...

Developmental vitamin D deficiency alters multiple neurotransmitter systems in the neonatal rat brain.

PubMed

Kesby, James P; Turner, Karly M; Alexander, Suzanne; Eyles, Darryl W; McGrath, John J; Burne, Thomas H J

2017-11-01

Epidemiological evidence suggests that developmental vitamin D (DVD) deficiency is a risk factor for neuropsychiatric disorders, such as schizophrenia. DVD deficiency in rats is associated with altered brain structure and adult behaviours indicating alterations in dopamine and glutamate signalling. Developmental alterations in dopamine neurotransmission have also been observed in DVD-deficient rats but a comprehensive assessment of brain neurochemistry has not been undertaken. Thus, the current study determined the regional concentrations of dopamine, noradrenaline, serotonin, glutamine, glutamate and γ-aminobutyric acid (GABA), and associated metabolites, in DVD-deficient neonates. Sprague-Dawley rats were fed a vitamin D deficient diet or control diet six weeks prior to mating until birth and housed under UVB-free lighting conditions. Neurotransmitter concentration was assessed by high-performance liquid chromatography on post-mortem neonatal brain tissue. Ubiquitous reductions in the levels of glutamine (12-24%) were observed in DVD-deficient neonates compared with control neonates. Similarly, in multiple brain regions DVD-deficient neonates had increased levels of noradrenaline and serine compared with control neonates. In contrast, increased levels of dopamine and decreased levels of serotonin in DVD-deficient neonates were limited to striatal subregions compared with controls. Our results confirm that DVD deficiency leads to changes in multiple neurotransmitter systems in the neonate brain. Importantly, this regionally-based assessment in DVD-deficient neonates identified both widespread neurotransmitter changes (glutamine/noradrenaline) and regionally selective neurotransmitter changes (dopamine/serotonin). Thus, vitamin D may have both general and local actions depending on the neurotransmitter system being investigated. Taken together, these data suggest that DVD deficiency alters neurotransmitter systems relevant to schizophrenia in the developing rat brain. Copyright © 2017 ISDN. All rights reserved.

Neonatal alcohol exposure disrupts hippocampal neurogenesis and contextual fear conditioning in adult rats

PubMed Central

Hamilton, G.F.; Murawski, N.J.; St. Cyr, S.A.; Jablonski, S.A.; Schiffino, F.L.; Stanton, M.E.; Klintsova, A.Y.

2011-01-01

Developmental alcohol exposure can permanently alter brain structures and produce functional impairments in many aspects of behavior, including learning and memory. This study evaluates the effect of neonatal alcohol exposure on adult neurogenesis in the dentate gyrus of the hippocampus and the implications of such exposure for hippocampus-dependent contextual fear conditioning. Alcohol-exposed rats (AE) received 5.25 g/kg/day of alcohol on postnatal days (PD) 4-9 (third trimester in humans), in a binge-like manner. Two control groups were included: sham-intubated (SI) and suckle-control (SC). Animals were housed in social cages (3/cage) after weaning. On PD80, animals were injected with 200 mg/kg BrdU. Half of the animals were sacrificed two hours later. The remainder were sacrificed on PD114 to evaluate cell survival; separate AE, SI, and SC rats not injected with BrdU were tested for the context preexposure facilitation effect (CPFE; ∼PD117). There was no difference in the number of BrdU+ cells in AE, SI and SC groups on PD80. On PD114, cell survival was significantly decreased in AE rats, demonstrating that developmental alcohol exposure damages new cells' ability to incorporate into the network and survive. Behaviorally tested SC and SI groups preexposed to the training context 24h prior to receiving a 1.5mA 2s footshock froze significantly more during the context test than their counterparts preexposed to an alternate context. AE rats failed to show the CPFE. The current study shows the detrimental, long-lasting effects of developmental alcohol exposure on hippocampal adult neurogenesis and contextual fear conditioning. PMID:21816390

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 ...

75 FR 27434 - [alpha]-(p-Nonylphenol)-[omega]-hydroxypoly(oxyethylene) Sulfate and Phosphate Esters; Time...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-17

.... study with the reproduction/ developmental toxicity screening test in rats (NPEPSD) LOAEL = 300 mg/kg... toxicity screening test. In the Harmonized Guideline 870.3650 study with the nonylphenol ethoxylate... Guideline 870.3650 study in rats following pre- and post-natal exposure to NPEPSDs. E. Aggregate Risks and...

Importance of maternal diabetes on the chronological deregulation of the intrauterine development: an experimental study in rat.

PubMed

Salazar García, Marcela; Reyes Maldonado, Elba; Revilla Monsalve, María Cristina; Villavicencio Guzmán, Laura; Reyes López, Alfonso; Sánchez-Gómez, Concepción

2015-01-01

We investigated whether maternal diabetes induced in rats using streptozotocin (STZ) on Day 5 of pregnancy affects the intrauterine developmental timeline. A total of 30 pregnant Sprague-Dawley diabetic rats (DRs) and 20 control rats (CRs) were used to obtain 21-day fetuses (F21) and newborn (NB) pups. Gestational age, weight, and body size were recorded as were the maxillofacial morphometry and morphohistological characteristics of the limbs. In DRs, pregnancy continued for ∼1.7 days, and delivery occurred 23 days postcoitus (DPC). In this group, the number of pups was lower, and 13% had maxillofacial defects. F21 in the DR group had lower weights and were smaller; moreover, the morphological characteristics of the maxillofacial structures, derived from the neural crest, were discordant with their chronological gestational age, resembling 18- to 19-day-old fetuses. These deficiencies were counterbalanced in NB pups. We conclude that hyperglycemia, which results from maternal diabetes and precedes embryo implantation, deregulates the intrauterine developmental timeline, restricts embryo-fetal growth, and primarily delays the remodeling and maturation of the structures derived from neural crest cells.

A novel mode-of-action mediated by the fetal muscle nicotinic acetylcholine receptor resulting in developmental toxicity in rats.

PubMed

Rasoulpour, Reza J; Ellis-Hutchings, Robert G; Terry, Claire; Millar, Neil S; Zablotny, Carol L; Gibb, Alasdair; Marshall, Valerie; Collins, Toby; Carney, Edward W; Billington, Richard

2012-06-01

Sulfoxaflor (X11422208), a novel agricultural molecule, induced fetal effects (forelimb flexure, hindlimb rotation, and bent clavicle) and neonatal death in rats at high doses (≥ 400 ppm in diet); however, no such effects occurred in rabbit dietary studies despite achieving similar maternal and fetal plasma exposure levels. Mode-of-action (MoA) studies were conducted to test the hypothesis that the effects in rats had a single MoA induced by sulfoxaflor agonism on the fetal rat muscle nicotinic acetylcholine receptor (nAChR). The studies included cross-fostering and critical windows of exposure studies in rats, fetal ((α1)(2)β1γδ) and adult ((α1)(2)β1δε) rat and human muscle nAChR in vitro agonism experiments, and neonatal rat phrenic nerve-hemidiaphragm contracture studies. The weight of evidence from these studies supported a novel MoA where sulfoxaflor is an agonist to the fetal, but not adult, rat muscle nAChR and that prolonged agonism on this receptor in fetal/neonatal rats causes sustained striated muscle contracture resulting in concomitant reduction in muscle responsiveness to physiological nerve stimulation. Fetal effects were inducible with as little as 1 day of exposure at the end of gestation, but were rapidly reversible after birth, consistent with a pharmacological MoA. With respect to human relevance, sulfoxaflor was shown to have no agonism on human fetal or adult muscle nAChRs. Taken together, the data support the hypothesis that the developmental effects of sulfoxaflor in rats are mediated via sustained agonism on the fetal muscle nAChR during late fetal development and are considered not relevant to humans.

Morphogenesis in bat wings: linking development, evolution and ecology.

PubMed

Adams, Rick A

2008-01-01

The evolution of powered flight in mammals required specific developmental shifts from an ancestral limb morphology to one adapted for flight. Through studies of comparative morphogenesis, investigators have quantified points and rates of divergence providing important insights into how wings evolved in mammals. Herein I compare growth,development and skeletogenesis of forelimbs between bats and the more ancestral state provided by the rat (Rattus norvegicus)and quantify growth trajectories that illustrate morphological divergence both developmentally and evolutionarily. In addition, I discuss how wing shape is controlled during morphogenesis by applying multivariate analyses of wing bones and wing membranes and discuss how flight dynamics are stabilized during flight ontogeny. Further, I discuss the development of flight in bats in relation to the ontogenetic niche and how juveniles effect populational foraging patterns. In addition, I provide a hypothetical ontogenetic landscape model that predicts how and when selection is most intense during juvenile morphogenesis and test this model with data from a population of the little brown bat, Myotis lucifugus. (c) 2007 S. Karger AG, Basel

Developmental effects and health aspects of soy protein isolate, casein, and whey in male and female rats.

PubMed

Badger, T M; Ronis, M J; Hakkak, R

2001-01-01

Dietary factors other than the traditional nutrients are found in the so-called functional foods. They are becoming increasingly recognized as potentially important for maintaining good health. Soybeans are rich in such factors thought to help prevent certain chronic diseases. Soy protein isolate (SPI) is one of the three major proteins used in infant formulas sold in the United States, with casein (CAS) and whey (WPH) proteins being the others. We have been studying the health effects of these proteins. Safety concerns have developed over the consumption of soy-based infant formula, partly because of the high circulating levels of the total isoflavones (phytoestrogens) during "critical periods of infant development." There is a paucity of data on developmental, physiological, neurophysiological, behavioral, metabolic, or molecular effects of soy phytochemicals in humans, especially during pregnancy and infancy. We have studied the effects of CAS, SPI, and WPH in short-term, long-term, and multigenerational studies in rats. Aside from minor differences in body weight gain profiles, CAS-, SPI- or WPH-fed rats did not differ in development, organ weights, in vitro hepatic metabolism of testosterone (T), or reproductive performance. However, some endocrine-related functions differed between rats fed these proteins. We found that SPI accelerated puberty in female rats (p < .05) and WPH delayed puberty in males and females, as compared with CAS (p < .05). Gender differences were also found in gonadectomy-induced steroid responses. Male rats had normal serum T levels, but female rats fed SPI had reduced serum 17beta-estradiol concentrations and a blunted 17beta-estradiol response to ovariectomy, as compared to rats fed CAS or WHP (p < .05). Female rats fed SPI or WHP or treated with genistein had reduced incidence of chemically induced mammary cancers (p < .05) compared to CAS controls, with WHP reducing tumor incidence by as much as 50%, findings that replicate previous results from our laboratory. Together, these results suggest gender-specific differences in development and certain endocrine responses among rats fed diets composed of a single protein source such as those used in infant formulas. Whether similar developmental effects occur in human infants is unknown, but unlikely because (1) most infants do not consume such diets throughout life as these rats did, and (2) no such effects have been reported in millions of American infants fed infant formula containing these proteins. The long-term health consequence implications of early diet exposure to SPI and WPH, such as reduced breast cancer incidence, are likely to be very positive.

mTOR inhibitor reverses autistic-like social deficit behaviours in adult rats with both Tsc2 haploinsufficiency and developmental status epilepticus.

PubMed

Schneider, Miriam; de Vries, Petrus J; Schönig, Kai; Rößner, Veit; Waltereit, Robert

2017-08-01

Epilepsy is a major risk factor for autism spectrum disorder (ASD) and complicates clinical manifestations and management of ASD significantly. Tuberous sclerosis complex (TSC), caused by TSC1 or TSC2 mutations, is one of the medical conditions most commonly associated with ASD and has become an important model to examine molecular pathways associated with ASD. Previous research showed reversal of autism-like social deficits in Tsc1 +/- and Tsc2 +/- mouse models by mammalian target of rapamycin (mTOR) inhibitors. However, at least 70 % of individuals with TSC also have epilepsy, known to complicate the severity and treatment responsiveness of the behavioural phenotype. No previous study has examined the impact of seizures on neurocognitive reversal by mTOR inhibitors. Adult Tsc2 +/- (Eker)-rats express social deficits similar to Tsc2 +/- mice, with additive social deficits from developmental status epilepticus (DSE). DSE was induced by intraperitoneal injection with kainic acid at post-natal days P7 and P14 (n = 12). The experimental group that modelled TSC pathology carried the Tsc2 +/- (Eker)-mutation and was challenged with DSE. The wild-type controls had not received DSE (n = 10). Four-month-old animals were analysed for social behaviour (T1), then treated three times during 1 week with 1 mg/kg everolimus and finally retested in the post-treatment behavioural analysis (T2). In the experimental group, both social interaction and social cognition were impaired at T1. After treatment at T2, behaviour in the experimental group was indistinguishable from controls. The mTOR inhibitor, everolimus, reversed social deficit behaviours in the Tsc2 haploinsufficiency plus DSE animal model to control levels.

Age-dependent salt hypertension in Dahl rats: fifty years of research.

PubMed

Zicha, J; Dobešová, Z; Vokurková, M; Rauchová, H; Hojná, S; Kadlecová, M; Behuliak, M; Vaněčková, I; Kuneš, J

2012-01-01

Fifty years ago, Lewis K. Dahl has presented a new model of salt hypertension - salt-sensitive and salt-resistant Dahl rats. Twenty years later, John P. Rapp has published the first and so far the only comprehensive review on this rat model covering numerous aspects of pathophysiology and genetics of salt hypertension. When we summarized 25 years of our own research on Dahl/Rapp rats, we have realized the need to outline principal abnormalities of this model, to show their interactions at different levels of the organism and to highlight the ontogenetic aspects of salt hypertension development. Our attention was focused on some cellular aspects (cell membrane function, ion transport, cell calcium handling), intra- and extrarenal factors affecting renal function and/or renal injury, local and systemic effects of renin-angiotensin-aldosterone system, endothelial and smooth muscle changes responsible for abnormal vascular contraction or relaxation, altered balance between various vasoconstrictor and vasodilator systems in blood pressure maintenance as well as on the central nervous and peripheral mechanisms involved in the regulation of circulatory homeostasis. We also searched for the age-dependent impact of environmental and pharmacological interventions, which modify the development of high blood pressure and/or organ damage, if they influence the salt-sensitive organism in particular critical periods of development (developmental windows). Thus, severe self-sustaining salt hypertension in young Dahl rats is characterized by pronounced dysbalance between augmented sympathetic hyperactivity and relative nitric oxide deficiency, attenuated baroreflex as well as by a major increase of residual blood pressure indicating profound remodeling of resistance vessels. Salt hypertension development in young but not in adult Dahl rats can be attenuated by preventive increase of potassium or calcium intake. On the contrary, moderate salt hypertension in adult Dahl rats is attenuated by superoxide scavenging or endothelin-A receptor blockade which do not affect salt hypertension development in young animals.

Cataracts in the Fat Sand Rat: An Ocular Complication of Diabetes

DTIC Science & Technology

2001-03-29

significantly elevated in the diabetic sand rats. Water-soluble protein levels were higher in the control sand rats. No significant differences were seen...chromosomes 7t 12 and 20 . These individuals present with diabetes at 25 years of age or earlier and have an abnormal pattern of glucose- stimulated insulin...excellent choice for the study of developmental mechanisms of diabetic cataracts, a common cause of blindness in man. U.S. Populations at Risk for Type 2

Methods for measurement of developmental reproductive ...

EPA Pesticide Factsheets

NR OP Abstract:The purpose of this SOP is to outline a procedure for the evaluation of the presence or absence of nipples/areola in the day 13 rodent pup. In the absence of androgens from the developing testes, female rats develop nipples/areola, while dihydrotestosterone induces regression or apoptosis of the nipple anlage in male rats. Thus, nipple development in male rats is a useful endpoint for evaluating the degree of demasculinization produced by in utero/lactational exposure to antiandrogenic compounds. AGD OP Abstract: As a sexually dimorphic secondary sex characteristic in mammals, anogenital distance may be used to measure the degree of demasculinization or feminization of males as a consequence of developmental exposure to androgen receptor (AR) antagonists (Vinclozolin, Procymidone and Flutamide), 5 alpha reductase inhibitors (finasteride) or compounds which inhibit steroidogenesis (some diester phthalates), (see Appendices 7.a). Likewise, AGD is useful in measuring the degree of masculinization or defeminization of females exposed during sexual differentiation to androgenic compounds such as the cattle growth stimulant Trenbolone (see Appendices 7.b). This OP should be used in all studies that include measurement of AGD in rats. NCEA, EPA scientists have requested a copy of two of our laboratory OPs used to measure Anogenital Distance in newborn rats and nipple retention/agenesis in infant male and female rats. These will be submitted to an up

Differences in the Rate of In Situ Mammary Gland Development and Other Developmental Endpoints in Three Strains of Female Rat Commonly Used in Mammary Carcinogenesis Studies: Implications for Timing of Carcinogen Exposure

PubMed Central

Stanko, Jason P.; Kissling, Grace E.; Chappell, Vesna A.; Fenton, Suzanne E.

2016-01-01

The potential of chemicals to alter susceptibility to mammary tumor formation is often assessed using a carcinogen-induced study design in various rat strains. The rate of mammary gland development must be considered so that the timing of carcinogen administration is impactful. In this study, in situ mammary gland (MG) development was assessed in females of the Harlan Sprague Dawley (Hsd:SD), Charles River Sprague Dawley (Crl:SD), and Charles River Long Evans (Crl:LE) rat strains at postnatal day (PND) 25, 33, and 45. Development was evaluated by physical assessment of growth parameters, developmental scoring, and quantitative morphometric analysis. Though body weight was consistently lower and day of vaginal opening (VO) occurred latest in female Hsd:SD rats, they exhibited accelerated pre-and peripubertal MG development compared to other strains. Glands of Crl:SD and Crl:LE rats exhibited significantly more terminal end buds (TEBs) and TEB/mm than Hsd:SD rats around the time of VO. These data suggest a considerable difference in rate of MG development across commonly used strains, which is independent of body weight and timing of VO. In mammary tumor induction studies employing these strains, administration of the carcinogen should be timed appropriately, based on strain, to specifically target the peak of TEB occurrence. PMID:27613105

Estimation of placental and lactational transfer and tissue distribution of atrazine and its main metabolites in rodent dams, fetuses, and neonates with physiologically based pharmacokinetic modeling

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

Lin, Zhoumeng; Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602; Fisher, Jeffrey W.

Atrazine (ATR) is a widely used chlorotriazine herbicide, a ubiquitous environmental contaminant, and a potential developmental toxicant. To quantitatively evaluate placental/lactational transfer and fetal/neonatal tissue dosimetry of ATR and its major metabolites, physiologically based pharmacokinetic models were developed for rat dams, fetuses and neonates. These models were calibrated using pharmacokinetic data from rat dams repeatedly exposed (oral gavage; 5 mg/kg) to ATR followed by model evaluation against other available rat data. Model simulations corresponded well to the majority of available experimental data and suggest that: (1) the fetus is exposed to both ATR and its major metabolite didealkylatrazine (DACT) atmore » levels similar to maternal plasma levels, (2) the neonate is exposed mostly to DACT at levels two-thirds lower than maternal plasma or fetal levels, while lactational exposure to ATR is minimal, and (3) gestational carryover of DACT greatly affects its neonatal dosimetry up until mid-lactation. To test the model's cross-species extrapolation capability, a pharmacokinetic study was conducted with pregnant C57BL/6 mice exposed (oral gavage; 5 mg/kg) to ATR from gestational day 12 to 18. By using mouse-specific parameters, the model predictions fitted well with the measured data, including placental ATR/DACT levels. However, fetal concentrations of DACT were overestimated by the model (10-fold). This overestimation suggests that only around 10% of the DACT that reaches the fetus is tissue-bound. These rodent models could be used in fetal/neonatal tissue dosimetry predictions to help design/interpret early life toxicity/pharmacokinetic studies with ATR and as a foundation for scaling to humans. - Highlights: • We developed PBPK models for atrazine in rat dams, fetuses, and neonates. • We conducted pharmacokinetic (PK) study with atrazine in pregnant mice. • Model predictions were in good agreement with experimental rat and mouse PK data. • The fetus is exposed to atrazine/its main metabolite at levels similar to the dam. • The nursing neonate is exposed primarily to atrazine's main metabolite DACT.« less

DEVELOPMENTAL LEAD (PB) EXPOSURE REDUCES THE ABILITY OF THE NNDA ANTAGONIST MK801 TO SUPPRESS LONG-TERM POTENTIATION (LTP) IN THE RAT DENTATE GYRUS, IN VIVO

EPA Science Inventory

Chronic developmental lead (Pb) exposure increases the threshold and enhances decay of long-term potentiation (LTP) in the dentate gyrus of the hippocampal formation. MK-801 and other antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor subtype impair induction of LT...

Cardiovascular Ultrasound of Neonatal Long Evans Rats ...

EPA Pesticide Factsheets

This abstract describes the use of a relatively new technology, cardiovascular ultrasound (echocardiography) for evaluating developmental toxicity affecting heart development. The abstract describes the effects of two known cardiac teratogens, trichloroacetic acid and dimethadione, and their effects as determined by echocardiography. This abstract describes the use and development of a relatively new technology, cardiovascular ultrasound (echocardiography) for evaluating developmental toxicity affecting heart development.

Developmental treatment with difluoromethylornithine has few effects on behavior or body weight in Sprague-Dawley rats.

PubMed

Ferguson, Sherry A; Cada, Amy M

2004-01-01

Developmental difluoromethylornithine (DFMO) treatment reduces cerebellar weight [Neuroscience 17 (1986) 399, Neurotoxicol. Teratol. 22 (2000) 415, Behav. Brain Res. 126 (2001) 135], but the functional alterations resulting from this have been little investigated. Here, Sprague-Dawley rats were subcutaneously injected with 500 mg/kg DFMO on postnatal days (PNDs) 5-12 and a comprehensive set of behavioral assessments measured early developmental behaviors (righting reflex, negative geotaxis), motor coordination, acoustic startle, short- and long-term activity, social behaviors, anxiety, and spatial learning and memory. DFMO treatment appeared to cause a decreased latency to perform the negative geotaxis behavior on PNDs 8-10 and increased latency to hang by the forelimbs on PNDs 12-14. Our previous study did not indicate similar effects, but age at testing differed between the two studies. DFMO treatment caused a decreased latency to maximum acoustic startle response in both the acoustic startle paradigm and in the pulse-alone trials of the prepulse inhibition test. This DFMO treatment paradigm induced a 10% decrease in adult cerebellar weight [Behav. Brain Res. 126 (2001) 135], but the results here imply that such developmental stunting has few functional alterations.

Testing strategies for embryo-fetal toxicity of human pharmaceuticals. Animal models vs. in vitro approaches: a workshop report.

PubMed

van der Laan, Jan Willem; Chapin, Robert E; Haenen, Bert; Jacobs, Abigail C; Piersma, Aldert

2012-06-01

Reproductive toxicity testing is characterized by high animal use. For registration of pharmaceutical compounds, developmental toxicity studies are usually conducted in both rat and rabbits. Efforts have been underway for a long time to design alternatives to animal use. Implementation has lagged, partly because of uncertainties about the applicability domain of the alternatives. The reproductive cycle is complex and not all mechanisms of development can be mimicked in vitro. Therefore, efforts are underway to characterize the available alternative tests with regard to the mechanism of action they include. One alternative test is the mouse embryonic stem cell test (EST), which has been studied since the late 1990s. It is a genuine 3R "alternative" assay as it is essentially animal-free. A meeting was held to review the state-of-the-art of various in vitro models for prediction of developmental toxicity. Although the predictivity of individual assays is improving, a battery of several assays is likely to have even higher predictivity, which is necessary for regulatory acceptance. The workshop concluded that an important first step is a thorough survey of the existing rat and rabbit studies, to fully characterize the frequency of responses and the types of effects seen. At the same time, it is important to continue the optimization of in vitro assays. As more experience accumulates, the optimal conditions, assay structure, and applicability of the alternative assays are expected to emerge. Copyright © 2012 Elsevier Inc. All rights reserved.

Deficits in response inhibition in male rats prenatally exposed to vapor condensates made from gasoline containing ethanol at 0% and 15%, but not 85%

EPA Science Inventory

The impact of developmental exposure to inhaled ethanol-gasoline fuel blends is a potential public health concern. We previously reported that rats whose mothers inhaled ethanol (21,000 ppm) during pregnancy had increased levels of anticipatory responding on a choice reaction tim...

COMPARING IMMUNOTOXICITY IN RATS AFTER IN UTERO VERSUS AN ADULT EXPOSURE: IS DEVELOPMENTAL EXPOSURE MORE SENSITIVE?

EPA Science Inventory

Using a known immunosuppresant, dexamethasone (DEX), pregnant Sprague Dawley (SD) rats were given subcutaneous (s.c.) injections of DEX (0.0, 0.0375, 0.075, 0.15, 0.3 mg/kg) during gestation days 6 to 21. Both male and female offspring were tested for immune dysfunction. In a ...

Effects of prenatal exposure to a low dose atrazine metabolite mixture onpubertal timing and prostate development of male Long-Evans rats

EPA Science Inventory

Atrazine (ATR) is a chlorotriazine herbicide extensively used in the US and other countries. Studies examining the effects of adult or developmental ATR exposure on the mammary gland (MG) have used either the Sprague Dawley (SD) or Long-Evans (LE) rat, but no strain comparisons h...

Protective effects of chronic mild stress during adolescence in the low-novelty responder rat.

PubMed

Rana, Samir; Nam, Hyungwoo; Glover, Matthew E; Akil, Huda; Watson, Stanley J; Clinton, Sarah M; Kerman, Ilan A

2016-01-01

Stress-elicited behavioral and physiologic responses vary widely across individuals and depend on a combination of environmental and genetic factors. Adolescence is an important developmental period when neural circuits that guide emotional behavior and stress reactivity are still maturing. A critical question is whether stress exposure elicits contrasting effects when it occurs during adolescence versus adulthood. We previously found that Sprague-Dawley rats selectively bred for low-behavioral response to novelty (bred Low Responders; bLRs) are particularly sensitive to chronic unpredictable mild stress (CMS) exposure in adulthood, which exacerbates their typically high levels of spontaneous depressive- and anxiety-like behavior. Given developmental processes known to occur during adolescence, we sought to determine whether the impact of CMS on bLR rats is equivalent when they are exposed to it during adolescence as compared with adulthood. Young bLR rats were either exposed to CMS or control condition from postnatal days 35-60. As adults, we found that CMS-exposed bLRs maintained high levels of sucrose preference and exhibited increased social exploration along with decreased immobility on the forced swim test compared with bLR controls. These data indicate a protective effect of CMS exposure during adolescence in bLR rats.

Effects of postnatal ethanol exposure at different developmental phases on neurotrophic factors and phosphorylated proteins on signal transductions in rat brain.

PubMed

Tsuji, Ryozo; Fattori, Vittorio; Abe, Shin-ichi; Costa, Lucio G; Kobayashi, Kumiko

2008-01-01

Exposure to ethanol during development induces severe brain damage resulting in a number of CNS dysfunctions including microencephaly and mental retardation in humans and in laboratory animals. The most vulnerable period to ethanol neurotoxicity coincides with the peak of brain growth spurt. Recently, neurotrophic factors and/or their signal transduction pathways have been reported as a potential relevant target for the developmental neurotoxicity of ethanol. The present studies were designed to investigate the effects of ethanol given in various developmental phases during the brain growth spurt in rats. Rat pups were assigned to the three treatment groups and treated with 5 g/kg of ethanol for three days, on postnatal days (PND) 2-4, 6-8 or 13-15. Whole brain weights were reduced only in the PND 6-8 group concurrently with the reduction of GDNF mRNA in cortex in this group. BDNF mRNA expression was reduced in both the PND 6-8 and 13-15 groups, while mRNA expressions of NT-3 and NGF were unchanged in all three groups. Phospho-Akt level was mostly reduced in the PND 6-8 group. Both phospho-MAPK and p-70S6 kinase levels were decreased in all groups whereas no changes were observed in either phospho-PKCzeta or CREB level. The phosphorylation of Akt was immediately inhibited after single administration of ethanol, and its inhibition was correlated with variations in blood ethanol concentration. These findings suggest that GDNF and the phosphorylation of Akt play a possible key role in the ethanol-induced developmental neurotoxicity.

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.

Developmental trajectory of contextual learning and 24-h acetylcholine release in the hippocampus

PubMed Central

Takase, Kenkichi; Sakimoto, Yuya; Kimura, Fukuko; Mitsushima, Dai

2014-01-01

To determine the developmental trajectory of hippocampal function in rats, we examined 24-h changes in extracellular acetylcholine (ACh) levels and contextual learning performance. Extracellular ACh significantly correlated with spontaneous behavior, exhibiting a 24-h rhythm in juvenile (4-week-old), pubertal (6-week-old), and adult (9- to 12-week-old) rats. Although juveniles of both sexes exhibited low ACh levels, adult males had higher ACh levels than adult females. Moreover, juveniles exhibited much more spontaneous activity than adults when they showed equivalent ACh levels. Similarly, juveniles of both sexes exhibited relatively low contextual learning performance. Because contextual learning performance was significantly increased only in males, adult males exhibited better performance than adult females. We also observed a developmental relationship between contextual learning and ACh levels. Scopolamine pretreatment blocked contextual learning and interrupted the correlation. Since long-term scopolamine treatment after weaning impaired contextual learning in juveniles, the cholinergic input may participate in the development of hippocampus. PMID:24435246

Fluoride-elicited developmental testicular toxicity in rats: Roles of endoplasmic reticulum stress and inflammatory response

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

Zhang, Shun; Jiang, Chunyang; Department of Thoracic Surgery, Tianjin Union Medicine Centre, 190 Jieyuan Road, Hongqiao District, Tianjin 300121, Tianjin

Long-term excessive fluoride intake is known to be toxic and can damage a variety of organs and tissues in the human body. However, the molecular mechanisms underlying fluoride-induced male reproductive toxicity are not well understood. In this study, we used a rat model to simulate the situations of human exposure and aimed to evaluate the roles of endoplasmic reticulum (ER) stress and inflammatory response in fluoride-induced testicular injury. Sprague–Dawley rats were administered with sodium fluoride (NaF) at 25, 50 and 100 mg/L via drinking water from pre-pregnancy to gestation, birth and finally to post-puberty. And then the testes of malemore » offspring were studied at 8 weeks of age. Our results demonstrated that fluoride treatment increased MDA accumulation, decreased SOD activity, and enhanced germ cell apoptosis. In addition, fluoride elevated mRNA and protein levels of glucose-regulated protein 78 (GRP78), inositol requiring ER-to-nucleus signal kinase 1 (IRE1), and C/EBP homologous protein (CHOP), indicating activation of ER stress signaling. Furthermore, fluoride also induced testicular inflammation, as manifested by gene up-regulation of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in a nuclear factor-κB (NF-κB)-dependent manner. These were associated with marked histopathological lesions including injury of spermatogonia, decrease of spermatocytes and absence of elongated spermatids, as well as severe ultrastructural abnormalities in testes. Taken together, our results provide compelling evidence that ER stress and inflammation would be novel and significant mechanisms responsible for fluoride-induced disturbance of spermatogenesis and germ cell loss in addition to oxidative stress. - Highlights: • We used a rat model to simulate the situations of human fluoride (F) exposure. • Developmental F exposure induces testicular damage related with oxidative stress. • Endoplasmic reticulum stress is involved in testis disorder and germ cell apoptosis. • Inflammatory response is implicated in impaired spermatogenesis and germ cell loss.« less

Prenatal programming of renal salt wasting resets postnatal salt appetite, which drives food intake in the rat.

PubMed

Alwasel, Saleh H; Barker, David J P; Ashton, Nick

2012-03-01

Sodium retention has been proposed as the cause of hypertension in the LP rat (offspring exposed to a maternal low-protein diet in utero) model of developmental programming because of increased renal NKCC2 (Na+/K+/2Cl- co-transporter 2) expression. However, we have shown that LP rats excrete more rather than less sodium than controls, leading us to hypothesize that LP rats ingest more salt in order to maintain sodium balance. Rats were fed on either a 9% (low) or 18% (control) protein diet during pregnancy; male and female offspring were studied at 4 weeks of age. LP rats of both sexes held in metabolism cages excreted more sodium and urine than controls. When given water to drink, LP rats drank more and ate more food than controls, hence sodium intake matched excretion. However, when given a choice between saline and water to drink, the total volume of fluid ingested by LP rats fell to control levels, but the volume of saline taken was significantly larger [3.8±0.1 compared with 8.8±1.3 ml/24 h per 100 g of body weight in control and LP rats respectively; P<0.001]. Interestingly food intake also fell to control levels. Total body sodium content and ECF (extracellular fluid) volumes were greater in LP rats. These results show that prenatal programming of renal sodium wasting leads to a compensatory increase in salt appetite in LP rats. We speculate that the need to maintain salt homoeostasis following malnutrition in utero stimulates greater food intake, leading to accelerated growth and raised BP (blood pressure).

Combined prenatal and postnatal butyl paraben exposure produces autism-like symptoms in offspring: comparison with valproic acid autistic model.

PubMed

Ali, Elham H A; Elgoly, Amany H Mahmoud

2013-10-01

The aim of this work is to evaluate the impact of butyl paraben (BP) in brain of the pups developed for mothers administered BP from early pregnancy till weaning and its effect on studying the behavior, brain neurotransmitters and brain derived neurotrophic factor BDNF via comparing the results with valproic acid (VA) autistic-rat model preparing by a single oral injection dose of VA (800 mg/kg b.wt) at the 12.5 days of gestation. Butyl paraben was orally and subcutaneously administered (200 mg/kg b.wt) to pregnant rats from gestation day 1 to lactation day 21. The offspring male rats were subjected at the last 3 days of lactation to Morris water maze and three chamber sociability test then decapitated and the brain was excised and dissected to the cortex, hippocampus, cerebellum, midbrain and pons for the determination of norepinephrine, dopamine and serotonin (NE, DA and 5-HT) and cortex amino acids and whole brain BDNF. The results showed similar social and learning and memory behavioral deficits in VA rat model and the butyl paraben offspring in comparison with the controls. Also, some similar alterations were observed in monoamine content, amino acids and BDNF factor in the autistic-like model and butyl paraben offspring in comparison with the controls. The alterations were recorded notably in hippocampus and pons NE, midbrain DA, hippocampus and midbrain 5-HT, and frontal cortex GABA and asparagine. These data suggest that prenatal exposure to butyl paraben induced neuro-developmental disorders similar to some of the neurodevelopmental disorders observed in the VA model of autism. © 2013 Elsevier Inc. All rights reserved.

Adverse effects of bisphenol A (BPA) on the dopamine system in two distinct cell models and corpus striatum of the Sprague-Dawley rat.

PubMed

Nowicki, Brittney A; Hamada, Matt A; Robinson, Gina Y; Jones, Douglas C

2016-01-01

The aim of this study was to examine the effects of bisphenol A (BPA) on the brain dopamine (DA) system utilizing both in vitro models (GH3 cells, a rat pituitary cell line, and SH-SY5Y cells, a human neuroblastoma cell line) and an animal model such as Sprague-Dawley (SD) rats. First, cellular DA uptake was measured 2 or 8 h following BPA exposure (0.1-400 μM) in SH-SY5Y cells, where a significant increase in DA uptake was noted. BPA exerted no marked effect on dopamine active transporter levels in GH3 cells exposed for 8 or 24 h. However, SH-SY5Y cells displayed an increase in dopamine transporter (DAT) levels following 24 h of exposure to BPA. In contrast to DAT levels, BPA exposure produced no marked effect on DA D1 receptor levels in SH-SY5Y cells, yet a significant decrease in GH3 cells following both 8- and 24-h exposure periods was noted, suggesting that BPA exerts differential effects dependent upon cell type. BPA produced no significant effects on prolactin levels at 2 h, but a marked fall occurred at 24 h of exposure in GH3 cells. Finally, to examine the influence of dietary developmental exposure to BPA on brain DA levels in F1 offspring, SD rats were exposed to BPA (0.5-20 mg/kg) through maternal transfer and/or diet and striatal DA levels were measured on postnatal day (PND) 60 using high-performance liquid chromatography (HPLC). Data demonstrated that chronic exposure to BPA did not significantly alter striatal DA levels in the SD rat.

Inhalation developmental toxicology studies: Teratology study of n-hexane in rats: Final report

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

Mast, T.J.

The straight chain hydrocarbon, n-hexane, is a volatile, ubiquitous solvent used in industrial, academic, and smaller commercial environments. The significant opportunity for women of child-bearing age to be exposed to this chemical prompted the undertaking of a study to assess the developmental toxicity of n-hexane in an animal model. Timed-pregnant (30 animals per group) and virgin (10 animals per group) Sprague-Dawley rats were exposed to 0 (filtered air), 200, 1000, and 5000 ppM n-hexane (99.9% purity) vapor in inhalation chambers for 20 h/day for a period of 14 consecutive days. Sperm-positive females were exposed for 6 to 19 days ofmore » gestation (dg) and virgins were exposed concurrently for 14 consecutive days. The day of sperm detection was designated as 0 dg for mated females. Adult female body weights were monitored prior to, throughout the exposure period, and at sacrifice. Uterine, placental, and fetal body weights were obtained for gravid females at sacrifice. Implants were enumerated and their status recorded as live fetus, early or late resorption, or dead. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. 16 refs., 3 figs., 7 tabs.« less

Dietary prevention of hormone refractory prostate cancer in Lobund-Wistar rats: a review of studies in a relevant animal model.

PubMed

Pollard, Morris; Suckow, Mark A

2006-12-01

Lobund-Wistar (LW) rats, which have high testosterone levels, are predisposed to develop hormone-refractory prostate cancer (HRPC) spontaneously and by methylnitrosourea (MNU) induction, and the development of HRPC progresses through 2 stages. This paper reviews several studies in which LW rats were placed on soy-containing diets and were evaluated for development of either spontaneous or MNU-induced prostate cancer. The premalignant, testosterone-dependent stage is inhibited by testosterone deprivation. In the absence of testosterone deprivation, tumorigenesis progresses spontaneously to the testosterone-independent refractory stage. In LW rats: moderate caloric restriction prevented development of spontaneous prostate cancer; dietary 4-hydroxyphenylretinamide prevented MNU-induced prostate cancer; and dietary supplementation with soy protein isolate with high isoflavones prevented spontaneous and induced tumors and led to moderate reduction of serum testosterone. In rats 12 mo of age and younger, changing from the control diet to the soy+isoflavone diet significantly prevented progression of spontaneous tumors to the refractory stage of disease. Tumors that developed spontaneously and after MNU induction showed similar developmental stages and morphology, but MNU-induced tumors had shorter latency periods before development. The accumulated data indicate that soy-based diets are effective in the prevention of prostate cancer.

Effects of chronic forced-swim stress on behavioral properties in rats with neonatal repeated MK-801 treatment.

PubMed

Kawabe, Kouichi

2017-08-01

The two-hit hypothesis has been used to explain the onset mechanism of schizophrenia. It assumes that predisposition to schizophrenia is originally attributed to vulnerability in the brain which stems from genetic or early developmental factors, and that onset is triggered by exposure to later detrimental factors such as stress in adolescence or adulthood. Based on this hypothesis, the present study examined whether rats that had received neonatal repeated treatment with an N-methyl-d-aspartate (NMDA) receptor antagonist (MK-801), an animal model of schizophrenia, were vulnerable to chronic stress. Rats were treated with MK-801 (0.2mg/kg) or saline twice daily on postnatal days 7-20, and animals in the stress subgroups were subjected to 20days (5days/week×4weeks) of forced-swim stress in adulthood. Following this, behavioral tests (prepulse inhibition, spontaneous alternation, open-field, and forced-swim tests) were carried out. The results indicate that neonatal repeated MK-801 treatment in rats inhibits an increase in immobility in the forced-swim test after they have experienced chronic forced-swim stress. This suggests that rats that have undergone chronic neonatal repeated NMDA receptor blockade could have a reduced ability to habituate or adapt to a stressful situation, and supports the hypothesis that these rats are sensitive or vulnerable to stress. Copyright © 2017 Elsevier Inc. All rights reserved.

