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The massive use of herbicides, particularly glyphosate‐based herbicides (GBHs), raises several worries, notably their neurotoxic effects. Several studies have explored the consequences of developmental exposure. Our work aims to determine the impact of maternal exposure to GBH on behavioral disorders and memory deficits, as well as the involvement of oxidative stress in the hippocampus and prefrontal cortex. In addition, our study explores the neuroprotective properties of melatonin in male and female offspring. Pregnant Wistar rats were injected with GBH 75 mg/kg during gestation and lactation. After weaning, the offspring were treated with melatonin (4 mg/kg) from postnatal days 30–58. Our results show that GBH increases anxiety‐like behavior levels in offspring, as well as depression‐like behavior. GBH also impairs working memory in progeny. While markers of oxidative stress show a disturbance in lipid peroxidation and catalase activity, with a more pronounced effect in females, on the other hand, melatonin considerably attenuated the neurotoxic impact observed in the offspring, with higher efficacy in females. The oxidative stress results confirm the antioxidant power of melatonin to counteract the damaging effects of exposure to environmental contaminants such as glyphosate‐based pesticides. It will then be interesting to further our work to fully understand the sex‐dependent effect of melatonin. [ABSTRACT FROM AUTHOR]

Bisphenol S (BPS), one of the substitutes for bisphenol A (BPA), is widely used in various commodities. The BPS concentrations in surface water have gradually increased in recent years, making it a predominant bisphenol analogue in the aquatic environment and raising concerns about its health and ecological effects on aquatic organisms. For this study, we conducted a 96 h acute toxicity test and a 15-day developmental exposure test to assess the adverse effects of BPS exposure in Chinese medaka (Oryzias sinensis), a new local aquatic animal model. The results indicate that the acute exposure of Chinese medaka embryos to BPS led to relatively low toxicity. However, developmental exposure to BPS was found to cause developmental abnormalities, such as decreased hatching rate and body length, at 15 dpf. A transcriptome analysis showed that exposure to different concentrations of bisphenol S often induced different reactions. In summary, environmental concentrations of BPS can have adverse effects on the hatching and physical development of Chinese medaka, and further attention needs to be paid to the potential toxicity of environmental BPS. [ABSTRACT FROM AUTHOR]

Studies have established associations between environmental and occupational manganese (Mn) exposure and executive and motor function deficits in children, adolescents, and adults. These health risks from elevated Mn exposure underscore the need for effective exposure biomarkers to improve exposure classification and help detect/diagnose Mn-related impairments. Here, neonate rats were orally exposed to 0, 25, or 50 mg Mn/kg/day during early life (PND 1-21) or lifelong through ∼ PND 500 to determine the relationship between oral Mn exposure and blood, brain, and bone Mn levels over the lifespan, whether Mn accumulates in bone, and whether elevated bone Mn altered the local atomic and mineral structure of bone, or its biomechanical properties. Additionally, we assessed levels of bone Mn compared to bone lead (Pb) in aged humans (age 41-91) living in regions impacted by historic industrial ferromanganese activity. The animal studies show that blood, brain, and bone Mn levels naturally decrease across the lifespan without elevated Mn exposure. With elevated exposure, bone Mn levels were strongly associated with blood Mn levels, bone Mn was more sensitive to elevated exposures than blood or brain Mn, and Mn did not accumulate with lifelong elevated exposure. Elevated early life Mn exposure caused some changes in bone mineral properties, including altered local atomic structure of hydroxyapatite, along with some biomechanical changes in bone stiffness in weanlings or young adult animals. In aged humans, blood Mn ranged from 5.4 to 23.5 ng/mL; bone Mn was universally low, and decreased with age, but did not vary based on sex or female parity history. Unlike Pb, bone Mn showed no evidence of accumulation over the lifespan, and may not be a biomarker of cumulative long-term exposure. Thus, bone may be a useful biomarker of recent ongoing Mn exposure in humans, and may be a relatively minor target of elevated exposure.

