Prenatal and early postnatal NOAEL-dose clothianidin exposure leads to a reduction of germ cells in juvenile male mice.
Ontology highlight
ABSTRACT:
SUBMITTER: Yanai S
PROVIDER: S-EPMC5559363 | biostudies-other | 2017 Jul
REPOSITORIES: biostudies-other
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Project description:Prenatal cocaine exposure has been associated with numerous behavioral phenotypes in clinical populations, including impulsivity, reduced attention, alterations in social behaviors, and delayed language and sensory-motor development. Detecting associated changes in brain structure in these populations has proven difficult, and results have been inconclusive and inconsistent. Due to their more controlled designs, animal models may shed light on the neuroanatomical changes caused by prenatal cocaine; however, to maximize clinical relevance, data must be carefully collected using translational methods. The goal of this study was two-fold: (1) to determine if prenatal cocaine alters developmental neuroanatomy using methods that are available to human researchers, specifically structural MRI and diffusion tensor imaging, and (2) to determine the feasibility of rodent in vivo neuroimaging for usage in longitudinal studies of developmental disorders. Cocaine-exposed (prenatal days 1-20, 30mg/kg/day) rat pups were sedated and imaged live using diffusion tensor imaging and postmortem (fixed) using magnetic resonance histology on postnatal day 14. Volume and diffusion properties in whole brain as well as specific regions of interest were then assessed from the resulting images. Whole brain analyses revealed that cocaine-exposed animals showed no change in whole brain volume. Additionally, we found alterations in fractional anisotropy across regions associated with reward processing and emotional regulation, especially in the thalamus and globus pallidus, as well as sex-dependent effects of cocaine in the right cortex. Reductions in fractional anisotropy were paired with reductions only in axial diffusivity, which preliminarily suggests that the changes observed here may be due to axonal damage, as opposed to reductions in myelination of the affected regions/pathways. Our data indicate that prenatal cocaine may target a number of developing brain structures but does not result in overt changes to brain volumes. These results highlight not only the brain alterations that result from prenatal cocaine but also the advancements in live imaging that allow longitudinal study designs in other models.
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Project description:Perinatal infection is a well-identified risk factor for a number of neurodevelopmental disorders, including brain white matter injury (WMI) and Autism Spectrum Disorders (ASD). The underlying mechanisms by which early life inflammatory events cause aberrant neural, cytoarchitectural, and network organization, remain elusive. This study is aimed to investigate how systemic lipopolysaccharide (LPS)-induced neuroinflammation affects microglia phenotypes and early neural developmental events in rats. We show here that LPS exposure at early postnatal day 3 leads to a robust microglia activation which is characterized with mixed microglial proinflammatory (M1) and anti-inflammatory (M2) phenotypes. More specifically, we found that microglial M1 markers iNOS and MHC-II were induced at relatively low levels in a regionally restricted manner, whereas M2 markers CD206 and TGF? were strongly upregulated in a sub-set of activated microglia in multiple white and gray matter structures. This unique microglial response was associated with a marked decrease in naturally occurring apoptosis, but an increase in cell proliferation in the subventricular zone (SVZ) and the dentate gyrus (DG) of hippocampus. LPS exposure also leads to a significant increase in oligodendrocyte lineage population without causing discernible hypermyelination. Moreover, LPS-exposed rats exhibited significant impairments in communicative and cognitive functions. These findings suggest a possible role of M2-like microglial activation in abnormal neural development that may underlie ASD-like behavioral impairments.
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Project description:The extent to which postnatal methylmercury exposure contributes to neurobehavioral delays is uncertain. Confounding may occur because the child's dietary exposure likely correlates with the mother's. This conundrum was examined in the Faroese birth cohort 1 born in 1986-1987. Exposure parameters included mercury concentrations in maternal hair at parturition, cord blood, and child blood and hair at the age-7 clinical examination (N=923). In regression analyses, the child's current blood-mercury at age 7 (N=694) showed only weak associations with the neuropsychological test variables, but visuospatial memory revealed a significant negative association. Mutual adjustment caused decreases of the apparent effect of the prenatal exposure. However, such adjustment may lead to underestimations due to the presence of correlated, error-prone exposure variables. In structural equation models, all methylmercury exposure parameters were instead entered into a latent exposure variable that reflected the total methylmercury load. This latent exposure showed significant associations with neurodevelopmental deficits, with prenatal exposure providing the main information. However, postnatal methylmercury exposure appeared to contribute to neurotoxic effects, in particular in regard to visuospatial processing and memory. Thus, addition in the regression analysis of exposure information obtained at a different point in time was not informative and should be avoided. Further studies with better information on exposure profiles are needed to characterize the effects of postnatal methylmercury exposure.