The International Society for Developmental Psychobiology Annual Meeting Symposium: Impact of Early Life Experiences on Brain and Behavioral Development

PubMed Central

Sullivan, Regina; Wilson, Donald A.; Feldon, Joram; Yee, Benjamin K.; Meyer, Urs; Richter-Levin, Gal; Avi, Avital; Michael, Tsoory; Gruss, Michael; Bock, Jörg; Helmeke, Carina; Braun, Katharina

2007-01-01

Decades of research in the area of developmental psychobiology have shown that early life experience alters behavioral and brain development, which canalizes development to suit different environments. Recent methodological advances have begun to identify the mechanisms by which early life experiences cause these diverse adult outcomes. Here we present four different research programs that demonstrate the intricacies of early environmental influences on behavioral and brain development in both pathological and normal development. First, an animal model of schizophrenia is presented that suggests prenatal immune stimulation influences the postpubertal emergence of psychosis-related behavior in mice. Second, we describe a research program on infant rats that demonstrates how early odor learning has unique characteristics due to the unique functioning of the infant limbic system. Third, we present work on the rodent Octodon degus, which shows that early paternal and/or maternal deprivation alters development of limbic system synaptic density that corresponds to heightened emotionality. Fourth, ajuvenile model of stress is presented that suggests this developmental period is important in determining adulthood emotional well being. The approach of each research program is strikingly different, yet all succeed in delineating a specific aspect of early development and its effects on infant and adult outcome that expands our understanding of the developmental impact of infant experiences on emotional and limbic system development. Together, these research programs suggest that the developing organism’s developmental trajectory is influenced by environmental factors beginning in the fetus and extending through adolescence, although the specific timing and nature of the environmental influence has unique impact on adult mental health. PMID:17016842

Autoshaping in micrencephalic rats.

PubMed

Goldstein, L H; Oakley, D A

1989-06-01

An autoshaping procedure in which the illumination of a lever was predictive of food reinforcement was used to compare learning in rats with micrencephaly induced by irradiation on the 16th day of gestation and in sham-irradiated controls. Both groups showed equivalent levels of lever-directed activity, and the micrencephalic animals differentiated as well as the control animals between the predictive lever and a nonpredictive lever. The micrencephalic animals were able to redistribute their lever-directed activity when the significance of the levers was reversed and did so more readily than the control animals. Results support the claim that association learning survives either traumatic or developmental neocortical damage and have implications for remedial procedures following both head injury and developmental cerebral pathology in humans.

Learning about cognition risk with the radial-arm maze in the developmental neurotoxicology battery.

PubMed

Levin, Edward D

2015-01-01

Cognitive dysfunction has been found in epidemiological studies to be among the most sensitive impairments associated with developmental exposure to a variety of environmental contaminants from heavy metals to polyhalogenated hydrocarbons and pesticides. These chemicals have been also shown to impair cognitive function after developmental exposure in experimental animal models. The radial-arm maze (RAM) has proven to be a sensitive and reliable way to assess both learning and memory in a variety of species, most often in rats and mice. The RAM is a very adaptable test method that takes advantage of rodents' instinct to explore new places in the environment to forage. That is, rodents do not need to be trained to run through the maze; they will normally do this from the initial session of testing. Training with differential reinforcement for arm choices provides a more rigorous test of learning and memory. The RAM is quite adaptable for assessing various aspects of cognition. Although the RAM has been mostly used to assess spatial learning and memory, it can be configured to assess non-spatial memory as well. Both working and reference memory can be easily distinguished. The RAM can be run with both appetitive (food reinforced) and aversive (water escape) motivators. The RAM has been found to be sensitive to a wide variety of developmental toxicants including heavy metals such as mercury and pesticides such as chlorpyrifos. There is an extremely rich literature especially with rats showing the effects of many types of brain lesions and drug effects so that the participation of a wide variety of neural systems in RAM performance is known. These systems, notably the hippocampus and frontal cortex, and acetylcholine and glutamate neurotransmitter systems, are the same neural systems that have been shown in humans to be critical for learning and memory. This considerably aids the interpretation of neurobehavioral toxicity studies. Copyright © 2015 Elsevier Inc. All rights reserved.

Comparison of the mouse Embryonic Stem cell Test, the rat Whole Embryo Culture and the Zebrafish Embryotoxicity Test as alternative methods for developmental toxicity testing of six 1,2,4-triazoles

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

Jong, Esther de, E-mail: Esther.de.Jong@rivm.nl; Laboratory for Health Protection Research, National Institute for Public Health and the Environment; Barenys, Marta

2011-06-01

The relatively high experimental animal use in developmental toxicity testing has stimulated the search for alternatives that are less animal intensive. Three widely studied alternative assays are the mouse Embryonic Stem cell Test (EST), the Zebrafish Embryotoxicity Test (ZET) and the rat postimplantation Whole Embryo Culture (WEC). The goal of this study was to determine their efficacy in assessing the relative developmental toxicity of six 1,2,4-triazole compounds, flusilazole, hexaconazole, cyproconazole, triadimefon, myclobutanil and triticonazole. For this purpose, we analyzed effects and relative potencies of the compounds in and among the alternative assays and compared the findings to their known inmore » vivo developmental toxicity. Triazoles are antifungal agents used in agriculture and medicine, some of which are known to induce craniofacial and limb abnormalities in rodents. The WEC showed a general pattern of teratogenic effects, typical of exposure to triazoles, mainly consisting of reduction and fusion of the first and second branchial arches, which are in accordance with the craniofacial malformations reported after in vivo exposure. In the EST all triazole compounds inhibited cardiomyocyte differentiation concentration-dependently. Overall, the ZET gave the best correlation with the relative in vivo developmental toxicities of the tested compounds, closely followed by the EST. The relative potencies observed in the WEC showed the lowest correlation with the in vivo developmental toxicity data. These differences in the efficacy between the test systems might be due to differences in compound kinetics, in developmental stages represented and in the relative complexity of the alternative assays.« less

Comparison of the mouse Embryonic Stem cell Test, the rat Whole Embryo Culture and the Zebrafish Embryotoxicity Test as alternative methods for developmental toxicity testing of six 1,2,4-triazoles.

PubMed

de Jong, Esther; Barenys, Marta; Hermsen, Sanne A B; Verhoef, Aart; Ossendorp, Bernadette C; Bessems, Jos G M; Piersma, Aldert H

2011-06-01

The relatively high experimental animal use in developmental toxicity testing has stimulated the search for alternatives that are less animal intensive. Three widely studied alternative assays are the mouse Embryonic Stem cell Test (EST), the Zebrafish Embryotoxicity Test (ZET) and the rat postimplantation Whole Embryo Culture (WEC). The goal of this study was to determine their efficacy in assessing the relative developmental toxicity of six 1,2,4-triazole compounds,(1) flusilazole, hexaconazole, cyproconazole, triadimefon, myclobutanil and triticonazole. For this purpose, we analyzed effects and relative potencies of the compounds in and among the alternative assays and compared the findings to their known in vivo developmental toxicity. Triazoles are antifungal agents used in agriculture and medicine, some of which are known to induce craniofacial and limb abnormalities in rodents. The WEC showed a general pattern of teratogenic effects, typical of exposure to triazoles, mainly consisting of reduction and fusion of the first and second branchial arches, which are in accordance with the craniofacial malformations reported after in vivo exposure. In the EST all triazole compounds inhibited cardiomyocyte differentiation concentration-dependently. Overall, the ZET gave the best correlation with the relative in vivo developmental toxicities of the tested compounds, closely followed by the EST. The relative potencies observed in the WEC showed the lowest correlation with the in vivo developmental toxicity data. These differences in the efficacy between the test systems might be due to differences in compound kinetics, in developmental stages represented and in the relative complexity of the alternative assays. Copyright © 2011 Elsevier Inc. All rights reserved.

Effects of Neonatal Methamphetamine and Stress on Brain Monoamines and Corticosterone in Preweanling Rats

PubMed Central

Jablonski, Sarah A.; Graham, Devon L.; Vorhees, Charles V.; Williams, Michael T.

2017-01-01

Neonatal exposure to methamphetamine (MA) and developmental chronic stress significantly alter neurodevelopmental profiles that show a variety of long-term physiological and behavioral effects. In the current experiment, Sprague-Dawley rats were exposed to one of two housing conditions along with MA. Rats were given 0 (saline), 5, or 7.5 mg/kg MA, four times per day from postnatal day (P)11 to 15 or P11 to 20. Half of the litters were reared in cages with standard bedding and half with no bedding. Separate litters were assessed at P15 or P20 for organ weights (adrenals, spleen, thymus); corticosterone; and monoamine assessments (dopamine, serotonin, norepinephrine) and their metabolites within the neostriatum, hippocampus, and prefrontal cortex. Findings show neonatal MA altered mono-amines, corticosterone, and organ characteristics alone, and as a function of developmental age and stress compared with controls. These alterations may in part be responsible for MA and early life stress-induced long-term learning and memory deficits. PMID:27817108

Gender considerations in ventilatory and metabolic development in rats: special emphasis on the critical period

PubMed Central

LIU, QIULI; WONG-RILEY, MARGARET T.T

2013-01-01

In rats, a critical period exists around postnatal day (P) 12-13, when an imbalance between heightened inhibition and suppressed excitation led to a weakened ventilatory and metabolic response to acute hypoxia. An open question was whether the two genders follow the same or different developmental trends throughout the first 3 postnatal weeks and whether the critical period exists in one or both genders. The present large-scale, in-depth ventilatory and metabolic study was undertaken to address this question. Our data indicated that: 1) the ventilatory and metabolic rates in both normoxia and acute hypoxia were comparable between the two genders from P0 to P21; thus, gender was never significant as a main effect; and 2) the age effect was highly significant in all parameters studies for both genders, and both genders exhibited a significantly weakened response to acute hypoxia during the critical period. Thus, the two genders have comparable developmental trends, and the critical period exists in both genders in rats. PMID:23797186

Recovery, growth and development of Macroorchis spinulosus in albino rats

PubMed Central

Woo, Ho-Chun; Chai, Jong-Yil

2003-01-01

The developmental features, growth and organogenesis of Macroorchis spinulosus were observed in albino rats. Globular and thick walled metacercariae, possessed a stylet, Y-shaped excretory bladder and extracecal testes. In albino rats, M. spinulosus showed habitat shifting. The majority of M. spinulosus reside in the jejunum for the first four days post infection (p.i.) and migrate to the duodenum at the later stage of infection. M. spinulosus grew rapidly during the first four days and reached full maturity at 14 days p.i. and later reduced in size. The ovary was separated from the genital primodium at one day p.i. The seminal vesicle appeared on the third day and divided into two sacs on the fourth day p.i. and intrauterine eggs and sperm mass were produced on the fourth day. Organogenesis and enlargement of reproductive organs governed the growth of M. spinulosus. The similarity of related species of the genus Macroorchis to M. spinulosus was discussed in consideration to developmental features. PMID:12666727

Developmental expression of VGF mRNA in the prenatal and postnatal rat.

PubMed

Snyder, S E; Pintar, J E; Salton, S R

1998-04-27

VGF is a developmentally regulated, secretory peptide precursor that is expressed by neurons and neuroendocrine cells and that has its transcription and secretion induced rapidly by neurotrophins and by depolarization. To gain insight into the possible functions and regulation of VGF in vivo, we have characterized the distribution of VGF mRNA in the developing rat nervous system. VGF expression was first detectable at embryonic day 11.5 in the primordia of cranial, sympathetic, and dorsal root ganglia, and its distribution expanded throughout development to include significant expression throughout the brain, spinal cord, and retina of the adult rat. The earliest expression of VGF, therefore, appeared in the peripheral nervous system as developing neurons settled in their designated ganglia. In many regions of the brain, VGF mRNA levels were found to be highest during periods when axonal outgrowth and synaptogenesis predominate. Areas of the central nervous system that contain predominantly dividing cells never displayed any VGF mRNA expression, nor did the vast majority of nonneural tissues.

In vivo longitudinal micro-CT study of bent long limb bones in rat offspring.

PubMed

De Schaepdrijver, Luc; Delille, Peter; Geys, Helena; Boehringer-Shahidi, Christian; Vanhove, Christian

2014-07-01

Micro-computed X-ray tomography (micro-CT) has been reported as a reliable method to assess ex vivo rat and rabbit fetal skeletons in embryo-fetal developmental toxicity studies. Since micro-CT is a non-invasive imaging modality it has the potential for longitudinal, in vivo investigation of postnatal skeletal development. This is the first paper using micro-CT to assess the reversibility of drug-induced bent long bones in a longitudinal study from birth to early adulthood in rat offspring. Analysis of the scans obtained on postnatal Day 0, 7, 21 and 80 showed complete recovery or repair of the bent long limb bones (including the scapula) within the first 3 weeks. When assessing risk the ability to demonstrate recovery is highly advantageous when interpreting such transient skeletal change. In summary, in vivo micro-CT of small laboratory animals can aid in non-clinical safety assessment, particularly for specific mechanistic purposes or to address a particular concern in developmental biology. Copyright © 2014 Elsevier Inc. All rights reserved.

Importance of Maternal Diabetes on the Chronological Deregulation of the Intrauterine Development: An Experimental Study in Rat

PubMed Central

Salazar García, Marcela; Reyes Maldonado, Elba; Revilla Monsalve, María Cristina; Villavicencio Guzmán, Laura; Reyes López, Alfonso; Sánchez-Gómez, Concepción

2015-01-01

We investigated whether maternal diabetes induced in rats using streptozotocin (STZ) on Day 5 of pregnancy affects the intrauterine developmental timeline. A total of 30 pregnant Sprague-Dawley diabetic rats (DRs) and 20 control rats (CRs) were used to obtain 21-day fetuses (F21) and newborn (NB) pups. Gestational age, weight, and body size were recorded as were the maxillofacial morphometry and morphohistological characteristics of the limbs. In DRs, pregnancy continued for ∼1.7 days, and delivery occurred 23 days postcoitus (DPC). In this group, the number of pups was lower, and 13% had maxillofacial defects. F21 in the DR group had lower weights and were smaller; moreover, the morphological characteristics of the maxillofacial structures, derived from the neural crest, were discordant with their chronological gestational age, resembling 18- to 19-day-old fetuses. These deficiencies were counterbalanced in NB pups. We conclude that hyperglycemia, which results from maternal diabetes and precedes embryo implantation, deregulates the intrauterine developmental timeline, restricts embryo-fetal growth, and primarily delays the remodeling and maturation of the structures derived from neural crest cells. PMID:25756053

Extinction, reacquisition, and rapid forgetting of eyeblink conditioning in developing rats

PubMed Central

Freeman, John H.

2014-01-01

Eyeblink conditioning is a well-established model for studying the developmental neurobiology of associative learning and memory. However, age differences in extinction and subsequent reacquisition have yet to be studied using this model. The present study examined extinction and reacquisition of eyeblink conditioning in developing rats. In Experiment 1, post-natal day (P) 17 and 24 rats were trained to a criterion of 80% conditioned responses (CRs) using stimulation of the middle cerebellar peduncle (MCP) as a conditioned stimulus (CS). Stimulation CS-alone extinction training commenced 24 h later, followed by reacquisition training after the fourth extinction session. Contrary to expected results, rats trained starting on P17 showed significantly fewer CRs to stimulation CS-alone presentations relative to P24s, including fewer CRs as early as the first block of extinction session 1. Furthermore, the P17 group was slower to reacquire following extinction. Experiment 2 was run to determine the extent to which the low CR percentage observed in P17s early in extinction reflected rapid forgetting versus rapid extinction. Twenty-four hours after reaching criterion, subjects were trained in a session split into 50 stimulation CS-unconditioned stimulus paired trials followed immediately by 50 stimulation CS-alone trials. With this “immediate” extinction protocol, CR percentages during the first block of stimulation CS-alone presentations were equivalent to terminal acquisition levels at both ages but extinction was more rapid in the P17 group. These findings indicate that forgetting is observed in P17 relative to P24 rats 24 h following acquisition. The forgetting in P17 rats has important implications for the neurobiological mechanisms of memory in the developing cerebellum. PMID:25403458

Dietary choline during periadolescence attenuates cognitive damage caused by neonatal maternal separation in male rats.

PubMed

Moreno Gudiño, Hayarelis; Carías Picón, Diamela; de Brugada Sauras, Isabel

2017-07-01

Choline (Ch) is an essential nutrient that acts as a cognitive facilitator when administered during perinatal periods, and it has been recognised as a 'pharmacological' agent that can ease cognitive dysfunctions provoked by exposure to damaging stimuli during early developmental stages. The aim of the present work is to determine whether providing a diet rich in Ch would reduce the severity of the memory deficit provoked by a neonatal stress episode in male adult rats. The effect of Ch on memory was measured using memory tasks such as object and place recognition. Ontogenetic manipulations were conducted during two sensitive developmental periods. During the first post-natal (PN) 14 days, only the male rat pups were selected and half of them were separated from the mother, group maternal separation (MS). Subsequently, during periadolescence (PN 21-60), the rats were exposed to a deficient (DEF = 0 g/kg Ch chloride), sufficient (CON = 1.1 g/kg Ch chloride), or supplemented (SUP = 5 g/kg Ch chloride) diets for this nutrient. The results indicated that for group MS, only rats fed with the SUP diet were able to recognise the familiar object and place that had been experienced 24 hours before, unlike groups DEF and CON. In addition, whereas rats in the non-separated group (No-MS) recognised the object independently of the diet, only rats that received a DEF diet failed to recognise the place, showing that a Ch deficit affects spatial memory tasks. These results show that Ch supplementation during periadolescence can attenuate the memory deficit provoked by extended neonatal stress.

Differences in Methylphenidate Dose Response between Periadolescent and Adult Rats in the Familiar Arena-Novel Alcove TaskS⃞

PubMed Central

Zarcone, Troy J.; Davis, Paul F.; Ozias, Marlies K.; Fowler, Stephen C.

2011-01-01

Methylphenidate is a psychostimulant widely used in the treatment of attention deficit hyperactivity disorder. In this study, the effects of two nonstereotypy-inducing doses of methylphenidate (2.5 and 5.0 mg/kg s.c.) were examined in periadolescent [postnatal days (P) 35 and 42] and young adult (P70), male Long-Evans rats using a three-period locomotor activity paradigm that affords inferences about exploration, habituation, and attention to a novel stimulus (an “alcove”) in a familiar environment in a single test session. In the first test period, P35 and P42 rats were more active than P70 rats, and methylphenidate increased locomotion in a dose-related manner. The introduction of a novel spatial stimulus in the third test period revealed a significant interaction of dose and age such that P70 rats exhibited dose-related increases in distance traveled, but P35 rats did not. Furthermore, methylphenidate dose-relatedly disrupted the rats' tendency to spend increasing amounts of time in the alcove across the test period at P70 but not at P35. Brain and serum methylphenidate concentrations were significantly lower at P35 than at P70, with intermediate levels at P42. Developmental differences in dopaminergic neurochemistry were also observed, including increased dopamine content in the caudate-putamen, nucleus accumbens, and frontal cortex and decreased densities of D1-like receptors in the frontal cortex in P70 than in P42 rats. These results raise the possibility that children and adults may respond differently when treated with this drug, particularly in situations involving response to novelty and that these effects involve developmental differences in pharmacokinetics and dopaminergic neurochemistry. PMID:21205916

Postnatal development of eupneic ventilation and metabolism in rats chronically exposed to moderate hyperoxia

PubMed Central

Bavis, Ryan W.; van Heerden, Eliza S.; Brackett, Diane G.; Harmeling, Luke H.; Johnson, Stephen M.; Blegen, Halward J.; Logan, Sarah; Nguyen, Giang N.; Fallon, Sarah C.

2014-01-01

Newborn rats chronically exposed to moderate hyperoxia (60% O2) exhibit abnormal respiratory control, including decreased eupneic ventilation. To further characterize this plasticity and explore its proximate mechanisms, rats were exposed to either 21% O2 (Control) or 60% O2 (Hyperoxia) from birth until studied at 3 – 14 days of age (P3 – P14). Normoxic ventilation was reduced in Hyperoxia rats when studied at P3, P4, and P6-7 and this was reflected in diminished arterial O2 saturations; eupneic ventilation spontaneously recovered by P13-14 despite continuous hyperoxia, or within 24 h when Hyperoxia rats were returned to room air. Normoxic metabolism was also reduced in Hyperoxia rats but could be increased by raising inspired O2 levels (to 60% O2) or by uncoupling oxidative phosphorylation within the mitochondrion (2, 4-dinitrophenol). In contrast, moderate increases in inspired O2 had no effect on sustained ventilation which indicates that hypoventilation can be dissociated from hypometabolism. The ventilatory response to abrupt O2 inhalation was diminished in Hyperoxia rats at P4 and P6-7, consistent with smaller contributions of peripheral chemoreceptors to eupneic ventilation at these ages. Finally, the spontaneous respiratory rhythm generated in isolated brainstem-spinal cord preparations was significantly slower and more variable in P3-4 Hyperoxia rats than in age-matched Controls. We conclude that developmental hyperoxia impairs both peripheral and central components of eupneic ventilatory drive. Although developmental hyperoxia diminishes metabolism as well, this appears to be a regulated hypometabolism and contributes little to the observed changes in ventilation. PMID:24703970

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

Zhang, Lei; Wang, Huaxi; Yang, Yan

Highlights: •Nerve growth factor has shown significant changes on mRNA levels during Adult Leydig cells regeneration. •We established the organ culture model of rat seminiferous tubules with ethane dimethyl sulphonate (EDS) treatment. •Nerve growth factor has shown proliferation and differentiation-promoting effects on Adult stem Leydig cells. •Nerve growth factor induces progenitor Leydig cells to proliferate and differentiate and immature Leydig cells to proliferate. -- Abstract: Nerve growth factor (NGF) has been reported to be involved in male reproductive physiology. However, few reports have described the activity of NGF during Leydig cell development. The objective of the present study was tomore » examine the role of NGF during stem-Leydig-cell (SLC) regeneration. We investigated the effects of NGF on Leydig-cell (LC) regeneration by measuring mRNA levels in the adult rat testis after ethane dimethanesulfonate (EDS) treatment. Furthermore, we used the established organ culture model of rat seminiferous tubules to examine the regulation of NGF during SLC proliferation and differentiation using EdU staining, real-time PCR and western blotting. Progenitor Leydig cells (PLCs) and immature Leydig cells (ILCs) were also used to investigate the effects of NGF on LCs at different developmental stages. NGF mRNA levels changed significantly during Leydig-cell regeneration in vivo. In vitro, NGF significantly promoted the proliferation of stem Leydig cells and also induced steroidogenic enzyme gene expression and 3β-HSD protein expression. The data from PLCs and ILCs showed that NGF could increase Cyclin D1 and Hsd 17b3 mRNA levels in PLCs and Cyclin D1 mRNA levels in ILCs. These results indicate that NGF may play an important role during LC regeneration by regulating the proliferation and differentiation of LCs at different developmental stages, from SLCs to PLCs and from PLCs to ILCs. The discovery of this effect of NGF on Leydig cells will provide useful information for developing new potential therapies for PADAM (Partial Androgen Deficiency in the Aging Male)« less

Developmental history and application of CRISPR in human disease.

PubMed

Liang, Puping; Zhang, Xiya; Chen, Yuxi; Huang, Junjiu

2017-06-01

Genome-editing tools are programmable artificial nucleases, mainly including zinc-finger nucleases, transcription activator-like effector nucleases and clustered regularly interspaced short palindromic repeat (CRISPR). By recognizing and cleaving specific DNA sequences, genome-editing tools make it possible to generate site-specific DNA double-strand breaks (DSBs) in the genome. DSBs will then be repaired by either error-prone nonhomologous end joining or high-fidelity homologous recombination mechanisms. Through these two different mechanisms, endogenous genes can be knocked out or precisely repaired/modified. Rapid developments in genome-editing tools, especially CRISPR, have revolutionized human disease models generation, for example, various zebrafish, mouse, rat, pig, monkey and human cell lines have been constructed. Here, we review the developmental history of CRISPR and its application in studies of human diseases. In addition, we also briefly discussed the therapeutic application of CRISPR in the near future. Copyright © 2017 John Wiley & Sons, Ltd.

In vitro Multi-Species Biofilms of Methicillin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa and Their Host Interaction during In vivo Colonization of an Otitis Media Rat Model

PubMed Central

Yadav, Mukesh K.; Chae, Sung-Won; Go, Yoon Young; Im, Gi Jung; Song, Jae-Jun

2017-01-01

Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA) are known to cause biofilm-related infections. MRSA and PA have been frequently isolated from chronically infected wounds, cystic fibrosis, chronic suppurative otitis media (CSOM), and from indwelling medical devices, and these bacteria co-exist; however, their interaction with each-other or with the host is not well known. In this study, we investigated MRSA and PA multi-species biofilm communities in vitro and their interaction with the host during in vivo colonization using an OM rat-model. In-vitro biofilm formation and in-vivo colonization were studied using CV-microtiter plate assay and OM rat-model respectively. The biofilms were viewed under scanning electron microscope and bacteria were enumerated using cfu counts. The differential gene expressions of rat mucosa colonized with single or multi-species of MRSA or PA were studied using RNA-sequencing of total transcriptome. In multi-species in-vitro biofilms PA partially inhibited SA growth. However, no significant inhibition of MRSA was detected during in-vivo colonization of multi-species in rat bullae. A total of 1,797 genes were significantly (p < 0.05) differentially expressed in MRSA or PA or MRSA + PA colonized rat middle ear mucosa with respect to the control. The poly-microbial colonization of MRSA and PA induced the differential expression of a significant number of genes that are involved in immune response, inflammation, signaling, development, and defense; these were not expressed with single species colonization by either MRSA or PA. Genes involved in defense, immune response, inflammatory response, and developmental process were exclusively up-regulated, and genes that are involved in nervous system signaling, development and transmission, regulation of cell growth and development, anatomical and system development, and cell differentiation were down-regulated after multi-species inoculation. These results indicate that poly-microbial colonization induces a host response that is different from that induced by single species infection. PMID:28459043

Peripheral nerve reconstruction with epsilon-caprolactone conduits seeded with vasoactive intestinal peptide gene-transfected mesenchymal stem cells in a rat model

NASA Astrophysics Data System (ADS)

Hernández-Cortés, P.; Toledo-Romero, M. A.; Delgado, M.; Sánchez-González, C. E.; Martin, F.; Galindo-Moreno, P.; O'Valle, F.

2014-08-01

Objective. Attempts have been made to improve nerve conduits in peripheral nerve reconstruction. We investigated the potential therapeutic effect of a vasoactive intestinal peptide (VIP), a neuropeptide with neuroprotective, trophic and developmental regulatory actions, in peripheral nerve regeneration in a severe model of nerve injury that was repaired with nerve conduits. Approach. The sciatic nerve of each male Wistar rat was transected unilaterally at 10 mm and then repaired with Dl-lactic-ɛ-caprolactone conduits. The rats were treated locally with saline, with the VIP, with adipose-derived mesenchymal stem cells (ASCs) or with ASCs that were transduced with the VIP-expressing lentivirus. The rats with the transected nerve, with no repairs, were used as untreated controls. At 12 weeks post-surgery, we assessed their limb function by measuring the ankle stance angle and the percentage of their muscle mass reduction, and we evaluated the histopathology, immunohistochemistry and morphometry of the myelinated fibers. Main results. The rats that received a single injection of VIP-expressing ASCs showed a significant functional recovery in the ankle stance angle (p = 0.049) and a higher number of myelinated fibers in the middle and distal segments of the operated nerve versus the other groups (p = 0.046). Significance. These results suggest that utilization of a cellular substrate, plus a VIP source, is a promising method for enhancing nerve regeneration using Dl-lactic-ɛ-caprolactone conduits and that this method represents a potential useful clinical approach to repairing peripheral nerve damage.

Neonatal manipulation of oxytocin prevents lipopolysaccharide-induced decrease in gene expression of growth factors in two developmental stages of the female rat.

PubMed

Bakos, Jan; Lestanova, Zuzana; Strbak, Vladimir; Havranek, Tomas; Bacova, Zuzana

2014-10-01

Oxytocin production and secretion is important for early development of the brain. Long-term consequences of manipulation of oxytocin system might include changes in markers of brain plasticity - cytoskeletal proteins and neurotrophins. The aim of the present study was (1) to determine whether neonatal oxytocin administration affects gene expression of nestin, microtubule-associated protein-2 (MAP-2), brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the brain of two developmental stages of rat and (2) to evaluate whether neonatal oxytocin administration protects against lipopolysaccharide (LPS) induced inflammation. Neonatal oxytocin did not prevent a decrease of body weight in the LPS treated animals. Oxytocin significantly increased gene expression of BDNF in the right hippocampus in 21-day and 2-month old rats of both sexes. Gene expression of NGF and MAP-2 significantly increased in males treated with oxytocin. Both, growth factors and intermediate filament-nestin mRNA levels, were reduced in females exposed to LPS. Oxytocin treatment prevented a decrease in the gene expression of only growth factors. In conclusion, neonatal manipulation of oxytocin has developmental and sex-dependent effect on markers of brain plasticity. These results also indicate, that oxytocin may be protective against inflammation particularly in females. Copyright © 2014 Elsevier Ltd. All rights reserved.

Metabolism of 2,2′,3,3′,6,6′-Hexachlorobiphenyl (PCB 136) Atropisomers in Tissue Slices from Phenobarbital or Dexamethasone-Induced Rats is Sex-Dependent

PubMed Central

Wu, Xianai; Kania-Korwel, Izabela; Chen, Hao; Stamou, Marianna; Dammanahalli, Karigowda J.; Duffel, Michael; Lein, Pamela J.; Lehmler, Hans-Joachim

2013-01-01

Chiral polychlorinated biphenyls (PCBs) such as PCB 136 enantioselectively sensitize the ryanodine receptor (RyR). In light of recent evidence that PCBs cause developmental neurotoxicity via RyR-dependent mechanisms, this suggests that enantioselective PCB metabolism may influence the developmental neurotoxicity of chiral PCBs. However, enantioselective disposition of PCBs has not been fully characterized.The effect of sex and cytochrome P450 (P450) enzyme induction on the enantioselective metabolism of PCB 136 was studied using liver tissue slices prepared from naïve control (CTL), phenobarbital (PB; CYP2B inducer) or dexamethasone (DEX; CYP3A inducer) pretreated adult Sprague-Dawley rats. PCB 136 metabolism was also examined in hippocampal slices derived from untreated rat pups.In liver tissue slices, hydroxylated PCB (OH-PCB) profiles depended on sex and inducer pretreatment, and OH-PCB levels followed the rank orders male > female and PB > DEX > CTL. In contrast, the enantiomeric enrichment of PCB 136 and its metabolites was independent of sex and inducer pretreatment. Only small amounts of PCB 136 partitioned into hippocampal tissue slices and no OH-PCB metabolites were detected.Our results suggest that enantioselective metabolism, sex and induction status of P450 enzymes in the liver may modulate the neurotoxic outcomes of developmental exposure to chiral PCBs. PMID:23581876

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

Rat pregnancy and parturition survive spaceflight challenge: new considerations of developmental consequences

NASA Technical Reports Server (NTRS)

Alberts, J. R.; Ronca, A. E.

1997-01-01

Results of the NASA-NIH.R1 and NASA-NIH.R2 pregnant rat studies are reported and compared with results of Cosmos-1514 study. Similarities and differences between the Cosmos and STS flights are reviewed. STS rats were videotaped so that in-flight and post-flight behavior could be observed. Rats were observed during readaptation to 1-g and labor and delivery. Results indicate that pregnancy can proceed after exposure to microgravity and that vaginal delivery can occur despite readaptation to 1-g. Analysis of videotape revealed that flight dams experienced almost twice as many labor contractions as controls.

Pathway modeling of microarray data: A case study of pathway activity changes in the testis following in utero exposure to dibutyl phthalate (DBP)

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

Ovacik, Meric A.; Sen, Banalata; Euling, Susan Y.

Pathway activity level analysis, the approach pursued in this study, focuses on all genes that are known to be members of metabolic and signaling pathways as defined by the KEGG database. The pathway activity level analysis entails singular value decomposition (SVD) of the expression data of the genes constituting a given pathway. We explore an extension of the pathway activity methodology for application to time-course microarray data. We show that pathway analysis enhances our ability to detect biologically relevant changes in pathway activity using synthetic data. As a case study, we apply the pathway activity level formulation coupled with significancemore » analysis to microarray data from two different rat testes exposed in utero to Dibutyl Phthalate (DBP). In utero DBP exposure in the rat results in developmental toxicity of a number of male reproductive organs, including the testes. One well-characterized mode of action for DBP and the male reproductive developmental effects is the repression of expression of genes involved in cholesterol transport, steroid biosynthesis and testosterone synthesis that lead to a decreased fetal testicular testosterone. Previous analyses of DBP testes microarray data focused on either individual gene expression changes or changes in the expression of specific genes that are hypothesized, or known, to be important in testicular development and testosterone synthesis. However, a pathway analysis may inform whether there are additional affected pathways that could inform additional modes of action linked to DBP developmental toxicity. We show that Pathway activity analysis may be considered for a more comprehensive analysis of microarray data.« less

Excessive apoptosis and defective autophagy contribute to developmental testicular toxicity induced by fluoride.

PubMed

Zhang, Shun; Niu, Qiang; Gao, Hui; Ma, Rulin; Lei, Rongrong; Zhang, Cheng; Xia, Tao; Li, Pei; Xu, Chunyan; Wang, Chao; Chen, Jingwen; Dong, Lixing; Zhao, Qian; Wang, Aiguo

2016-05-01

Fluoride, a ubiquitous environmental contaminant, is known to impair testicular functions and fertility; however the underlying mechanisms remain obscure. In this study, we used a rat model to mimic human exposure and sought to investigate the roles of apoptosis and autophagy in testicular toxicity of fluoride. Sprague-Dawley rats were developmentally exposed to 25, 50, or 100 mg/L sodium fluoride (NaF) via drinking water from pre-pregnancy to post-puberty, and then the testes of offspring were excised on postnatal day 56. Our results demonstrated that developmental NaF exposure induced an enhanced testicular apoptosis, as manifested by a series of hallmarks such as caspase-3 activation, chromatin condensation and DNA fragmentation. Further study revealed that fluoride exposure elicited significant elevations in the levels of cell surface death receptor Fas with a parallel increase in cytoplasmic cytochrome c, indicating the involvement of both extrinsic and intrinsic apoptotic pathways. Intriguingly, fluoride treatment also simultaneously increased the number of autophagosomes and the levels of autophagy marker LC3-II but not Beclin1. Unexpectedly, the expression of p62, a substrate that is degraded by autophagy, was also significantly elevated, suggesting that the accumulated autophagosomes resulted from impaired autophagy degradation rather than increased formation. Importantly, these were associated with marked histopathological lesions including spermatogenic failure and germ cell loss, along with severe ultrastructural abnormalities in testes. Taken together, our findings provide deeper insights into roles of excessive apoptosis and defective autophagy in the aggravation of testicular damage, which could contribute to a better understanding of fluoride-induced male reproductive toxicity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Neonatal Nicotine Exposure Increases Excitatory Synaptic Transmission and Attenuates Nicotine-stimulated GABA release in the Adult Rat Hippocampus

PubMed Central

Damborsky, Joanne C.; Griffith, William H.; Winzer-Serhan, Ursula H.

2014-01-01

Developmental exposure to nicotine has been linked to long-lasting changes in synaptic transmission which may contribute to behavioral abnormalities seen in offspring of women who smoke during pregnancy. Here, we examined the long-lasting effects of developmental nicotine exposure on glutamatergic and GABAergic neurotransmission, and on acute nicotine-induced glutamate and GABA release in the adult hippocampus, a structure important in cognitive and emotional behaviors. We utilized a chronic neonatal nicotine treatment model to administer nicotine (6 mg/kg/day) to rat pups from postnatal day (P) 1–7, a period that falls developmentally into the third human trimester. Using whole-cell voltage clamp recordings from CA1 pyramidal neurons in hippocampal slices, we measured excitatory and inhibitory postsynaptic currents in neonatally control- and nicotine-treated young adult males. Neonatal nicotine exposure significantly increased AMPA receptor-mediated spontaneous and evoked excitatory signaling, with no change in glutamate release probability in adults. Conversely, there was no increase in spontaneous GABAergic neurotransmission in nicotine-males. Chronic neonatal nicotine treatment had no effect on acute nicotine-stimulated glutamate release in adults, but acute nicotine-stimulated GABA release was significantly attenuated. Thus, neonatal nicotine exposure results in a persistent net increase in excitation and a concurrent loss of nicotinic acetylcholine receptor (nAChR)-mediated regulation of presynaptic GABA but not glutamate release, which would exacerbate excitation following endogenous or exogenous nAChR activation. Our data underscore an important role for nAChRs in hippocampal excitatory synapse development, and suggest selective long-term changes at specific presynaptic nAChRs which together could explain some of the behavioral abnormalities associated with maternal smoking. PMID:24950455

Effects of developmental exposure to bisphenol A on spatial navigational learning and memory in rats: A CLARITY-BPA study.

PubMed

Johnson, Sarah A; Javurek, Angela B; Painter, Michele S; Ellersieck, Mark R; Welsh, Thomas H; Camacho, Luísa; Lewis, Sherry M; Vanlandingham, Michelle M; Ferguson, Sherry A; Rosenfeld, Cheryl S

2016-04-01

Bisphenol A (BPA) is a ubiquitous industrial chemical used in the production of a wide variety of items. Previous studies suggest BPA exposure may result in neuro-disruptive effects; however, data are inconsistent across animal and human studies. As part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA), we sought to determine whether female and male rats developmentally exposed to BPA demonstrated later spatial navigational learning and memory deficits. Pregnant NCTR Sprague-Dawley rats were orally dosed from gestational day 6 to parturition, and offspring were directly orally dosed until weaning (postnatal day 21). Treatment groups included a vehicle control, three BPA doses (2.5μg/kg body weight (bw)/day-[2.5], 25μg/kg bw/day-[25], and 2500μg/kg bw/day-[2500]) and a 0.5μg/kg/day ethinyl estradiol (EE)-reference estrogen dose. At adulthood, 1/sex/litter was tested for seven days in the Barnes maze. The 2500 BPA group sniffed more incorrect holes on day 7 than those in the control, 2.5 BPA, and EE groups. The 2500 BPA females were less likely than control females to locate the escape box in the allotted time (p value=0.04). Although 2.5 BPA females exhibited a prolonged latency, the effect did not reach significance (p value=0.06), whereas 2.5 BPA males showed improved latency compared to control males (p value=0.04), although the significance of this result is uncertain. No differences in serum testosterone concentration were detected in any male or female treatment groups. Current findings suggest developmental exposure of rats to BPA may disrupt aspects of spatial navigational learning and memory. Copyright © 2015 Elsevier Inc. All rights reserved.

Effects of Developmental Exposure to Bisphenol A on Spatial Navigational Learning and Memory in Rats: A CLARITY-BPA Study

PubMed Central

Johnson, Sarah A.; Javurek, Angela B.; Painter, Michele S.; Ellersieck, Mark R.; Welsh, Thomas H.; Camacho, Luísa; Lewis, Sherry M.; Vanlandingham, Michelle M.; Ferguson, Sherry A.; Rosenfeld, Cheryl S.

2015-01-01

Bisphenol A (BPA) is a ubiquitous industrial chemical used in the production of a wide variety of items. Previous studies suggest BPA exposure may result in neuro-disruptive effects; however, data are inconsistent across animal and human studies. As part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA), we sought to determine whether female and male rats developmentally exposed to BPA demonstrated later spatial navigational learning and memory deficits. Pregnant NCTR Sprague-Dawley rats were orally dosed from gestational day 6 to parturition, and offspring were directly orally dosed until weaning (postnatal day 21). Treatment groups included a vehicle control, three BPA doses (2.5 μg/kg/day-[2.5], 25 μg/kg/day-[25], and 2500 μg/kg/day-[2500]) and a 0.5 μg/kg/day ethinyl estradiol (EE)-reference estrogen dose. At adulthood, 1/sex/litter was tested for seven days in the Barnes maze. The 2500 BPA group sniffed more incorrect holes on day 7 than those in the control, 2.5 BPA, and EE groups. The 2500 BPA females were less likely than control females to locate the escape box in the allotted time (P value= 0.04). Although 2.5 BPA females exhibited a prolonged latency, the effect did not reach significance (P value = 0.06), whereas 2.5 BPA males showed improved latency compared to control males (P value = 0.04), although the significance of this result is uncertain. No differences in serum testosterone concentration were detected in any male or female treatment groups. Current findings suggest developmental exposure of rats to BPA may disrupt aspects of spatial navigational learning and memory. PMID:26436835

Altered behavior in experimental cortical dysplasia.