Polybrominated diphenyl ethers (PBDEs) are ubiquitous persistent organic pollutants (POPs) that are known neuroendocrine disrupting chemicals with adverse neurodevelopmental effects. PBDEs may act as risk factors for autism spectrum disorders (ASD), characterized by abnormal psychosocial functioning, although direct evidence is currently lacking. Using a translational exposure model, we tested the hypothesis that maternal transfer of a commercial mixture of PBDEs, DE-71, produces ASD-relevant behavioral and neurochemical deficits in female offspring. C57Bl6/N mouse dams (F0) were exposed to DE-71 via oral administration of 0 (VEH/CON), 0.1 (L-DE-71) or 0.4 (H-DE-71) mg/kg bw/d from 3 wk prior to gestation through end of lactation. Mass spectrometry analysis indicated in utero and lactational transfer of PBDEs (in ppb) to F1 female offspring brain tissue at postnatal day (PND) 15 which was reduced by PND 110. Neurobehavioral testing of social novelty preference (SNP) and social recognition memory (SRM) revealed that adult L-DE-71 F1 offspring display deficient short- and long-term SRM, in the absence of reduced sociability, and increased repetitive behavior. These effects were concomitant with reduced olfactory discrimination of social odors. Additionally, L-DE-71 exposure also altered short-term novel object recognition memory but not anxiety or depressive-like behavior. Moreover, F1 L-DE-71 displayed downregulated mRNA transcripts for oxytocin (Oxt) in the bed nucleus of the stria terminalis (BNST) and supraoptic nucleus, and vasopressin (Avp) in the BNST and upregulated Avp1ar in BNST, and Oxtr in the paraventricular nucleus. Our work demonstrates that developmental PBDE exposure produces ASD-relevant neurochemical, olfactory processing and behavioral phenotypes that may result from early neurodevelopmental reprogramming within central social and memory networks.

Polybrominated diphenyl ethers (PBDEs) are ubiquitous persistent organic pollutants (POPs) that are known neuroendocrine disrupting chemicals with adverse neurodevelopmental effects. PBDEs may act as risk factors for autism spectrum disorders (ASD), characterized by abnormal psychosocial functioning, although direct evidence is currently lacking. Using a translational exposure model, we tested the hypothesis that maternal transfer of a commercial mixture of PBDEs, DE-71, produces ASD-relevant behavioral and neurochemical deficits in female offspring. C57Bl6/N mouse dams (F0) were exposed to DE-71 via oral administration of 0 (VEH/CON), 0.1 (L-DE-71) or 0.4 (H-DE-71) mg/kg bw/d from 3 wk prior to gestation through end of lactation. Mass spectrometry analysis indicated in utero and lactational transfer of PBDEs (in ppb) to F1 female offspring brain tissue at postnatal day (PND) 15 which was reduced by PND 110. Neurobehavioral testing of social novelty preference (SNP) and social recognition memory (SRM) revealed that adult L-DE-71 F1 offspring display deficient short- and long-term SRM, in the absence of reduced sociability, and increased repetitive behavior. These effects were concomitant with reduced olfactory discrimination of social odors. Additionally, L-DE-71 exposure also altered short-term novel object recognition memory but not anxiety or depressive-like behavior. Moreover, F1 L-DE-71 displayed downregulated mRNA transcripts for oxytocin (Oxt) in the bed nucleus of the stria terminalis (BNST) and supraoptic nucleus, and vasopressin (Avp) in the BNST and upregulated Avp1ar in BNST, and Oxtr in the paraventricular nucleus. Our work demonstrates that developmental PBDE exposure produces ASD-relevant neurochemical, olfactory processing and behavioral phenotypes that may result from early neurodevelopmental reprogramming within central social and memory networks.

Concerns have been raised regarding the potential adverse health effects of the ubiquitous herbicide glyphosate. Here, we investigated long-term effects of developmental exposure to a glyphosate-based herbicide (GBH) by analyzing serum melatonin levels and cellular changes in the striatum of adult male rats (90 days old). Pregnant and lactating rats were exposed to 3% GBH (0.36% glyphosate) through drinking water from gestational day 5 to postnatal day 15. The offspring showed reduced serum melatonin levels (43%) at the adult age compared with the control group. The perinatal exposure to GBH also induced long-term oxidative stress-related changes in the striatum demonstrated by increased lipid peroxidation (45%) and DNA/RNA oxidation (39%) together with increased protein levels of the antioxidant enzymes, superoxide dismutase (SOD1, 24%), glutamate–cysteine ligase (GCLC, 58%), and glutathione peroxidase 1 (GPx1, 31%). Moreover, perinatal GBH exposure significantly increased the total number of neurons (20%) and tyrosine hydroxylase (TH)-positive neurons (38%) in the adult striatum. Mechanistic in vitro studies with primary rat pinealocytes exposed to 50 µM glyphosate demonstrated a decreased melatonin secretion partially through activation of metabotropic glutamate receptor 3 (mGluR3), while higher glyphosate levels (100 or 500 µM) also reduced the pinealocyte viability. Since decreased levels of the important antioxidant and neuroprotector melatonin have been associated with an increased risk of developing neurodegenerative disorders, this demonstrates the need to consider the melatonin hormone system as a central endocrine-related target of glyphosate and other environmental contaminants. [ABSTRACT FROM AUTHOR]