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Project description:MethodsTimed-pregnant C57BL/6J mice were exposed to 2.4% nicotine in propylene glycol (PG) or 0% nicotine /PG once a day from gestational day 15 until delivery. After delivery, offspring and mothers were exposed to E-cigarette vapors for an additional 14 days from postnatal day 2 through 16. Following their last exposure serum cotinine levels were measured in female juvenile mice. Male mice underwent behavioral testing at 14 weeks of age to assess sensorimotor, affective, and cognitive functional domains.ResultsAdult male mice exposed to 2.4% nicotine/PG E-cigarette vapors had significantly more head dips in the zero maze test and higher levels of rearing activity in the open field test compared to 0% nicotine/PG exposed mice and untreated controls. In the water maze test after reversal training, the 2.4% nicotine/PG mice spent more than 25% of time in the new location whereas the other groups did not.ConclusionAdult male mice exhibited increased levels of activity in the zero maze and open field tests when exposed to E-cigarette vapor containing nicotine during late prenatal and early postnatal life. These findings indicate that nicotine exposure from E-cigarettes may cause persistent behavioral changes when exposure occurs during a period of rapid brain growth.
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Project description:Cadmium (Cd) is generally found in low concentrations in the environment due to its widespread and continual use, however, its concentration in some foods and cigarette smoke is high. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports of immunomodulatory effects of prenatal exposure to Cd. This study was designed to investigate the effects of prenatal exposure to Cd on the immune system of the offspring. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose of CdCl(2) (10ppm) and the effects on the immune system of the offspring were assessed at two time points following birth (2 and 7weeks of age). Thymocyte and splenocyte phenotypes were analyzed by flow cytometry. Prenatal Cd exposure did not affect thymocyte populations at 2 and 7weeks of age. In the spleen, the only significant effect on phenotype was a decrease in the number of macrophages in male offspring at both time points. Analysis of cytokine production by stimulated splenocytes demonstrated that prenatal Cd exposure decreased IL-2 and IL-4 production by cells from female offspring at 2weeks of age. At 7weeks of age, splenocyte IL-2 production was decreased in Cd-exposed males while IFN-? production was decreased from both male and female Cd-exposed offspring. The ability of the Cd-exposed offspring to respond to immunization with a S. pneumoniae vaccine expressing T-dependent and T-independent streptococcal antigens showed marked increases in the levels of both T-dependent and T-independent serum antibody levels compared to control animals. CD4(+)FoxP3(+)CD25(+) (nTreg) cell percentages were increased in the spleen and thymus in all Cd-exposed offspring except in the female spleen where a decrease was seen. CD8(+)CD223(+) T cells were markedly decreased in the spleens in all offspring at 7weeks of age. These findings suggest that even very low levels of Cd exposure during gestation can result in long term detrimental effects on the immune system of the offspring and these effects are to some extent sex-specific.