PubMed

Zhou, Fu-Wen; Rani, Asha; Martinez-Diaz, Hildabelis; Foster, Thomas C; Roper, Steven N

2011-12-01

Developmental delay and cognitive impairment are common comorbidities in people with epilepsy associated with malformations of cortical development (MCDs). We studied cognition and behavior in an animal model of diffuse cortical dysplasia (CD), in utero irradiation, using a battery of behavioral tests for neuromuscular and cognitive function. Fetal rats were exposed to 2.25 Gy external radiation on embryonic day 17 (E17). At 1 month of age they were tested using an open field task, a grip strength task, a grid walk task, inhibitory avoidance, an object recognition task, and the Morris water maze task. Rats with CD showed reduced nonlocomotor activity in the open field task and impaired motor coordination for grid walking but normal grip strength. They showed a reduced tendency to recognize novel objects and reduced retention in an inhibitory avoidance task. Water maze testing showed that learning and memory were impaired in irradiated rats for both cue discrimination and spatially oriented tasks. These results demonstrate significant deficits in cortex- and hippocampus-dependent cognitive functions associated with the diffuse abnormalities of cortical and hippocampal development that have been documented in this model. This study documents multimodal cognitive deficits associated with CD and can serve as the foundation for future investigations into the mechanisms of and possible therapeutic interventions for this problem. Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

Final report on the developmental toxicity of methacrylonitrile (CAS No. 126-98-7) in Sprague-Dawley (CS[trademark]) rats. Report for March-June 1992

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

Not Available

The study was conducted to assess the potential for orally administered methacrylonitrile (MILE) to cause developmental toxicity. Human exposure to MILE occurs in industrial settings, as a component of mainstream cigarette smoke from unfiltered cigarettes, and possibly as a result of ingestion of beverages bottled in plastic containers. MILE (CAS No. 126-98-7) was administered by gavage in water to mated CD rats (26/group) on gestation days (GD) 6 through 15 at levels of 0, 5, 25 or 50 mg/kg/day. Animals were observed daily for clinical signs of toxicity. Body weight was recorded on the mornings of gd 0, 3, 6more » through 15, 18 and 20. Mean food and water consumption was recorded for the animals in each group on GD 0, 3, 6, 9, 12, 15, 18, and 20. All animals in the developmental toxicity study were killed on GD 20 and examined for maternal body and organ weights, implant status, fetal weight, sex, and morphological development.« less

The Effects of Caffeine on Sleep and Maturational Markers in the Rat

PubMed Central

Olini, Nadja; Kurth, Salomé; Huber, Reto

2013-01-01

Adolescence is a critical period for brain maturation during which a massive reorganization of cortical connectivity takes place. In humans, slow wave activity (<4.5 Hz) during NREM sleep was proposed to reflect cortical maturation which relies on use-dependent processes. A stimulant like caffeine, whose consumption has recently increased especially in adolescents, is known to affect sleep wake regulation. The goal of this study was to establish a rat model allowing to assess the relationship between cortical maturation and sleep and to further investigate how these parameters are affected by caffeine consumption. To do so, we assessed sleep and markers of maturation by electrophysiological recordings, behavioral and structural readouts in the juvenile rat. Our results show that sleep slow wave activity follows a similar inverted U-shape trajectory as already known in humans. Caffeine treatment exerted short-term stimulating effects and altered the trajectory of slow wave activity. Moreover, caffeine affected behavioral and structural markers of maturation. Thus, caffeine consumption during a critical developmental period shows long lasting effects on sleep and brain maturation. PMID:24023748

Gender-dependent behavioral and sensory effects of a commercial mixture of polychlorinated biphenyls (Aroclor 1254) in rats.

PubMed

Geller, A M; Oshiro, W M; Haykal-Coates, N; Kodavanti, P R; Bushnell, P J

2001-02-01

Developmental exposure to polychlorinated biphenyls (PCBs) has been associated with behavioral and cognitive deficits in humans and animal models. Perinatal exposure to PCBs has also been associated with sensory deficits in animal models. These effects were hypothesized to be mediated in part by ortho-substituted PCBs, which do not or weakly bind to the aryl hydrocarbon (Ah) receptor. The present studies were designed to determine whether perinatal exposure to Aroclor 1254, a commercial mixture of > 99% ortho-substituted PCBs, would affect cognitive and sensory function in Long-Evans rats. Adult male and female offspring of female rats fed Aroclor 1254 (Lot #124-191; doses of 0, 1, or 6 mg/kg/day; gestational day 6 through postnatal day 21; n = eight/group) were trained to perform a signal detection task capable of assessing sensory thresholds. Training included autoshaping and operant conditioning. Thresholds for detecting a 1-s light stimulus were determined under background illuminations ranging from 2 lux to complete darkness. Female rats exposed to Aroclor 1254 autoshaped more rapidly than control females, at a rate akin to control males. Control females had lower thresholds than control males at all levels of background illumination. These differences were abolished by Aroclor 1254, which reduced thresholds in males and increased thresholds in females. These data extend previous findings of gender-specific effects of PCBs on neurobehavioral development to measures of acquisition and sensory function.

Irradiation exacerbates cortical cytopathology in the Eker rat model of Tuberous Sclerosis Complex, but does not induce hyperexcitability

PubMed Central

Tschuluun, Naranzogt; Wenzel, H. Jürgen

2007-01-01

Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder characterized by multi-organ pathologies. Most TSC patients exhibit seizures, usually starting in early childhood. The neuropathological hallmarks of the disease - cortical tubers, containing cytopathological neuronal and glial cell types – appear to be the source of seizure initiation. However, the contribution of these aberrant cell populations to TSC-associated epilepsies is not fully understood. To gain further insight, investigators have attempted to generate animal models with TSC-like brain abnormalities. In the current study, we focused on the Eker rat, in which there is a spontaneous mutation of the TSC2 gene (TSC2+/−). We attempted to exacerbate TSC-like brain pathologies with a “second-hit” strategy - exposing young pups to ionizing irradiation of different intensities, and at different developmental timepoints (between E18 and P6). We found that the frequency of occurrence of dysmorphic neurons and giant astrocytes was strongly dependent on irradiation dose, and weakly dependent on timing of irradiation – in Eker rats, but not in irradiated normal controls. The frequency of TSC-like pathology was progressive; there were many more abnormal cells at 3 months compared to 1 month post-irradiation. Measures of seizure propensity (flurothyl seizure latency) and brain excitability (paired-pulse and post-tetanic stimulation studies in vitro), however, showed no functional changes associated with the appearance of TSC-like cellular abnormalities in irradiated Eker rats. PMID:17011168

In vivo detection of c-MET expression in a rat hepatocarcinogenesis model using molecularly targeted magnetic resonance imaging.

PubMed

Towner, Rheal A; Smith, Nataliya; Tesiram, Yasvir A; Abbott, Andrew; Saunders, Debbie; Blindauer, Rebecca; Herlea, Oana; Silasi-Mansat, Robert; Lupu, Florea

2007-01-01

The multifunctional growth factor scatter factor/hepatocyte growth factor and its tyrosine kinase receptor, c-MET, have been implicated in the genesis and malignant progression of numerous human malignancies, including hepatocellular carcinomas. The incidence of hepatocellular carcinomas in the United States has increased noticeably over the past two decades and is listed as the fifth major cancer in men worldwide. In this study, we used a choline-deficient l-amino acid (CDAA)-defined rat hepatocarcinogenesis model to visualize increased in vivo expression of the c-MET antigen in neoplastic lesion formation with the use of a super paramagnetic iron oxide (SPIO)-anti-c-MET molecularly targeted magnetic resonance imaging (MRI) contrast agent. SPIO-anti-c-MET was used for the first time to detect overexpression of c-MET in neoplastic nodules and tumors within the livers of CDAA-treated rats, as determined by a decrease in MRI signal intensity and a decrease in regional T(2) values. Specificity for the binding of the molecularly targeted anti-c-MET contrast agent was determined using rat hepatoma (H4-II-E-C3) cell cultures and immunofluorescence microscopic imaging of the targeting agents within neoplastic liver tissue 1 to 2 hours following intravenous administration of SPIO-anti-c-MET and MRI investigation. This method has the ability to visualize in vivo the overexpression of c-MET at early developmental stages of tumor formation.

The effect of feeding a low iron diet prior to and during gestation on fetal and maternal iron homeostasis in two strains of rat

PubMed Central

2013-01-01

Background Iron deficiency anaemia during pregnancy is a global problem, with short and long term consequences for maternal and child health. Animal models have demonstrated that the developing fetus is vulnerable to maternal iron restriction, impacting on postnatal metabolic and blood pressure regulation. Whilst long-term outcomes are similar across different models, the commonality in mechanistic events across models is unknown. This study examined the impact of iron deficiency on maternal and fetal iron homeostasis in two strains of rat. Methods Wistar (n=20) and Rowett Hooded Lister (RHL, n=19) rats were fed a control or low iron diet for 4 weeks prior to and during pregnancy. Tissues were collected at day 21 of gestation for analysis of iron content and mRNA/protein expression of regulatory proteins and transporters. Results A reduction in maternal liver iron content in response to the low iron diet was associated with upregulation of transferrin receptor expression and a reduction in hepcidin expression in the liver of both strains, which would be expected to promote increased iron absorption across the gut and increased turnover of iron in the liver. Placental expression of transferrin and DMT1+IRE were also upregulated, indicating adaptive responses to ensure availability of iron to the fetus. There were considerable differences in hepatic maternal and fetal iron content between strains. The higher quantity of iron present in livers from Wistar rats was not explained by differences in expression of intestinal iron transporters, and may instead reflect greater materno-fetal transfer in RHL rats as indicated by increased expression of placental iron transporters in this strain. Conclusions Our findings demonstrate substantial differences in iron homeostasis between two strains of rat during pregnancy, with variable impact of iron deficiency on the fetus. Whilst common developmental processes and pathways have been observed across different models of nutrient restriction during pregnancy, this study demonstrates differences in maternal adaptation which may impact on the trajectory of the programmed response. PMID:23635304

Developmental Vitamin D (DVD) Deficiency Reduces Nurr1 and TH Expression in Post-mitotic Dopamine Neurons in Rat Mesencephalon.

PubMed

Luan, Wei; Hammond, Luke Alexander; Cotter, Edmund; Osborne, Geoffrey William; Alexander, Suzanne Adele; Nink, Virginia; Cui, Xiaoying; Eyles, Darryl Walter

2018-03-01

Developmental vitamin D (DVD) deficiency has been proposed as an important risk factor for schizophrenia. Our previous study using Sprague Dawley rats found that DVD deficiency disrupted the ontogeny of mesencephalic dopamine neurons by decreasing the mRNA level of a crucial differentiation factor of dopamine cells, the nuclear receptor related 1 protein (Nurr1). However, it remains unknown whether this reflects a reduction in dopamine cell number or in Nurr1 expression. It is also unclear if any particular subset of developing dopamine neurons in the mesencephalon is selectively affected. In this study, we employed state-of-the-art spinning disk confocal microscopy optimized for the imaging of tissue sections and 3D segmentation to assess post-mitotic dopamine cells on a single-cell basis in the rat mesencephalon at embryonic day 15. Our results showed that DVD deficiency did not alter the number, morphology, or positioning of post-mitotic dopamine cells. However, the ratio of Nurr1+TH+ cells in the substantia nigra pars compacta (SNc) compared with the ventral tegmental area (VTA) was increased in DVD-deficient embryos. In addition, the expression of Nurr1 in immature dopamine cells and mature dopamine neurons in the VTA was decreased in DVD-deficient group. Tyrosine hydroxylase was selectively reduced in SNc of DVD-deficient mesencephalon. We conclude that DVD deficiency induced early alterations in mesencephalic dopamine development may in part explain the abnormal dopamine-related behaviors found in this model. Our findings may have broader implications for how certain environmental risk factors for schizophrenia may shape the ontogeny of dopaminergic systems and by inference increase the risk of schizophrenia.

ToxCast Profiling in a Human Stem Cell Assay for ...

EPA Pesticide Factsheets

Standard practice for assessing disruptions in embryogenesis involves testing pregnant animals of two species, typically rats and rabbits, exposed during major organogenesis and evaluated just prior to term. Under this design the major manifestations of developmental toxicity are observed as one or more apical endpoints including intrauterine death, fetal growth retardation, structural malformations and variations. Alternative approaches to traditional developmental toxicity testing have been proposed in the form of in vitro data (e.g., embryonic stem cells, zebrafish embryos, HTS assays) and in silico models (e.g., computational toxicology). To increase the diversity of assays used to assess developmental toxicity in EPA’s ToxCast program, we tested the chemicals in Stemina’s metabolomics-based platform that utilizes the commecrially available H9 human embryonic stem cell line. The devTOXqP dataset for ToxCast of high-quality based on replicate samples and model performance (82% balanced accuracy, 0.71 sensitivity and 1.00 specificity). To date, 136 ToxCast chemicals (12.8% of 1065 tested) were positive in this platform; 48 triggered the biomarker signal without any change in hESC viability and 88 triggered activity concurrent with effects on cell viability. Work is in progress to complete the STM dataset entry into the TCPL, compare data with results from zFish and mESC platforms, profile bioactivity (ToxCastDB), endpoints (ToxRefDB), chemotypes (DSSTox)

POST-PUBERTAL DECREASE IN HIPPOCAMPAL DENDRITIC SPINES OF FEMALE RATS

PubMed Central

Yildirim, Murat; Mapp, Oni M.; Janssen, William G.M.; Yin, Weiling; Morrison, John H.; Gore, Andrea C.

2011-01-01

Hippocampal dendritic spine and synapse numbers in female rats vary across the estrous cycle and following experimental manipulation of hormone levels in adulthood. Based on behavioral studies demonstrating that learning patterns are altered following puberty, we hypothesized that dendritic spine number in rat hippocampal CA1 region would change post-pubertally. Female Sprague-Dawley rats were divided into prepubertal (postnatal day (P) 22), peripubertal (P35) and post-pubertal (P49) groups, with the progression of puberty evaluated by vaginal opening, and estrous cyclicity subsequently assessed by daily vaginal smears. Spinophilin immunoreactivity in dendritic spines was used as an index of spinogenesis in area CA1 stratum radiatum (CA1sr) of hippocampus. First, electron microscopy analyses confirmed the presence of spinophilin specifically in dendritic spines of CA1sr, supporting spinophilin as a reliable marker of hippocampal spines in young female rats. Second, stereologic analysis was performed to assess the total number of spinophilin-immunoreactive puncta (i.e. spines) and CA1sr volume in developing rats. Our results indicated that the number of spinophilin-immunoreactive spines in CA1sr was decreased 46% in the post-pubertal group compared to the two younger groups, whereas the volume of the hippocampus underwent an overall increase during this same developmental time frame. Third, to determine a potential role of estradiol in this process, an additional group of rats was ovariectomized (OVX) prepubertally at P22, then treated with estradiol or vehicle at P35, and spinophilin quantified as above in rats perfused on P49. No difference in spinophilin puncta number was found in OVX rats between the two hormone groups, suggesting that this developmental decrease is independent of peripheral estradiol. These changes in spine density coincident with puberty may be related to altered hippocampal plasticity and synaptic consolidation at this phase of maturity. PMID:18096161

Sex-specific effect of the anabolic steroid, 17α-methyltestosterone, on inhibitory avoidance learning in periadolescent rats

PubMed Central

Ramos-Pratts, Keyla; Rosa-González, Dariana; Pérez-Acevedo, Nivia L.; Cintrón-López, Dahima; Barreto-Estrada, Jennifer L.

2013-01-01

The illicit use of anabolic androgenic steroids (AAS) has gained popularity among adolescents in the last decade. However, although it is known that exposure to AAS impairs cognition in adult animal models, the cognitive effects during adolescence remain undetermined. An inhibitory avoidance task (IAT) was used to assess the effect of AAS (17α-methyltestosterone; 17α-meT-7.5 mg/kg) in male and female periadolescent rats. A single injection of 17α-meT immediately before the footshock produced significant impairment of inhibitory avoidance learning in males but not females. Generalized anxiety, locomotion, and risk assessment behaviors (RAB) were not affected. Our results show that exposure to a single pharmacological dose of 17α-meT during periadolescence exerts sex-specific cognitive effects without affecting anxiety. Thus, disruption of the hormonal milieu during this early developmental period might have negative impact on learning and memory. PMID:23792034

Repeated-Dose and Reproductive/Developmental Toxicity of NTO (3-Nitro-1,2,4-Triazol-5-One) in the Rat

DTIC Science & Technology

2014-03-21

caused by a parasitic problem or contact dermatitis , the lacerations resolved with topical treatment prior to the skin scrape being performed. Several...14 8 Discussion 16 9 Conclusions 18 10 Point of Contact 19 Appendices A References...postpartum did not indicate that NTO presents a developmental hazard. 18 Toxicology Study No. 85-XC-OFP4-12, April-July 2012 10 Point of Contact

Bcl-2 expression during the development and degeneration of RCS rat retinae.

PubMed

Sharma, R K

2001-12-14

In various hereditary retinal degenerations, including that in Royal College of Surgeons (RCS) rats, the photoreceptors ultimately die by apoptosis. Bcl-2 is one of the genes, which regulates apoptosis and is thought to promote survival of cells. This study has investigated the developmental expression of Bcl-2 in RCS rat, which is a well-studied animal model for hereditary retinal degeneration. An antibody against Bcl-2 was used for its immunohistochemical localization in dystrophic RCS rat retinae from postnatal (PN) days 4, 7, 13, 35, 45, 70, 202 and 14 months. Results were compared with Bcl-2 localization in congenic non-dystrophic rats from PN 4, 7, 13, 44, 202 and 14 months. Bcl-2 immunoreactivity in non-dystrophic retinae was already present in PN 4 retinae in the nerve fiber layer (presumably in the endfeet of immature Müller cells) and in the proximal parts of certain radially aligned neuroepithelial cells/immature Müller cell radial processes. With increasing age the immunoreactivity in relatively more mature Müller cell radial processes spread distally towards the outer retina and between PN 13 and 44 it reached the adult distribution. No cell bodies in the ganglion cell layer were found to be immunoreactive. Expression of Bcl-2 immunoreactivity in dystrophic RCS rat retinae closely resembled that of non-dystrophic retinae. No immunoreactivity was seen in photoreceptors or retinal pigment epithelium in dystrophic or non-dystrophic retinae. In conclusion, Bcl-2 expression is not altered, either in terms of its chronology or the cell type expressing it, during retinal degeneration in RCS rats.

Prepuberal Stimulation of 5-HT7-R by LP-211 in a Rat Model of Hyper-Activity and Attention-Deficit: Permanent Effects on Attention, Brain Amino Acids and Synaptic Markers in the Fronto-Striatal Interface

PubMed Central

Treno, Concetta; Gironi Carnevale, Ugo A.; Arra, Claudio; Nieddu, Maria; Pagano, Cristina; Illiano, Placido; Barbato, Fabiana; Carboni, Ezio; Laviola, Giovanni; Lacivita, Enza; Leopoldo, Marcello; Adriani, Walter; Sadile, Adolfo G.

2014-01-01

The cross-talk at the prefronto-striatal interface involves excitatory amino acids, different receptors, transducers and modulators. We investigated long-term effects of a prepuberal, subchronic 5-HT7-R agonist (LP-211) on adult behaviour, amino acids and synaptic markers in a model for Attention-Deficit/Hyperactivity Disorder (ADHD). Naples High Excitability rats (NHE) and their Random Bred controls (NRB) were daily treated with LP-211 in the 5th and 6th postnatal week. One month after treatment, these rats were tested for indices of activity, non selective (NSA), selective spatial attention (SSA) and emotionality. The quantity of L-Glutamate (L-Glu), L-Aspartate (L-Asp) and L-Leucine (L-Leu), dopamine transporter (DAT), NMDAR1 subunit and CAMKIIα, were assessed in prefrontal cortex (PFC), dorsal (DS) and ventral striatum (VS), for their role in synaptic transmission, neural plasticity and information processing. Prepuberal LP-211 (at lower dose) reduced horizontal activity and (at higher dose) increased SSA, only for NHE but not in NRB rats. Prepuberal LP-211 increased, in NHE rats, L-Glu in the PFC and L-Asp in the VS (at 0.250 mg/kg dose), whereas (at 0.125 mg/kg dose) it decreased L-Glu and L-Asp in the DS. The L-Glu was decreased, at 0.125 mg/kg, only in the VS of NRB rats. The DAT levels were decreased with the 0.125 mg/kg dose (in the PFC), and increased with the 0.250 mg/kg dose (in the VS), significantly for NHE rats. The basal NMDAR1 level was higher in the PFC of NHE than NRB rats; LP-211 treatment (at 0.125 mg/kg dose) decreased NMDAR1 in the VS of NRB rats. This study represents a starting point about the impact of developmental 5-HT7-R activation on neuro-physiology of attentive processes, executive functions and their neural substrates. PMID:24709857

Teratological studies in defatted jojoba meal-supplemented rats.

PubMed

Cokelaere, M; Flo, G; Lievens, S; Van Boven, M; Vermaut, S; Decuypere, E

2001-03-01

To look for possible developmental effects in the offspring of jojoba meal-treated Wistar rats, and to distinguish between the effects of reduced food intake and the specific developmental effects of jojoba meal itself, mated female rats were divided into three groups of 20 rats. They received during gestation: (a) normal rodent food (control group); (b) normal rodent food supplemented with 3% defatted jojoba meal (jojoba group); or (c) normal rodent food pair-fed with the jojoba group (pair-fed group). The jojoba meal group showed approximately 30% inhibition of food intake. Ten rats from each group were killed on gestation day 21. Compared to the control group, foetal body weight was reduced in both the jojoba and pair-fed groups, with a greater reduction in the jojoba group. Skeletal ossification was retarded to the same extent in both the jojoba and pair-fed groups. The other 10 rats from each group were left to produce litters. Compared with controls, the body weight of the pups was lower in both the jojoba and pair-fed groups; the reduction was slightly greater in the jojoba group, but this difference disappeared after 1 week. The offspring showed no other abnormalities and reproduced normally. We conclude that, at the dose used, the retardation in foetal skeletal ossification, induced by jojoba meal supplementation during gestation, is due to food intake inhibition. Moreover, the lower birth weight of the young of jojoba-treated dams compared with the pair-fed group is merely due to a lower body weight gain during gestation.

Hazardous effects of fried potato chips on the development of retina in albino rats.

PubMed

El-Sayyad, Hassan I; Sakr, Saber A; Badawy, Gamal M; Afify, Hanaa S

2011-08-01

To evaluate the hazardous effects of fried potato chips upon the retina of two developmental stages of the albino rats aged 7 and 14 days from parturition. PREGNANT RATS WERE ARRANGED INTO TWO GROUPS: control pregnant rats and consequently their delivered newborns until reaching 7 and 14 days old from parturition and fried potato chips group in which pregnant rats at the 6th day of gestation maintained on diet formed of fried potato chips supplied from the market mixed with standard diet at a concentration of 50% per each till 7 and 14 post-partum. Three fold integrated approaches were adopted, namely, histological, ultrastructural and proteomic analysis. Histological examination of the retina of the experimental offsprings revealed many histopathological changes, including massive degeneration, vacuolization and cell loss in the ganglion cell layer, as well as general reduction in retinal size. At the ultrastructural level, the retina of experimental offsprings exhibited number of deformities, including ill differentiated and degenerated nuclear layer, malformed and vacuolated pigment epithelium with vesiculated and fragmented rough endoplasmic reticulum, degenerated outer segment of photoreceptors, as well as swollen choriocapillaris and loss of neuronal cells. Proteomic analysis of retina of the two experimental developmental stages showed variations in the expressed proteins as a result of intoxication which illustrated the adverse toxic effects of fried potato chips upon the retina. It can be concluded that the effect of fried potato chips on the development of retina in rats may be due to the presence of acrylamide or its metabolite.

Finasteride inhibited brain dopaminergic system and open-field behaviors in adolescent male rats.

PubMed

Li, Li; Kang, Yun-Xiao; Ji, Xiao-Ming; Li, Ying-Kun; Li, Shuang-Cheng; Zhang, Xiang-Jian; Cui, Hui-Xian; Shi, Ge-Ming

2018-02-01

Finasteride inhibits the conversion of testosterone to dihydrotestosterone. Because androgen regulates dopaminergic system in the brain, it could be hypothesized that finasteride may inhibit dopaminergic system. The present study therefore investigates the effects of finasteride in adolescent and early developmental rats on dopaminergic system, including contents of dopamine and its metabolites (dihydroxy phenyl acetic acid and homovanillic acid) and tyrosine hydroxylase expressions both at gene and protein levels. Meanwhile, open-field behaviors of the rats are examined because of the regulatory effect of dopaminergic system on the behaviors. Open-field behaviors were evaluated by exploratory and motor behaviors. Dopamine and its metabolites were assayed by liquid chromatography-mass spectrometry. Tyrosine hydroxylase mRNA and protein expressions were determined by real-time qRT-PCR and western blot, respectively. It was found that in adolescent male rats, administration of finasteride at doses of 25 and 50 mg/kg for 14 days dose dependently inhibited open-field behaviors, reduced contents of dopamine and its metabolites in frontal cortex, hippocampus, caudate putamen, nucleus accumbens, and down-regulated tyrosine hydroxylase mRNA and protein expressions in substantia nigra and ventral tegmental area. However, there was no significant change of these parameters in early developmental rats after finasteride treatment. These results suggest that finasteride inhibits dopaminergic system and open-field behaviors in adolescent male rats by inhibiting the conversion of testosterone to dihydrotestosterone, and imply finasteride as a potential therapeutic option for neuropsychiatric disorders associated with hyperactivities of dopaminergic system and androgen. © 2017 John Wiley & Sons Ltd.

Developmental Toxic Effects of Exposure to Chemical Warfare Nerve Agents in Rats: Effects on Brain and Behavior

DTIC Science & Technology

2014-10-01

stimulation of acetylcholine receptors. Common consequences of this cholinergic crisis include seizure activity, neuronal damage and behavioral deficits. The...recurrent seizures (SRS) were observed. The current results demonstrate the vulnerability of a juvenile population to motor impairments, cognitive deficits...spontaneous recurrent seizures compared to adult rats (data not shown), which may lead to more extensive neuropathology. In addition, a small

Behavior of carbonate and magnesium ions in the initial crystallites at the early developmental stages of the rat calvaria.

PubMed

Kakei, M; Nakahara, H; Tamura, N; Itoh, H; Kumegawa, M

1997-08-01

Analysis of the contents of calcium (Ca), magnesium (Mg), phosphate, and carbonate ions in the mineral phase of rat calvaria specimens obtained at different developmental stages indicated that the mineral at the newborn stage contained a negligible amount of carbonate, but a high content of Mg. There was no significant difference in Ca and phosphate (as PO4) contents between the newborn material and that from later stages. A relatively large amount of carbonate was detected in the calvaria from 6-day-old rats, in which only immature crystals were observed, thus indicating the beginning of apatite formation. Furthermore, using laser Raman microprobe analysis we confirmed that the Raman peak at 1120 cm-1 band, indicative of a Mg-CO3 compound, appeared at the 6-day stage. We also observed that the Raman peak at 988 cm-1 found in the samples from the newborn seemed to have shifted to 963-962 cm-1 in the case of those obtained from 6-day-old rats, a shift which suggests the conversion from the non-apatitic to the apatitic form. These results indicate that carbonate ions might facilitate the initiation of crystal development by converting the inhibitory Mg ion into its inactive form (Mg-carbonate compound).

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.

Morphological abnormalities of embryonic cranial nerves after in utero exposure to valproic acid: implications for the pathogenesis of autism with multiple developmental anomalies.

PubMed

Tashiro, Yasura; Oyabu, Akiko; Imura, Yoshio; Uchida, Atsuko; Narita, Naoko; Narita, Masaaki

2011-06-01

Autism is often associated with multiple developmental anomalies including asymmetric facial palsy. In order to establish the etiology of autism with facial palsy, research into developmental abnormalities of the peripheral facial nerves is necessary. In the present study, to investigate the development of peripheral cranial nerves for use in an animal model of autism, rat embryos were treated with valproic acid (VPA) in utero and their cranial nerves were visualized by immunostaining. Treatment with VPA after embryonic day 9 had a significant effect on the peripheral fibers of several cranial nerves. Following VPA treatment, immunoreactivity within the trigeminal, facial, glossopharyngeal and vagus nerves was significantly reduced. Additionally, abnormal axonal pathways were observed in the peripheral facial nerves. Thus, the morphology of several cranial nerves, including the facial nerve, can be affected by prenatal VPA exposure as early as E13. Our findings indicate that disruption of early facial nerve development is involved in the etiology of asymmetric facial palsy, and may suggest a link to the etiology of autism. Copyright © 2011 ISDN. Published by Elsevier Ltd. All rights reserved.

Behavior and Monoamine Deficits in Prenatal and Perinatal Iron Deficiency Are Not Corrected by Early Postnatal Moderate-Iron or High-Iron Diets in Rats12

PubMed Central

Unger, Erica L.; Hurst, Amy R.; Georgieff, Michael K.; Schallert, Tim; Rao, Raghavendra; Connor, James R.; Kaciroti, Niko; Lozoff, Betsy; Felt, Barbara

2012-01-01

Developmental iron deficiency anemia (IDA) causes brain and behavioral deficits in rodent models, which cannot be reversed when treated at periods equivalent to later infancy in humans. This study sought to determine whether earlier iron treatment can normalize deficits of IDA in rats and what iron dose is optimal. The offspring of dams with IDA during gestation were cross-fostered at postnatal d (P) 8 to dams receiving diets with 1 of 3 iron concentrations until weaning (P21): 0.003–0.01 g/kg [totally iron deficient (TID)]; 0.04 g/kg [formerly iron deficient (FID-40)]; or 0.4 g/kg (FID-400). Always iron-sufficient control dams (CN-40) received a 0.04-g/kg iron diet. At P21, TID pups received a 0.01 g iron/kg diet; all others received a 0.04 g iron/kg diet. Hematocrit and brain iron and monoamine concentrations were assessed at P21 and P100. Pup growth, development, activity, object recognition, hesitancy, and watermaze performance were evaluated. Regional brain iron was restored by iron treatment. Regional monoamine and metabolite concentrations were elevated in FID-40 rats and reduced in FID-400 and TID rats compared with CN-40 rats. FID-40 offspring had motor delays similar to TID during lactation and FID-400 rats had elevated thigmotaxis similar to TID rats at P25 and P100 in the spatial watermaze. In conclusion, iron treatment at P8 in rats did not normalize all monoamine or behavioral measures after early IDA. Moderate iron treatment improved adult behavior, but higher iron treatment caused brain and behavioral patterns similar to TID in the short and long term. PMID:22990465

Postnatal overfeeding promotes early onset and exaggeration of high-fat diet-induced nonalcoholic fatty liver disease through disordered hepatic lipid metabolism in rats.

PubMed

Ji, Chenlin; Dai, Yanyan; Jiang, Weiwei; Liu, Juan; Hou, Miao; Wang, Junle; Burén, Jonas; Li, Xiaonan

2014-11-01

Exposure to overnutrition in critical or sensitive developmental periods may increase the risk of developing obesity and metabolic syndrome in adults. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome, but the relationship among postnatal nutrition, lipid metabolism, and NAFLD progression during development remains poorly understood. Here we investigated in a rat model whether postnatal overfeeding increases susceptibility to NAFLD in response to a high-fat diet. Litters from Sprague-Dawley dams were culled to three (small litters) or ten (normal litters) pups and then weaned onto a standard or high-fat diet at postnatal day 21 to generate normal-litter, small-litter, normal-litter/high-fat, and small-litter/high-fat groups. At age 16 weeks, the small-litter and both high-fat groups showed obesity, dyslipidemia, and insulin resistance. Hepatic disorders appeared earlier in the small-litter/high-fat rats with greater liver mass gain and higher hepatic triglycerides and steatosis score versus normal-litter/high-fat rats. Hepatic acetyl-CoA carboxylase activity and mRNA expression were increased in small-litter rats and aggravated in small-litter/high-fat rats but not in normal-litter/high-fat rats. The high expression in small-litter/high-fat rats coincided with high sterol regulatory element-binding protein-1c mRNA and protein expression. However, mRNA expression of enzymes involved in hepatic fatty acid oxidation (carnitine palmitoyltransferase 1) and output (microsomal triglyceride transfer protein) was decreased under a high-fat diet regardless of litter size. In conclusion, overfeeding related to small-litter rearing during lactation contributes to the NAFLD phenotype when combined with a high-fat diet, possibly through up-regulated hepatic lipogenesis. Copyright © 2014 Elsevier Inc. All rights reserved.

Expression of nitric oxide synthase during the development of RCS rat retinas.

PubMed

Sharma, R K; Warfvinge, K; Ehinger, B

2001-01-01

Nitric oxide (NO) has been reported to be both neurodestructive and neuroprotective in the central nervous system and could possibly play an important role in neurodegenerative disorders. On the assumption that NO synthesis may influence degenerative processes in the retina, we have examined the development and distribution of nitric-oxide-synthase(NOS)-immunoreactive cells in developing Royal College of Surgeons (RCS) rat retinas, which is an animal model for retinal degeneration. An antibody against constitutive neuronal NOS was used for immunocytochemistry on RCS rat retinas from postnatal (PN) days 3, 7, 10, 14, 35, 70 and 281 and compared with that in the normal rats of PN days 3, 7, 10, 14, 54 and adults. Immunoreactive cells were not seen in PN 3 retinas but were distinctly seen in the PN 7 retina along with a plexus in the inner plexiform layer. In both groups (normal and RCS rats) a distinct sublayering of the plexus in the inner plexiform layer could be seen at PN 10, which became more distinct at PN 14. The immunoreactive cells were detected also in the oldest retina examined, which was PN 281 in the case of RCS rats. In both groups, certain amacrine cells, certain bipolar cells and certain horizontal cells were found to be immunoreactive. In conclusion, the developmental timetable of the NOS immunoreactivity was identical in the normal and the RCS rat retinas. The NOS-immunoreactive cells persisted in the RCS retinas even when the retina had degenerated extensively. Abnormalities with the inducible isoforms of NOS cannot be ruled out from this study. We conclude that the chronological and qualitative development of the constitutive neuronal NOS immunoreactivity is normal in RCS rat retinas. Copyright 2001 S. Karger AG, Basel

Oral (drinking water) developmental toxicity studies of bromodichloromethane (BDCM) in rats and rabbits.

PubMed

Christian, M S; York, R G; Hoberman, A M; Diener, R M; Fisher, L C

2001-01-01

Crl:CD(SD)IGS BR VAF/Plus (Crl SD) rats and Hra(NZW) SPF rabbits were tested for potential developmental toxicity from bromodichloromethane (BDCM) provided continuously in the drinking water during gestation (gestation days [GDs] 6 to 21 in rats and GDs 6 to 29 in rabbits). Concentrations of 0, 50, 150, 450, or 900 ppm of BDCM were used for rats; 0, 15, 150, 450, or 900 ppm were used for rabbits (in dose range-finding studies, 1350 ppm was excessively maternotoxic to both species). Investigated maternal parameters included viability, clinical signs, water and feed consumption, and body weights. Maternal gross lesions, gravid uterine weights, abnormal placentas, and numbers of corpora lutea, implantation sites, live and dead fetuses, and early and late resorptions were observed at time of Caesarean sectioning (GD 21 in rats; GD 29 in rabbits). Body weights, sex ratios, and morphological abnormalities (external, soft tissue, and skeletal) were noted in the fetuses. Mean consumed doses of BDCM were calculated to be 0, 2.2, 18.4, 45.0, or 82.0 mg/kg/day for the rats, and 0, 1.4, 13.4, 35.6, or 55.3 mg/kg/day for the rabbits (approximate human intake is 0.8 microg/kg/day [0.0008 mg/kg/day] in adults). In pregnant rats, toxicologically important, statistically significant effects included reduced absolute (g/day) and relative (g/kg/day) water consumption values at > or =50 ppm (2.2 mg/kg/day) and reduced body weight gains (also when corrected for gravid uterine weight) and absolute (g/day) and relative (g/kg/day) feed consumption values at >450 ppm (45.0 mg/kg/day). These parameters were also significantly reduced at > or =450 ppm (35.6 mg/kg/day) in pregnant rabbits (significant weight loss occurred in the rabbits at 900 ppm, i.e., 55.3 mg/kg/day). Thus, the maternal no-observable-adverse-effect level (NOAEL) for BDCM was 150 ppm, i.e., 18.4 and 13.4 mg/kg/day in rats and rabbits, respectively. No adverse effects on embryofetal viability, growth, sex ratio, gross external, soft tissue, or skeletal morphology occurred at 900 ppm in rats or rabbits. Minimal delays in the ossification of forepaw phalanges and hindpaw metatarsals and phalanges occurred in rat fetuses at 900 ppm; delays were considered marginal, reversible, and associated with severely reduced maternal weight gain. Therefore, the developmental NOAEL for rats was 450 ppm (45.0 mg/kg/day), whereas in rabbits it was 900 ppm (55.3 mg/kg/day). These NOAELs are 56,250 and 69,120 times the human adult exposure level of 0.0008 mg/kg/day, respectively. Based on the results of these studies, BDCM should not be identified as a risk to development of human conceptuses.

Investigation for methods of anesthesia and euthanasia for rat fetuses in developmental toxicity studies.

PubMed

Kato, Hirohito; Dokai, Momoko; Katagiri, Ryuichi; Arima, Akihiro; Ooshima, Yojiro

2013-03-01

Japan Association for Laboratory Animal Medicine (JALAM) recommends humane handling of rat fetuses. However, it is a challenge to accept proposed euthanizing methods such as cervical dislocation, decapitation and/or intracardiac injection of potassium chloride, because these methods would damage fetal specimens for skeletal and visceral examinations in developmental toxicity studies. The present study aimed at seeking better methodologies for fetal euthanasia and anesthesia. We were unable to accomplish fetal euthanasia directly, but instead, we could euthanize fetuses under pain-controlled anesthesia. It is recommended that hypothermia by immersion in cold physiological saline is an appropriate method for anesthesia. Moreover, we recommend that the anesthetized fetuses should be euthanized immediately by removal of the vital organs or immersion in appropriate fixatives. © 2012 The Authors. Congenital Anomalies © 2012 Japanese Teratology Society.

Alterations in the Rat Serum Proteome Induced by Prepubertal Exposure to Bisphenol A and Genistein

PubMed Central

2015-01-01

Humans are exposed to an array of chemicals via the food, drink and air, including a significant number that can mimic endogenous hormones. One such chemical is Bisphenol A (BPA), a synthetic chemical that has been shown to cause developmental alterations and to predispose for mammary cancer in rodent models. In contrast, the phytochemical genistein has been reported to suppress chemically induced mammary cancer in rodents, and Asians ingesting a diet high in soy containing genistein have lower incidence of breast and prostate cancers. In this study, we sought to: (1) identify protein biomarkers of susceptibility from blood sera of rats exposed prepubertally to BPA or genistein using Isobaric Tandem Mass Tags quantitative mass spectrometry (TMT-MS) combined with MudPIT technology and, (2) explore the relevance of these proteins to carcinogenesis. Prepubertal exposures to BPA and genistein resulted in altered expression of 63 and 28 proteins in rat sera at postnatal day (PND) 21, and of 9 and 18 proteins in sera at PND35, respectively. This study demonstrates the value of using quantitative proteomic techniques to explore the effect of chemical exposure on the rat serum proteome and its potential for unraveling cellular targets altered by BPA and genistein involved in carcinogenesis. PMID:24552547

Selective breeding for infant rat separation-induced ultrasonic vocalizations: developmental precursors of passive and active coping styles.

PubMed

Brunelli, Susan A; Hofer, Myron A

2007-09-04

Human depression and anxiety disorders show inherited biases across generations, as do antisocial disorders characterized by aggression. Each condition is preceded in children by behavioral inhibition or aggressive behavior, respectively, and both are characterized by separation anxiety disorders. In affected families, adults and children exhibit different forms of altered autonomic nervous system regulation and hypothalamic-pituitary-adrenal activity in response to stress. Because it is difficult to determine mechanisms accounting for these associations, animal studies are useful for studying the fundamental relationships between biological and behavioral traits. Pharmacologic and behavioral studies suggest that infant rat ultrasonic vocalizations (USV) are a measure of an early anxiety-like state related to separation anxiety. However, it was not known whether or not early ultrasound emissions in infant rats are markers for genetic risk for anxiety states later in life. To address these questions, we selectively bred two lines of rats based on high and low rates of USV to isolation at postnatal (P) 10 days of age. To our knowledge, ours is the only laboratory that has ever selectively bred on the basis of an infantile trait related to anxiety. The High and Low USV lines show two distinct sets of patterns of behavior, physiology and neurochemistry from infancy through adulthood. As adults High line rats demonstrate "anxious"/"depressed" phenotypes in behavior and autonomic nervous system (ANS) regulation to standard laboratory tests. In Lows, on the other hand, behavior and autonomic regulation are consistent with an "aggressive" phenotype. The High and Low USV lines are the first genetic animal models implicating long-term associations of contrasting "coping styles" with early attachment responses. They thus present a potentially powerful model for examining gene-environment interactions in the development of life-long affective regulation.