Studies have reported associations between environmental manganese (Mn) exposure and impaired cognition, attention, impulse control, and fine motor function in children. Our recent rodent studies established that elevated Mn exposure causes these impairments. Here, rats were exposed orally to 0, 25, or 50 mg Mn kg-1  day-1 during early postnatal life (PND 1-21) or lifelong to determine whether early life Mn exposure causes heightened behavioral reactivity in the open field, lasting changes in the catecholaminergic systems in the medial prefrontal cortex (mPFC), altered dendritic spine density, and whether lifelong exposure exacerbates these effects. We also assessed astrocyte reactivity (glial fibrillary acidic protein, GFAP), and astrocyte complement C3 and S100A10 protein levels as markers of A1 proinflammatory or A2 anti-inflammatory reactive astrocytes. Postnatal Mn exposure caused heightened behavioral reactivity during the first 5-10 min intervals of daily open field test sessions, consistent with impairments in arousal regulation. Mn exposure reduced the evoked release of norepinephrine (NE) and caused decreased protein levels of tyrosine hydroxylase (TH), dopamine (DA) and NE transporters, and DA D1 receptors, along with increased DA D2 receptors. Mn also caused a lasting increase in reactive astrocytes (GFAP) exhibiting increased A1 and A2 phenotypes, with a greater induction of the A1 proinflammatory phenotype. These results demonstrate that early life Mn exposure causes broad lasting hypofunctioning of the mPFC catecholaminergic systems, consistent with the impaired arousal regulation, attention, impulse control, and fine motor function reported in these animals, suggesting that mPFC catecholaminergic dysfunction may underlie similar impairments reported in Mn-exposed children.

Air pollution (AirPoll) accelerates human aging, as assessed by increased adult mortality and earlier onset of cardiovascular diseases, and dementia. Socio-economic strata (SES) of wealth and education have parallel differences of mortality and these diseases. Children from impoverished homes differ in brain development at birth and in risk of early fat excess and hypertension. To further enhance the healthspan, biogerontologists may consider a wider range of environmental exposures from gestation through later life morbidity that comprise the Gero-Exposome. Experimental studies with rodents and nematodes document shared transcriptional responses to AirPoll. In rodents, AirPoll exposure activates gene systems for body-wide detoxification through Nrf2 and NFkB transcription factors that mediate multiple aging processes. Gestational environmental factors include maternal diet and exposure to AirPoll and cigarette smoke. Correspondingly, gestational exposure of mice to AirPoll increased adult body fat, impaired glucose clearance, and decreased adult neurogenesis in the hippocampus, a brain region damaged in dementia. Nematode larvae also respond to AirPoll with Alzheimer relevant responses. These experimental approaches could identify to interventions for expanded human health and longevity across SES gradients.

Mercury is a widespread pollutant of increasing global concern that exhibits a broad range of deleterious effects on organisms, including birds. Because the developing brain is well-known to be particularly vulnerable to the neurotoxic insults of mercury, many studies have focused on developmental effects such as on the embryonic brain and resulting behavioral impairment in adults. It is not well understood how the timing of exposure, for example exclusively in ovo versus throughout life, influences the impact of mercury. Using dietary exposure to environmentally relevant methylmercury concentrations, we examined the role that timing and duration of exposure play on spatial learning and memory in a model songbird species, the domesticated zebra finch (Taeniopygia guttata castanotis). We hypothesized that developmental exposure was both necessary and sufficient to disrupt spatial memory in adult finches. We documented profound disruption of memory for locations of hidden food at two spatial scales, cage- and room-sized enclosures, but found that both developmental and ongoing adult exposure were required to exhibit this behavioral impairment. Methylmercury-exposed birds made more mistakes before mastering the spatial task, because they revisited unrewarded locations repeatedly even after discovering the rewarded location. Contrary to our prediction, hippocampal volume was not affected in birds exposed to methylmercury over their lifetimes. The disruption of spatial cognition that we detected is severe and would likely have implications for survival and reproduction in wild birds; however, it appears that individuals that disperse or migrate from a contaminated site might recover later in life if no longer exposed to the toxicant.