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Project description:Maternal viral infections can have pathological effects on the developing fetus which last long after birth. Recently, maternal-fetal transmission of respiratory syncytial virus (RSV) was shown to cause postnatal airway hyperreactivity (AHR) during primary early-life reinfection; however, the influence of prenatal exposure to RSV on offspring airway immunity and smooth muscle contractility during recurrent postnatal reinfections remains unknown. Therefore, we sought to determine whether maternal RSV infection impairs specific aspects of cell-mediated offspring immunity during early-life reinfections and the mechanisms leading to AHR. Red fluorescent protein-expressing recombinant RSV (rrRSV) was inoculated into pregnant rat dams at midterm, followed by primary and secondary postnatal rrRSV inoculations of their offspring at early-life time points. Pups and weanlings were tested for specific lower airway leukocyte populations by flow cytometry; serum cytokine/chemokine concentrations by multiplex ELISA and neurotrophins concentrations by standard ELISA; and ex vivo lower airway smooth muscle (ASM) contraction by physiological tissue bath. Pups born to RSV-infected mothers displayed elevated total CD3+ T cells largely lacking CD4+ and CD8+ surface expression after both primary and secondary postnatal rrRSV infection. Cytokine/chemokine analyses revealed reduced IFN-?, IL-2, IL-12, IL-17A, IL-18, and TNF-?, as well as elevated nerve growth factor (NGF) expression. Prenatal exposure to RSV also increased ASM reactivity and contractility during early-life rrRSV infection compared to non-exposed controls. We conclude that maternal RSV infection can predispose offspring to postnatal lower airways dysfunction by altering immunity development, NGF signaling, and ASM contraction during early-life RSV reinfections.
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Project description:Prenatal ethanol exposure increases collagen deposition and alters surfactant protein (SP) expression and immune status in lungs of near-term fetal sheep. Our objectives were to determine 1) whether these prenatal effects of repeated gestational ethanol exposure persist after birth and 2) whether surfactant phospholipid composition is altered following prenatal ethanol exposure. Pregnant ewes were chronically catheterized at 90 days of gestational age (DGA) and given a 1-h daily infusion of ethanol (0.75 g/kg, n = 9) or saline (n = 7) from 95 to 135 DGA; ethanol administration ceased after 135 DGA. Lambs were born naturally at full term (146 ± 0.5 DGA). Lung tissue was examined at 9 wk postnatal age for alterations in structure, SP expression, and inflammation; bronchoalveolar lavage fluid was examined for alterations in surfactant phospholipid composition. At 134 DGA, surfactant phospholipid concentration in amniotic fluid was significantly reduced (P < 0.05) by ethanol exposure, and the composition was altered. In postnatal lambs, there were no significant differences between treatment groups in birth weight, postnatal growth, blood gas parameters, and lung weight, volume, tissue fraction, mean linear intercept, collagen content, proinflammatory cytokine gene expression, and bronchoalveolar lavage fluid surfactant phospholipid composition. Although SP-A, SP-B, and SP-C mRNA levels were not significantly different between treatment groups, SP-D mRNA levels were significantly greater (P < 0.05) in ethanol-treated animals; as SP-D has immunomodulatory roles, innate immunity may be altered. The adverse effects of daily ethanol exposure during late gestation on the fetal lung do not persist to 2 mo after birth, indicating that the developing lung is capable of repair.
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Project description:BackgroundThe hippocampus is particularly vulnerable to the teratogenic effects of prenatal ethanol exposure (PNEE), and hippocampal structural and functional deficits are thought to contribute to the learning and memory deficits that are a hallmark feature of fetal alcohol spectrum disorders.MethodsSprague Dawley dams were exposed to a liquid diet that contained EtOH (35.5% EtOH-derived calories) throughout gestation, and then, PNEE juvenile (P21-28) male and female offspring were used for in vitro electrophysiological recordings. We examined long-term potentiation (LTP), long-term depression (LTD), and depotentiation in the medial perforant path input to the dentate gyrus (DG) to determine the impact of PNEE on the dynamic range of bidirectional synaptic plasticity in both sexes.ResultsPNEE reduced the responsiveness of the DGs of male but not in female offspring, and this effect was no longer apparent when GABAergic signaling was inhibited. There was also a sex-specific LTD impairment in males, but increasing the duration of the conditioning stimulus could overcome this deficit. The magnitude of LTP was also reduced, but in both sexes following PNEE. This appears to be an increase in the threshold for induction, not in capacity, as the level of LTP induced in PNEE animals was increased to control levels when additional conditioning stimuli were administered.ConclusionsThese data are the first to describe, in a single study, the impact of PNEE on the dynamic range of bidirectional synaptic plasticity in the juvenile DG in both males and in females. The data suggest that PNEE increases the threshold for LTP in the DG in both sexes, but produces a sex-specific increase in the threshold for LTD in males These alterations reduce the dynamic range for synaptic plasticity in both sexes.