Gene expression in dopamine and GABA systems in an animal model of schizophrenia: effects of antipsychotic drugs.

PubMed

Lipska, Barbara K; Lerman, Daniel N; Khaing, Zin Z; Weickert, Cynthia Shannon; Weinberger, Daniel R

2003-07-01

We used in situ hybridization histochemistry to assess expression of dopamine receptors (D1R, D2R and D3R), neurotensin, proenkephalin and glutamate decarboxylase-67 (GAD67) in the prefrontal cortex, striatum, and/or nucleus accumbens in adult rats with neonatal ventral hippocampal (VH) lesions and in control animals after acute and chronic treatment with antipsychotic drugs clozapine and haloperidol. We also acquired these measures in a separate cohort of treatment-naïve sham and neonatally VH-lesioned rats used as an animal model of schizophrenia. Our results indicate that the neonatal VH lesion did not alter expression of D1R, D3R, neurotensin or proenkephalin expression in any brain region examined. However, D2R mRNA expression was down-regulated in the striatum, GAD67 mRNA was down-regulated in the prefrontal cortex and prodynorphin mRNA was up-regulated in the striatum of the VH-lesioned rats as compared with sham controls. Antipsychotic drugs did not alter expression of D1R, D2R or D3R receptor mRNAs but elevated neurotensin and proenkephalin expression in both groups of rats; patterns of changes were dependent on the duration of treatment and brain area examined. GAD67 mRNA was up-regulated by chronic antispychotics in the nucleus accumbens and the striatum and by chronic haloperidol in the prefrontal cortex in both sham and lesioned rats. These results indicate that the developmental VH lesion changed the striatal expression of D2R and prodynorphin and robustly compromised prefrontal GAD67 expression but did not modify drug-induced expression of any genes examined in this study.

Postinjury Exercise and Platelet-Rich Plasma Therapies Improve Skeletal Muscle Healing in Rats But Are Not Synergistic When Combined.

PubMed

Contreras-Muñoz, Paola; Torrella, Joan Ramon; Serres, Xavier; Rizo-Roca, David; De la Varga, Meritxell; Viscor, Ginés; Martínez-Ibáñez, Vicente; Peiró, José Luis; Järvinen, Tero A H; Rodas, Gil; Marotta, Mario

2017-07-01

Skeletal muscle injuries are the most common sports-related injury and a major concern in sports medicine. The effect of platelet-rich plasma (PRP) injections on muscle healing is still poorly understood, and current data are inconclusive. To evaluate the effects of an ultrasound-guided intramuscular PRP injection, administered 24 hours after injury, and/or posttraumatic daily exercise training for 2 weeks on skeletal muscle healing in a recently established rat model of skeletal muscle injury that highly mimics the muscle trauma seen in human athletes. Controlled laboratory study. A total of 40 rats were assigned to 5 groups. Injured rats (medial gastrocnemius injury) received a single PRP injection (PRP group), daily exercise training (Exer group), or a combination of a single PRP injection and daily exercise training (PRP-Exer group). Untreated and intramuscular saline-injected animals were used as controls. Muscle force was determined 2 weeks after muscle injury, and muscles were harvested and evaluated by means of histological assessment and immunofluorescence microscopy. Both PRP (exhibiting 4.8-fold higher platelet concentration than whole blood) and exercise training improved muscle strength (maximum tetanus force, TetF) in approximately 18%, 20%, and 30% of rats in the PRP, PRP-Exer, and Exer groups, respectively. Specific markers of muscle regeneration (developmental myosin heavy chain, dMHC) and scar formation (collagen I) demonstrated the beneficial effect of the tested therapies in accelerating the muscle healing process in rats. PRP and exercise treatments stimulated the growth of newly formed regenerating muscle fibers (1.5-, 2-, and 2.5-fold increase in myofiber cross-sectional area in PRP, PRP-Exer, and Exer groups, respectively) and reduced scar formation in injured skeletal muscle (20%, 34%, and 41% of reduction in PRP, PRP-Exer, and Exer groups, respectively). Exercise-treated muscles (PRP-Exer and Exer groups) had significantly reduced percentage of dMHC-positive regenerating fibers (35% and 47% decrease in dMHC expression, respectively), indicating that exercise therapies accelerated the muscle healing process witnessed by the more rapid replacement of the embryonic-developmental myosin isoform by mature muscle myosin isoforms. Intramuscular PRP injection and, especially, treadmill exercise improve histological outcome and force recovery of the injured skeletal muscle in a rat injury model that imitates sports-related muscle injuries in athletes. However, there was not a synergistic effect when both treatments were combined, suggesting that PRP does not add any beneficial effect to exercise-based therapy in the treatment of injured skeletal muscle. This study demonstrates the efficacy of an early active rehabilitation protocol or single intramuscular PRP injection on muscle recovery. The data also reveal that the outcome of the early active rehabilitation is adversely affected by the PRP injection when the two therapies are combined, and this could explain why PRP therapies have failed in randomized clinical trials where the athletes have adhered to postinjection rehabilitation protocols based on the principle of early, active mobilization.

Early neuromodulation prevents the development of brain and behavioral abnormalities in a rodent model of schizophrenia.

PubMed

Hadar, R; Bikovski, L; Soto-Montenegro, M L; Schimke, J; Maier, P; Ewing, S; Voget, M; Wieske, F; Götz, T; Desco, M; Hamani, C; Pascau, J; Weiner, I; Winter, C

2018-04-01

The notion that schizophrenia is a neurodevelopmental disorder in which neuropathologies evolve gradually over the developmental course indicates a potential therapeutic window during which pathophysiological processes may be modified to halt disease progression or reduce its severity. Here we used a neurodevelopmental maternal immune stimulation (MIS) rat model of schizophrenia to test whether early targeted modulatory intervention would affect schizophrenia's neurodevelopmental course. We applied deep brain stimulation (DBS) or sham stimulation to the medial prefrontal cortex (mPFC) of adolescent MIS rats and respective controls, and investigated its behavioral, biochemical, brain-structural and -metabolic effects in adulthood. We found that mPFC-DBS successfully prevented the emergence of deficits in sensorimotor gating, attentional selectivity and executive function in adulthood, as well as the enlargement of lateral ventricle volumes and mal-development of dopaminergic and serotonergic transmission. These data suggest that the mPFC may be a valuable target for effective preventive treatments. This may have significant translational value, suggesting that targeting the mPFC before the onset of psychosis via less invasive neuromodulation approaches may be a viable preventive strategy.

Cross-modal transfer of the conditioned eyeblink response during interstimulus interval discrimination training in young rats

PubMed Central

Brown, Kevin L.; Stanton, Mark E.

2008-01-01

Eyeblink classical conditioning (EBC) was observed across a broad developmental period with tasks utilizing two interstimulus intervals (ISIs). In ISI discrimination, two distinct conditioned stimuli (CSs; light and tone) are reinforced with a periocular shock unconditioned stimulus (US) at two different CS-US intervals. Temporal uncertainty is identical in design with the exception that the same CS is presented at both intervals. Developmental changes in conditioning have been reported in each task beyond ages when single-ISI learning is well developed. The present study sought to replicate and extend these previous findings by testing each task at four separate ages. Consistent with previous findings, younger rats (postnatal day – PD - 23 and 30) trained in ISI discrimination showed evidence of enhanced cross-modal influence of the short CS-US pairing upon long CS conditioning relative to older subjects. ISI discrimination training at PD43-47 yielded outcomes similar to those in adults (PD65-71). Cross-modal transfer effects in this task therefore appear to diminish between PD30 and PD43-47. Comparisons of ISI discrimination with temporal uncertainty indicated that cross-modal transfer in ISI discrimination at the youngest ages did not represent complete generalization across CSs. ISI discrimination undergoes a more protracted developmental emergence than single-cue EBC and may be a more sensitive indicator of developmental disorders involving cerebellar dysfunction. PMID:18726989

Epigenetic dysregulation of key developmental genes in radiation-induced rat mammary carcinomas.

PubMed

Daino, Kazuhiro; Nishimura, Mayumi; Imaoka, Tatsuhiko; Takabatake, Masaru; Morioka, Takamitsu; Nishimura, Yukiko; Shimada, Yoshiya; Kakinuma, Shizuko

2018-02-13

With the increase in the number of long-term cancer survivors worldwide, there is a growing concern about the risk of secondary cancers induced by radiotherapy. Epigenetic modifications of genes associated with carcinogenesis are attractive targets for the prevention of cancer owing to their reversible nature. To identify genes with possible changes in functionally relevant DNA methylation patterns in mammary carcinomas induced by radiation exposure, we performed microarray-based global DNA methylation and expression profiling in γ-ray-induced rat mammary carcinomas and normal mammary glands. The gene expression profiling identified dysregulation of developmentally related genes, including the downstream targets of polycomb repressive complex 2 (PRC2) and overexpression of enhancer of zeste homolog 2, a component of PRC2, in the carcinomas. By integrating expression and DNA methylation profiles, we identified ten hypermethylated and three hypomethylated genes that possibly act as tumor-suppressor genes and oncogenes dysregulated by aberrant DNA methylation; half of these genes encode developmental transcription factors. Bisulfite sequencing and quantitative PCR confirmed the dysregulation of the polycomb-regulated developmentally related transcription-factor genes Dmrt2, Hoxa7, Foxb1, Sox17, Lhx8, Gata3 and Runx1. Silencing of Hoxa7 was further verified by immunohistochemistry. These results suggest that, in radiation-induced mammary gland carcinomas, PRC2-mediated aberrant DNA methylation leads to dysregulation of developmentally related transcription-factor genes. Our findings provide clues to molecular mechanisms linking epigenetic regulation and radiation-induced breast carcinogenesis and underscore the potential of such epigenetic mechanisms as targets for cancer prevention. © 2018 UICC.

Development of REM sleep drive and clinical implications

PubMed Central

Kobayashi, T.; Good, C.; Mamiya, K.; Skinner, R.D.; Garcia-Rill, E.

2015-01-01

REM sleep in the human declines from about 50% of total sleep time (~8 hours) in the newborn to about 15% of total sleep time (~1 hour) in the adult, and this decrease takes place mainly between birth and the end of puberty. We hypothesize that, if this developmental decrease in REM drive does not occur, lifelong increases in REM sleep drive may ensue. In the rat, the developmental decrease in REM sleep occurs between 10 and 30 days after birth, declining from over 70% of total sleep time in the newborn to the adult level of about 15% of sleep time during this period. Rats aged 12–21 days were anaesthetized with Ketamine, decapitated and brainstem slices cut for intracellular recordings. We found that excitatory responses of pedunculopontine nucleus (PPN) neurons to NMDA decrease, while responses to kainic acid increase, over this critical period. Serotonergic type 1 agonists have increasing inhibitory responses, while serotonergic type 2 agonists do not change, during this developmental period. The results suggest that, as PPN neurons develop, they are increasingly activated by kainic acid and increasingly inhibited by serotonergic type 1 receptors. These processes may be related to the developmental decrease in REM sleep. Developmental disturbances in each of these systems could induce differential increases in REM sleep drive, accounting for the post-pubertal onset of a number of different disorders manifesting increases in REM sleep drive. Examination of modulation by PPN projections to ascending and descending targets revealed the presence of common signals modulating both ascending arousal-related functions and descending postural/locomotor-related functions. PMID:14527968

Environmental Impact on Vascular Development Predicted by High-Throughput Screening

PubMed Central

Judson, Richard S.; Reif, David M.; Sipes, Nisha S.; Singh, Amar V.; Chandler, Kelly J.; DeWoskin, Rob; Dix, David J.; Kavlock, Robert J.; Knudsen, Thomas B.

2011-01-01

Background: Understanding health risks to embryonic development from exposure to environmental chemicals is a significant challenge given the diverse chemical landscape and paucity of data for most of these compounds. High-throughput screening (HTS) in the U.S. Environmental Protection Agency (EPA) ToxCast™ project provides vast data on an expanding chemical library currently consisting of > 1,000 unique compounds across > 500 in vitro assays in phase I (complete) and Phase II (under way). This public data set can be used to evaluate concentration-dependent effects on many diverse biological targets and build predictive models of prototypical toxicity pathways that can aid decision making for assessments of human developmental health and disease. Objective: We mined the ToxCast phase I data set to identify signatures for potential chemical disruption of blood vessel formation and remodeling. Methods: ToxCast phase I screened 309 chemicals using 467 HTS assays across nine assay technology platforms. The assays measured direct interactions between chemicals and molecular targets (receptors, enzymes), as well as downstream effects on reporter gene activity or cellular consequences. We ranked the chemicals according to individual vascular bioactivity score and visualized the ranking using ToxPi (Toxicological Priority Index) profiles. Results: Targets in inflammatory chemokine signaling, the vascular endothelial growth factor pathway, and the plasminogen-activating system were strongly perturbed by some chemicals, and we found positive correlations with developmental effects from the U.S. EPA ToxRefDB (Toxicological Reference Database) in vivo database containing prenatal rat and rabbit guideline studies. We observed distinctly different correlative patterns for chemicals with effects in rabbits versus rats, despite derivation of in vitro signatures based on human cells and cell-free biochemical targets, implying conservation but potentially differential contributions of developmental pathways among species. Follow-up analysis with antiangiogenic thalidomide analogs and additional in vitro vascular targets showed in vitro activity consistent with the most active environmental chemicals tested here. Conclusions: We predicted that blood vessel development is a target for environmental chemicals acting as putative vascular disruptor compounds (pVDCs) and identified potential species differences in sensitive vascular developmental pathways. PMID:21788198

Validation of a Preclinical Spinal Safety Model: Effects of Intrathecal Morphine in the Neonatal Rat

PubMed Central

Westin, B. David; Walker, Suellen M.; Deumens, Ronald; Grafe, Marjorie; Yaksh, Tony L.

2010-01-01

Background Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long term function following intrathecal morphine in the neonatal rat. Methods Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P)3, 10 and 21. The relationship between injectate volume and segmental spread was assessed post mortem and by in-vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 minutes following intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis and glial response were evaluated 1 and 7 days following P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Results Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally-mediated analgesia at all ages with lower dose requirements in younger pups. High dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. Conclusions The therapeutic ratio for intrathecal morphine (toxic dose / antinociceptive dose) was at least 300 at P3, and at least 20 at P21 (latter doses limited by side effects). This data provides relative efficacy and safety data for comparison with other analgesic preparations and contributes supporting evidence for the validity of this preclinical neonatal safety model. PMID:20526189

Validation of a preclinical spinal safety model: effects of intrathecal morphine in the neonatal rat.

PubMed

Westin, B David; Walker, Suellen M; Deumens, Ronald; Grafe, Marjorie; Yaksh, Tony L

2010-07-01

Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long-term function after intrathecal morphine in the neonatal rat. Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P) 3, 10, and 21. The relationship between injectate volume and segmental spread was assessed postmortem and by in vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 min after intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis, and glial response were evaluated 1 and 7 days after P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally mediated analgesia at all ages with lower dose requirements in younger pups. High-dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. The therapeutic ratio for intrathecal morphine (toxic dose/antinociceptive dose) was at least 300 at P3 and at least 20 at P21 (latter doses limited by side effects). These data provide relative efficacy and safety for comparison with other analgesic preparations and contribute supporting evidence for the validity of this preclinical neonatal safety model.

Caspase Activation in Fetal Rat Brain Following Experimental Intrauterine Inflammation

PubMed Central

Sharangpani, Aditi; Takanohashi, Asako; Bell, Michael J.

2009-01-01

Intrauterine inflammation has been implicated in developmental brain injuries, including the development of periventricular leukomalacia (PVL) and cerebral palsy (CP). Previous studies in our rat model of intrauterine inflammation demonstrated apoptotic cell death in fetal brains within the first 5 days after lipopolysaccharide (LPS) administration to mothers and eventual dysmyelination. Cysteine-containing, aspartate-specific proteases, or caspases, are proteins involved with apoptosis through both intracellular (intrinsic pathway) and extracellular (extrinsic pathway) mechanisms. We hypothesized that cell death in our model would occur mainly via activation of the extrinsic pathway. We further hypothesized that Fas, a member of the tumor necrosis factor receptor (TNFR) superfamily, would be increased and the death inducing signaling complex (DISC) would be detectable. Pregnant rats were injected intracervically with LPS at E15 and immunoblotting, immunohistochemical and immunoprecipitation analyses were performed. The presence of the activated form of the effector caspase (caspase-3) was observed 24 h after LPS administration. Caspase activity assays demonstrated rapid increases in (i) caspases-9 and -10 within 1 h, (ii) caspase-8 at 2 h and (iii) caspase-3 at 4 h. At 24 h after LPS, activated caspase-3+/Fas+ cells were observed within the developing white matter. Lastly, the DISC complex (caspase-8, Fas and Fas-associated Death Domain (FADD)) was observed within 30 min by immunoprecipitation. Apoptosis in our model occurs via both extrinsic and intrinsic pathways, and activation of Fas may play a role. Understanding the mechanisms of cell death in models of intrauterine inflammation may affect development of future strategies to mitigate these injuries in children. PMID:18289516

The developmental effects of extremely low frequency electric fields on visual and somatosensory evoked potentials in adult rats.

PubMed

Gok, Deniz Kantar; Akpinar, Deniz; Hidisoglu, Enis; Ozen, Sukru; Agar, Aysel; Yargicoglu, Piraye

2016-01-01

The purpose of our study was to investigate the developmental effects of extremely low frequency electric fields (ELF-EFs) on visual evoked potentials (VEPs) and somatosensory-evoked potentials (SEPs) and to examine the relationship between lipid peroxidation and changes of these potentials. In this context, thiobarbituric acid reactive substances (TBARS) levels were determined as an indicator of lipid peroxidation. Wistar albino female rats were divided into four groups; Control (C), gestational (prenatal) exposure (Pr), gestational+ postnatal exposure (PP) and postnatal exposure (Po) groups. Pregnant rats of Pr and PP groups were exposed to 50 Hz electric field (EF) (12 kV/m; 1 h/day), while those of C and Po groups were placed in an inactive system during pregnancy. Following parturition, rats of PP and Po groups were exposed to ELF-EFs whereas rats of C and Pr groups were kept under the same experimental conditions without being exposed to any EF during 68 days. On postnatal day 90, rats were prepared for VEP and SEP recordings. The latencies of VEP components in all experimental groups were significantly prolonged versus C group. For SEPs, all components of PP group, P2, N2 components of Pr group and P1, P2, N2 components of Po group were delayed versus C group. As brain TBARS levels were significantly increased in Pr and Po groups, retina TBARS levels were significantly elevated in all experimental groups versus C group. In conclusion, alterations seen in evoked potentials, at least partly, could be explained by lipid peroxidation in the retina and brain.

Regulation of renal NaPi-2 expression and tubular phosphate reabsorption by growth hormone in the juvenile rat.

PubMed

Woda, Craig B; Halaihel, Nabil; Wilson, Paul V; Haramati, Aviad; Levi, Moshe; Mulroney, Susan E

2004-07-01

Growth hormone (GH) is an important factor in the developmental adaptation to enhance P(i) reabsorption; however, the nephron sites and mechanisms by which GH regulates renal P(i) uptake remain unclear and are the focus of the present study. Micropuncture experiments were performed after acute thyroparathyroidectomy in the presence and absence of parathyroid hormone (PTH) in adult (14- to 17-wk old), juvenile (4-wk old), and GH-suppressed juvenile male rats. While the phosphaturic effect of PTH was blunted in the juvenile rat compared with the adult, suppression of GH in the juvenile restored fractional P(i) excretion to adult levels. In the presence or absence of PTH, GH suppression in the juvenile rat caused a significant increase in the fractional P(i) delivery to the late proximal convoluted (PCT) and early distal tubule, so that delivery was not different from that in adults. These data were confirmed by P(i) uptake studies into brush-border membrane (BBM) vesicles. Immunofluorescence studies indicate increased BBM type IIa NaP(i) cotransporter (NaPi-2) expression in the juvenile compared with adult rat, and GH suppression reduced NaPi-2 expression to levels observed in the adult. GH replacement in the [N-acetyl-Tyr(1)-d-Arg(2)]-GRF-(1-29)-NH(2)-treated juveniles restored high NaPi-2 expression and P(i) uptake. Together, these novel results demonstrate that the presence of GH in the juvenile animal is crucial for the early developmental upregulation of BBM NaPi-2 and, most importantly, describe the enhanced P(i) reabsorption along the PCT and proximal straight nephron segments in the juvenile rat.

Normal radial migration and lamination are maintained in dyslexia-susceptibility candidate gene homolog Kiaa0319 knockout mice.

PubMed

Martinez-Garay, Isabel; Guidi, Luiz G; Holloway, Zoe G; Bailey, Melissa A G; Lyngholm, Daniel; Schneider, Tomasz; Donnison, Timothy; Butt, Simon J B; Monaco, Anthony P; Molnár, Zoltán; Velayos-Baeza, Antonio

2017-04-01

Developmental dyslexia is a common disorder with a strong genetic component, but the underlying molecular mechanisms are still unknown. Several candidate dyslexia-susceptibility genes, including KIAA0319, DYX1C1, and DCDC2, have been identified in humans. RNA interference experiments targeting these genes in rat embryos have shown impairments in neuronal migration, suggesting that defects in radial cortical migration could be involved in the disease mechanism of dyslexia. Here we present the first characterisation of a Kiaa0319 knockout mouse line. Animals lacking KIAA0319 protein do not show anatomical abnormalities in any of the layered structures of the brain. Neurogenesis and radial migration of cortical projection neurons are not altered, and the intrinsic electrophysiological properties of Kiaa0319-deficient neurons do not differ from those of wild-type neurons. Kiaa0319 overexpression in cortex delays radial migration, but does not affect final neuronal position. However, knockout animals show subtle differences suggesting possible alterations in anxiety-related behaviour and in sensorimotor gating. Our results do not reveal a migration disorder in the mouse model, adding to the body of evidence available for Dcdc2 and Dyx1c1 that, unlike in the rat in utero knockdown models, the dyslexia-susceptibility candidate mouse homolog genes do not play an evident role in neuronal migration. However, KIAA0319 protein expression seems to be restricted to the brain, not only in early developmental stages but also in adult mice, indicative of a role of this protein in brain function. The constitutive and conditional knockout lines reported here will be useful tools for further functional analyses of Kiaa0319.

Altered metabolic activity in the developing brain of rats predisposed to high versus low depression-like behavior

PubMed Central

Melendez-Ferro, Miguel; Perez-Costas, Emma; Glover, Matthew E.; Jackson, Nateka L.; Stringfellow, Sara A.; Pugh, Phyllis C.; Fant, Andrew D.; Clinton, Sarah M.

2016-01-01

Individual differences in human temperament can increase risk for psychiatric disorders like depression and anxiety. Our laboratory utilized a rat model of temperamental differences to assess neurodevelopmental factors underlying emotional behavior differences. Rats selectively bred for low novelty exploration (Low Responders, LR) display high levels of anxiety- and depression-like behavior compared to High Novelty Responder (HR) rats. Using transcriptome profiling, the present study uncovered vast gene expression differences in the early postnatal HR versus LR limbic brain, including changes in genes involved in cellular metabolism. These data led us to hypothesize that rats prone to high (versus low) anxiety/depression-like behavior exhibit distinct patterns of brain metabolism during the first weeks of life, which may reflect disparate patterns of synaptogenesis and brain circuit development. Thus, in a second experiment we examined activity of Cytochrome C Oxidase (COX), an enzyme responsible for ATP production and a correlate of metabolic activity, to explore functional energetic differences in HR/LR early postnatal brain. We found that HR rats display higher COX activity in the amygdala and specific hippocampal subregions compared to LRs during the first 2 weeks of life. Correlational analysis examining COX levels across several brain regions and multiple early postnatal time points suggested desynchronization in the developmental timeline of the limbic HR versus LR brain during the first two postnatal weeks. These early divergent COX activity levels may reflect altered circuitry or synaptic activity in the early postnatal HR/LR brain, which could contribute to the emergence of their distinct behavioral phenotypes. PMID:26979051

Cacna1c haploinsufficiency leads to pro-social 50-kHz ultrasonic communication deficits in rats.

PubMed

Kisko, Theresa M; Braun, Moria D; Michels, Susanne; Witt, Stephanie H; Rietschel, Marcella; Culmsee, Carsten; Schwarting, Rainer K W; Wöhr, Markus

2018-06-20

The cross-disorder risk gene CACNA1C is strongly implicated in multiple neuropsychiatric disorders, including autism spectrum disorder (ASD), bipolar disorder (BPD) and schizophrenia (SCZ), with deficits in social functioning being common for all major neuropsychiatric disorders. In the present study, we explored the role of Cacna1c in regulating disorder-relevant behavioral phenotypes, focusing on socio-affective communication after weaning during the critical developmental period of adolescence in rats. To this aim, we used a newly developed genetic Cacna1c rat model and applied a truly reciprocal approach for studying communication through ultrasonic vocalizations, including both sender and receiver. Our results show that a deletion of Cacna1c leads to deficits in social behavior and pro-social 50-kHz ultrasonic communication in rats. Reduced levels of 50-kHz ultrasonic vocalizations emitted during rough-and-tumble play may suggest that Cacna1c haploinsufficient rats derive less reward from playful social interactions. Besides the emission of fewer 50-kHz ultrasonic vocalizations in the sender, Cacna1c deletion reduced social approach behavior elicited by playback of 50-kHz ultrasonic vocalizations. This indicates that Cacna1c haploinsufficiency has detrimental effects on 50-kHz ultrasonic communication in both sender and receiver. Together, these data suggest that Cacna1c plays a prominent role in regulating socio-affective communication in rats with relevance for ASD, BPD and SCZ.This article has an associated First Person interview with the first author of the paper. © 2018. Published by The Company of Biologists Ltd.

Detection of expressional changes induced by intrauterine growth restriction in the developing rat pancreas

PubMed Central

Zhang, Lin; Chen, Wei; Dai, Yuee

2016-01-01

Intrauterine growth retardation (IUGR) is a disorder that can result in permanent changes in the physiology and metabolism of the newborn, which increased the risk of disease in adulthood. Evidence supports IUGR as a risk factor for the development of diabetes mellitus, which could reflect changes in pancreas developmental pathways. We sought to characterize the IUGR-induced alterations of the complex pathways of pancreas development in a rat model of IUGR. We analyzed the pancreases of Sprague Dawley rats after inducing IUGR by feeding a maternal low calorie diet from gestational day 1 until term. IUGR altered the pancreatic structure, islet areas, and islet quantities and resulted in abnormal morphological changes during pancreatic development, as determined by HE staining and light microscopy. We identified multiple differentially expressed genes in the pancreas by RT-PCR. The genes of the insulin/FoxO1/Pdx1/MafA signaling pathway were first expressed at embryonic day 14 (E14). The expressions of insulin and MafA increased as the fetus grew while the expressions of FoxO1 and Pdx1 decreased. Compared with the control rats, the expressions of FoxO1, Pdx1, and MafA were lower in the IUGR rats, whereas insulin levels showed no change. Microarray profiling, in combination with quantitative real-time PCR, uncovered a subset of microRNAs that changed in their degree of expression throughout pancreatic development. In conclusion, our data support the hypothesis that IUGR influences the development of the rat pancreas. We also identified new pathways that appear to be programmed by IUGR. PMID:27190278

Developmental lead exposure attenuates methamphetamine dose-effect self-administration performance and progressive ratio responding in the male rat.

PubMed

Rocha, Angelica; Valles, Rodrigo; Hart, Nigel; Bratton, Gerald R; Nation, Jack R

2008-06-01

Perinatal (gestation/lactation) lead exposure modifies the reinforcement efficacy of various psychoactive drugs (e.g., cocaine, opiates) across the phases of initial selection, use, and abuse [Nation J.R., Cardon A.L., Heard H.M., Valles R., Bratton G.R. Perinatal lead exposure and relapse to drug-seeking behavior in the rat: a cocaine reinstatement study. Psychopharmacol 2003;168: 236-243.; Nation J.R., Smith K.R., Bratton G.R. Early developmental lead exposure increases sensitivity to cocaine in a self-administration paradigm. Pharmacol Biochem Behave 2004; 77: 127-13; Rocha A., Valles R., Cardon A.L., Bratton G.R., Nation J.R. Enhanced acquisition of cocaine self-administration in rats developmentally exposed to lead. Neuropsychopharmacol 2005; 30: 2058-2064.]. However, changes in sensitivity to methamphetamine across the phases of drug abuse have not been examined in animals perinatally exposed to lead. Because the mainstream popularity of methamphetamine in the United States is increasing and lead exposure continues to be widespread, an examination of this drug and how it may be modified by perinatal exposure to lead is warranted. The studies reported here examined the effects of perinatal lead exposure on adult self-administration of intravenous (i.v.) methamphetamine across the maintenance phase of drug addiction. Experiment 1 examined dose-effect patterns in control and lead-exposed animals. Experiment 2 evaluated control and lead-exposed animals in a progressive ratio task. Female rats were administered a 16-mg lead or a control solution for 30 days prior to breeding with non-exposed males. Exposure continued through pregnancy and lactation and was discontinued at weaning (postnatal day [PND] 21). Animals born to control or lead-exposed dams received indwelling jugular catheters as adults (PND 70) and subsequently were randomly assigned to one of the two studies, using only one male rat per litter for each study. The data showed a general attenuation of the reinforcement efficacy of methamphetamine in animals perinatally exposed to lead, as compared to control animals.

40 CFR 721.9928 - Urea, tetraethyl-.

Code of Federal Regulations, 2011 CFR

2011-07-01

.... Requirements as specified in § 721.80(r) (445,000 kg) (a dermal developmental toxicity study in mice and rats and either a chromosome aberration assay in mice (40 CFR 798.5385) or a micronucleus assay in mice (40...

40 CFR 721.9928 - Urea, tetraethyl-.

Code of Federal Regulations, 2010 CFR

2010-07-01

.... Requirements as specified in § 721.80(r) (445,000 kg) (a dermal developmental toxicity study in mice and rats and either a chromosome aberration assay in mice (40 CFR 798.5385) or a micronucleus assay in mice (40...

40 CFR 721.9928 - Urea, tetraethyl-.

Code of Federal Regulations, 2013 CFR

2013-07-01

.... Requirements as specified in § 721.80(r) (445,000 kg) (a dermal developmental toxicity study in mice and rats and either a chromosome aberration assay in mice (40 CFR 798.5385) or a micronucleus assay in mice (40...

40 CFR 721.9928 - Urea, tetraethyl-.

Code of Federal Regulations, 2012 CFR

2012-07-01

.... Requirements as specified in § 721.80(r) (445,000 kg) (a dermal developmental toxicity study in mice and rats and either a chromosome aberration assay in mice (40 CFR 798.5385) or a micronucleus assay in mice (40...

40 CFR 721.9928 - Urea, tetraethyl-.

Code of Federal Regulations, 2014 CFR

2014-07-01

.... Requirements as specified in § 721.80(r) (445,000 kg) (a dermal developmental toxicity study in mice and rats and either a chromosome aberration assay in mice (40 CFR 798.5385) or a micronucleus assay in mice (40...

Twitching in Sensorimotor Development from Sleeping Rats to Robots

PubMed Central

Marques, Hugo Gravato; Iida, Fumiya

2013-01-01

It is still not known how the “rudimentary” movements of fetuses and infants are transformed into the coordinated, flexible, and adaptive movements of adults. In addressing this important issue, we consider a behavior that has been perennially viewed as a functionless by-product of a dreaming brain: the jerky limb movements called myoclonic twitches. Recent work has identified the neural mechanisms that produce twitching as well as those that convey sensory feedback from twitching limbs to the spinal cord and brain. In turn, these mechanistic insights have helped inspire new ideas about the functional roles that twitching might play in the self-organization of spinal and supraspinal sensorimotor circuits. Striking support for these ideas is coming from the field of developmental robotics: When twitches are mimicked in robot models of the musculoskeletal system, basic neural circuitry self-organizes. Mutually inspired biological and synthetic approaches promise not only to produce better robots, but also to solve fundamental problems concerning the developmental origins of sensorimotor maps in the spinal cord and brain. PMID:23787051

What the laboratory rat has taught us about social play behavior: role in behavioral development and neural mechanisms.

PubMed

Vanderschuren, Louk J M J; Trezza, Viviana

2014-01-01

Social play behavior is the most vigorous and characteristic form of social interaction displayed by developing mammals. The laboratory rat is an ideal species to study this behavior, since it shows ample social play that can be easily recognized and quantified. In this chapter, we will first briefly describe the structure of social play behavior in rats. Next, we will discuss studies that used social isolation rearing during the period in life when social play is most abundant to investigate the developmental functions of social play behavior in rats, focusing on the consequences of play deprivation on social, cognitive, emotional, and sensorimotor development. Last, we will discuss the neural substrates of social play behavior in rats, with emphasis on the limbic corticostriatal circuits that underlie emotions and their influence on behavior.

Developmental toxicity study in rats exposed dermally to clarified slurry oil for a limited period of gestation

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

Feuston, M.H.; Mackerer, C.R.

1996-10-11

Clarified slurry oil (CSO, CAS number 64741-62-4), a refinery stream produced by processing crude oil, is a developmental toxicant when administered dermally throughout gestation to pregnant rats. The manifestations of developmental toxicity observed included embryolethlity and growth retardation; evidence of teratogenicity was limited, and not conclusive. The present study was undertaken to further explore the teratogenic potential of CSO. In an attempt to limit emnbryolethality and thereby promote detection of terata, CSO was administered once daily for a limited period of gestation i[gestation days (GD) 9-12], via dermal application, to pregnant Sprague-Dawley rats at doses of 0, 10, 100, andmore » 1000 mg/kg. All animals were sacrificed on GD 20. Detailed examination of the dams was performed. Due to the screening nature of this investigation, fetal evaluations were limited to body weight measurements, external examinations, and evaluation of select visceral endpoints. In the dams exposed to CSO, significant decreases in body weight [absolute and gain (GD 9-13, GD 0-20)] and in the amount of food consumed were observed at 100 and 1000 mg/kg. Additional evidence of maternal toxicity observed at 1000 mg/kg included decreased absolute and relative thymus weights, increased absolute and relative liver weights, and aberrant serum chemistry. Ingestion of the test material was evident at the high dose. Developmental toxicity was observed at 1000 mg/kg and included increased embryolethality, decreased body weight, and anomalous development (cleft palate, brachydactyly, edema). Although a low incidence of abnormal fetal development was observed at 100 mg/kg, it was not conclusive that the alterations were due to CSO exposure. It is likely that three- to seven-ring polycyclic aromatic compounds present in CSO were responsible for the toxic effects observed. 33 refs., 5 tabs.« less

A dissociation between renewal and contextual fear conditioning in juvenile rats.

PubMed

Park, Chun Hui J; Ganella, Despina E; Kim, Jee Hyun

2017-05-01

We investigated whether juvenile rats do not express renewal following extinction of conditioned fear due to their inability to form a long-term contextual fear memory. In experiment 1, postnatal day (P) 18 and 25 rats received 3 white-noise and footshock pairings, followed by 60 white-noise alone presentations the next day. When tested in a different context to extinction, P25 rats displayed renewal whereas P18 rats did not. Experiments 2A and 2B surprisingly showed that P18 and P25 rats do not show differences in contextual and cued fear, regardless of the conditioning-test intervals and the number of white-noise-footshock pairings received. Finally, we observed age differences in contextual fear when P25 rats were weaned at P21 in experiment 3. These results indicate that the developmental dissociation observed in renewal of extinguished fear is not related to the widely believed late emergence of contextual fear learning. © 2017 Wiley Periodicals, Inc.

Subchronic (13-week) toxicity and prenatal developmental toxicity studies of dietary astaxanthin in rats.

PubMed

Vega, Katherine; Edwards, James; Beilstein, Paul

2015-12-01

Two studies examined the effects of dietary astaxanthin on Hanlbm Wistar (SPF) rats. Male and female rats receiving astaxanthin concentrations up to 1.52% of the feed for 13 weeks showed no evidence of toxicity; no effects were noted in the offspring of female rats exposed to astaxanthin at up to 1.39% of the feed during the period of organogenesis (GD 7-16). Discoloration of the feces and yellow pigmentation of adipose tissue was seen in the 13-week study, an intrinsic property of the substance, and not a sign of toxicity. Differences between the control and astaxanthin groups, some of which reached statistical significance, were generally sporadic (i.e., transient and/or not related to astaxanthin concentration) and not considered of biological or toxicological significance. Blood cholesterol levels, for example, were greater in animals receiving astaxanthin for 13 weeks, but remained within the normal range. The highest dietary concentration of astaxanthin in each of the studies is proposed as a no-observable-adverse-effect level (NOAEL). Specifically, 1.52% for the 13-week study, corresponding to a mean intake of 1033 mg/kg bw/day (range: 880-1240 mg/kg bw/day), and 1.39% for the developmental toxicity study, corresponding to a mean intake of approximately 830 mg/kg bw/day (range: 457-957 mg/kg bw/day). Copyright © 2015 Elsevier Inc. All rights reserved.

RIFM fragrance ingredient safety assessment, α-Methylbenzyl acetate, CAS Registry Number 93-92-5.

PubMed

Api, A M; Belsito, D; Bhatia, S; Bruze, M; Calow, P; Dagli, M L; Dekant, W; Fryer, A D; Kromidas, L; La Cava, S; Lalko, J F; Lapczynski, A; Liebler, D C; Politano, V T; Ritacco, G; Salvito, D; Schultz, T W; Shen, J; Sipes, I G; Wall, B; Wilcox, D K

2016-11-01

The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization potential, as well as, environmental safety. Developmental toxicity was determined to have the most conservative systemic exposure derived NO[A]EL of 100 mg/kg/day. A gavage developmental toxicity study conducted in rats on a suitable read across analog resulted in aMOE of 3571 while considering 78.7% absorption from skin contact and 100% from inhalation. A MOE of >100 is deemed acceptable. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of NMDA receptor blockade during the early development period on the retest performance of adult Wistar rats in the elevated plus maze.

PubMed

Kocahan, Sayad; Akillioglu, Kubra

2013-07-01

The elevated plus maze (EPM) is an animal model of anxiety used to test the effects of anxioselective drugs. The loss of the anxiolytic effect of drugs during the second exposure to the EPM is called the "one trial tolerance" (OTT) phenomenon. The present study was designed to investigate the relationship between the OTT phenomenon and N-methyl-D-aspartate (NMDA) receptor blockade in the early developmental period of rats. NMDA receptor blockade was accomplished using MK-801 treatment given between postnatal days 20-30. Beginning on postnatal day 20, the rats were subcutaneously injected with MK-801 twice a day at the nape of the neck for a period of 10 days (0.25 mg/kg). Increased open arm exploration was observed in MK-801-treated rats during trial 1 (p = 0.001) and trial 2 (p = 0.003). The rats spent less time in the closed arms as compared to the saline animals in trial 1 (p = 0.006), and this time decreased further in trial 2 (p = 0.02). The fecal boli of the MK-801 group was decreased in trial 1 as compared to the saline group (p = 0.01), but was not significantly different in trial 2 (p = 0.08). In conclusion, NMDA receptor blockade using MK-801 produced an anxiolytic-like effect in trials 1 and 2. Furthermore, OTT was not affected by NMDA receptor blockade.

Contextual learning and context effects during infancy: 30 years of controversial research revisited.

PubMed

Revillo, D A; Cotella, E; Paglini, M G; Arias, C

2015-09-01

Over the last 30years a considerable number of reports have explored learning about context during infancy in both humans and rats. This research was stimulated by two different theoretical frameworks. The first, known as the neuromaturational model, postulates that learning and behavior are context-independent during early ontogeny, a hypothesis based on the idea that contextual learning is dependent on the hippocampal function, and that this brain structure does not reach full maturity until late in infancy. The second theoretical framework views infants not as immature organisms, but rather as perfectly matured ones, given that their behavioral and cognitive capacities allow them to adapt appropriately to the demands of their specific environment in accordance with their maturational level. This model predicts significant ontogenetic variations in learning and memory due to developmental differences in what is perceived and attended to during learning episodes, which can result in ontogenetic differences in contextual learning depending on the specific demands of the task. The present manuscript reviews those studies that have examined potential developmental differences in contextual learning and context effects in rats. The reviewed results show that, during infancy, context can exert a similar influence over learning and memory as that described for the adult rat. Moreover, in some cases, contextual learning and context effects were greater in infants than in adults. In contrast, under other experimental conditions, no evidence of contextual learning or context effects was observed. We analyzed the procedural factors of these studies with the aim of detecting those that favor or impede contextual learning during infancy, and we discussed whether existing empirical evidence supports the claim that the functionality of the hippocampus is a limiting factor for this type of learning during infancy. Finally, conclusions from human research into contextual learning capacities during infancy were also examined. In view of the wealth of evidence showing contextual learning and context effects during infancy, we suggest that future research aimed at exploring the involvement of the hippocampus in this type of learning should be conducted using parameters which allow the expression of contextual learning during each ontogenetic period. Copyright © 2015 Elsevier Inc. All rights reserved.