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Project description:Human male reproductive development has a prolonged prepubertal period characterized by juvenile quiescence of germ cells with immature spermatogonial stem cell (SSC) precursors (gonocytes) present in the testis for an extended period of time. The metabolism of gonocytes is not defined. We demonstrate with mitochondrial ultrastructure studies via TEM and IHC and metabolic flux studies with UHPLC-MS that a distinct metabolic transition occurs during the maturation to SSCs. The mitochondrial ultrastructure of prepubertal human spermatogonia is shared with prepubertal pig spermatogonia. The metabolism of early prepubertal porcine spermatogonia (gonocytes) is characterized by the reliance on OXPHOS fuelled by oxidative decarboxylation of pyruvate. Interestingly, at the same time, a high amount of the consumed pyruvate is also reduced and excreted as lactate. With maturation, prepubertal spermatogonia show a metabolic shift with decreased OXHPOS and upregulation of the anaerobic metabolism-associated uncoupling protein 2 (UCP2). This shift is accompanied with stem cell specific promyelocytic leukemia zinc finger protein (PLZF) protein expression and glial cell-derived neurotropic factor (GDNF) pathway activation. Our results demonstrate that gonocytes differently from mature spermatogonia exhibit unique metabolic demands that must be attained to enable their maintenance and growth in vitro.
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Project description:ImportanceFew studies have investigated the association between the exposure window (prenatal, early postnatal, and current period) of secondhand smoke (SHS) and attention-deficit/hyperactivity disorder (ADHD) symptoms and subtypes in children.ObjectiveTo evaluate the associations of prenatal, early postnatal, or current SHS exposure with ADHD symptoms and subtypes among school-aged children.Design, setting, and participantsIn this cross-sectional study, 48 612 children aged 6 to 18 years from elementary and middle schools in Liaoning province, China, between April 2012 and January 2013 were eligible for participation. Data on SHS exposure and ADHD symptoms and subtypes for each child were collected via questionnaires administered to parents or guardians by school teachers. Data were analyzed from September 14 to December 2, 2020.Main outcomes and measuresThe ADHD symptoms and subtypes (inattention, hyperactivity-impulsivity, and combined) were measured based on a validated tool developed from the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). Generalized linear mixed models were evaluated to estimate the association of SHS exposure with ADHD symptoms and subtypes.ResultsA total of 45 562 participants completed the questionnaires and were included in this study (22 905 girls [50.3%]; mean [SD] age, 11.0 [2.6] years; 2170 [4.8%] with ADHD symptoms). Compared with their unexposed counterparts, children who were ever exposed (odds ratio [OR], 1.50; 95% CI, 1.36-1.66) or always exposed to SHS (OR, 2.88; 95% CI, 2.55-3.25) from pregnancy to childhood had higher odds of having ADHD symptoms and subtypes (ORs ranged from 1.46 [95% CI, 1.31-1.62] to 2.94 [95% CI, 2.09-4.13]). Compared with their unexposed counterparts, children with SHS exposure had higher odds of having ADHD symptoms when exposed in the prenatal period (OR, 2.28; 95% CI, 2.07-2.51), early postnatal period (OR, 1.47; 95% CI, 1.29-1.68), or current period (OR, 1.20; 95% CI, 1.09-1.31). Compared with their unexposed counterparts, children whose fathers smoked 10 or more cigarettes/d on both weekdays and weekends had higher odds of having ADHD symptoms and subtypes (ORs ranged from 1.48 [95% CI, 1.28-1.70] to 2.25 [95% CI, 1.29-3.93]).Conclusions and relevanceBeing exposed to SHS from pregnancy to childhood was associated with higher odds of having ADHD symptoms and subtypes among school-aged children, and the associations were somewhat stronger for SHS exposure during prenatal and early postnatal periods. Our findings highlight the important public health implications of reducing SHS exposure, which may decrease the health and economic burdens of individuals with ADHD.
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