Postnatal developmental changes in activation profiles of the respiratory neuronal network in the rat ventral medulla

PubMed Central

Oku, Yoshitaka; Masumiya, Haruko; Okada, Yasumasa

2007-01-01

Two putative respiratory rhythm generators (RRGs), the para-facial respiratory group (pFRG) and the pre-Bötzinger complex (preBötC), have been identified in the neonatal rodent brainstem. To elucidate their functional roles during the neonatal period, we evaluated developmental changes of these RRGs by optical imaging using a voltage-sensitive dye. Optical signals, recorded from the ventral medulla of brainstem–spinal cord preparations of neonatal (P0–P4) rats (n = 44), were analysed by a cross correlation method. With development during the first few postnatal days, the respiratory-related activity in the pFRG reduced and shifted from a preinspiratory (P0–P1) to an inspiratory (P2–P4) pattern, whereas preBötC activity remained unchanged. The μ-opioid agonist [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) augmented preinspiratory activity in the pFRG, while the μ-opioid antagonist naloxone induced changes in spatiotemporal activation profiles that closely mimicked the developmental changes. These results are consistent with the recently proposed hypothesis by Janczewski and Feldman that the pFRG is activated to compensate for the depression of the preBötC by perinatal opiate surge. We conclude that significant reorganization of the respiratory neuronal network, characterized by a reduction of preinspiratory activity in the pFRG, occurs at P1–P2 in rats. The changes in spatiotemporal activation profiles of the pFRG neurones may reflect changes in the mode of coupling of the two respiratory rhythm generators. PMID:17884928

Developmental subchronic exposure to diphenylarsinic acid induced increased exploratory behavior, impaired learning behavior, and decreased cerebellar glutathione concentration in rats.

PubMed

Negishi, Takayuki; Matsunaga, Yuki; Kobayashi, Yayoi; Hirano, Seishiro; Tashiro, Tomoko

2013-12-01

In Japan, people using water from the well contaminated with high-level arsenic developed neurological, mostly cerebellar, symptoms, where diphenylarsinic acid (DPAA) was a major compound. Here, we investigated the adverse effects of developmental exposure to 20mg/l DPAA in drinking water (early period [0-6 weeks of age] and/or late period [7-12]) on behavior and cerebellar development in male rats. In the open field test at 6 weeks of age, early exposure to DPAA significantly increased exploratory behaviors. At 12 weeks of age, late exposure to DPAA similarly increased exploratory behavior independent of the early exposure although a 6-week recovery from DPAA could reverse that change. In the passive avoidance test at 6 weeks of age, early exposure to DPAA significantly decreased the avoidance performance. Even at 12 weeks of age, early exposure to DPAA significantly decreased the test performance, which was independent of the late exposure to DPAA. These results suggest that the DPAA-induced increase in exploratory behavior is transient, whereas the DPAA-induced impairment of passive avoidance is long lasting. At 6 weeks of age, early exposure to DPAA significantly reduced the concentration of cerebellar total glutathione. At 12 weeks of age, late, but not early, exposure to DPAA also significantly reduced the concentration of cerebellar glutathione, which might be a primary cause of oxidative stress. Early exposure to DPAA induced late-onset suppressed expression of NMDAR1 and PSD95 protein at 12 weeks of age, indicating impaired glutamatergic system in the cerebellum of rats developmentally exposed to DPAA.

Developmental Exposure to Perchlorate Alters Synaptic Transmission in Hippocampus of the Adult Rat

PubMed Central

Gilbert, Mary E.; Sui, Li

2008-01-01

Background Perchlorate is an environmental contaminant that blocks iodine uptake into the thyroid gland and reduces thyroid hormones. This action of perchlorate raises significant concern over its effects on brain development. Objectives The purpose of this study was to evaluate neurologic function in rats after developmental exposure to perchlorate. Methods Pregnant rats were exposed to 0, 30, 300, or 1,000 ppm perchlorate in drinking water from gestational day 6 until weaning. Adult male offspring were evaluated on a series of behavioral tasks and neurophysiologic measures of synaptic function in the hippocampus. Results At the highest perchlorate dose, triiodothyronine (T3) and thyroxine (T4) were reduced in pups on postnatal day 21. T4 in dams was reduced relative to controls by 16%, 28%, and 60% in the 30-, 300-, and 1,000-ppm dose groups, respectively. Reductions in T4 were associated with increases in thyroid-stimulating hormone in the high-dose group. No changes were seen in serum T3. Perchlorate did not impair motor activity, spatial learning, or fear conditioning. However, significant reductions in baseline synaptic transmission were observed in hippocampal field potentials at all dose levels. Reductions in inhibitory function were evident at 300 and 1,000 ppm, and augmentations in long-term potentiation were observed in the population spike measure at the highest dose. Conclusions Dose-dependent deficits in hippocampal synaptic function were detectable with relatively minor perturbations of the thyroid axis, indicative of an irreversible impairment in synaptic transmission in response to developmental exposure to perchlorate. PMID:18560531

Maternal fructose and/or salt intake and reproductive outcome in the rat: effects on growth, fertility, sex ratio, and birth order.

PubMed

Gray, Clint; Long, Sophie; Green, Charlotte; Gardiner, Sheila M; Craigon, Jim; Gardner, David S

2013-09-01

Maternal diet can significantly skew the secondary sex ratio away from the expected value of 0.5 (proportion males), but the details of how diet may do this are unclear. Here, we altered dietary levels of salt (4% salt in the feed) and/or fructose (10% in the drinking water) of pregnant rats to model potential effects that consumption of a "Western diet" might have on maternofetal growth, development, and sex ratio. We demonstrate that excess fructose consumption before and during pregnancy lead to a marked skew in the secondary sex ratio (proportion of males, 0.60; P < 0.006). The effect was not mediated by selective developmental arrest of female embryos or influenced by fetal position in the uterine horn or sex-specific effects on sperm motility, suggesting a direct effect of glycolyzable monosaccharide on the maternal ovary and/or ovulated oocyte. Furthermore, combined excess maternal consumption of salt and fructose-sweetened beverage significantly reduced fertility, reflected as a 50% reduction in preimplantation and term litter size. In addition, we also noted birth order effects in the rat, with sequential implantation sites tending to be occupied by the same sex.

Developmental-stage-dependent radiosensitivity of neural cells in the ventricular zone of telencephalon in mouse and rat fetuses

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

Hoshino, K.; Kameyama, Y.

1988-03-01

Pregnant ICR mice were treated with single whole-body X-radiation at a dose of 0.24 Gy on day 10, 13, or 15 of gestation. Fetuses were obtained from mothers during 1 and 24 hours after irradiation. Pyknotic cells in the ventricular zone of telencephalon were counted in serial histological sections. Incidence of pyknotic cells peaked during 6 and 9 hours after irradiation in each gestation day group. Then, dose-response curves were obtained 6 hours after 0-0.48 Gy of irradiation. All three dose-response curves showed clear linearity in the dose range lower than 0.24 Gy. Ratios of radiosensitivity estimated from the slopesmore » of dose-response curves in day 10, 13, and 15 groups were 1, 1.4, and 0.4, respectively. These demonstrated that ventricular cells in the day 13 fetal telencephalon were the most radiosensitive among the three different age groups. In order to confirm the presence of the highly radiosensitive stage common to mammalian cerebral cortical histogenesis, pregnant F344 rats were treated with single whole-body gamma-irradiation at a dose of 0.48 Gy on day 13, 14, 15, 17, or 19 of gestation. The incidence of pyknotic cells in the ventricular zone of telencephalon was examined microscopically during 1 and 24 hours after irradiation. The peak incidence was shown 6 hours after irradiation in all the treated groups, and the highest peak incidence was shown in day-15-treated group. The developmental stage of telencephalon of day 15 rat fetuses was comparable to that of day 13 mouse fetuses. Thus, the highest radiosensitivity in terms of acute cell death was shown in the same developmental stage of brain development, i.e., the beginning phase of cerebral cortical histogenesis, in both mice and rats.« less

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.

Estrogen-Induced Developmental Disorders of the Rat Penis Involve Both Estrogen Receptor (ESR)- and Androgen Receptor (AR)-Mediated Pathways1

PubMed Central

Goyal, H.O.; Braden, T.D.; Williams, C.S.; Williams, J.W.

2009-01-01

This study tested the hypothesis that the estrogen receptor (ESR) pathway, androgen receptor (AR) pathway, or both mediate estrogen-induced developmental penile disorders. Rat pups received diethylstilbestrol (DES), with or without the ESR antagonist ICI 182,780 (ICI) or the AR agonist dihydrotestosterone (DHT) or testosterone (T), from Postnatal Days 1 to 6. Testicular T concentration, penile morphology and morphometry, and/or fertility was determined at age 7, 28, or 150 days. DES treatment alone caused 90% reduction in the neonatal intratesticular T surge; this reduction was prevented by ICI coadministration, but not by DHT or T coadministration. Unlike the T surge, coadministration of ICI and coadministration of DHT or T mitigated penile deformities and loss of fertility. Generally, ICI, DHT, or T treatment alone did not alter penile morphology; however, fertility was 20% that of controls in ICI-treated rats vs. 70%–90% in DHT- or T-treated rats. The lower fertility in the rats treated with ICI alone could be due to altered sexual behavior, as these males did not deposit vaginal plugs. In conclusion, observations that both an ESR antagonist and AR agonists prevent penile deformities and infertility suggest that both pathways are involved in estrogen-induced penile disorders. Observations that coadministration of ICI, but not DHT or T, prevents the DES-induced reduction in the neonatal T surge suggest that, although ICI exerts its mitigating effect both at the level of Leydig cells and penile stromal cells, DHT and T do so only at the level of stromal cells. PMID:19420389

Use of the light/dark test for anxiety in adult and adolescent male rats

PubMed Central

Arrant, Andrew E.; Schramm-Sapyta, Nicole L.; Kuhn, Cynthia M.

2014-01-01

The light/dark (LD) test is a commonly used rodent test of unconditioned anxiety-like behavior that is based on an approach/avoidance conflict between the drive to explore novel areas and an aversion to brightly lit, open spaces. We used the LD test to investigate developmental differences in behavior between adolescent (postnatal day (PN) 28–34) and adult (PN67–74) male rats. We investigated whether LD behavioral measures reflect anxiety-like behavior similarly in each age group using factor analysis and multiple regression. These analyses showed that time in the light compartment, percent distance in the light, rearing, and latency to emerge into the light compartment were measures of anxiety-like behavior in each age group, while total distance traveled and distance in the dark compartment provided indices of locomotor activity. We then used these measures to assess developmental differences in baseline LD behavior and the response to anxiogenic drugs. Adolescent rats emerged into the light compartment more quickly than adults and made fewer pokes into the light compartment. These age differences could reflect greater risk taking and less risk assessment in adolescent rats than adults. Adolescent rats were less sensitive than adults to the anxiogenic effects of the benzodiazepine inverse agonist N-methyl-β-carboline-3-carboxamide (FG-7142) and the α2 adrenergic antagonist yohimbine on anxiety-like behaviors validated by factor analysis, but locomotor variables were similarly affected. These data support the results of the factor analysis and indicate that GABAergic and noradrenergic modulation of LD anxiety-like behavior may be immature during adolescence. PMID:23721963

Thrifty metabolic programming in rats is induced by both maternal undernutrition and postnatal leptin treatment, but masked in the presence of both: implications for models of developmental programming

PubMed Central

2014-01-01

Background Maternal undernutrition leads to an increased risk of metabolic disorders in offspring including obesity and insulin resistance, thought to be due to a programmed thrifty phenotype which is inappropriate for a subsequent richer nutritional environment. In a rat model, both male and female offspring of undernourished mothers are programmed to become obese, however postnatal leptin treatment gives discordant results between males and females. Leptin treatment is able to rescue the adverse programming effects in the female offspring of undernourished mothers, but not in their male offspring. Additionally, in these rats, postnatal leptin treatment of offspring from normally-nourished mothers programmes their male offspring to develop obesity in later life, while there is no comparable effect in their female offspring. Results We show by microarray analysis of the female liver transcriptome that both maternal undernutrition and postnatal leptin treatment independently induce a similar thrifty transcriptional programme affecting carbohydrate metabolism, amino acid metabolism and oxidative stress genes. Paradoxically, however, the combination of both stimuli restores a more normal transcriptional environment. This demonstrates that “leptin reversal” is a global phenomenon affecting all genes involved in fetal programming by maternal undernourishment and leptin treatment. The thrifty transcriptional programme was associated with pro-inflammatory markers and downregulation of adaptive immune mediators, particularly MHC class I genes, suggesting a deficit in antigen presentation in these offspring. Conclusions We propose a revised model of developmental programming reconciling the male and female observations, in which there are two competing programmes which collectively drive liver transcription. The first element is a thrifty metabolic phenotype induced by early life growth restriction independently of leptin levels. The second is a homeostatic set point calibrated in response to postnatal leptin surge, which is able to over-ride the metabolic programme. This “calibration model” for the postnatal leptin surge, if applicable in humans, may have implications for understanding responses to catch-up growth in infants. Additionally, the identification of an antigen presentation deficit associated with metabolic thriftiness may relate to a previously observed correlation between birth season (a proxy for gestational undernutrition) and infectious disease mortality in rural African communities. PMID:24447410

A developmental study of glutamatergic neuron populations in the ventrobasal and the lateral geniculate nucleus of the thalamus: Comparing Genetic Absence Rats from Strasbourg (GAERS) and normal control wistar rats.

PubMed

Kirazlı, Özlem; Çavdar, Safiye; Yıldızel, Sercan; Onat, Filiz; Kaptanoğlu, Erkan

2017-02-01

An imbalance of GABAergic inhibition and glutamatergic excitation is suspected to be the cause of absence epileptic seizures. Absence seizures are known to be generated in thalamocortical circuitry. In the present study we used light microscopy immunohistochemistry to quantify the density of glutamate+ve neurons at two developmental stages (P10 and P60) in two thalamic nuclei, the ventrobasal (VB) and lateral geniculate nucleus (LGN) in Wistar rats and compared the results with similar data obtained from genetic absence epilepsy rats from Strasbourg (GAERS). Rats were perfused transcardially with glutaraldehyde and paraformaldehyde fixative, then samples from VB and LGN were removed from each animal and sectioned. The glutamatergic neurons were labelled using light-microscopic glutamate immunohistochemistry. The disector method was used to quantify the glutamate+ve neurons in VB and LGN of GAERS and Wistar rats. The data were statistically analyzed. The distribution of the glutamate+ve neurons in the VB thalamic nucleus showed a significant reduction in the neuronal profiles per unit thalamic area from P10 to P60 in both Wistar and GAERS. The decrease was greater in the GAERS compared to the Wistar animals. However, in the LGN no reduction was observed either in the Wistar or in the GAERS. Comparing the density of glutamate+ve neurons in the VB thalamic nucleus of P10 of Wistar animals with of P10 GAERS showed statistically significant greater densities of these neurons in GAERS than in the Wistar rats. However no significant difference was present at P60 between the Wistar and GAERS animals. The disproportional decrease in GAERS may be related to the onset of absence seizures or may be related to neurogenesis of absence epilepsy. Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.

Disturbances in the positioning, proliferation, and apoptosis of neural progenitors contribute to subcortical band heterotopia formation

PubMed Central

Fitzgerald, MP; Covio, M; Lee, KS

2011-01-01

Cortical malformations are commonly associated with intractable epilepsy and other developmental disorders. Our studies utilize the tish rat, a spontaneously occurring genetic model of subcortical band heterotopia (SBH) associated with epilepsy, to evaluate the developmental events underlying SBH formation in the neocortex. Our results demonstrate that Pax6+ and Tbr2+ progenitors are mislocalized in tish+/− and tish−/− neocortex throughout neurogenesis. In addition, mislocalized tish−/− progenitors possess a longer cell cycle than wildtype or normally-positioned tish−/− progenitors, owing to a lengthened G2+M+G1 time. This mislocalization is not associated with adherens junction breakdown or loss of radial glial polarity in the ventricular zone, as assessed by immunohistochemistry against phalloidin (to identify F-actin), aPKC-λ, and Par3. However, vimentin immunohistochemistry indicates that the radial glial scaffold is disrupted in the region of the tish−/− heterotopia. Moreover, lineage tracing experiments using in utero electroporation in tish−/− neocortex demonstrate that mislocalized progenitors do not retain contact with the ventricular surface and that ventricular/subventricular zone progenitors produce neurons that migrate into both the heterotopia and cortical plate. Taken together, these findings define a series of developmental errors contributing to SBH formation that differs fundamentally from a primary error in neuronal migration. PMID:21145942

Homeobox genes in the rodent pineal gland: roles in development and phenotype maintenance.

PubMed

Rath, Martin F; Rohde, Kristian; Klein, David C; Møller, Morten

2013-06-01

The pineal gland is a neuroendocrine gland responsible for nocturnal synthesis of melatonin. During early development of the rodent pineal gland from the roof of the diencephalon, homeobox genes of the orthodenticle homeobox (Otx)- and paired box (Pax)-families are expressed and are essential for normal pineal development consistent with the well-established role that homeobox genes play in developmental processes. However, the pineal gland appears to be unusual because strong homeobox gene expression persists in the pineal gland of the adult brain. Accordingly, in addition to developmental functions, homeobox genes appear to be key regulators in postnatal phenotype maintenance in this tissue. In this paper, we review ontogenetic and phylogenetic aspects of pineal development and recent progress in understanding the involvement of homebox genes in rodent pineal development and adult function. A working model is proposed for understanding the sequential action of homeobox genes in controlling development and mature circadian function of the mammalian pinealocyte based on knowledge from detailed developmental and daily gene expression analyses in rats, the pineal phenotypes of homebox gene-deficient mice and studies on development of the retinal photoreceptor; the pinealocyte and retinal photoreceptor share features not seen in other tissues and are likely to have evolved from the same ancestral photodetector cell.

Development as adaptation: a paradigm for gravitational and space biology

NASA Technical Reports Server (NTRS)

Alberts, Jeffrey R.; Ronca, April E.

2005-01-01

Adaptation is a central precept of biology; it provides a framework for identifying functional significance. We equate mammalian development with adaptation, by viewing the developmental sequence as a series of adaptations to a stereotyped sequence of habitats. In this way development is adaptation. The Norway rat is used as a mammalian model, and the sequence of habitats that is used to define its adaptive-developmental sequence is (a) the uterus, (b) the mother's body, (c) the huddle, and (d) the coterie of pups as they gain independence. Then, within this framework and in relation to each of the habitats, we consider problems of organismal responses to altered gravitational forces (micro-g to hyper-g), especially those encountered during space flight and centrifugation. This approach enables a clearer identification of simple "effects" and active "responses" with respect to gravity. It focuses our attention on functional systems and brings to the fore the manner in which experience shapes somatic adaptation. We argue that this basic developmental approach is not only central to basic issues in gravitational biology, but that it provides a natural tool for understanding the underlying processes that are vital to astronaut health and well-being during long duration flights that will involve adaptation to space flight conditions and eventual re-adaptation to Earth's gravity.

Homeobox genes in the rodent pineal gland: roles in development and phenotype maintenance

PubMed Central

Rath, Martin F.; Rohde, Kristian; Klein, David C.; Møller, Morten

2012-01-01

The pineal gland is a neuroendocrine gland responsible for nocturnal synthesis of melatonin. During early development of the rodent pineal gland from the roof of the diencephalon, homeobox genes of the orthodenticle homeobox (Otx)- and paired box (Pax)-families are expressed and are essential for normal pineal development consistent with the well-established role that homeobox genes play in developmental processes. However, the pineal gland appears to be unusual because strong homeobox gene expression persists in the pineal gland of the adult brain. Accordingly, in addition to developmental functions, homeobox genes appear to be key regulators in postnatal phenotype maintenance in this tissue. In this paper, we review ontogenetic and phylogenetic aspects of pineal development and recent progress in understanding the involvement of homebox genes in rodent pineal development and adult function. A working model is proposed for understanding the sequential action of homeobox genes in controlling development and mature circadian function of the mammalian pinealocyte based on knowledge from detailed developmental and daily gene expression analyses in rats, the pineal phenotypes of homebox gene-deficient mice and studies on development of the retinal photoreceptor; the pinealocyte and retinal photoreceptor share features not seen in other tissues and are likely to have evolved from the same ancestral photodetector cell. PMID:23076630

Magnetic resonance spectroscopic analysis of neurometabolite changes in the developing rat brain at 7T.

PubMed

Ramu, Jaivijay; Konak, Tetyana; Liachenko, Serguei

2016-11-15

We utilized proton magnetic resonance spectroscopy to evaluate the metabolic profile of the hippocampus and anterior cingulate cortex of the developing rat brain from postnatal days 14-70. Measured metabolite concentrations were modeled using linear, exponential, or logarithmic functions and the time point at which the data reached plateau (i.e. when the portion of the data could be fit to horizontal line) was estimated and was interpreted as the time when the brain has reached maturity with respect to that metabolite. N-acetyl-aspartate and myo-inositol increased within the observed period. Gluthathione did not vary significantly, while taurine decreased initially and then stabilized. Phosphocreatine and total creatine had a tendency to increase towards the end of the experiment. Some differences between our data and the published literature were observed in the concentrations and dynamics of phosphocreatine, myo-inositol, and GABA in the hippocampus and creatine, GABA, glutamine, choline and N-acetyl-aspartate in the cortex. Such differences may be attributed to experimental conditions, analysis approaches and animal species. The latter is supported by differences between in-house rat colony and rats from Charles River Labs. Spectroscopy provides a valuable tool for non-invasive brain neurochemical profiling for use in developmental neurobiology research. Special attention needs to be paid to important sources of variation like animal strain and commercial source. Published by Elsevier B.V.

Developmental profile of localized spontaneous Ca2+ release events in the dendrites of rat hippocampal pyramidal neurons

PubMed Central

Miyazaki, Kenichi; Manita, Satoshi; Ross, William N.

2012-01-01

Summary Recent experiments demonstrate that localized spontaneous Ca2+ release events can be detected in the dendrites of pyramidal cells in the hippocampus and other neurons (J. Neurosci. 29:7833-7845, 2009). These events have some properties that resemble ryanodine receptor mediated “sparks” in myocytes, and some that resemble IP3 receptor mediated “puffs” in oocytes. They can be detected in the dendrites of rats of all tested ages between P3 and P80 (with sparser sampling in older rats), suggesting that they serve a general signaling function and are not just important in development. However, in younger rats the amplitudes of the events are larger than the amplitudes in older animals and almost as large as the amplitudes of Ca2+ signals from backpropagating action potentials (bAPs). The rise time of the event signal is fast at all ages and is comparable to the rise time of the bAP fluorescence signal at the same dendritic location. The decay time is slower in younger animals, primarily because of weaker Ca2+ extrusion mechanisms at that age. Diffusion away from a brief localized source is the major determinant of decay at all ages. A simple computational model closely simulates these events with extrusion rate the only age dependent variable. PMID:22951184

Abnormal branching and regression of the notochord and its relationship to foregut abnormalities.

PubMed

Vleesch Dubois, V N; Quan Qi, B; Beasley, S W; Williams, A

2002-04-01

An abnormally positioned notochord has been reported in embryos that develop foregut abnormalities, vertebral defects and other abnormalities of the VATER association. This study examines the patterns of regression of the abnormal notochord in the rat model of the VATER association and investigates the relationship between developmental abnormalities of the notochord and those of the vertebra and foregut. Timed-pregnant Sprague-Dawley rats were given daily intraperitoneal injections of 1.75 mg/kg adriamycin on gestational days 6 - 9 inclusive. Rats were sacrificed between days 14 and 20 and their embryos harvested, histologically sectioned and stained and examined serially. The location and appearance of the degenerating notochord and its relationship to regional structural defects were analysed. All 26 embryos exposed to adriamycin developed foregut abnormalities and had an abnormal notochord. The notochord disappeared by a process of apoptotic degeneration that lagged behind that of the normal embryo: the notochord persisted in the abnormal embryo beyond day 17, whereas in the normal rat it had already disappeared. Similarly, formation of the nucleus pulposus was delayed. Vertebral abnormalities occurred when the notochord was ventrally-positioned. The notochord disappears during day 16 in the normal embryo whereas abnormal branches of the notochord persist until day 19 in the adriamycin-treated embryo. Degeneration of the notochord is dominated by apoptosis. An excessively ventrally-placed notochord is closely associated with abnormalities of the vertebral column, especially hemivertebrae.

GC-MS/MS Analyses of Biological Samples in Support of Developmental Toxic Effects on Percutaneous Exposure of Rats to VX

DTIC Science & Technology

2016-07-01

of blood, tissues, and organs (heart, lung, liver, kidney , brain, eye, diaphragm, and skin) that were obtained from rats (postnatal days 42 and 70...of blood, tissues, and organs (heart, lung, liver, kidney , brain, eye, and diaphragm) that were used to quantify the amounts of free and regenerated...Biosamples (brain, diaphragm, eye, heart, lung, liver, and kidney ) were collected at time of death or 48 h post-exposure for survivors. All

Cloning of rat MLH1 and expression analysis of MSH2, MSH3, MSH6, and MLH1 during spermatogenesis.

PubMed

Geeta Vani, R; Varghese, C M; Rao, M R

1999-12-15

The mismatch repair system has been highly conserved in various species. In eukaryotic cells, the Mut S and Mut L homologues play crucial roles in both DNA mismatch repair and meiotic recombination. A full-length rat cDNA clone for rat MLH1 has been constructed using the RT-PCR method. The cDNA has an open reading frame of 2274 nucleotides for a protein of 757 amino acids. We have also obtained partial cDNA clones for MSH3 and MSH6. Northern blot analysis of rat MLH1, MSH2, MSH3, and MSH6 in the testes of rats of different ages showed differential expression of these genes as a function of developmental maturation of the testes. The expression analysis suggests that MSH3 may have a more predominant role in the meiotic recombination process. Copyright 1999 Academic Press.

Developmental vitamin D deficiency causes abnormal brain development.

PubMed

Eyles, D W; Feron, F; Cui, X; Kesby, J P; Harms, L H; Ko, P; McGrath, J J; Burne, T H J

2009-12-01

There is now clear evidence that vitamin D is involved in brain development. Our group is interested in environmental factors that shape brain development and how this may be relevant to neuropsychiatric diseases including schizophrenia. The origins of schizophrenia are considered developmental. We hypothesised that developmental vitamin D (DVD) deficiency may be the plausible neurobiological explanation for several important epidemiological correlates of schizophrenia namely: (1) the excess winter/spring birth rate, (2) increased incidence of the disease in 2nd generation Afro-Caribbean migrants and (3) increased urban birth rate. Moreover we have published two pieces of direct epidemiological support for this hypothesis in patients. In order to establish the "Biological Plausibility" of this hypothesis we have developed an animal model to study the effect of DVD deficiency on brain development. We do this by removing vitamin D from the diet of female rats prior to breeding. At birth we return all dams to a vitamin D containing diet. Using this procedure we impose a transient, gestational vitamin D deficiency, while maintaining normal calcium levels throughout. The brains of offspring from DVD-deficient dams are characterised by (1) a mild distortion in brain shape, (2) increased lateral ventricle volumes, (3) reduced differentiation and (4) diminished expression of neurotrophic factors. As adults, the alterations in ventricular volume persist and alterations in brain gene and protein expression emerge. Adult DVD-deficient rats also display behavioural sensitivity to agents that induce psychosis (the NMDA antagonist MK-801) and have impairments in attentional processing. In this review we summarise the literature addressing the function of vitamin D on neuronal and non-neuronal cells as well as in vivo results from DVD-deficient animals. Our conclusions from these data are that vitamin D is a plausible biological risk factor for neuropsychiatric disorders and that vitamin D acts as a neurosteroid with direct effects on brain development.

IN VITRO METABOLISM OF TRIADIMEFON BY RAT LIVER MICROSOMES

EPA Science Inventory

Triadimefon (TDF) is an azole used as an agricultural pesticide. TDF exposures in laboratory studies have resulted in neurological, developmental and reproductive toxicities as well as tumors. Other classes of conazoles serve as effective pharmaceutical agents in controlling lo...

NEOCORTICAL HYPERTROPHY FOLLOWING DEVELOPMENTAL HYPOTHYROIDISM IN RATS

EPA Science Inventory

Thyroid hormones (TH) are essential to the normal development of the brain. Although severe congenital hypothyroidism has long been associated with mental retardation and motor defects, it has only recently been established that even subtle decreases in maternal TH alter fetal br...

IMMUNE SYSTEM ONTOGENY AND DEVELOPMENTAL IMMUNOTOXICOLOGY

EPA Science Inventory

Animal testing for the identification and characterization of hazard(s), associated with exposure to toxic chemicals, is an accepted approach for identifying the potential risk to humans. The rodent, in particular the rat, has been the most commonly used species for routine toxi...

76 FR 7712 - Clothianidin; Time-Limited Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-11

... registration of this seed treatment. Valent has requested an experimental use permit and this tolerance to... evidence of increased quantitative or qualitative susceptibility of rat or rabbit fetuses following in utero exposure to clothianidin in developmental studies; however, increased quantitative susceptibility...

Antagonistic effects of gestational dietary exposure to low-dose vinclozolin and genistein on rat fetal germ cell development.

PubMed

Lehraiki, Abdelali; Messiaen, Sébastien; Berges, Raymond; Canivenc-Lavier, Marie-Chantal; Auger, Jacques; Habert, René; Levacher, Christine

2011-05-01

Continuous, low-dose exposure to a phytoestrogen (1 mg/kg/day genistein) and/or to an antiandrogenic food contaminant (1 mg/kg/day vinclozolin) has been recently reported to affect male reproductive tract and fertility [1] in adults. We investigated whether alterations of the testis are already present at the end of in utero exposure using the same rat model and doses following exposure from conception to delivery. After vinclozolin exposure, we observed in the neonate a slight but significant alteration of steroidogenesis and gametogenesis with a reduction of testosterone secretion and of the number of gonocytes. In contrast, genistein exposure had no effect. While the vinclozolin-genistein mixture acts in a synergistic manner to induce the most significant alterations in the adult, interestingly, genistein antagonized the deleterious effect of vinclozolin on germ cells in the neonate. This difference emphasizes the importance of studying the effects of endocrine disruptors during various developmental stages to understand their effects. Copyright © 2011 Elsevier Inc. All rights reserved.

Sex-specific effect of the anabolic steroid, 17α-methyltestosterone, on inhibitory avoidance learning in periadolescent rats.

PubMed

Ramos-Pratts, Keyla; Rosa-González, Dariana; Pérez-Acevedo, Nivia L; Cintrón-López, Dahima; Barreto-Estrada, Jennifer L

2013-10-01

The illicit use of anabolic androgenic steroids (AAS) has gained popularity among adolescents in the last decade. However, although it is known that exposure to AAS impairs cognition in adult animal models, the cognitive effects during adolescence remain undetermined. An inhibitory avoidance task (IAT) was used to assess the effect of AAS (17α-methyltestosterone; 17α-meT--7.5 mg/kg) in male and female periadolescent rats. A single injection of 17α-meT immediately before the footshock produced significant impairment of inhibitory avoidance learning in males but not females. Generalized anxiety, locomotion, and risk assessment behaviors (RAB) were not affected. Our results show that exposure to a single pharmacological dose of 17α-meT during periadolescence exerts sex-specific cognitive effects without affecting anxiety. Thus, disruption of the hormonal milieu during this early developmental period might have negative impact on learning and memory. Copyright © 2013 Elsevier B.V. All rights reserved.

Relationship between histology, development and tumorigenesis of mammary gland in female rat

PubMed Central

LÍŠKA, Ján; BRTKO, Július; DUBOVICKÝ, Michal; MACEJOVÁ, Dana; KISSOVÁ, Viktória; POLÁK, Štefan; UJHÁZY, Eduard

2015-01-01

The mammary gland is a dynamic organ that undergoes structural and functional changes associated with growth, reproduction, and post-menopausal regression. The postnatal transformations of the epithelium and stromal cells of the mammary gland may contribute to its susceptibility to carcinogenesis. The increased cancer incidence in mammary glands of humans and similarly of rodents in association with their development is believed to be partly explained by proliferative activity together with lesser degree of differentiation, but it is not completely understood how the virgin gland retains its higher susceptibility to carcinogenesis. During its developmental cycle, the mammary gland displays many of the properties associated with breast cancer. An early first full-term pregnancy may have a protective effect. Rodent models are useful for investigating potential breast carcinogens. The purpose of this review is to help recognizing histological appearance of the epithelium and the stroma of the normal mammary gland in rats, and throughout its development in relation to tumorigenic potential. PMID:26424555

Infralimbic EphB2 Modulates Fear Extinction in Adolescent Rats

PubMed Central

Cruz, Emmanuel; Soler-Cedeño, Omar; Negrón, Geovanny; Criado-Marrero, Marangelie; Chompré, Gladys

2015-01-01

Adolescent rats are prone to impaired fear extinction, suggesting that mechanistic differences in extinction could exist in adolescent and adult rats. Since the infralimbic cortex (IL) is critical for fear extinction, we used PCR array technology to identify gene expression changes in IL induced by fear extinction in adolescent rats. Interestingly, the ephrin type B receptor 2 (EphB2), a tyrosine kinase receptor associated with synaptic development, was downregulated in IL after fear extinction. Consistent with the PCR array results, EphB2 levels of mRNA and protein were reduced in IL after fear extinction compared with fear conditioning, suggesting that EphB2 signaling in IL regulates fear extinction memory in adolescents. Finally, reducing EphB2 synthesis in IL with shRNA accelerated fear extinction learning in adolescent rats, but not in adult rats. These findings identify EphB2 in IL as a key regulator of fear extinction during adolescence, perhaps due to the increase in synaptic remodeling occurring during this developmental phase. PMID:26354908

Functional changes in glutamate transporters and astrocyte biophysical properties in a rodent model of focal cortical dysplasia

PubMed Central

Campbell, Susan L.; Hablitz, John J.; Olsen, Michelle L.

2014-01-01

Cortical dysplasia is associated with intractable epilepsy and developmental delay in young children. Recent work with the rat freeze-induced focal cortical dysplasia (FCD) model has demonstrated that hyperexcitability in the dysplastic cortex is due in part to higher levels of extracellular glutamate. Astrocyte glutamate transporters play a pivotal role in cortical maintaining extracellular glutamate concentrations. Here we examined the function of astrocytic glutamate transporters in a FCD model in rats. Neocortical freeze lesions were made in postnatal day (PN) 1 rat pups and whole cell electrophysiological recordings and biochemical studies were performed at PN 21–28. Synaptically evoked glutamate transporter currents in astrocytes showed a near 10-fold reduction in amplitude compared to sham operated controls. Astrocyte glutamate transporter currents from lesioned animals were also significantly reduced when challenged exogenously applied glutamate. Reduced astrocytic glutamate transport clearance contributed to increased NMDA receptor-mediated current decay kinetics in lesioned animals. The electrophysiological profile of astrocytes in the lesion group was also markedly changed compared to sham operated animals. Control astrocytes demonstrate large-amplitude linear leak currents in response to voltage-steps whereas astrocytes in lesioned animals demonstrated significantly smaller voltage-activated inward and outward currents. Significant decreases in astrocyte resting membrane potential and increases in input resistance were observed in lesioned animals. However, Western blotting, immunohistochemistry and quantitative PCR demonstrated no differences in the expression of the astrocytic glutamate transporter GLT-1 in lesioned animals relative to controls. These data suggest that, in the absence of changes in protein or mRNA expression levels, functional changes in astrocytic glutamate transporters contribute to neuronal hyperexcitability in the FCD model. PMID:25565960

Postnatal LPS Challenge Impacts Escape Learning and Expression of Plasticity Factors Mmp9 and Timp1 in Rats: Effects of Repeated Training.

PubMed

Trofimov, Alexander; Strekalova, Tatyana; Mortimer, Niall; Zubareva, Olga; Schwarz, Alexander; Svirin, Evgeniy; Umriukhin, Aleksei; Svistunov, Andrei; Lesch, Klaus-Peter; Klimenko, Victor

2017-08-01

Bacterial intoxication associated with inflammatory conditions during development can impair brain functions, in particular evolutionarily novel forms of memory, such as explicit learning. Little is known about the dangers of early-life inflammation on more basic forms of learning, for example, the acquisition of motor escape abilities, which are generally better preserved under pathological conditions. To address this limitation in knowledge, an inflammatory response was elicited in Wistar pups by lipopolysaccharide (LPS) injections (25 μg/kg) on postnatal days P15, P18 and P21. The acquisition of escape behaviour was tested from P77 by active avoidance footshock model and water maze. Open-field behaviour and blood corticosterone levels were also measured. Rat brain tissue was collected from pups 2 h post-injection and from adult rats which either underwent escape training on P77-P81 or remained untrained. mRNA levels of developmental brain plasticity factors MMP-9 and TIMP-1 were investigated in the medial prefrontal cortex and ventral/dorsal hippocampus. LPS-challenged rats displayed moderately deficient escape responses in both memory tests, increased freezing behaviour and, surprisingly, reduced blood cortisol levels. Mmp9 and Timp1, and their ratio to one another, were differentially altered in pups versus adult untrained rats but remained unchanged overall in rats trained in either learning task. Together, our data indicate that systemic pro-inflammatory response during early postnatal development has long-lasting effects, including on the acquisition of motor escape abilities and plasticity factor expression, into adulthood. Our data suggest that altered stress response could possibly mediate these deviations and repeated training might generate positive effects on plasticity under the employed conditions.

Detection of expressional changes induced by intrauterine growth restriction in the developing rat pancreas.

PubMed

Zhang, Lin; Chen, Wei; Dai, Yuee; Zhu, Ziyang; Liu, Qianqi

2016-07-01

Intrauterine growth retardation (IUGR) is a disorder that can result in permanent changes in the physiology and metabolism of the newborn, which increased the risk of disease in adulthood. Evidence supports IUGR as a risk factor for the development of diabetes mellitus, which could reflect changes in pancreas developmental pathways. We sought to characterize the IUGR-induced alterations of the complex pathways of pancreas development in a rat model of IUGR. We analyzed the pancreases of Sprague Dawley rats after inducing IUGR by feeding a maternal low calorie diet from gestational day 1 until term. IUGR altered the pancreatic structure, islet areas, and islet quantities and resulted in abnormal morphological changes during pancreatic development, as determined by HE staining and light microscopy. We identified multiple differentially expressed genes in the pancreas by RT-PCR. The genes of the insulin/FoxO1/Pdx1/MafA signaling pathway were first expressed at embryonic day 14 (E14). The expressions of insulin and MafA increased as the fetus grew while the expressions of FoxO1 and Pdx1 decreased. Compared with the control rats, the expressions of FoxO1, Pdx1, and MafA were lower in the IUGR rats, whereas insulin levels showed no change. Microarray profiling, in combination with quantitative real-time PCR, uncovered a subset of microRNAs that changed in their degree of expression throughout pancreatic development. In conclusion, our data support the hypothesis that IUGR influences the development of the rat pancreas. We also identified new pathways that appear to be programmed by IUGR. © 2016 by the Society for Experimental Biology and Medicine.

Effects of Low-Dose Developmental Bisphenol A Exposure on Metabolic Parameters and Gene Expression in Male and Female Fischer 344 Rat Offspring

PubMed Central

Lejonklou, Margareta H.; Dunder, Linda; Bladin, Emelie; Pettersson, Vendela; Rönn, Monika; Lind, Lars; Waldén, Tomas B.

2017-01-01

Background: Bisphenol A (BPA) is an endocrine-disrupting chemical that may contribute to development of obesity and metabolic disorders. Humans are constantly exposed to low concentrations of BPA, and studies support that the developmental period is particularly sensitive. Objectives: The aim was to investigate the effects of low-dose developmental BPA exposure on metabolic parameters in male and female Fischer 344 (F344) rat offspring. Methods: Pregnant F344 rats were exposed to BPA via their drinking water, corresponding to 0.5μg/kg BW/d (BPA0.5; n=21) or 50μg/kg BW/d (BPA50; n=16), from gestational day (GD) 3.5 until postnatal day (PND) 22, and controls were given vehicle (n=26). Body weight (BW), adipose tissue, liver (weight, histology, and gene expression), heart weight, and lipid profile were investigated in the 5-wk-old offspring. Results: Males and females exhibited differential susceptibility to the different doses of BPA. Developmental BPA exposure increased plasma triglyceride levels (0.81±0.10 mmol/L compared with 0.57±0.03 mmol/L, females BPA50 p=0.04; 0.81±0.05 mmol/L compared with 0.61±0.04 mmol/L, males BPA0.5 p=0.005) in F344 rat offspring compared with controls. BPA exposure also increased adipocyte cell density by 122% in inguinal white adipose tissue (iWAT) of female offspring exposed to BPA0.5 compared with controls (68.2±4.4 number of adipocytes/HPF compared with 55.9±1.5 number of adipocytes/HPF; p=0.03) and by 123% in BPA0.5 females compared with BPA50 animals (68.2±4.4 number of adipocytes/high power field (HPF) compared with 55.3±2.9 number of adipocytes/HPF; p=0.04). In iWAT of male offspring, adipocyte cell density was increased by 129% in BPA50-exposed animals compared with BPA0.5-exposed animals (69.9±5.1 number of adipocytes/HPF compared with 54.0±3.4 number of adipocytes/HPF; p=0.03). Furthermore, the expression of genes involved in lipid and adipocyte homeostasis was significantly different between exposed animals and controls depending on the tissue, dose, and sex. Conclusions: Developmental exposure to 0.5μg/kg BW/d of BPA, which is 8–10 times lower than the current preliminary EFSA (European Food Safety Authority) tolerable daily intake (TDI) of 4μg/kg BW/d and is within the range of environmentally relevant levels, was associated with sex-specific differences in the expression of genes in adipose tissue plasma triglyceride levels in males and adipocyte cell density in females when F344 rat offspring of dams exposed to BPA at 0.5μg/kg BW/d were compared with the offspring of unexposed controls. https://doi.org/10.1289/EHP505 PMID:28657538

Ontogeny and adolescent alcohol exposure in Wistar rats: open field conflict, light/dark box and forced swim test

PubMed Central

Desikan, Anita; Wills, Derek N.; Ehlers, Cindy L.

2014-01-01

Epidemiological studies have demonstrated that heavy drinking and alcohol abuse and dependence peak during the transition between late adolescence and early adulthood. Studies in animal models have demonstrated that alcohol exposure during adolescence can cause a modification in some aspects of behavioral development, causing the “adolescent phenotype” to be retained into adulthood. However, the “adolescent phenotype” has not been studied for a number of behavioral tests. The objective of the present study was to investigate the ontogeny of behaviors over adolescence/young adulthood in the light/dark box, open field conflict and forced swim test in male Wistar rats. These data were compared to previously published data from rats that received intermittent alcohol vapor exposure during adolescence (AIE) to test whether they retained the “adolescent phenotype” in these behavioral tests. Three age groups of rats were tested (post-natal day (PD) 34–42; PD55-63; PD69-77). In the light/dark box test, younger rats escaped the light box faster than older adults, whereas AIE rats returned to the light box faster and exhibited more rears in the light than controls. In the open field conflict test, both younger and AIE rats had shorter times to first enter the center, spent more time in the center of the field, were closer to the food, and consumed more food than controls. In the forced swim test no clear developmental pattern emerged. The results of the light/dark box and the forced swim test do not support the hypothesis that adolescent ethanol vapor exposure can “lock-in” all adolescent phenotypes. However, data from the open field conflict test suggest that the adolescent and the AIE rats both engaged in more “disinhibited” and food motivated behaviors. These data suggest that, in some behavioral tests, AIE may result in a similar form of behavioral disinhibition to what is seen in adolescence. PMID:24785000

Ontogeny and adolescent alcohol exposure in Wistar rats: open field conflict, light/dark box and forced swim test.

PubMed

Desikan, Anita; Wills, Derek N; Ehlers, Cindy L

2014-07-01

Epidemiological studies have demonstrated that heavy drinking and alcohol abuse and dependence peak during the transition between late adolescence and early adulthood. Studies in animal models have demonstrated that alcohol exposure during adolescence can cause a modification in some aspects of behavioral development, causing the "adolescent phenotype" to be retained into adulthood. However, the "adolescent phenotype" has not been studied for a number of behavioral tests. The objective of the present study was to investigate the ontogeny of behaviors over adolescence/young adulthood in the light/dark box, open field conflict and forced swim test in male Wistar rats. These data were compared to previously published data from rats that received intermittent alcohol vapor exposure during adolescence (AIE) to test whether they retained the "adolescent phenotype" in these behavioral tests. Three age groups of rats were tested (post-natal day (PD) 34-42; PD55-63; PD69-77). In the light/dark box test, younger rats escaped the light box faster than older adults, whereas AIE rats returned to the light box faster and exhibited more rears in the light than controls. In the open field conflict test, both younger and AIE rats had shorter times to first enter the center, spent more time in the center of the field, were closer to the food, and consumed more food than controls. In the forced swim test no clear developmental pattern emerged. The results of the light/dark box and the forced swim test do not support the hypothesis that adolescent ethanol vapor exposure can "lock-in" all adolescent phenotypes. However, data from the open field conflict test suggest that the adolescent and the AIE rats both engaged in more "disinhibited" and food motivated behaviors. These data suggest that, in some behavioral tests, AIE may result in a similar form of behavioral disinhibition to what is seen in adolescence. Copyright © 2014. Published by Elsevier Inc.

Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. I: maternal and prenatal evaluations.

PubMed

Thibodeaux, Julie R; Hanson, Roger G; Rogers, John M; Grey, Brian E; Barbee, Brenda D; Richards, Judy H; Butenhoff, John L; Stevenson, Lisa A; Lau, Christopher

2003-08-01

The maternal and developmental toxicities of perfluorooctane sulfonate (PFOS, C8F17SO3-) were evaluated in the rat and mouse. PFOS is an environmentally persistent compound used as a surfactant and occurs as a degradation product of both perfluorooctane sulfonyl fluoride and substituted perfluorooctane sulfonamido components found in many commercial and consumer applications. Pregnant Sprague-Dawley rats were given 1, 2, 3, 5, or 10 mg/kg PFOS daily by gavage from gestational day (GD) 2 to GD 20; CD-1 mice were similarly treated with 1, 5, 10, 15, and 20 mg/kg PFOS from GD 1 to GD 17. Controls received 0.5% Tween-20 vehicle (1 ml/kg for rats and 10 ml/kg for mice). Maternal weight gain, food and water consumption, and serum chemistry were monitored. Rats were euthanized on GD 21 and mice on GD 18. PFOS levels in maternal serum and in maternal and fetal livers were determined. Maternal weight gains in both species were suppressed by PFOS in a dose-dependent manner, likely attributed to reduced food and water intake. Serum PFOS levels increased with dosage, and liver levels were approximately fourfold higher than serum. Serum thyroxine (T4) and triiodothyronine (T3) in the PFOS-treated rat dams were significantly reduced as early as one week after chemical exposure, although no feedback response of thyroid-stimulating hormone (TSH) was observed. A similar pattern of reduction in T4 was also seen in the pregnant mice. Maternal serum triglycerides were significantly reduced, particularly in the high-dose groups, although cholesterol levels were not affected. In the mouse dams, PFOS produced a marked enlargement of the liver at 10 mg/kg and higher dosages. In the rat fetuses, PFOS was detected in the liver but at levels nearly half of those in the maternal counterparts, regardless of administered doses. In both rodent species, PFOS did not alter the numbers of implantations or live fetuses at term, although small deficits in fetal weight were noted in the rat. A host of birth defects, including cleft palate, anasarca, ventricular septal defect, and enlargement of the right atrium, were seen in both rats and mice, primarily in the 10 and 20 mg/kg dosage groups, respectively. Our results demonstrate both maternal and developmental toxicity of PFOS in the rat and mouse.

Sex-dependent effects of developmental exposure to different pesticides on spatial learning. The role of induced neuroinflammation in the hippocampus.

PubMed

Gómez-Giménez, Belén; Llansola, Marta; Hernández-Rabaza, Vicente; Cabrera-Pastor, Andrea; Malaguarnera, Michele; Agusti, Ana; Felipo, Vicente

2017-01-01

The use of pesticides has been associated with impaired neurodevelopment in children. The aims of this work were to assess: 1) the effects on spatial learning of developmental exposure to pesticides 2) if the effects are sex-dependent and 3) if hippocampal neuroinflammation is associated with the impairment of spatial learning. We analyzed the effects of developmental exposure to four pesticides: chlorpyrifos, carbaryl, endosulfan and cypermethrin. Exposure was from gestational day 7 to post-natal day 21 and spatial learning and memory was assessed when the rats were young adults. The effects of pesticides on spatial learning were pesticide and gender-dependent. Carbaryl did not affect spatial learning in males or females. Endosulfan and chlorpyrifos impaired learning in males but not in females. Cypermethrin improved spatial learning in the Morris water maze both in males and females while impaired learning in the radial maze only in males. Spatial learning ability was lower in control female rats than in males. All pesticides induced neuroinflammation, increasing IL-1b content in the hippocampus and there is a negative correlation between IL-1b levels in the hippocampus and spatial learning. Neuroinflammation would contribute to the effects of pesticides on spatial learning. Copyright © 2016 Elsevier Ltd. All rights reserved.

Reproductive and developmental toxicity of degradation products of refrigerants in experimental animals.

PubMed

Ema, Makoto; Naya, Masato; Yoshida, Kikuo; Nagaosa, Ryuichi

2010-01-01

The present paper summarizes the results of animal studies on the reproductive and developmental toxicity of the degradation products of refrigerants, including trifluoroacetic acid (TFA), carbon dioxide (CO(2)), carbon monoxide (CO), carbonyl fluoride (CF), hydrogen fluoride (HF) and formic acid (FA). Excessive CO(2) in the atmosphere is testicular and reproductive toxic, embryolethal, developmentally neurotoxic and teratogenic in experimental animals. As for CO, maternal exposure causes prenatal and postnatal lethality and growth retardation, skeletal variations, cardiomegaly, blood biochemical, immunological and postnatal behavioral changes, and neurological impairment in offspring of several species. Very early studies of CO in rats and guinea pigs reported fetal malformations in exposed dams. The results of toxicological studies on sodium fluoride (NaF) were used to obtain insight into the toxicity of CF and HF, because CF is rapidly hydrolyzed in contact with water yielding CO(2) and HF, and NaF is similar in kinetics and dynamics to HF. Increased fetal skeletal variation, but not malformation, was noted after the maternal administration of NaF. Rat multiple-generation studies revealed that NaF caused retarded ossification and degenerative changes in the lung and kidney in offspring. There is a lack of information about the toxicity of TFA and FA. Copyright 2009 Elsevier Inc. All rights reserved.

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.

The neuroprotective effects of MK-801 on the induction of microgyria by freezing injury to the newborn rat neocortex.

PubMed

Rosen, G D; Sigel, E A; Sherman, G F; Galaburda, A M

1995-11-01

Four-layered microgyria is associated with many developmental disorders, including mental retardation, epilepsy, and developmental dyslexia. Freezing lesions to the newborn rodent neocortex result in the formation of four-layered microgyria. Previous research had suggested this type of injury acts as an hypoxic/ischemic event to the developing cortical plate. The current study examines the effectiveness of the non-competitive N-methyl-D-aspartate receptor antagonist dizocilpine (MK-801) in protecting against freezing injury to the newborn rat cortical plate. Three groups of rats received freezing injury to the cortical plate on the first day of life (postnatal day 1). Two groups were treated with MK-801 (1 or 2 mg/kg) 0.5 h before the lesion and 6 and 14 h after, while one group received saline injections. A fourth group received MK-801 injections, but did not have a freezing lesion. The volume of neocortical abnormality was determined for all three groups in rats killed after postnatal day 7. Treatment with the higher dose of MK-801 (3 x 2 mg/kg) dramatically reduced the effects of freezing injury but also resulted in over 50% mortality in both lesioned and unlesioned groups. Animals in the lesioned group, however, had a decreased volume of abnormal cortex, and there were fewer animals with microsulci than in the untreated group. This is the first demonstration of a significant anatomical neuroprotective effect in newborns leading to a reduction of cortical malformation.

Exposure assessment of boron in Bandırma boric acid production plant.

PubMed

Duydu, Yalçin; Başaran, Nurşen; Bolt, Hermann M

2012-06-01

Boric acid and sodium borates have been considered as being "toxic to reproduction and development", following results of animal studies with high doses. Experimentally, a NOAEL of 17.5mg B/kg-bw/day (corresponds to ∼2020 ng boron/g blood) has been identified for the (male) reproductive effects of boron in a multigenerational study of rats, and a NOAEL for the developmental effects in rats was identified at 9.6 mg B/kg-bw/day (corresponds to 1270 ng boron/g blood). These values are being taken as the basis of current EU safety assessments. The present study was conducted to assess the boron exposure under extreme exposure conditions in a boric acid production plant located in Bandırma, Turkey. The mean blood boron concentrations of low and high exposure groups were 72.94 ± 15.43 (48.46-99.91) and 223.89 ± 60.49 (152.82-454.02)ng/g respectively. The mean blood boron concentration of the high exposure group is still ≈ 6 times lower than the highest no effect level of boron in blood with regard to the developmental effects in rats and ≈ 9 times lower than the highest no effect level of boron in blood with regard to the reprotoxic effects in male rats. In this context, boric acid and sodium borates should not be considered as toxic to reproduction for humans in daily life. Copyright © 2012 Elsevier GmbH. All rights reserved.

Maternal administration of melatonin prevents spatial learning and memory deficits induced by developmental ethanol and lead co-exposure.

PubMed

Soleimani, Elham; Goudarzi, Iran; Abrari, Kataneh; Lashkarbolouki, Taghi

2017-05-01

Melatonin is a radical scavenger with the ability to remove reactive oxidant species. There is report that co-exposure to lead and ethanol during developmental stages induces learning and memory deficits and oxidative stress. Here, we studied the effect of melatonin, with strong antioxidant properties, on memory deficits induced by lead and ethanol co-exposure and oxidative stress in hippocampus. Pregnant rats in lead and ethanol co-exposure group received lead acetate of 0.2% in distilled drinking water and ethanol (4g/kg) by oral gavages once daily from the 5th day of gestation until weaning. Rats received 10mg/kg melatonin by oral gavages. On postnatal days (PD) 30, rats trained with six trials per day for 6 consecutive days in the water maze. On day 37, a probe test was done and oxidative stress markers in the hippocampus were evaluated. Results demonstrated lead and ethanol co-exposed rats exhibited higher escape latency during training trials and reduced time spent in target quadrant, higher escape location latency in probe trial test and had significantly higher malondialdehyde (MDA) levels, significantly lower superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities in the hippocampus. Melatonin treatment could improve memory deficits, antioxidants activity and reduced MDA levels in the hippocampus. We conclude, co-exposure to lead and ethanol impair memory and melatonin can prevent from it by oxidative stress modulation. Copyright © 2017 Elsevier Inc. All rights reserved.

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

Behavioral Differences Between Late Preweanling and Adult Female Sprague-Dawley Rat Exploration of Animate and Inanimate Stimuli and Food

PubMed Central

Smith, Kiersten S.; Morrell, Joan I.

2010-01-01

The late preweanling rat has potential as a preclinical model for disorders initially manifested in early childhood that are characterized by dysfunctional interactions with specific stimuli (e.g., obsessive-compulsive disorder and autism). No reports, however, of specific-stimulus exploration in the late preweanling rat are found in the literature. We examined the behavioral responses of normal late preweanling (PND 18-19) and adult rats when presented with exemplars of categorically-varied stimuli, including inanimate objects systematically varied in size and interactive properties, biological stimuli, and food. Preweanlings were faster to initiate specific stimulus exploration and were more interactive with most specific stimuli than adults; the magnitude of these preweanling-adult quantitative differences ranged from fairly small to very large depending upon the stimulus. In contrast, preweanlings were adult-like in their interaction with food and prey. Preweanling response to some stimuli, for example to live pups, was qualitatively different from that of adults; the preweanling behavioral repertoire was characterized by pup-seeking while the adult response was characterized by pup-avoidance. The specific stimulus interactions of preweanlings were less impacted than those of adults by the time of day of testing and placement of a stimulus in an anxiety-provoking location. The impact of novelty was stimulus dependent. The differences in interactions of preweanlings versus adults with specific stimuli suggests that CNS systems underlying these behavior patterns are at different stages of immaturity at PND 18 such that there may be an array of developmental trajectories for various categories of specific stimuli. These data provide a basis for the use of the preweanling as a preclinical model for understanding and medicating human disorders during development that are characterized by dysfunctional interactions with specific stimuli. PMID:21056059

Effects of centrifugation on gonadal and adrenocortical steroids in rats

NASA Technical Reports Server (NTRS)

Kakihana, R.; Butte, J. C.

1980-01-01

Many endocrine systems are sensitive to external changes in the environment. Both the pituitary adrenal and pituitary gonadal systems are affected by stress including centrifugation stress. The effect of centrifugation on the pituitary gonadal and pituitary adrenocortical systems was examined by measuring the gonadal and adrenal steroids in the plasma and brain following different duration and intensity of centrifugation stress in rats. Two studies were completed and the results are presented. The second study was carried out to describe the developmental changes of brain, plasma and testicular testosterone and dihydrotestosterone in Sprague Dawley rats so that the effect of centrifugation stress on the pituitary gonadal syatem could be better evaluated in future studies.

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.

Developmental Subchronic Exposure to Diphenylarsinic Acid Induced Increased Exploratory Behavior, Impaired Learning Behavior, and Decreased Cerebellar Glutathione Concentration in Rats

PubMed Central

Negishi, Takayuki; Matsunaga, Yuki

2013-01-01

In Japan, people using water from the well contaminated with high-level arsenic developed neurological, mostly cerebellar, symptoms, where diphenylarsinic acid (DPAA) was a major compound. Here, we investigated the adverse effects of developmental exposure to 20mg/l DPAA in drinking water (early period [0–6 weeks of age] and/or late period [7–12]) on behavior and cerebellar development in male rats. In the open field test at 6 weeks of age, early exposure to DPAA significantly increased exploratory behaviors. At 12 weeks of age, late exposure to DPAA similarly increased exploratory behavior independent of the early exposure although a 6-week recovery from DPAA could reverse that change. In the passive avoidance test at 6 weeks of age, early exposure to DPAA significantly decreased the avoidance performance. Even at 12 weeks of age, early exposure to DPAA significantly decreased the test performance, which was independent of the late exposure to DPAA. These results suggest that the DPAA-induced increase in exploratory behavior is transient, whereas the DPAA-induced impairment of passive avoidance is long lasting. At 6 weeks of age, early exposure to DPAA significantly reduced the concentration of cerebellar total glutathione. At 12 weeks of age, late, but not early, exposure to DPAA also significantly reduced the concentration of cerebellar glutathione, which might be a primary cause of oxidative stress. Early exposure to DPAA induced late-onset suppressed expression of NMDAR1 and PSD95 protein at 12 weeks of age, indicating impaired glutamatergic system in the cerebellum of rats developmentally exposed to DPAA. PMID:24008832

Discriminative stimulus effects of cocaine and amphetamine in rats following developmental exposure to polychlorinated biphenyls (PCBs)

PubMed Central

Sable, Helen J. K.; Monaikul, Supida; Poon, Emily; Eubig, Paul A.; Schantz, Susan L.

2010-01-01

Polychlorinated biphenyls (PCBs) are environmental neurotoxicants known to affect the brain dopaminergic (DA) system. This project investigated whether developmental exposure to PCBs would alter the discriminative stimulus effects of psychostimulant drugs known to act on the DA system. Female Long-Evans rats were orally exposed to 0, 3, or 6 mg/kg/day of an environmentally relevant PCB mixture from four weeks prior to breeding through weaning of their litters on PND 21. When they reached adulthood one male and female/litter were trained to discriminate cocaine (10.0 mg/kg, IP) from saline by repeatedly pairing cocaine injections with reinforcement on one operant response lever, and saline injections with reinforcement on the other lever. After response training, generalization tests to four lower doses of cocaine (7.5, 5.0, 2.5, and 1.25 mg/kg, IP) and to amphetamine (1.0, 0.5, 0.25, and 0.125 mg/kg, IP) were given two days/week, with additional training dose days in-between. Percent responding of the PCB-exposed rats on the cocaine-paired lever was significantly higher than that of controls for the highest generalization dose of cocaine, and lower than that of controls for the highest dose of amphetamine. Response rate and percent responding on the cocaine lever did not differ among the exposure groups on the days when the training dose of cocaine was given, suggesting the generalization test results were not due to pre-existing differences in discrimination ability or rate of responding. These findings suggest developmental PCB exposure can alter the interoceptive cues of psychostimulants. PMID:20933596

Short-term withdrawal from developmental exposure to cocaine activates the glucocorticoid receptor and alters spine dynamics.

PubMed

Caffino, Lucia; Giannotti, Giuseppe; Malpighi, Chiara; Racagni, Giorgio; Fumagalli, Fabio

2015-10-01

Although glucocorticoid receptors (GRs) contribute to the action of cocaine, their role following developmental exposure to the psychostimulant is still unknown. To address this issue, we exposed adolescent male rats to cocaine (20mg/kg/day) from post-natal day (PND) 28 to PND 42 and sacrificed them at PND 45 or 90. We studied the medial prefrontal cortex (mPFC), a brain region that is still developing during adolescence. In PND 45 rats we found enhanced GR transcription and translation as well as increased trafficking toward the nucleus of the receptor, with no alteration in plasma corticosterone levels. We also showed reduced expression of the GR co-chaperone FKBP51, that normally keeps the receptor in the cytoplasm, and increased expression of Src1, which cooperates in the activation of GR transcriptional activity, revealing that short withdrawal alters the finely tuned mechanisms regulating GR action. Since activation of GRs regulate dendritic spine morphology, we next investigated spine dynamics in cocaine-withdrawn rats. We found that PSD95, cofilin and F-actin, molecules regulating spine actin network, are reduced in the mPFC of PND 45 rats suggesting reduced spine density, confirmed by confocal imaging. Further, formation of filopodia, i.e. the inactive spines, is enhanced suggesting the formation of non-functional spines. Of note, no changes were found in molecules related to GR machinery or spine dynamics following long-term abstinence, i.e. in adult rats (PND 90). These findings demonstrate that short withdrawal promotes plastic changes in the developing brain via the dysregulation of the GR system and alterations in the spine network. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Use of the light/dark test for anxiety in adult and adolescent male rats.

PubMed

Arrant, Andrew E; Schramm-Sapyta, Nicole L; Kuhn, Cynthia M

2013-11-01

The light/dark (LD) test is a commonly used rodent test of unconditioned anxiety-like behavior that is based on an approach/avoidance conflict between the drive to explore novel areas and an aversion to brightly lit, open spaces. We used the LD test to investigate developmental differences in behavior between adolescent (postnatal day (PN) 28-34) and adult (PN67-74) male rats. We investigated whether LD behavioral measures reflect anxiety-like behavior similarly in each age group using factor analysis and multiple regression. These analyses showed that time in the light compartment, percent distance in the light, rearing, and latency to emerge into the light compartment were measures of anxiety-like behavior in each age group, while total distance traveled and distance in the dark compartment provided indices of locomotor activity. We then used these measures to assess developmental differences in baseline LD behavior and the response to anxiogenic drugs. Adolescent rats emerged into the light compartment more quickly than adults and made fewer pokes into the light compartment. These age differences could reflect greater risk taking and less risk assessment in adolescent rats than adults. Adolescent rats were less sensitive than adults to the anxiogenic effects of the benzodiazepine inverse agonist N-methyl-β-carboline-3-carboxamide (FG-7142) and the α₂ adrenergic antagonist yohimbine on anxiety-like behaviors validated by factor analysis, but locomotor variables were similarly affected. These data support the results of the factor analysis and indicate that GABAergic and noradrenergic modulation of LD anxiety-like behavior may be immature during adolescence. Copyright © 2013 Elsevier B.V. All rights reserved.

Regulation of the neurotensin NT1 receptor in the developing rat brain following chronic treatment with the antagonist SR 48692

PubMed Central

Lépée-Lorgeoux, Isabelle; Betancur, Catalina; Souazé, Frédérique; Rostène, William; Bérod, Anne; Pélaprat, Didier

2000-01-01

The aim of the present study was to investigate the role of neurotensin in the regulation of NT1 receptors during postnatal development in the rat brain. Characterization of the ontogeny of neurotensin concentration and [125I]neurotensin binding to NT1 receptors in the brain at different embryonic and postnatal stages showed that neurotensin was highly expressed at birth, reaching peak levels at postnatal day 5 (P5), and decreasing thereafter. The transient rise in neurotensin levels preceded the maximal expression of NT1 receptors, observed at P10, suggesting that neurotensin may influence the developmental profile of NT1 receptors. Using primary cultures of cerebral cortex neurons from fetal rats, we showed that exposure to the neurotensin agonist JMV 449 (1 nM) decreased (−43%) the amount of NT1 receptor mRNA measured by reverse transcription-PCR, an effect that was abolished by the non-peptide NT1 receptor antagonist SR 48692 (1 μM). However, daily injection of SR 48692 to rat pups from birth for 5, 9 or 15 days, did not modify [125I]neurotensin binding in brain membrane homogenates. Moreover, postnatal blockade of neurotensin transmission did not alter the density and distribution of NT1 receptors assessed by quantitative autoradiography nor NT1 receptor mRNA expression measured by in situ hybridization in the cerebral cortex, caudate-putamen and midbrain. These results suggest that although NT1 receptor expression can be regulated in vitro by the agonist at an early developmental stage, neurotensin is not a major factor in the establishment of the ontogenetic pattern of these receptors in the rat brain. PMID:10797539

Distinct roles of the endocannabinoids anandamide and 2-arachidonoylglycerol in social behavior and emotionality at different developmental ages in rats.

PubMed

Manduca, Antonia; Morena, Maria; Campolongo, Patrizia; Servadio, Michela; Palmery, Maura; Trabace, Luigia; Hill, Matthew N; Vanderschuren, Louk J M J; Cuomo, Vincenzo; Trezza, Viviana

2015-08-01

To date, our understanding of the relative contribution and potential overlapping roles of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the regulation of brain function and behavior is still limited. To address this issue, we investigated the effects of systemic administration of JZL195, that simultaneously increases AEA and 2-AG signaling by inhibiting their hydrolysis, in the regulation of socio-emotional behavior in adolescent and adult rats. JZL195, administered at the dose of 0.01mg/kg, increased social play behavior, that is the most characteristic social activity displayed by adolescent rats, and increased social interaction in adult animals. At both ages, these behavioral effects were antagonized by the CB1 cannabinoid receptor antagonist SR141716A and were associated with increased brain levels of 2-AG, but not AEA. Conversely, at the dose of 1mg/kg, JZL195 decreased general social exploration in adolescent rats without affecting social play behavior, and induced anxiogenic-like effects in the elevated plus-maze test both in adolescent and adult animals. These effects, mediated by activation of CB1 cannabinoid receptors, were paralleled by simultaneous increase in AEA and 2-AG levels in adolescent rats, and by an increase of only 2-AG levels in adult animals. These findings provide the first evidence for a role of 2-AG in social behavior, highlight the different contributions of AEA and 2-AG in the modulation of emotionality at different developmental ages and suggest that pharmacological inhibition of AEA and 2-AG hydrolysis is a useful approach to investigate the role of these endocannabinoids in neurobehavioral processes. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Expression of developmental myosin and morphological characteristics in adult rat skeletal muscle following exercise-induced injury.

PubMed

Smith, H K; Plyley, M J; Rodgers, C D; McKee, N H

1999-07-01

The extent and stability of the expression of developmental isoforms of myosin heavy chain (MHCd), and their association with cellular morphology, were determined in adult rat skeletal muscle fibres following injury induced by eccentrically-biased exercise. Adult female Wistar rats [274 (10) g] were either assigned as non-exercised controls or subjected to 30 min of treadmill exercise (grade, -16 degrees; speed, 15 m x min(-1)), and then sacrificed following 1, 2, 4, 7, or 12 days of recovery (n = 5-6 per group). Histologically and immunohistologically stained serial, transverse cryosections of the soleus (S), vastus intermedius (VI), and tibialis anterior (TA) muscles were examined using light microscopy and digital imaging. Fibres staining positively for MHCd (MHCd+) were seldom detected in the TA. In the VI and S, higher proportions of MHCd+ fibres (0.8% and 2.5%, respectively) were observed in rats at 4 and 7 days post-exercise, in comparison to all other groups combined (0.2%, 1.2%; P < or = 0.01). In S, MHCd+ fibres were observed less frequently by 12 days (0.7%) than at 7 days (2.6%) following exercise. The majority (85.1%) of the MHCd+ fibres had morphological characteristics indicative of either damage, degeneration, repair or regeneration. Most of the MHCd+ fibres also expressed adult slow, and/or fast myosin heavy chain. Quantitatively, the MHCd+ fibres were smaller (< 2500 microm2) and more angular than fibres not expressing MHCd. Thus, there was a transient increase in a small, but distinct population of MHCd+ fibres following unaccustomed, functional exercise in adult rat S and VI muscles. The observed close coupling of MHCd expression with morphological changes within muscle fibres suggests that these characteristics have a common, initial exercise-induced injury-related stimulus.

Colocalization of dentin matrix protein 1 and dentin sialoprotein at late stages of rat molar development.

PubMed

Baba, Otto; Qin, Chunlin; Brunn, Jan C; Wygant, James N; McIntyre, Bradley W; Butler, William T

2004-10-01

Dentin matrix protein 1 (DMP1) and dentin sialophosphoprotein (DSPP) are acidic proteins found in the extracellular matrices of bones and teeth. Recent data from gene knockouts, along with those of gene mutations, indicate that these two phosphoproteins are critical for bone and tooth development and/or maintenance. However, the precise functions of the two proteins have not been elucidated. In order to gain insights into their functions in tooth formation, we performed systematic, comparative investigations on the immunolocalization of DMP1 and dentin sialoprotein (DSP, a cleaved fragment of DSPP), using the rat first molar at different developmental stages as a model. Immunohistochemistry (IHC) was performed with specific, monoclonal antibodies against the COOH-terminal fragments of DMP1 and against DSP. In 1-day- and 1-week-old rats, weak immunoreactions for DMP1 were observed in dentinal tubules while stronger reactions for DSP were seen in the tubules and predentin. In rats older than 2 weeks, immunoreactions for DMP1 were found in dentinal tubules, predentin and odontoblasts. In 5-week- and 8-week-old rats, strong immunoreactions for DMP1 were widely distributed in odontoblasts and predentin. The distribution pattern of DSP was strikingly similar to that of DMP1 after 2 weeks and the localization of each was distinctly different from that of bone sialoprotein (BSP). The unique colocalization of DMP1 and DSPP in tooth development suggests that the two proteins play complementary and/or synergistic roles in formation and maintenance of healthy teeth.

Effects of lead exposure on hippocampal metabotropic glutamate receptor subtype 3 and 7 in developmental rats.

PubMed

Xu, Jian; Yan, Huai C; Yang, Bo; Tong, Lu S; Zou, Yu X; Tian, Ying

2009-04-20

A complete explanation of the mechanisms by which Pb2+ exerts toxic effects on developmental central nervous system remains unknown. Glutamate is critical to the developing brain through various subtypes of ionotropic or metabotropic glutamate receptors (mGluRs). Ionotropic N-methyl-D-aspartate receptors have been considered as a principal target in lead-induced neurotoxicity. The relationship between mGluR3/mGluR7 and synaptic plasticity had been verified by many recent studies. The present study aimed to examine the role of mGluR3/mGluR7 in lead-induced neurotoxicity. Twenty-four adult and female rats were randomly selected and placed on control or 0.2% lead acetate during gestation and lactation. Blood lead and hippocampal lead levels of pups were analyzed at weaning to evaluate the actual lead content at the end of the exposure. Impairments of short -term memory and long-term memory of pups were assessed by tests using Morris water maze and by detection of hippocampal ultrastructural alterations on electron microscopy. The impact of lead exposure on mGluR3 and mGluR7 mRNA expression in hippocampal tissue of pups were investigated by quantitative real-time polymerase chain reaction and its potential role in lead neurotoxicity were discussed. Lead levels of blood and hippocampi in the lead-exposed rats were significantly higher than those in the controls (P < 0.001). In tests using Morris Water Maze, the overall decrease in goal latency and swimming distance was taken to indicate that controls had shorter latencies and distance than lead-exposed rats (P = 0.001 and P < 0.001 by repeated-measures analysis of variance). On transmission electron microscopy neuronal ultrastructural alterations were observed and the results of real-time polymerase chain reaction showed that exposure to 0.2% lead acetate did not substantially change gene expression of mGluR3 and mGluR7 mRNA compared with controls. Exposure to lead before and after birth can damage short-term and long-term memory ability of young rats and hippocampal ultrastructure. However, the current study does not provide evidence that the expression of rat hippocampal mGluR3 and mGluR7 can be altered by systemic administration of lead during gestation and lactation, which are informative for the field of lead-induced developmental neurotoxicity noting that it seems not to be worthwhile to include mGluR3 and mGluR7 in future studies.

Selective Breeding for Infant Rat Separation-Induced Ultrasonic Vocalizations: Developmental Precursors of Passive and Active Coping Styles

PubMed Central

Brunelli, Susan A.; Hofer, Myron A.

2009-01-01

Human depression and anxiety disorders show inherited biases across generations, as do antisocial disorders characterized by aggression. Each condition is preceded in children by behavioral inhibition or aggressive behavior, respectively, and both are characterized by separation anxiety disorders. In affected families, adults and children exhibit different forms of altered autonomic nervous system regulation and hypothalamic-pituitary-adrenal activity in response to stress. Because it is difficult to determine mechanisms accounting for these associations, animal studies are useful for studying the fundamental relationships between biological and behavioral traits. Pharmacologic and behavioral studies suggest that infant rat ultrasonic vocalizations (USV) are a measure of an early anxiety-like state related to separation anxiety. However, it was not known whether or not early ultrasound emissions in infant rats are markers for genetic risk for anxiety states later in life. To address these questions, we selectively bred two lines of rats based on high and low rates of USV to isolation at postnatal (P) 10 days of age. To our knowledge, ours is the only laboratory that has ever selectively bred on the basis of an infantile trait related to anxiety. The High and Low USV lines show two distinct sets of patterns of behavior, physiology and neurochemistry from infancy through adulthood. As adults High line rats demonstrate “anxious”/“depressed” phenotypes in behavior and autonomic nervous system (ANS) regulation to standard laboratory tests. In Lows, on the other hand, behavior and autonomic regulation are consistent with an “aggressive” phenotype. The High and Low USV lines are the first genetic animal models implicating long-term associations of contrasting “coping styles” with early attachment responses. They thus present a potentially powerful model for examining gene-environment interactions in the development of life-long affective regulation. PMID:17543397

BEHAVIORAL DEVELOPMENT FOLLOWING DAILY EPISODES OF MOTHER-INFANT SEPARATION IN THE RAT

EPA Science Inventory

Use of dermal or inhalation routes of maternal exposure during the postnatal period in rodent developmental neurotoxicity evaluations would be most practical if dams could be separated from their pups during the exposure period. owever, this procedure raises questions concerning ...

Developmentally-regulated sodium channel subunits are differentially sensitive to α–cyano containing pyrethroids

EPA Science Inventory

Juvenile rats have been reported to be more sensitive to the acute neurotoxic effects of the pyrethroid deltamethrin than adults. While toxicokinetic differences between juveniles and adults are documented, toxicodynamic differences have not been examined. Voltage-gated sodium ch...

EFFECTS OF DEVELOPMENTAL HYPOTHYROIDISM ON AUDITORY AND MOTOR FUNCTION IN THE RAT

EPA Science Inventory

Deafness is a common result of severe hypothyroidism during development in humans and laboratory animals, however little is known regarding the sensitivity of the auditory system to more moderate changes in thyroid hormone homeostasis. he present investigation compared the relati...

Developmental Exposure to A Commercial PBDE Mixture: Effects on Protein Networks in the Cerebellum and Hippocampus of Rats

EPA Science Inventory

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are structurally similar topolychlorinated biphenyls (PCBs) and have both central (learning and memory deficits) and peripheral (motor dysfunction) neurotoxic effects at concentrations/doses similar to those of PCBs. The cellular...

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...

IMMUNE FUNCTION IN RATS DEVELOPMENTALLY EXPOSED TO DIBUTYLTIN DICHLORIDE

EPA Science Inventory

Organotins are used commercially as pesticides, antifouling agents and stabilizers for polyvinyl chloride (PVC) pipe. Mono- and di-substituted methyl and butyltins, used in PVC pipe production, are of concern to the USEPA as they leach from supply pipes into drinking water and ha...

URINARY BIOMARKERS OF DI-ISONONYL PHTHALATE IN RATS

EPA Science Inventory

Commercial di-isononyl phthalate (DiNP) is a mixture of various branched-chain dialkyl phthalates mainly containing ninecarbon alkyl isomers. At high doses in rodents, DiNP is a carcinogen, and a developmental toxicant. After exposure, the diester isomers are de-esterified to for...

Developmental exposure to polychlorinated biphenyls (PCBs) interferes with experience-dependent dendritic plasticity and ryanodine receptor expression in weanling rats.

EPA Science Inventory

BACKGROUND: Neurodevelopmental disorders are associated with altered patterns of neuronal connectivity. A critical determinant of neuronal connectivity is the dendritic morphology of individual neurons, which is shaped by experience. The identification of environmental exposures ...

PRENATAL AND POSTNATAL EFFECTS IN RATS OF PERFLUORONONANOIC ACID EXPOSURE IN UTERO

EPA Science Inventory

In recent years, our understanding of the developmental toxicity of perfluoroalkyl acids (PFAAs) has focused on the C8 compounds. Ubiquitous environmental contaminants, PFAA’s are utilized as surfactants in a variety of industrial applications. Although several PFAAs have been ex...

DEVELOPMENTAL EXPRESSION OF ALDEHYDE DEHYDROGENASE IN RAT: A COMPARISON OF LIVER AND LUNG DEVELOPMENT

EPA Science Inventory

Metabolism is one of the major determinants for age-related susceptibility changes to chemicals. Aldehydes are highly reactive molecules present in the environment and can be produced during biotransformation of xenobiotics. Aldehyde dehydrogenases (ALDH) are important in aldehyd...

Evaluation of developmental toxicity of guaifenesin using pregnant female rats.

PubMed

Shabbir, Arham; Shamsi, Sadia; Shahzad, Muhammad; Butt, Hajra Ikram; Aamir, Khurram; Iqbal, Javed

2016-01-01

Guaifenesin possesses expectorant, muscle relaxant, and anticonvulsive properties. To the best of our knowledge, the promising data regarding the developmental toxicity of guaifenesin are scarce. The current study investigates the developmental toxic effects of guaifenesin in detail using female rats. Twenty-five dams were divided into five groups. Group 1 served as a control, while Group-2, -3, -4, and -5 were administered with 250, 350, 500, and 600 (mg/kg b.w.) doses of guaifenesin, respectively, starting from gestation day 6 to day 17. Half of the total recovered fetuses was subjected to morphologic and morphometric analysis, while other half was subjected to skeletal examination. A significant reduction in maternal weight, and food/water intake, was observed, however, no mortality and morbidity were observed. About 14 dead fetuses were found in Group-3 and -4 each, while 26 in Group 5. Morphological analysis revealed 21.2%, 45.4%, 67.2%, and 86.9% of total fetuses having hemorrhagic spots in Group-2, -3, -4, and -5, respectively. Dropping wrist/ankle and kinky tail were found in Group-4 and -5 only. Morphometric analysis showed a significant decline in fetal weight, full body length, skull length, forelimb length, hindlimb length, and tail length in all guaifenesin treated groups. Skeletal examination displayed that only Group 5 fetuses had increased intercostal space between 7(th) and 8(th) rib. We also observed improper development of carpals, metacarpals, tarsals, and metatarsals of the Group 5 fetuses. Guaifenesin showed a significant developmental toxicity at selected test doses; therefore, a careful use is suggested during pregnancy.

Evaluation of developmental toxicity of guaifenesin using pregnant female rats

PubMed Central

Shabbir, Arham; Shamsi, Sadia; Shahzad, Muhammad; Butt, Hajra Ikram; Aamir, Khurram; Iqbal, Javed

2016-01-01

Objectives: Guaifenesin possesses expectorant, muscle relaxant, and anticonvulsive properties. To the best of our knowledge, the promising data regarding the developmental toxicity of guaifenesin are scarce. The current study investigates the developmental toxic effects of guaifenesin in detail using female rats. Materials and Methods: Twenty-five dams were divided into five groups. Group 1 served as a control, while Group-2, -3, -4, and -5 were administered with 250, 350, 500, and 600 (mg/kg b.w.) doses of guaifenesin, respectively, starting from gestation day 6 to day 17. Half of the total recovered fetuses was subjected to morphologic and morphometric analysis, while other half was subjected to skeletal examination. Results: A significant reduction in maternal weight, and food/water intake, was observed, however, no mortality and morbidity were observed. About 14 dead fetuses were found in Group-3 and -4 each, while 26 in Group 5. Morphological analysis revealed 21.2%, 45.4%, 67.2%, and 86.9% of total fetuses having hemorrhagic spots in Group-2, -3, -4, and -5, respectively. Dropping wrist/ankle and kinky tail were found in Group-4 and -5 only. Morphometric analysis showed a significant decline in fetal weight, full body length, skull length, forelimb length, hindlimb length, and tail length in all guaifenesin treated groups. Skeletal examination displayed that only Group 5 fetuses had increased intercostal space between 7th and 8th rib. We also observed improper development of carpals, metacarpals, tarsals, and metatarsals of the Group 5 fetuses. Conclusion: Guaifenesin showed a significant developmental toxicity at selected test doses; therefore, a careful use is suggested during pregnancy. PMID:27298495

Male reproductive tract lesions at 6, 12, and 18 months of age following in utero exposure to di(n-butyl) phthalate.

PubMed

Barlow, Norman J; McIntyre, Barry S; Foster, Paul M D

2004-01-01

In utero exposure of male rats to the antiandrogen di(n-butyl) phthalate (DBP) leads to decreased anogenital distance (AGD) on postnatal day (PND) 1, increased areolae retention on PND 13, malformations in the male reproductive tract, and histologic testicular lesions including marked seminiferous epithelial degeneration and a low incidence of Leydig cell (LC) adenomas on PND 90. One objective of this study was to determine the incidence and persistence of decreased AGD, increased areolae retention, and LC adenomas in adult rats following in utero DBP exposure. A second objective was to determine whether AGD and areolae retention during the early postnatal period are associated with lesions in the male reproductive tract. Pregnant Crl:CD(SD)BR rats were gavaged with corn oil or DBP at 100 or 500 mg/kg/day, 10 dams per group. Three replicates of rats (n = 30 rats per replicate) were exposed from gestation day 12 to 21 and the male offspring allowed to mature to 6, 12, or 18 months of age. Gross malformations in the male reproductive tract and histologic lesions in the testes were similar to those previously described. However, testicular dysgenesis, a lesion of proliferating LCs and aberrant tubules that has not been previously described in DBP-exposed testes, was diagnosed. The incidence of this lesion was approximately 20% unilateral and 7-18% bilateral in the high-dose group and was similar among all ages examined, implicating a developmental alteration rather than an age-related change. AGD and areolae retention were found to be permanent changes following in utero exposure to 500 mg/kg/day of DBP. Decreased AGD was a sensitive predictor of lesions in the male reproductive tract, relatively small changes in AGD were associated with a significant incidence of male reproductive malformations. In utero DBP exposure induced proliferative developmental lesions, some of which would have been diagnosed as LC adenomas by the morphological criteria set forth by the Society of Toxicologic Pathology. However, these lesions were dissimilar to traditional LC adenomas as the LCs were poorly differentiated and the lesions contained aberrant seminiferous tubules. While the morphology and incidence of this DBP-induced testicular developmental lesion has been fully characterized by this study, the detailed pathogenesis warrants further investigation.

Developmental changes in the hypothalamic mRNA expression levels of brain-derived neurotrophic factor and serum leptin levels: Their responses to fasting in male and female rats.

PubMed

Iwasa, Takeshi; Matsuzaki, Toshiya; Yano, Kiyohito; Munkhzaya, Munkhsaikhan; Tungalagsuvd, Altankhuu; Yiliyasi, Maira; Kuwahara, Akira; Irahara, Minoru

2016-11-01

The actions and responses of hypothalamic appetite regulatory factors change markedly during the neonatal to pre-pubertal period in order to maintain appropriate metabolic and nutritional conditions. In this study, we examined the developmental changes in the hypothalamic mRNA levels of brain-derived neurotrophic factor (BDNF), which is a potent anorectic factor and the changes in the sensitivity of the hypothalamic expression of this factor to fasting during the neonatal to pre-pubertal period. Under fed conditions, hypothalamic BDNF mRNA expression decreased during development in both male and female rats. Similarly, the serum levels of leptin, which is a positive regulator of hypothalamic BDNF expression, also tended to fall during the developmental period. The serum leptin level and the hypothalamic BDNF mRNA level were found to be positively correlated in both sexes under the fed conditions. Hypothalamic BDNF mRNA expression was decreased by 24h fasting (separating the rats from their mothers) in the early neonatal period (postnatal day 10) in both males and females, but no such changes were seen at postnatal day 20. Twenty-four hours' fasting (food deprivation) did not affect hypothalamic BDNF mRNA expression in the pre-pubertal period (postnatal day 30). On the other hand, the rats' serum leptin levels were decreased by 24h fasting (separating the rats from their mothers at postnatal day 10 and 20, and food deprivation at postnatal day 30) throughout the early neonatal to pre-pubertal period. The correlation between serum leptin and hypothalamic BDNF mRNA levels was not significant under the fasted conditions. It can be speculated that leptin partially regulates hypothalamic BDNF mRNA levels, but only in fed conditions. Such changes in hypothalamic BDNF expression might play a role in maintaining appropriate metabolic and nutritional conditions and promoting normal physical development. In addition, because maternal separation induces a negative energy balance and short- and long-term stress responses, it is also possible that reductions in hypothalamic BDNF mRNA levels in the early neonatal period (postnatal day 10) may be partially induced by stress responses of the maternal deprivation. Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.

Health Risk Assessment of Women in Submarines: Reproductive and Developmental Toxicity Evaluation of Major Submarine Atmosphere Components (CO, CO2, and O2) in Rats (Rattus norvegicus) - Phase 1 (Range Finding Study)

DTIC Science & Technology

2011-06-27

study will incorporate new phlebotomy procedures that will reduce the potential for clotting and hemolysis in the blood . The increase of RDW in the...observed blood clotting or hemolysis (≤ 5% of data), which can frequently result in anomalous hematological and/or serum chemistry values, anomalous...exposure concentrations were identified for both males and females, including: (1) increased red blood cell distribution width (RDW) in rats from the

Early life experience contributes to the developmental programming of depressive-like behaviour, neuroinflammation and oxidative stress.

PubMed

Réus, Gislaine Z; Fernandes, Gabrielly C; de Moura, Airam B; Silva, Ritele H; Darabas, Ana Caroline; de Souza, Thays G; Abelaira, Helena M; Carneiro, Celso; Wendhausen, Diogo; Michels, Monique; Pescador, Bruna; Dal-Pizzol, Felipe; Macêdo, Danielle S; Quevedo, João

2017-12-01

This study used an animal model of depression induced by maternal care deprivation (MCD) to investigate whether depressive behaviour, neuroinflammation and oxidative stress were underlying factors in developmental programming after early life stress. At postnatal days (PND) 20, 30, 40, and 60, individual subsets of animals were evaluated in behavioural tests and then euthanized to assess cytokine levels and oxidative stress parameters in the prefrontal cortex (PFC), hippocampus and serum. The results showed that MCD did not induce behavioural changes at PND 30 and 40. However, at PND 20 and 60, the rats displayed a depressive-like behaviour in the forced swimming test, without changes in locomotor spontaneous activity. In the brain and serum, the levels of pro-inflammatory cytokines (interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α)) were increased, and the anti-inflammatory cytokine (interleukin-10) level was reduced throughout developmental programming (PND 20, 30, 40 and 60). Protein carbonyl levels increased in the brain at PND 30, 40 and 60. Superoxide dismutase (SOD) activity was decreased during all developmental programming phases evaluated in the brain. Catalase (CAT) activity was decreased at PND 20, 40 and 60 in the brain. Our results revealed that "critical episodes" in early life stressful events are able to induce behavioural alterations that persist into adulthood and can stimulate inflammation and oxidative damage in both central and peripheral systems, which are required for distinct patterns of resilience against psychiatric disorders later in life. Copyright © 2017 Elsevier Ltd. All rights reserved.

Marginal iodide deficiency and thyroid function: dose-response analysis for quantitative pharmacokinetic modeling.

PubMed

Gilbert, M E; McLanahan, E D; Hedge, J; Crofton, K M; Fisher, J W; Valentín-Blasini, L; Blount, B C

2011-04-28

Severe iodine deficiency (ID) results in adverse health outcomes and remains a benchmark for understanding the effects of developmental hypothyroidism. The implications of marginal ID, however, remain less well known. The current study examined the relationship between graded levels of ID in rats and serum thyroid hormones, thyroid iodine content, and urinary iodide excretion. The goals of this study were to provide parametric and dose-response information for development of a quantitative model of the thyroid axis. Female Long Evans rats were fed casein-based diets containing varying iodine (I) concentrations for 8 weeks. Diets were created by adding 975, 200, 125, 25, or 0 μg/kg I to the base diet (~25 μg I/kg chow) to produce 5 nominal I levels, ranging from excess (basal+added I, Treatment 1: 1000 μg I/kg chow) to deficient (Treatment 5: 25 μg I/kg chow). Food intake and body weight were monitored throughout and on 2 consecutive days each week over the 8-week exposure period, animals were placed in metabolism cages to capture urine. Food, water intake, and body weight gain did not differ among treatment groups. Serum T4 was dose-dependently reduced relative to Treatment 1 with significant declines (19 and 48%) at the two lowest I groups, and no significant changes in serum T3 or TSH were detected. Increases in thyroid weight and decreases in thyroidal and urinary iodide content were observed as a function of decreasing I in the diet. Data were compared with predictions from a recently published biologically based dose-response (BBDR) model for ID. Relative to model predictions, female Long Evans rats under the conditions of this study appeared more resilient to low I intake. These results challenge existing models and provide essential information for development of quantitative BBDR models for ID during pregnancy and lactation. Published by Elsevier Ireland Ltd.

Life-long protein malnutrition in the rat (Rattus norvegicus) results in altered patterns of craniofacial growth and smaller individuals

PubMed Central

Lobe, Shannon L; Bernstein, Marica C; German, Rebecca Z

2006-01-01

Dietary protein is a limiting factor in mammalian growth, significantly affecting the non-linear trajectories of skeletal growth. Young females may be particularly vulnerable to protein malnutrition if the restriction is not lifted before they become reproductive. With such early malnutrition, limited amino acids would be partitioned between two physiological objectives, successful reproduction vs. continued growth. Thus, the consequences of protein malnutrition could affect more than one generation. However, few studies have quantified these cross-generational effects. Our objective was to test for differences in skeletal growth in a second generation of malnourished rats compared with rats malnourished only post-weaning, the first generation and with controls. In this longitudinal study we modelled the growth of 22 craniofacial measurements with the logistic Gompertz equation, and tested for differences in the equation's parameters among the diet groups. The female offspring of post-weaning malnourished dams did not catch up in size to the first generation or to controls, although certain aspects of their craniofacial skeleton were less affected than others. The second generation's growth trajectories resembled the longer and slower growth of the first malnourished generation. There was a complex interaction between developmental processes and early nutritional environment, which affected variation of adult size. PMID:16761979

Developmental reprogramming of rat GLUT-5 requires de novo mRNA and protein synthesis.

PubMed

Jiang, L; Ferraris, R P

2001-01-01

Fructose transporter (GLUT-5) expression is low in mid-weaning rat small intestine, increases normally after weaning is completed, and can be precociously induced by premature consumption of a high-fructose (HF) diet. In this study, an in vivo perfusion model was used to determine the mechanisms regulating this substrate-induced reprogramming of GLUT-5 development. HF (100 mM) but not high-glucose (HG) perfusion increased GLUT-5 activity and mRNA abundance. In contrast, HF and HG perfusion had no effect on Na(+)-dependent glucose transporter (SGLT-1) expression but increased c-fos and c-jun expression. Intraperitoneal injection of actinomycin D before intestinal perfusion blocked the HF-induced increase in fructose uptake rate and GLUT-5 mRNA abundance. Actinomycin D also prevented the perfusion-induced increase in c-fos and c-jun mRNA abundance but did not affect glucose uptake rate and SGLT-1 mRNA abundance. Cycloheximide blocked the HF-induced increase in fructose uptake rate but not the increase in GLUT-5 mRNA abundance and had no effect on glucose uptake rate and SGLT-1 mRNA abundance. In neonatal rats, the substrate-induced reprogramming of intestinal fructose transport is likely to involve transcription and translation of the GLUT-5 gene.

Oxidative mechanisms contributing to the developmental neurotoxicity of nicotine and chlorpyrifos

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

Qiao, Dan; Seidler, Frederic J.; Slotkin, Theodore A.

Nicotine and chlorpyrifos are developmental neurotoxicants that, despite their differences in structure and mechanism of action, share many aspects for damage to the developing brain. Both are thought to generate oxidative radicals; in the current study, we evaluated their ability to produce lipid peroxidation in two in vitro models of neural cell development (PC12 and SH-SY5Y cells) and for nicotine, with treatment of adolescent rats in vivo. Nicotine and chlorpyrifos, in concentrations relevant to human exposures, elicited an increase in thiobarbituric-acid-reactive species (TBARS) in undifferentiated cells, an effect that was prevented by addition of the antioxidant, Vitamin E. Initiating differentiationmore » with nerve growth factor, which enhances nicotinic acetylcholine receptor expression, increased the TBARS response to nicotine but not chlorpyrifos, suggesting that the two agents act by different originating mechanisms to converge on the endpoint of oxidative damage. Furthermore, nicotine protected the cells from oxidative damage evoked by chlorpyrifos and similarly blocked the antimitotic effect of chlorpyrifos. Treatment of adolescent rats with nicotine elicited increases in TBARS in multiple brain regions when given in doses that simulate plasma nicotine concentrations found in smokers or at one-tenth the dose. Our results indicate that nicotine and chlorpyrifos elicit oxidative damage to developing neural cells both in vitro and in vivo, a mechanism that explains some of the neurodevelopmental endpoints that are common to the two agents. The balance between neuroprotectant and neurotoxicant actions of nicotine may be particularly important in situations where exposure to tobacco smoke is combined with other prooxidant insults.« less

Developmental programming of aging of isolated pancreatic islet glucose-stimulated insulin secretion in female offspring of mothers fed low-protein diets in pregnancy and/or lactation.

PubMed

Morimoto, S; Sosa, T C; Calzada, L; Reyes-Castro, L A; Díaz-Díaz, E; Morales, A; Nathanielsz, P W; Zambrano, E

2012-12-01

Diabetes predisposition is determined by pancreatic islet insulin secretion and insulin resistance. We studied female rat offspring exposed to low-protein maternal diet (50% control protein diet) in pregnancy and/or lactation at postnatal days 36, 110 and 450. Rats were fed either control 20% casein diet (C) or restricted diet (R - 10% casein) during pregnancy. After delivery, mothers received either C or R diet until weaning to provide four offspring groups: CC, RR, CR and RC (first letter denoting maternal pregnancy diet and the second lactation diet). Serum glucose, insulin and homeostatic model assessment (HOMA) were measured. Pancreatic islets were isolated and in vitro insulin secretion quantified in low glucose (5 mM) and high glucose (11 mM). Serum glucose, insulin and HOMA were similar in all groups at 36 and 110 postnatal days. HOMA was only higher in RR at 450 postnatal days. Only CC demonstrated differences in glucose sensitivity of β-cells to high and low doses at the three ages studied. At 36 days, RR, CR and RC and at 450 days RR and RC groups did not show glucose-stimulated insulin secretion differences between low and high glucose. Aging-associated glucose-stimulated insulin secretion loss was affected by maternal dietary history, indicating that developmental programming must be considered a major factor in aging-related development of predisposition to later-life dysfunctional insulin metabolism. Female offspring islets' insulin secretion was higher than previously reported in males.

Developmental changes in the role of a pertussis toxin sensitive guanine nucleotide binding protein in the rat cardiac alpha sub 1 -adrenergic system

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

Han, H.M.

1989-01-01

During development, the cardiac alpha{sub 1}-adrenergic chronotropic response changes from positive in the neonate to negative in the adult. This thesis examined the possibility of a developmental change in coupling of a PT-sensitive G-protein to the alpha{sub 1}-adrenergic receptor. Radioligand binding experiments performed with the iodinated alpha{sub 1}-selective radioligand ({sup 125}I)-I-2-({beta}-(4-hydroxphenyl)ethylaminomethyl)tetralone (({sup 125}I)-IBE 2254) demonstrated that the alpha{sub 1}-adrenergic receptor is coupled to a G-protein in both neonatal and adult rat hearts. However, in the neonate the alpha{sub 1}-adrenergic receptor is coupled to a PT-insensitive G-protein, whereas in the adult the alpha{sub 1}-adrenergic receptor is coupled to both a PT-insensitivemore » and a PT-sensitive G-protein. Consistent with the results from binding experiments, PT did not have any effect on the alpha{sub 1}-mediated positive chronotropic response in the neonate, whereas in the adult the alpha{sub 1}-mediated negative chronotropic response was completely converted to a positive one after PT-treatment. This thesis also examined the possibility of an alteration in coupling of the alpha{sub 1}-adrenergic receptor to its effector under certain circumstances such as high potassium (K{sup +}) depolarization in nerve-muscle (NM) co-cultures, a system which has been previously shown to be a convenient in vitro model to study the mature inhibitory alpha{sub 1}-response.« less

Structure-activity comparison of organotin species: dibutyltin is a developmental neurotoxicant in vitro and in vivo.

PubMed

Jenkins, Scott M; Ehman, Kimberly; Barone, Stanley

2004-07-19

Human exposure to the organotins can occur due to their use as polyvinyl chloride heat stabilizers and as marine biocides. The consequences of this exposure for human health are unknown. We initially compared the toxicity of monomethyltin, dimethyltin, and dibutyltin to the known neurotoxicant trimethyltin using an in vitro model of neuronal development in PC12 cells. Dibutyltin, a compound traditionally thought to target the immune system, was the most potent neurotoxicant. Dibutyltin significantly inhibited neurite outgrowth and caused cell death at concentrations approximately 40-fold lower than the lowest toxic concentrations of trimethyltin. Dimethyltin was less potent than trimethyltin and monomethyltin was not toxic at any concentration examined. These results suggested the importance of prioritizing in vivo neurotoxicity testing with dibutyltin. To accomplish this, pregnant rats were dosed orally with low levels of dibutyltin from gestational day 6 through weaning. In response to developmental dibutyltin exposure, the incidence of apoptotic cell death, measured by DNA fragmentation and TUNEL staining, was increased in the neocortex and hippocampus of postnatal day 38 offspring. No effect was observed at other ages examined.

Animal models for assessment of infection and inflammation: contributions to elucidating the pathophysiology of sudden infant death syndrome.

PubMed

Blood-Siegfried, Jane

2015-01-01

Sudden infant death syndrome (SIDS) is still not well understood. It is defined as the sudden and unexpected death of an infant without a definitive cause. There are numerous hypotheses about the etiology of SIDS but the exact cause or causes have never been pinpointed. Examination of theoretical pathologies might only be possible in animal models. Development of these models requires consideration of the environmental and/or developmental risk factors often associated with SIDS, as they need to explain how the risk factors could contribute to the cause of death. These models were initially developed in common laboratory animals to test various hypotheses to explain these infant deaths - guinea pig, piglet, mouse, neonatal rabbit, and neonatal rat. Currently, there are growing numbers of researchers using genetically altered animals to examine specific areas of interest. This review describes the different systems and models developed to examine the diverse hypotheses for the cause of SIDS and their potential for defining a causal mechanism or mechanisms.

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...

EVALUATION OF DEVELOPMENTAL NEUROTOXICITY OF ORGANOTINS VIA DRINKING WATER IN RATS: MONOMETHYL TIN

EPA Science Inventory

Organotins such as monomethyltin (MMT) are widely used as heat stabilizers in PVC and CPVC piping. Because human exposure to organotins is widespread via drinking water and the health consequences unknown, organotins were listed on the US EPA Candidate Contaminant List. Particu...

Selective Cognitive Deficits in Adult Rats after Prenatal Exposure to Inhaled Ethanol

EPA Science Inventory

Increased use of ethanol blends in gasoline suggests a need to assess the potential public health risks of exposure to these fuels. Ethanol consumed during pregnancy is a teratogen. However, little is known about the potential developmental neurotoxicity of ethanol delivered by i...

THE ROLE OF PROLACTIN IN THE DEVELOPMENTAL TOXICOLOGY OF THE RAT PROSTATE

EPA Science Inventory

Many investigators have examined the effects of peri- or postnatal exposure to steroids and compounds with steroidogenic activity on the development of the offspring. Such exposures are known to affect sexual differentiation of the brain or the development of accessory sex tissue...

Assessment of Diiodoacetic Effects on Eye Malformations in a Developmental Toxicity Screen with F344 Rats

EPA Science Inventory

Diiodoacetic acid (DIA) is an iodinated haloacetic acid and a drinking water disinfection by-product (DBP) formed in drinking water treated by chloramination (chlorine plus ammonia) to prevent microbial contamination and regrowth. Although disinfection of drinking water has prove...

CROSS-FOSTER STUDY OF THE DEVELOPMENTAL EFFECTS OF PFOA

EPA Science Inventory

Perflourooctanoic acid (PFOA), a commercial surfactant, has recently been found in wildlife and human blood. Exposure of pregnant rats and mice to PFOA results in low body weight and poor survival of pups. However, it has not been determined whether the reduction in weight and ...

Thermoregulatory deficits in adult long evans rat offspring exposed perinatally to the antithyroidal drug, propylthiouracil

EPA Science Inventory

Developmental exposure to endocrine disrupting toxicants has been shown to alter a variety of physiological processes in mature offspring. Body (core) temperature (Tc) is a tightly regulated homeostatic system but is susceptible to disruptors of the hypothalamic-pituitary-thyroid...

EVALUTION OF COGNITIVE FUNCTION IN WEANLING RATS: A REVIEW OF METHODS SUITABLE FOR CHEMICAL SCREENING.

EPA Science Inventory

The current developmental neurotoxicity (DNT) guidelines for environmental agents require cognitive testing around the age of weaning as well as adulthood. There are challenges associated with testing weanling rodents that are not present with testing older subjects, including r...

Cardiovascular Ultrasound of Neonatal Long Evans Rats Exposed Prenatally to Trichloroacetic Acid: Effects on Heart Rate, Ejection Fraction, and Cardiac Output

EPA Science Inventory

This abstract describes the use of a relatively new technology, cardiovascular ultrasound (echocardiography) for evaluating developmental toxicity affecting heart development. The abstract describes the effects of two known cardiac teratogens, trichloroacetic acid and dimethadio...

Effects of Inhaled Ethanol on Developmental Outcomes in Rats

EPA Science Inventory

Use of biofuels is increasing in the US automotive fleet. The primary alternative to petroleum fuels is ethanol, and the health risk associated with more than 10% ethanol in gasoline is uncertain. To address this uncertainty, we are assessing the effects of prenatal exposure to i...

Altered cardiovascular reactivity and osmoregulation during hyperosmotic stress in adult rats developmentally exposed to polybrominated diphenyl ethers (PBDEs)

EPA Science Inventory

Polybrominated diphenyl ethers (PBDEs) and the structurally similar chemicals polychlorinated biphenyls (PCBs) disrupt the function of multiple endocrine systems. PCBs and PBDEs disrupt the secretion of vasopressin (VP) from the hypothalamus during osmotic activation. Since the p...

Brief Social Isolation in the Adolescent Wistar-Kyoto Rat Model of Endogenous Depression Alters Corticosterone and Regional Monoamine Concentrations.

PubMed

Shetty, Reshma A; Sadananda, Monika

2017-05-01

The Wistar-Kyoto rat (WKY) model has been suggested as a model of adult and adolescent depression though face, predictive and construct validities of the model to depression remain equivocal. The suitability of the WKY as a diathesis model that tests the double-hit hypothesis, particularly during critical periods of brain and behavioural development remains to be established. Here, effects of post-weaning social isolation were assessed during early adolescence (~30pnd) on behavioural despair and learned helplessness in the forced swim test (FST), plasma corticosterone levels and tissue monoamine concentrations in brain areas critically involved in depression, such as prefrontal cortex, nucleus accumbens, striatum and hippocampus. Significantly increased immobility in the FST was observed in socially-isolated, adolescent WKY with a concomitant increase in corticosterone levels over and above the FST-induced stress. WKY also demonstrated a significantly increased release and utilization of dopamine, as manifested by levels of metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid in nucleus accumbens, indicating that the large dopamine storage pool evident during adolescence induces greater dopamine release when stimulated. The serotonin metabolite 5-hydroxy-indoleacetic acid was also significantly increased in nucleus accumbens, indicating increased utilization of serotonin, along with norepinephrine levels which were also signficantly elevated in socially-isolated adolescent WKY. Differences in neurochemistry suggest that social or environmental stimuli during critical periods of brain and behavioural development can determine the developmental trajectories of implicated pathways.

Rat pup social motivation: A critical component of early psychological development

PubMed Central

Cromwell, Howard Casey

2011-01-01

Examining the role of the offspring in early social dynamics is especially difficult. Human developmental psychology has found infant behavior to be a vital part of the early environmental setting. In the rodent model, the different ways that a rodent neonate or pup can influence social dynamics are not well known. Typically, litters of neonates or pups offer complex social interactions dominated by behavior seemingly initiated and maintained by the primary caregiver (e.g., the dam). Despite this strong role for the caregiver, the young most likely influence the litter dynamics in many powerful ways including communication signals, discrimination abilities and early approach behavior. Nelson and Panksepp (1996) developed a preference task to examine early rodent pup social motivation. We have used the same task to examine how variations in maternal care or different environmental perturbations could alter the rat pup preferences for social-related stimuli. Rat pups receiving low levels of maternal licking and grooming were impaired in maternal odor cue learning and emitted lower levels of 22 kHz ultrasounds compared to pups from the high licking and grooming cohort. Prenatal stress or early exposure to a toxicant (polychlorinated biphenyl) altered early social preferences in the rat pup in different ways indicating that diverse strategies are expressed and specific to the type of perturbation exposure. A greater focus on the offspring motivation following early ‘stressors’ will allow for more complete understanding of the dynamics in behavior during early social development. PMID:21251926

Prenatal choline supplementation ameliorates the long-term neurobehavioral effects of fetal-neonatal iron deficiency in rats.

PubMed

Kennedy, Bruce C; Dimova, Jiva G; Siddappa, Asha J M; Tran, Phu V; Gewirtz, Jonathan C; Georgieff, Michael K

2014-11-01

Gestational iron deficiency in humans and rodents produces long-term deficits in cognitive and socioemotional function and alters expression of plasticity genes in the hippocampus that persist despite iron treatment. Prenatal choline supplementation improves cognitive function in other rodent models of developmental insults. The objective of this study was to determine whether prenatal choline supplementation prevents the long-term effects of fetal-neonatal iron deficiency on cognitive and social behaviors and hippocampal gene expression. Pregnant rat dams were administered an iron-deficient (2-6 g/kg iron) or iron-sufficient (IS) (200 g/kg iron) diet from embryonic day (E) 3 to postnatal day (P) 7 with or without choline supplementation (5 g/kg choline chloride, E11-18). Novel object recognition (NOR) in the test vs. acquisition phase, social approach (SA), and hippocampal mRNA expression were compared at P65 in 4 male adult offspring groups: formerly iron deficient (FID), FID with choline supplementation (FID-C), IS, and IS with choline supplementation. Relative to the intact NOR in IS rats (acquisition: 47.9%, test: 60.2%, P < 0.005), FID adult rats had impaired recognition memory at the 6-h delay (acquisition: 51.4%, test: 55.1%, NS), accompanied by a 15% reduction in hippocampal expression of brain-derived neurotrophic factor (Bdnf) (P < 0.05) and myelin basic protein (Mbp) (P < 0.05). Prenatal choline supplementation in FID rats restored NOR (acquisition: 48.8%, test: 64.4%, P < 0.0005) and increased hippocampal gene expression (FID-C vs. FID group: Bdnf, Mbp, P < 0.01). SA was also reduced in FID rats (P < 0.05 vs. IS rats) but was only marginally improved by prenatal choline supplementation. Deficits in recognition memory, but not social behavior, resulting from gestational iron deficiency are attenuated by prenatal choline supplementation, potentially through preservation of hippocampal Bdnf and Mbp expression. Prenatal choline supplementation may be a promising adjunct treatment for fetal-neonatal iron deficiency. © 2014 American Society for Nutrition.

[Models and Foundations of Developmental Education.

ERIC Educational Resources Information Center

Boylan, Hunter R., Ed.; Kerstiens, Gene, Ed.

1988-01-01

These five issues of "Research in Developmental Education," examine the theoretical models and foundations of developmental education. Included are the following: (1) "Theoretical Foundations of Developmental Education," by Hunter R. Boylan, which examines the behaviorist, humanist, and developmental theories underpinning developmental education;…

Low-dose developmental bisphenol A exposure alters fatty acid metabolism in Fischer 344 rat offspring.

PubMed

Dunder, Linda; Halin Lejonklou, Margareta; Lind, Lars; Risérus, Ulf; Lind, P Monica

2018-06-06

Bisphenol A (BPA) is an endocrine disruptor and also a suggested obesogen and metabolism-disrupting chemical. Accumulating data indicates that the fatty acid (FA) profile and their ratios in plasma and other metabolic tissues are associated with metabolic disorders. Stearoyl-CoA desaturase 1 (SCD-1) is a key regulator of lipid metabolism and its activity can be estimated by dividing the FA product by its precursor measured in blood or other tissues. The primary aim of this study was to investigate the effect of low-dose developmental BPA exposure on tissue-specific FA composition including estimated SCD-1 activity, studied in 5- and 52-week (wk)-old Fischer 344 (F344) rat offspring. Pregnant F344 rats were exposed to BPA via their drinking water corresponding to 0: [CTRL], 0.5: [BPA0.5], or 50 µg/kg BW/day: [BPA50], from gestational day 3.5 until postnatal day 22. BPA0.5 increased SCD-16 (estimated as the 16:1n-7/16:0 ratio) and SCD-18 (estimated as the 18:1n-9/18:0 ratio) indices in inguinal white adipose tissue triglycerides (iWAT-TG) and in plasma cholesterol esters (PL-CE), respectively, in 5-wk-old male offspring. In addition, BPA0.5 altered the FA composition in male offspring, e.g. by decreasing levels of the essential polyunsaturated FA linoleic acid (18:2n-6) in iWAT-and liver-TG. No differences were observed regarding the studied FAs in 52-wk-old offspring, although a slightly increased BW was observed in 52-wk-old female offspring. Low-dose developmental BPA exposure increased SCD-16 in iWAT-TG and SCD-18 in PL-CE of male offspring, which may reflect higher SCD-1 activity in these tissues. Altered desaturation activity and signs of altered FA composition are novel findings that may indicate insulin resistance in the rat offspring. These aforementioned results, together with the observed increased BW, adds to previously published data demonstrating that BPA can act as a metabolism disrupting chemical. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Effect of chemical form of selenium on tissue glutathione peroxidase activity in developing rats

NASA Technical Reports Server (NTRS)

Lane, Helen W.; Strength, Ralph; Johnson, Janet; White, Marguerite T.

1991-01-01

The hypothesis that the stage of development of rats may affect the availability of various forms of selenium for the activity of glutathione peroxidase (GSHPx) in the rat was experimentally investigated. One experiment evaluated the availability of selenium as selenite or selenomethionine for GSPHx activity during three developmental states in rats: fetus and 7-day old and 14-day old nursing pups. In all tissues studied, GSHPx activity was highest in the 14-day-old pups whose dams were in the selenomethionine group. Rat pups given intraperitoneal selenite had higher liver and kidney GSHPx activity than pups given the same amount of selenium as intraperitoneal selenomethionine. In a second experiment, all dams were fed the same basal diet and pups were weaned to diets containing one of two levels of selenium and one of three forms of selenium (selenite, selenomethionine, or selenocystine). The results also supported the hypothesis these dietary forms of selenium are differentially available for GSHPx activity.

A novel lens epithelium gene, LEP503, is highly conserved in different vertebrate species and is developmentally regulated in postnatal rat lens.

PubMed

Wen, Y; Sachs, G; Athmann, C

2000-02-01

The development of the lens is dependent on the proliferation of lens epithelial cells and their differentiation into fiber cells near the lens bow/equator. Identification of genes specifically expressed in the lens epithelial cells and their functions may provide insight into molecular events that regulate the processes of lens epithelial cell differentiation. In this study, a novel lens epithelium gene product, LEP503, identified from rat by a subtractive cDNA cloning strategy was investigated in the genome organization, mRNA expression and protein localization. The genomic sequences for LEP503 isolated from rat, mouse and human span 1754 bp, 1694 bp and 1895 bp regions encompassing the 5'-flanking region, two exons, one intron and 3'-flanking region. All exon-intron junction sequences conform to the GT/AG rule. Both mouse and human LEP503 genes show very high identity (93% for mouse and 79% for human) to rat LEP503 gene in the exon 1 that contains an open reading frame coding for a protein of 61 amino acid residues with a leucine-rich domain. The deduced protein sequences also show high identity (91% between mouse and rat and 77% between human and rat). Western blot shows that LEP503 is present as a specific approximately 6.9 kDa band in the water-insoluble-urea-soluble fraction of lens cortex where lens epithelium is included. Immuno-staining shows that LEP503 is localized in the epithelial cells along the entire anterior surface of rat lens. Developmentally, LEP503 is expressed at a low level at newborn, and then the expression level increases by about ten-fold around postnatal day 14 and remains at this high level for about 25 days before it drops back to the low level by postnatal day 84. These data suggest that the LEP503 may be an important lens epithelial cell gene involving the processes of epithelial cell differentiation. Copyright 2000 Academic Press.

Hyperthyroidism modifies ecto-nucleotidase activities in synaptosomes from hippocampus and cerebral cortex of rats in different phases of development.

PubMed

Bruno, Alessandra Nejar; Da Silva, Rosane Souza; Bonan, Carla Denise; Battastini, Ana Maria Oliveira; Barreto-chaves, Maria Luiza M; Sarkis, João José Freitas

2003-11-01

Here we investigate the possible effects of the hyperthyroidism on the hydrolysis of the ATP to adenosine in the synaptosomes of hippocampus, cerebral cortex and blood serum of rats in different developmental phases. Manifestations of hyperthyroidism include anxiety, nervousness, tachycardia, physical hyperactivity and weight loss amongst others. The thyroid hormones modulate a number of physiological functions in central nervous system, including development, function, expression of adenosine A(1) receptors and transport of neuromodulator adenosine. Thus, hyperthyroidism was induced in male Wistar rats (5-, 60-, 150- and 330-day old) by daily injections of L-thyroxine (T4) for 14 days. Nucleotide hydrolysis was decreased by about 14-52% in both hippocampus and cerebral cortex in 5 to 60-day-old rats. These changes were also observed in rat blood serum. In addition, in 11-month-old rats, inhibition of ADP and AMP hydrolysis persisted in the hippocampus, whereas, in cerebral cortex, an increase in AMP hydrolysis was detected. Thus, hyperthyroidism affects the extracellular nucleotides balance and adenosine production, interfering in neurotransmitter release, development and others physiological processes in different systems.

Infralimbic EphB2 Modulates Fear Extinction in Adolescent Rats.

PubMed

Cruz, Emmanuel; Soler-Cedeño, Omar; Negrón, Geovanny; Criado-Marrero, Marangelie; Chompré, Gladys; Porter, James T

2015-09-09

Adolescent rats are prone to impaired fear extinction, suggesting that mechanistic differences in extinction could exist in adolescent and adult rats. Since the infralimbic cortex (IL) is critical for fear extinction, we used PCR array technology to identify gene expression changes in IL induced by fear extinction in adolescent rats. Interestingly, the ephrin type B receptor 2 (EphB2), a tyrosine kinase receptor associated with synaptic development, was downregulated in IL after fear extinction. Consistent with the PCR array results, EphB2 levels of mRNA and protein were reduced in IL after fear extinction compared with fear conditioning, suggesting that EphB2 signaling in IL regulates fear extinction memory in adolescents. Finally, reducing EphB2 synthesis in IL with shRNA accelerated fear extinction learning in adolescent rats, but not in adult rats. These findings identify EphB2 in IL as a key regulator of fear extinction during adolescence, perhaps due to the increase in synaptic remodeling occurring during this developmental phase. Copyright © 2015 the authors 0270-6474/15/3512394-10$15.00/0.

An overview of butanol-induced developmental neurotoxicity and the potential mechanisms related to these observed effects.

PubMed

Bale, Ambuja S; Lee, Janice S

2016-01-01

The purpose of this article is to briefly review the published literature on the developmental neurotoxic effects, including potential mechanisms, of four butanols: n-butanol, sec-butanol, tert-butanol, isobutanol, and identify data gaps and research needs for evaluation of human health risks in this area. Exposure potential to these four butanols is considerable given the high production volume (>1 billion lb) of n- and tert-butanol and moderate production volumes (100-500 million lb) of sec- and isobutanol. With the impetus to derive cleaner gasoline blends, butanols are being considered for use as fuel oxygenates. Notable signs of neurotoxicity and developmental neurotoxicity have been observed in some studies where laboratory animals (rodents) were gestationally exposed to n- or tert-butanol. Mechanistic data relevant to the observed developmental neurotoxicity endpoints were also reviewed to hypothesize potential mechanisms associated with the developmental neurotoxicity outcome. Data from the related and highly characterized alcohol, ethanol, were included to examine consistencies between this compound and the four butanols. It is widely known that alcohols, including butanols, interact with several ion channels and modulate the function of these targets following both acute and chronic exposures. In addition, n- and sec-butanol have been demonstrated to inhibit fetal rat brain astroglial cell proliferation. Further, rat pups exposed to n-butanol in utero were also reported to have significant increases in brain levels of dopamine and serotonin, but decreases in serotonin levels were noted with gestational exposure to tert-butanol. tert-Butanol was reported to inhibit muscarinic receptor-stimulated phosphoinositide metabolism which has been hypothesized to be a possible target for the neurotoxic effects of ethanol during brain development. The mechanistic data for the butanols support developmental neurotoxicity that has been observed in some of the rodent studies. However, careful studies evaluating the neurobehavior of developing pups in sensitive strains, as well as characterizing the plausible mechanisms involved, need to be conducted in order to further elucidate the neurodevelopmental effects of butanols for risk evaluation. Published by Elsevier Inc.

Teratology studies in the rat.

PubMed

Leroy, Mariline; Allais, Linda

2013-01-01

The rat is the rodent species of choice for the regulatory safety testing of xenobiotics, such as medicinal products, food additives, and other chemicals. Many decades of experience and extensive data have accumulated for both general and developmental toxicology investigations in this species. The high fertility and large litter size of the rat are advantages for teratogenicity testing. The study designs are well defined in the regulatory guidelines and are relatively standardized between testing laboratories across the world. Teratology studies address maternal- and embryo-toxicity following exposure during the period of organogenesis. This chapter describes the design and conduct of a teratology study in the rat in compliance with the regulatory guidelines. The procedures for the handling and housing of the pregnant animals, the caesarean examinations and the sampling of fetuses for morphological examinations are described. The utility and design of preliminary studies and the inclusion of satellite animals in the main study for toxicokinetic sampling are discussed.

MAMMARY GLAND DEVELOPMENT AS A SENSITIVE END-POINT FOLLOWING ACUTE PERNATAL EXPOSURE TO A LOW DOSE ATRAZINE METABOLITE MIXTURE IN FEMALE LONG EVANS RATS

EPA Science Inventory

In order to characterize the potential developmental effects of atrazine (ATR) metabolites at low doses, an environmentally-based mixture (EBM) of ATR and its metabolites hydroxyatrazine, diaminochlorotriazine, deethylatrazine, and deisopropylatrazine was formulated based on surv...

PERINATAL DIMETHYLTIN EXPOSURE ALTERS SPATIAL LEARNING ABILITY IN ADULT RATS.

EPA Science Inventory

Dimethyltin (DMT) is widely used as a heat and light stabilizer in PVC and CPVC piping, and has been detected in domestic water supplies. Due to the lack of developmental neurotoxicity data on DMT, we initiated studies to evaluate long-term neurobehavioral changes in offspring fo...

Developmental exposure to a mixture of two mechanistically distinct antiandrogens results in cumulative adverse reproductive effects in adult male rats

EPA Science Inventory

Typically, toxicological studies have focused on the adverse effects from exposure to single chemicals. However, endocrine disrupting chemicals (EDCs) are detected in the environment as mixtures. Empirical evidence suggests that mixtures of EDCs with the same mechanism of action...

Developmental Exposure to Perfluorohexane Sulfonate (PFHxS) Induces Hypothyroxinemia in Rat Dams and Offspring: Examination of Thyroid Gland and Behavior

EPA Science Inventory

The developing mammalian central nervous system is dependent on thyroid hormones (TH) to control neurogenesis, differentiation and migration. In humans, low maternal serum thyroxine (T4) levels have been correlated to impaired child brain development. Perfluorinated chemicals are...

Gestational exposure to atrazine has little effect on female reproductive parameters in Sprague-Dawley (SD) rats

EPA Science Inventory

Atrazine (ATR), a commonly used herbicide, has been shown to exert reproductive effects in animals; however, most ofthese studies have focused on adult exposure. In contrast, there is limited information available on the reproductive and developmental effects of gestational expos...

PRENATAL TESTOSTERONE EXPOSURE PERMANENTLY MASCULINIZES ANOGENITAL DISTANCE, NIPPLE DEVELOPMENT, AND REPRODUCTIVE TRACT MORPHOLOGY IN FEMALE SPRAGUE-DAWLEY RATS.

EPA Science Inventory

In mammals, abnormal increases in fetal androgens disrupt normal development of the female phenotype. Due to the recent concern regarding environmental androgen-active chemicals, there is a need to identify sources of fetal androgen variation and sensitive developmental markers f...

IN VITRO EFFECTS OF BROMINATED FLAME RETARDANS ON CALCIUM BUFFERING MECHANISMS IN RAT BRAINS.

EPA Science Inventory

Polybrominated diphenyl ethers (PBDEs) are widely used as additive flame-retardants and have been detected in human blood, adipose tissue, and breast milk. Developmental and long-term exposures to these chemicals may pose a human health risk, especially to children. It has been d...

Effects of brominated flame retardants on calcium buffering mechanisms in rat brain in vitro.

EPA Science Inventory

Polybrominated diphenyl ethers (PBDEs; used as additive flame-retardants) have been detected in human blood, adipose tissue, and breast milk. Developmental and long-term exposures to these chemicals may pose a human health risk, especially to children. It has been demonstrated th...

Mechanisms of perfluoroalkyl acid (PFAA) toxicity: Involvement of peroxisome proliferator activator receptor alpha (PPAR) molecular signals.

EPA Science Inventory

Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are members of a family of environmentally persistent perfluorinated compounds and are found in the serum of wildlife and humans. PFOS and PFOA are developmentally toxic in rats and mice. Exposure in utero reduces...

75 FR 44181 - Mevinphos; Proposed Data Call-in Order for Pesticide Tolerance

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-28

... are most often collected in a study called the comparative cholinesterase assay (CCA). Since that time....1520 Processing studies Not Required 24 months (tomatoes) 870.6300 Comparative 6 months 12 months... mevinphos including: 1. A developmental neurotoxicity (DNT) study in rats (with expanded protocol to extend...

EALUATION OF COGNITIVE FUNCTION IN WEANLING RATS: A REVIEW OF METHODS SUITABLE FOR CHEMICAL SCREENING

EPA Science Inventory

Current developmental neurotoxicity (DNT) tests that are used for environmental agents call for cognitive testing around the age of weaning as well as adulthood. There are challenges associated with testing weanling rodents that are not present with testing older subjects, inclu...

NEUROBEHAVIORAL AND COGNITIVE OUTCOMES OF PERINATAL/JUVENILE EXPOSURE TO HEPTACHLOR IN RATS.

EPA Science Inventory

The developing nervous system has been identified as a potential target of pesticide exposure. Heptachlor is a cyclodiene pesticide that was widely used for many years, yet little is known regarding the developmental neurotoxicity of it and other cyclodienes. The aim of this st...

Developmental exposure to perchlorate alters synaptic transmission in hippocampus of the adult rat.

EPA Science Inventory

The Food Quality Protection Act and Safe Drinking Water Act mandate the EPA to identify potential health risks associated with chemicals that act on the endocrine system. Perchlorate, a contaminant found in food and water supplies throughout the USA, blocks iodine uptake into the...

Neurobehavioral and Thyroid Evaluations of Rats Developmentally Exposed to Tris(1,3-dichloro-2-propyl)phosphate(TDCPP)

EPA Science Inventory

TDCPP is an organophosphate flame retardant with widespread usage and documented human exposures through food, inhalation, dust ingestion, and breast milk. Findings of decreased neural proliferation in cell culture and abnormal development and altered thyroid hormones in larval z...

Concentration and persistence of tin in rat brain and blood following dibutyltin exposure during development

EPA Science Inventory

Dibutyltin (DBT), a widely used plastic stabilizer, has been detected in the environment as well as human tissues. Although teratological and developmental effects are well documented, there are no published reports of DBT effects on the developing nervous system. As part of a de...

A Review of Human Spatial Representations Computational, Neuroscience, Mathematical, Developmental, and Cognitive Psychology Considerations

DTIC Science & Technology

2000-12-18

Gallistel , 1988). Hermer and Spelke (1996) found that the young children were able to detect, remember, and use the same nongeometric information...America, 50, 637-642. Margules, J., & Gallistel , C. R. (1988). Heading in the rat: Determination by environmental shape. Animal Learning & Behavior, 16(4

NEUROBEHAVIORAL ASSESSMENT USING A FUNCTIONAL OBSERVATIONAL BATTERY AND MOTOR ACTIVITY IN RATS PERINATALLY EXPOSED TO DE-71.

EPA Science Inventory

Polybrominated Diphenyl ethers (PBDEs) have been widely used as flame retardants in a variety of commercial products. Their persistence in the environment and detection in populations throughout the world has raised concern about their toxic effects. Developmental Neurotoxic ef...

DEVELOPMENTAL EXPOSURE TO AN ENVIRONMENTAL ANDROGEN, 17 B TRENBOLONE, CAUSES REPRODUCTIVE MALFORMATIONS AND REDUCED REPRODUCTIVE OUTPUT IN FEMALE RATS

EPA Science Inventory

Recently, studies have detected environmental androgen-active chemicals in effluents from pulp mills and animal feedlot operations. One such chemical present in feedlot discharge is the growth promoter, trenbolone acetate. A primary metabolite of trenbolone acetate, 17ß trenbolon...

Effects of maternal and pre-weaning undernutrition in rat offspring: Age at reproductive senescence and intergenerational pup growth and viability

EPA Science Inventory

Maternal and/or postnatal undernutrition are widespread in human populations and are components of many experimental developmental and reproductive toxicology bio-assays. This study investigated in utero and/or pre-weaning undernutrition effects on reproductive maturation and se...

Characterization of cell types during rat liver development.

PubMed

Fiegel, Henning C; Park, Jonas J h; Lioznov, Michael V; Martin, Andreas; Jaeschke-Melli, Stefan; Kaufmann, Peter M; Fehse, Boris; Zander, Axel R; Kluth, Dietrich

2003-01-01

Hepatic stem cells have been identified in adult liver. Recently, the origin of hepatic progenitors and hepatocytes from bone marrow was demonstrated. Hematopoietic and hepatic stem cells share the markers CD 34, c-kit, and Thy1. Little is known about liver stem cells during liver development. In this study, we investigated the potential stem cell marker Thy1 and hepatocytic marker CK-18 during liver development to identify putative fetal liver stem cell candidates. Livers were harvested from embryonic and fetal day (ED) 16, ED 18, ED 20, and neonatal ED 22 stage rat fetuses from Sprague-Dawley rats. Fetal livers were digested by collagenase-DNAse solution and purified by percoll centrifugation. Magnetic cell sorting (MACS) depletion of fetal liver cells was performed using OX43 and OX44 antibodies. Cells were characterized by immunocytochemistry for Thy1, CK-18, and proliferating cell antigen Ki-67 and double labeling for Thy1 and CK-18. Thy1 expression was found at all stages of liver development before and after MACS in immunocytochemistry. Thy1 positive cells were enriched after MACS only in early developmental stages. An enrichment of CK-18 positive cells was found after MACS at all developmental stages. Cells coexpressing Thy1 and CK-18 were identified by double labeling of fetal liver cell isolates. In conclusion, hepatic progenitor cells (CK-18 positive) in fetal rat liver express Thy1. Other progenitors express only CK-18. This indicates the coexistence of different hepatic cell compartments. Isolation and further characterization of such cells is needed to demonstrate their biologic properties.

Development of the oxytalan fiber system in the periodontal space of rat incisors.

PubMed

Inoue, Kouji; Hara, Yaiko; Kuroda, Noriyuki; Sato, Tetsuji

2013-10-01

The present study clarifies developmental organization of the oxytalan fiber system in the periodontal space of both the enamel (labial) and cementum (lingual) sides of rat incisors. The number of oxytalan fibers per unit area (μm(2)) was counted in rat incisors at stages of embryonic day 20 (E20) to postnatal day 35 (P35). Oxytalan fibers in the periodontal space of the enamel side were apt to decrease in number during the postnatal period, whereas their number remained almost unchanged on the cementum side during the developmental period. When the incisor emerged through the gum at P11, thinner oxytalan fibers distributed in the apical growing periodontium of the cementum side seemed to be fused with one another to become thicker fibers as has been reported for rat molars (Inoue et al., 2012). Thus, the oxytalan fiber system in the periodontal space represented significant differences in its distributional density between the enamel and cementum sides after E23. At the stage of P35, oxytalan fibers presented significantly denser distribution in all territories of the periodontal ligament of the cementum side versus the enamel side. The present findings claim that the oxytalan fiber system might bind the tooth to the periodontal ligament and provide equilibrium of vascular system and control of blood flow in the periodontal ligament of the cementum side, while it might exclusively regulate the high level of physiologically adapted vasculature in the periodontal space of the enamel side. Copyright © 2013 Elsevier GmbH. All rights reserved.

Developmental exposure to glyphosate-based herbicide and depressive-like behavior in adult offspring: Implication of glutamate excitotoxicity and oxidative stress.

PubMed

Cattani, Daiane; Cesconetto, Patrícia Acordi; Tavares, Mauren Kruger; Parisotto, Eduardo Benedetti; De Oliveira, Paulo Alexandre; Rieg, Carla Elise Heinz; Leite, Marina Concli; Prediger, Rui Daniel Schröder; Wendt, Nestor Cubas; Razzera, Guilherme; Filho, Danilo Wilhelm; Zamoner, Ariane

2017-07-15

We have previously demonstrated that maternal exposure to glyphosate-based herbicide (GBH) leads to glutamate excitotoxicity in 15-day-old rat hippocampus. The present study was conducted in order to investigate the effects of subchronic exposure to GBH on some neurochemical and behavioral parameters in immature and adult offspring. Rats were exposed to 1% GBH in drinking water (corresponding to 0.36% of glyphosate) from gestational day 5 until postnatal day (PND)-15 or PND60. Results showed that GBH exposure during both prenatal and postnatal periods causes oxidative stress, affects cholinergic and glutamatergic neurotransmission in offspring hippocampus from immature and adult rats. The subchronic exposure to the pesticide decreased L-[ 14 C]-glutamate uptake and increased 45 Ca 2+ influx in 60-day-old rat hippocampus, suggesting a persistent glutamate excitotoxicity from developmental period (PND15) to adulthood (PND60). Moreover, GBH exposure alters the serum levels of the astrocytic protein S100B. The effects of GBH exposure were associated with oxidative stress and depressive-like behavior in offspring on PND60, as demonstrated by the prolonged immobility time and decreased time of climbing observed in forced swimming test. The mechanisms underlying the GBH-induced neurotoxicity involve the NMDA receptor activation, impairment of cholinergic transmission, astrocyte dysfunction, ERK1/2 overactivation, decreased p65 NF-κB phosphorylation, which are associated with oxidative stress and glutamate excitotoxicity. These neurochemical events may contribute, at least in part, to the depressive-like behavior observed in adult offspring. Copyright © 2017 Elsevier B.V. All rights reserved.

Developmental Changes in Sensory-Evoked Optical Intrinsic Signals in the Rat Barrel Cortex.

PubMed

Sintsov, Mikhail; Suchkov, Dmitrii; Khazipov, Rustem; Minlebaev, Marat

2017-01-01

Optical Intrinsic Signal imaging (OISi) is a powerful technique for optical brain studies. OIS mainly reflects the hemodynamic response (HR) and metabolism, but it may also involve changes in tissue light scattering (LS) caused by transient cellular swelling in the active tissue. Here, we explored the developmental features of sensory-evoked OIS in the rat barrel cortex during the first 3 months after birth. Multispectral OISi revealed that two temporally distinct components contribute to the neonatal OIS: an early phase of LS followed by a late phase of HR. The contribution of LS to the early response was also evidenced by an increase in light transmission through the active barrel. The early OIS phase correlated in time and amplitude with the sensory-evoked electrophysiological response. Application of the Modified Beer-Lambert Law (MBLL) to the OIS data revealed that HR during the early phase involved only a slight decrease in blood oxygenation without any change in blood volume. In contrast, HR during the late phase manifested an adult-like increase in blood volume and oxygenation. During development, the peak time of the delayed HR progressively shortened with age, nearly reaching the stimulus onset and overlapping with the early LS phase by the fourth postnatal week. Thus, LS contributes to the sensory-evoked OIS in the barrel cortex of rats at all ages, and it dominates the early OIS phase in neonatal rats due to delayed HR. Our results are also consistent with the delayed blood oxygen level dependent (BOLD) signal in human preterm infants.

Developmental Changes in Sensory-Evoked Optical Intrinsic Signals in the Rat Barrel Cortex

PubMed Central

Sintsov, Mikhail; Suchkov, Dmitrii; Khazipov, Rustem; Minlebaev, Marat

2017-01-01

Optical Intrinsic Signal imaging (OISi) is a powerful technique for optical brain studies. OIS mainly reflects the hemodynamic response (HR) and metabolism, but it may also involve changes in tissue light scattering (LS) caused by transient cellular swelling in the active tissue. Here, we explored the developmental features of sensory-evoked OIS in the rat barrel cortex during the first 3 months after birth. Multispectral OISi revealed that two temporally distinct components contribute to the neonatal OIS: an early phase of LS followed by a late phase of HR. The contribution of LS to the early response was also evidenced by an increase in light transmission through the active barrel. The early OIS phase correlated in time and amplitude with the sensory-evoked electrophysiological response. Application of the Modified Beer-Lambert Law (MBLL) to the OIS data revealed that HR during the early phase involved only a slight decrease in blood oxygenation without any change in blood volume. In contrast, HR during the late phase manifested an adult-like increase in blood volume and oxygenation. During development, the peak time of the delayed HR progressively shortened with age, nearly reaching the stimulus onset and overlapping with the early LS phase by the fourth postnatal week. Thus, LS contributes to the sensory-evoked OIS in the barrel cortex of rats at all ages, and it dominates the early OIS phase in neonatal rats due to delayed HR. Our results are also consistent with the delayed blood oxygen level dependent (BOLD) signal in human preterm infants. PMID:29311827

Negative visuospatial priming in isolation-reared rats: Evidence of resistance to the disruptive effects of amphetamine

PubMed Central

Amitai, Nurith; Powell, Susan; Weber, Martin; Swerdlow, Neal R.

2015-01-01

Negative visuospatial priming (NP) represents a quantifiable measure of inhibitory information processing that is disrupted in several neurodevelopmental and psychiatric disorders, including schizophrenia. We developed a novel rodent NP task to investigate mechanisms underlying NP and its role in various disorders, and to test potential therapeutics. In the present studies, we further characterized this novel paradigm by investigating whether NP is disrupted in rats reared in isolation, a developmental manipulation that produces a range of abnormalities in behavior, neurochemistry, and brain structure that mirror aspects of schizophrenia pathology. We also further explored the role of monoaminergic signaling in NP and the effects of isolation rearing by challenging both socially reared and isolation-reared rats with D-amphetamine during the NP task. Although fewer isolation-reared animals learned the complex NP task, those that learned exhibited unaffected NP compared with socially reared rats. Consistent with previous reports, D-amphetamine impaired NP and increased motor impulsivity in socially reared rats. In contrast, D-amphetamine did not affect NP or motor impulsivity in isolation-reared rats. These data confirm a monoaminergic influence on NP behavior and indicate that rats reared in isolation have altered dopaminergic sensitivity. PMID:26220402

Erythropoietin Improved Cognitive Function and Decreased Hippocampal Caspase Activity in Rat Pups after Traumatic Brain Injury

PubMed Central

Requena, Daniela F.; Block, Benjamin; Davis, Lizeth J.; Rodesch, Christopher; Casper, T. Charles; Juul, Sandra E.; Kesner, Raymond P.; Lane, Robert H.

2014-01-01

Abstract Traumatic brain injury (TBI) is a leading cause of acquired neurologic disability in children. Erythropoietin (EPO), an anti-apoptotic cytokine, improved cognitive outcome in adult rats after TBI. To our knowledge, EPO has not been studied in a developmental TBI model. Hypothesis: We hypothesized that EPO would improve cognitive outcome and increase neuron fraction in the hippocampus in 17-day-old (P17) rat pups after controlled cortical impact (CCI). Methods: EPO or vehicle was given at 1, 24, and 48 h after CCI and at post injury day (PID) 7. Cognitive outcome at PID14 was assessed using Novel Object Recognition (NOR). Hippocampal EPO levels, caspase activity, and mRNA levels of the apoptosis factors Bcl2, Bax, Bcl-xL, and Bad were measured during the first 14 days after injury. Neuron fraction and caspase activation in CA1, CA3, and DG were studied at PID2. Results: EPO normalized recognition memory after CCI. EPO blunted the increased hippocampal caspase activity induced by CCI at PID1, but not at PID2. EPO increased neuron fraction in CA3 at PID2. Brain levels of exogenous EPO appeared low relative to endogenous. Timing of EPO administration was associated with temporal changes in hippocampal mRNA levels of EPO and pro-apoptotic factors. Conclusion/Speculation: EPO improved recognition memory, increased regional hippocampal neuron fraction, and decreased caspase activity in P17 rats after CCI. We speculate that EPO improved cognitive outcome in rat pups after CCI as a result of improved neuronal survival via inhibition of caspase-dependent apoptosis early after injury. PMID:23972011

Early IGF-1 primes visual cortex maturation and accelerates developmental switch between NKCC1 and KCC2 chloride transporters in enriched animals.

PubMed

Baroncelli, Laura; Cenni, Maria Cristina; Melani, Riccardo; Deidda, Gabriele; Landi, Silvia; Narducci, Roberta; Cancedda, Laura; Maffei, Lamberto; Berardi, Nicoletta

2017-02-01

Environmental enrichment (EE) has a remarkable impact on brain development. Continuous exposure to EE from birth determines a significant acceleration of visual system maturation both at retinal and cortical levels. A pre-weaning enriched experience is sufficient to trigger the accelerated maturation of the visual system, suggesting that factors affected by EE during the first days of life might prime visual circuits towards a faster development. The search for such factors is crucial not only to gain a better understanding of the molecular hierarchy of brain development but also to identify molecular pathways amenable to be targeted to correct atypical brain developmental trajectories. Here, we showed that IGF-1 levels are increased in the visual cortex of EE rats as early as P6 and this is a crucial event for setting in motion the developmental program induced by EE. Early intracerebroventricular (i.c.v.) infusion of IGF-1 in standard rats was sufficient to mimic the action of EE on visual acuity development, whereas blocking IGF-1 signaling by i.c.v. injections of the IGF-1 receptor antagonist JB1 prevented the deployment of EE effects. Early IGF-1 decreased the ratio between the expression of NKCC1 and KCC2 cation/chloride transporters, and the reversal potential for GABA A R-driven Cl - currents (E Cl ) was shifted toward more negative potentials, indicating that IGF-1 is a crucial factor in accelerating the maturation of GABAergic neurotransmission and promoting the developmental switch of GABA polarity from excitation to inhibition. In addition, early IGF-1 promoted a later occurring increase in its own expression, suggesting a priming effect of early IGF-1 in driving post-weaning cortical maturation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Maternal dietary free or bound fructose diversely influence developmental programming of lipogenesis.

PubMed

Yuruk, Armagan Aytug; Nergiz-Unal, Reyhan

2017-12-01

Maternal dietary choices throughout preconception, pregnancy, and lactation irreversibly affect the development of fetal tissues and organs, known as fetal programming. Recommendations tend to emphasize reducing added sugars. However, the impact of maternal dietary free or bound fructose in added sugars on developmental programming of lipogenesis is unknown. Virgin Sprague-Dawley rats were randomly divided into five groups. Rats were given feed and plain water (control) or water containing maltodextrin (vehicle), fructose, high-fructose corn syrup (HFCS) containing 55% fructose, sucrose (20% w/v) for 12 weeks before mating and throughout the pregnancy and lactation periods. Body weight, water, and feed intake were measured throughout the study. At the end of the lactation period, blood was drawn to determine the fasting levels of glucose, insulin, triglycerides, and non-esterified fatty acids (NEFA) in blood. Triglycerides and acetyl Co-A Carboxylase-1 (ACC1) levels in livers were analyzed, and insulin resistance was calculated. The energy intake of dams in the HFCS group was higher than in the fructose group, while weight gain was less in the HFCS group than in the fructose group. HFCS resulted in greater insulin resistance in dams, whereas free fructose had a robust effect on the fetal programming of insulin resistance. Free fructose and HFCS in the maternal diet increased blood and liver triglycerides and NEFA content in pups. Furthermore, fructose and HFCS exposure increased phosphorylated ACC1 as compared to maltodextrin and control, indicating greater fatty acid synthesis in pups and dams. Different types of added sugar in the maternal diet have different metabolic effects on the developmental programming of lipogenesis. Consequently, high fructose intake via processed foods may increase the risk for chronic diseases, and free fructose might contribute to developmental programming of chronic diseases more than bound fructose.

Developmental toxicity evaluation of Bendectin in CD rats.

PubMed

Tyl, R W; Price, C J; Marr, M C; Kimmel, C A

1988-06-01

Bendectin, composed of doxylamine succinate and pyridoxine HCl (1:1), is an antinauseant previously prescribed for nausea and vomiting during pregnancy. The present study examined the maternal and developmental effects of Bendectin (0, 200, 500, or 800 mg/kg/day, po) administered to timed-pregnant CD rats (36-41/group) during organogenesis (gestational days [gd] 6-15). At death (gd 20), all live fetuses were examined for external, visceral, and skeletal abnormalities. At 500 and 800 mg/kg/day, maternal toxicity included reduced food consumption during treatment and for the gestation period, increased water consumption in the posttreatment period, reduced weight gain during treatment, and sedation; water consumption was reduced during treatment and for the gestation period, and maternal mortality (17.1%) was observed only at the high dose. Developmental toxicity included reduced prenatal viability (800 mg/kg/day) and reduced fetal body weight/litter (500 and 800 mg/kg/day). In addition, reduced ossification of metacarpals (800 mg/kg/day), phalanges of the forelimbs (500 and 800 mg/kg/day), and of caudal vertebral centra (all doses) was observed. No increase in percent malformed live fetuses/litter was observed. The proportion of litters with one or more malformed fetuses was higher than vehicle controls only at 800 mg/kg/day, with short 13th rib (to which the test species is predisposed) as the predominant observation. By contrast, a positive control agent (nitrofen, 50 mg/kg/day, po, 14 dams) produced 85% malformed fetuses/litter with the predominant malformation being diaphragmatic hernia. In conclusion, the incidence of litters with one or more malformed fetuses was increased only at a dose of Bendectin which produced maternal mortality (17.1%) and other indices of maternal and developmental toxicity (see Discussion).

Developmental lead exposure induces opposite effects on ethanol intake and locomotion in response to central vs. systemic cyanamide administration.

PubMed

Mattalloni, Mara Soledad; Deza-Ponzio, Romina; Albrecht, Paula Alejandra; Cancela, Liliana Marina; Virgolini, Miriam Beatriz

2017-02-01

Lead (Pb) is a developmental neurotoxicant that elicits differential responses to drugs of abuse. Particularly, ethanol consumption has been demonstrated to be increased as a consequence of environmental Pb exposure, with catalase (CAT) and brain acetaldehyde (ACD, the first metabolite of ethanol) playing a role. The present study sought to interfere with ethanol metabolism by inhibiting ALDH2 (mitochondrial aldehyde dehydrogenase) activity in both liver and brain from control and Pb-exposed rats as a strategy to accumulate ACD, a substance that plays a major role in the drug's reinforcing and/or aversive effects. To evaluate the impact on a 2-h chronic voluntary ethanol intake test, developmentally Pb-exposed and control rats were administered with cyanamide (CY, an ALDH inhibitor) either systemically or intracerebroventricularly (i.c.v.) on the last 4 sessions of the experiment. Furthermore, on the last session and after locomotor activity was assessed, all animals were sacrificed to obtain brain and liver samples for ALDH2 and CAT activity determination. Systemic CY administration reduced the elevated ethanol intake already reported in the Pb-exposed animals (but not in the controls) accompanied by liver (but not brain) ALDH2 inactivation. On the other hand, a 0.3 mg i.c.v. CY administration enhanced both ethanol intake and locomotor activity accompanied by brain ALDH2 inactivation in control animals, while an increase in ethanol consumption was also observed in the Pb-exposed group, although in the absence of brain ALDH2 blockade. No changes were observed in CAT activity as a consequence of CY administration. These results support the participation of liver and brain ACD in ethanol intake and locomotor activity, responses that are modulated by developmental Pb exposure. Copyright © 2016 Elsevier Inc. All rights reserved.

Sexually dimorphic effects of postnatal treatment on the development of activity-based anorexia in adolescent and adult rats.

PubMed

Hancock, Stephanie D; Grant, Virginia L

2009-12-01

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is a marked feature of anorexia nervosa. Using a modified version of the activity-based animal model of anorexia nervosa, we examine whether factors known to affect HPA axis activity influence the development of activity-based anorexia (ABA). Male and female rats were subjected to maternal separation or handling procedures during the first two postnatal weeks and tested in a mild version of the ABA paradigm, comprised of 2-hr daily running wheel access followed by 1-hr food access, either in adolescence or adulthood. Compared to handled females, maternally separated females demonstrated greater increases in wheel running and a more pronounced running-induced suppression of food intake during adolescence, but not in adulthood. In contrast, it was only in adulthood that wheel running produced more prolonged anorexic effects in maternally separated than in handled males. These findings highlight the interplay between early postnatal treatment, sex of the animal, and developmental age on running, food intake, and rate of body weight loss in a mild version of the ABA paradigm.

Neonatal isolation delays the developmental decline of long-term depression in the CA1 region of rat hippocampus.

PubMed

Ku, Hsiao-Yun; Huang, Yu-Fei; Chao, Pei-Hsuan; Huang, Chiung-Chun; Hsu, Kuei-Sen

2008-11-01

Activity-dependent alterations of synaptic efficacy or connectivity are essential for the development, signal processing, and learning and memory functions of the nervous system. It was observed that, in particular in the CA1 region of the hippocampus, low-frequency stimulation (LFS) became progressively less effective at inducing long-term depression (LTD) with advancing developmental age. The physiological factors regulating this developmental plasticity change, however, have not yet been elucidated. Here we examined the hypothesis that neonatal isolation (once per day for 1 h from postnatal days 1-7) is able to alter processes underlying the developmental decline of LTD. We confirm that the magnitude of LTD induced by LFS (900 stimuli at 1 Hz) protocol correlates negatively with developmental age and illustrates that neonatal isolation delays this developmental decline via the activation of corticotrophin-releasing factor (CRF) system. Furthermore, this modulation appears to be mediated by an increased transcription of N-methyl-D-aspartate receptor NR2B subunits. We also demonstrate that intracerebroventricular injection of CRF postnatally mimicked the effect of neonatal isolation to increase the expression of NR2B subunits and delayed the developmental decline of LTD, which was specifically blocked by CRF receptor 1 antagonist NBI27914 pretreatment. These results suggest a novel role for CRF in regulating developmental events in the hippocampus and indicate that although maternal deprivation is stressful for neonate, appropriate neonatal isolation can serve to promote an endocrine state that may regulate the gradual developmental change in the induction rules for synaptic plasticity in the hippocampal CA1 region.

Concerns about the widespread use of rodent models for human risk assessments of endocrine disruptors

PubMed Central

Habert, René; Muczynski, Vincent; Grisin, Tiphany; Moison, Delphine; Messiaen, Sébastien; Frydman, René; Benachi, Alexandra; Delbes, Géraldine; Lambrot, Romain; Lehraiki, Abdelali; N'Tumba-Byn, Thierry; Guerquin, Marie-Justine; Levacher, Christine; Rouiller-Fabre, Virginie; Livera, Gabriel

2014-01-01

Fetal testis is a major target of endocrine disruptors (EDs). During the last 20 years, we have developed an organotypic culture system that maintains the function of the different fetal testis cell types and have used this approach as a toxicological test to evaluate the effects of various compounds on gametogenesis and steroidogenesis in rat, mouse and human testes. We named this test rat, mouse and human fetal testis assay. With this approach, we compared the effects of six potential EDs ((mono-(2-ethylhexyl) phthalate (MEHP), cadmium, depleted uranium, diethylstilboestrol (DES), bisphenol A (BPA) and metformin) and one signalling molecule (retinoic acid (RA)) on the function of rat, mouse and human fetal testis at a comparable developmental stage. We found that the response is similar in humans and rodents for only one third of our analyses. For instance, RA and MEHP have similar negative effects on gametogenesis in the three species. For another third of our analyses, the threshold efficient concentrations that disturb gametogenesis and/or steroidogenesis differ as a function of the species. For instance, BPA and metformin have similar negative effects on steroidogenesis in human and rodents, but at different threshold doses. For the last third of our analyses, the qualitative response is species specific. For instance, MEHP and DES affect steroidogenesis in rodents, but not in human fetal testis. These species differences raise concerns about the extrapolation of data obtained in rodents to human health risk assessment and highlight the need of rigorous comparisons of the effects in human and rodent models, when assessing ED risk. PMID:24497529

The abrupt development of adult-like grid cell firing in the medial entorhinal cortex

PubMed Central

Wills, Thomas J.; Barry, Caswell; Cacucci, Francesca

2012-01-01

Understanding the development of the neural circuits subserving specific cognitive functions such as navigation remains a central problem in neuroscience. Here, we characterize the development of grid cells in the medial entorhinal cortex, which, by nature of their regularly spaced firing fields, are thought to provide a distance metric to the hippocampal neural representation of space. Grid cells emerge at the time of weaning in the rat, at around 3 weeks of age. We investigated whether grid cells in young rats are functionally equivalent to those observed in the adult as soon as they appear, or if instead they follow a gradual developmental trajectory. We find that, from the very youngest ages at which reproducible grid firing is observed (postnatal day 19): grid cells display adult-like firing fields that tessellate to form a coherent map of the local environment; that this map is universal, maintaining its internal structure across different environments; and that grid cells in young rats, as in adults, also encode a representation of direction and speed. To further investigate the developmental processes leading up to the appearance of grid cells, we present data from individual medial entorhinal cortex cells recorded across more than 1 day, spanning the period before and after the grid firing pattern emerged. We find that increasing spatial stability of firing was correlated with increasing gridness. PMID:22557949

Developmental toxic effects of N-ethyl-2-pyrrolidone administered orally to rats.

PubMed

Saillenfait, A M; Gallissot, F; Sabaté, J P

2007-01-01

The developmental toxicity of N-ethyl-2-pyrrolidone (NEP) was studied in Sprague-Dawley rats after oral administration. Pregnant rats were given NEP at doses of 0 (distilled water), 50, 250, 500 and 750 mg kg(-1) day(-1), by gavage (5 ml kg(-1)), on gestational days (GD) 6-20. Maternal toxicity, as evidenced by reduction in body weight gain and food consumption, was observed in all NEP groups at the beginning of treatment (GD 6-9). The incidence of resorptions was significantly increased at 500 mg kg(-1) day(-1), and reached 83% at 750 mg kg(-1) day(-1). There was a dose-related decrease in fetal weight, which was significantly lower than control at 250 mg kg(-1) day(-1) and higher doses. The incidence of malformed fetuses per litter and the number of litters with malformed fetuses were significantly increased at 500 and 750 mg kg(-1) day(-1). Malformations mainly consisted of edema, anal atresia with absent tail, cardiovascular defects and fused cervical arches. Ossification of skull bones and sternebrae was significantly reduced at 500 and 750 mg kg(-1) day(-1). The incidence of supernumerary ribs was significantly elevated at 250 mg kg(-1) day(-1) and higher doses. In conclusion, NEP administered by gavage is embryotoxic and teratogenic at maternal toxic doses. (c) 2007 John Wiley & Sons, Ltd.

Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring.

PubMed

Boulle, Fabien; Pawluski, Jodi L; Homberg, Judith R; Machiels, Barbie; Kroeze, Yvet; Kumar, Neha; Steinbusch, Harry W M; Kenis, Gunter; van den Hove, Daniel L A

2016-04-01

A growing number of infants are exposed to selective serotonin reuptake inhibitor (SSRI) medications during the perinatal period. Perinatal exposure to SSRI medications alter neuroplasticity and increase depressive- and anxiety-related behaviors, particularly in male offspring as little work has been done in female offspring to date. The long-term effects of SSRI on development can also differ with previous exposure to prenatal stress, a model of maternal depression. Because of the limited work done on the role of developmental SSRI exposure on neurobehavioral outcomes in female offspring, the aim of the present study was to investigate how developmental fluoxetine exposure affects anxiety and depression-like behavior, as well as the regulation of hippocampal brain-derived neurotrophic factor (BDNF) signaling in the hippocampus of adult female offspring. To do this female Sprague-Dawley rat offspring were exposed to prenatal stress and fluoxetine via the dam, for a total of four groups of female offspring: 1) No Stress+Vehicle, 2) No Stress+Fluoxetine, 3) Prenatal Stress+Vehicle, and 4) Prenatal Stress+Fluoxetine. Primary results show that, in adult female offspring, developmental SSRI exposure significantly increases behavioral despair measures on the forced swim test, decreases hippocampal BDNF exon IV mRNA levels, and increases levels of the repressive histone 3 lysine 27 tri-methylated mark at the corresponding promoter. There was also a significant negative correlation between hippocampal BDNF exon IV mRNA levels and immobility in the forced swim test. No effects of prenatal stress or developmental fluoxetine exposure were seen on tests of anxiety-like behavior. This research provides important evidence for the long-term programming effects of early-life exposure to SSRIs on female offspring, particularily with regard to affect-related behaviors and their underlying molecular mechanisms. Copyright © 2016 Elsevier Inc. All rights reserved.

EFFECT OF VARYING MATERNAL FOLATE STATUS AND DIETARY FOLATE INTAKE ON RESPONSE TO DIVERSE DEVELOPMENTAL TOXICANTS IN THE RAT

EPA Science Inventory

Periconceptional and early pregnancy folate supplements are associated with reduced recurrence and occurrence of birth defects in humans. This study was undertaken to assess the influence of maternal folate status and dietary folate intake on outcome of exposures to diverse terat...

PERINATAL EXPOSURE TO POLYCHLORINATED BIPHENYLS AROCLOR 1016 OR 1254 DID NOT ALTER BRAIN CATECHOLAMINES NOR DELAYED ALTERNATION PERFORMANCE IN LONG EVANS RATS

EPA Science Inventory

Several reports have indicated that polychlorinated biphenyls (PCB) altered development of biogenic amine systems in the brain, impaired behavioral performances and disrupted maturation of the thyroid axis. The current study examines whether these developmental effects of PCB ar...

DOSE-DEPENDENT REDUCTIONS IN SPATIAL LEARING AND SYNAPTIC FUNCTION IN THE DENTATE GYRUS OF ADULT RATS FOLLOWING DEVELOPMENTAL THYROID HORMONE INSUFFICIENCY.

EPA Science Inventory

The EPA must evaluate the risk of exposure of the developing brain to chemicals with the potential to disrupt thyroid hormone homeostasis. The existing literature identifies morphological and neurochemical indices of severe neonatal hypothyroidism in the early postnatal period i...

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...

Prenatal Antidepressants and Autism Spectrum Disorder

DTIC Science & Technology

2014-09-01

citalopram, fluoxetine, bupropion, valproic acid, autism spectrum disorder, developmental disorders, prenatal effects, neurodevelopment , rat, behavior...1 AWARD NUMBER: W81XWH-13-1-0306 TITLE: Prenatal Antidepressants and Autism Spectrum Disorder PRINCIPAL INVESTIGATOR...TYPE Annual 3. DATES COVERED 1Sept 2013-31Aug2014 4. TITLE AND SUBTITLE Prenatal Antidepressants and Autism Spectrum Disorder 5a

EFFECTS ON BIRTH WEIGHT AND ADULT HEALTH IN RATS PRENATALLY EXPOSED TO TOXICANTS OR UNDERNUTRITION

EPA Science Inventory

Low fetal weight is a sensitive indicator of developmental toxicity in animal studies. While low birth weight may be permanent or transitory, the long-term effects of low birth weight on adult health have not been elucidated. Previous research has shown in humans an inverse rela...

THE EFFECT OF GESTATIONAL MERCURY VAPOR EXPOSURE ON RAT BRAIN A-SYNUCLEIN EXPRESSION.

EPA Science Inventory

Alpha-synuclein is a highly conserved protein that localizes to pre-synaptic terminals and is thought to play a role in neuronal plasticity. It is upregulated developmentally and continues to be expressed at high levels in the adult brain. Its presence in a number of neuronal (A...

75 FR 22234 - Phosphate Ester, Tallowamine, Ethoxylated; Exemption from the Requirement of a Tolerance

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-28

.../Developmental Toxicity Screening Test, clinical signs of toxicity (abnormal respiratory sounds, dyspnea... the AAPs are carcinogenic. The Agency used a qualitative structure activity relationship (QSAR... = 10x MOE = 300 in rats (MRID FQPA SF = 3x 47600707) (10% Dermal absorption; LOAEL = 200 mg/kg/day 100...

Developmental toxicity of mixtures: the water disinfection by-products dichloro-, dibromo- and bromochloro acetic acid in rat embryo culture

EPA Science Inventory

The chlorination of drinking water results in production of numerous disinfection by-products (DBPs). One of the important classes of DBPs is the haloacetic acids. We have previously shown that the haloacetic acids (HAs), dichloro (DCA), dibromo (DBA) and bromochloro (BCA) acetic...

EFFECTS OF DEVELOPMENTAL EXPOSURE TO THE POLYCHLORINATED BIPHENYL CONGENER 153 ON AUDITORY AND MOTOR FUNCTION.

EPA Science Inventory

Polychlorinated biphenyls (PCBs) are pervasive environmental contaminants that have been shown to detrimentally affect somatic and behavioral endpoints. In the present study, primiparous Long-Evans rats were exposed to 0, 1, 5, 20 or 60mg/kg/day PCB153 via oral gavage from Gesta...

DEVELOPMENTAL EXPOSURE TO POLYBROMINATED DIPHENYL ETHERS DOES IMPAIRS SYNAPTIC TRANSMISSION AND LTP IN HIPPOCAMPUS.

EPA Science Inventory

Polybrominated diphenyl ether (PBDE) flame retardants bioaccumulate in wildlife and in humans and reduce circulating levels of thyroxine (T4). The present work examined hippocampal function in adult offspring of LE rats treated daily by oral gavage with 0, 30 or 100 mg/kg of a ...

IN VITRO EFFECTS OF ENVIRONMENTALLY RELEVANT POLYBROMINATED DIPHENYL ETHER (PBDE) CONGENERS ON CALCIUM BUFFERING MECHANISMS IN RAT BRAIN

EPA Science Inventory

Polybrominated diphenyl ethers (PBDEs) are widely used as additive flame-retardants and have been detected in human blood, adipose tissue, and breast milk. Developmental and long-term exposures to these chemicals may pose a human health risk, especially to children. We have previ...

NEURONS COMPRISING A HETEROTOPIA INDUCED BY DEVELOPMENTAL HYPOTHYROIDISM ARE BORN LATE IN GESTATION.

EPA Science Inventory

We previously described an abnormal cluster of neurons, a heterotopia, located in the corpus callosum in rat pups born to dams exposed to the goitrogen, propylthiouracil (PTU, Goodman et al., SfN 2004). In this study we determined 1) whether the formation of the heterotopia was u...

DEVELOPMENTAL EXPOSURE TO DI-N-BUTYL PHTHALATE AFFECTS CORD ORGANIZATION AND SERTOLI CELL-GONOCYTE INTERACTIONS IN THE FETAL RAT TESTIS. (R830766)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...