As wildfire frequency and severity increases, smoke exposures will cause increasingly more adverse respiratory effects. While acute respiratory effects of smoke exposure have been documented in children, longer term sequelae are largely unstudied. Our objective here was to examine the association between gestational and postnatal exposure to wildfire smoke and prolonged use of prescription medication for respiratory conditions in early childhood. Using Merative MarketScan claims data, we created cohorts of term children born in western states between 1 January 2010–31 December 2014 followed for at least three years. Using NOAA Hazard Mapping System data, we determined the average number of days a week that >25% of the population in a metropolitan statistical area (MSA) was covered by smoke within each exposure period. The exposure periods were defined by trimester and two 12 week postnatal periods. Medication use was based on respiratory indication (upper respiratory, lower respiratory, or any respiratory condition) and categorized into outcomes of prolonged use (⩾30 d use) (PU) and multiple prolonged uses (at least two prolonged uses) (MPU). We used logistic regression models with random intercepts for MSAs adjusted for child sex, birth season, and birth year. Associations differed by exposure period and respiratory outcome, with elevated risk of MPU of lower respiratory medications following exposure in the third trimester and the first 12 postnatal weeks (RR 1.15, 95% CI 0.98, 1.35; RR 1.21, 95% CI 1.05, 1.40, respectively). Exposure in the third trimester was associated with an increase in MPU of any respiratory among males infants only (male RR 1.22, 95% CI 1.00, 1.50; female RR 0.93, 95% CI 0.66, 1.31). Through novel use of prescription claims data, this work identifies critical developmental windows in the 3rd trimester and first 12 postnatal weeks during which environmental inhalational disaster events may impact longer-term respiratory health.

Gender is viewed by many as strictly binary based on a collection of body traits typical of a female or male phenotype, presence of a genotype that includes at least one copy of a Y chromosome, or ability to produce either egg or sperm cells. A growing non-binary view is that these descriptors, while compelling, may nonetheless fail to accurately capture an individual's true gender. The position of the American Psychological Association (APA) agrees with this view and is that transgender people are a defendable and real part of the human population. The considerable diversity of transgender expression then argues against any unitary or simple explanations, however, prenatal hormone levels, genetic influences, and early and later life experiences have been suggested as playing roles in development of transgender identities. The present review considers existing and emerging toxicologic data that may also support an environmental chemical contribution to some transgender identities, and suggest the possibility of a growing nonbinary brain gender continuum in the human population. [ABSTRACT FROM AUTHOR]

Per- and polyfluoroalkyl substances (PFAS) comprise a diverse class of chemicals used in industrial processes, consumer products, and fire-fighting foams which have become environmental pollutants of concern due to their persistence, ubiquity, and associations with adverse human health outcomes, including in pregnant persons and their offspring. Multiple PFAS are associated with adverse liver outcomes in adult humans and toxicological models, but effects on the developing liver are not fully described. Here we performed transcriptomic analyses in the mouse to investigate the molecular mechanisms of hepatic toxicity in the dam and its fetus after exposure to two different PFAS, perfluorooctanoic acid (PFOA) and its replacement, hexafluoropropylene oxide-dimer acid (HFPO-DA, known as GenX). Pregnant CD-1 mice were exposed via oral gavage from embryonic day (E) 1.5–17.5 to PFOA (0, 1, or 5 mg/kg-d) or GenX (0, 2, or 10 mg/kg-d). Maternal and fetal liver RNA was isolated (N = 5 per dose/group) and the transcriptome analyzed by Affymetrix Array. Differentially expressed genes (DEG) and differentially enriched pathways (DEP) were obtained. DEG patterns were similar in maternal liver for 5 mg/kg PFOA, 2 mg/kg GenX, and 10 mg/kg GenX (R2: 0.46–0.66). DEG patterns were similar across all 4 dose groups in fetal liver (R2: 0.59–0.81). There were more DEGs in fetal liver compared to maternal liver at the low doses for both PFOA (fetal = 69, maternal = 8) and GenX (fetal = 154, maternal = 93). Upregulated DEPs identified across all groups included Fatty Acid Metabolism, Peroxisome, Oxidative Phosphorylation, Adipogenesis, and Bile Acid Metabolism. Transcriptome-phenotype correlation analyses demonstrated > 1000 maternal liver DEGs were significantly correlated with maternal relative liver weight (R2 >0.92). These findings show shared biological pathways of liver toxicity for PFOA and GenX in maternal and fetal livers in CD-1 mice. The limited overlap in specific DEGs between the dam and fetus suggests the developing liver responds differently than the adult liver to these chemical stressors. This work helps define mechanisms of hepatic toxicity of two structurally unique PFAS and may help predict latent consequences of developmental exposure.

Concerns have been raised regarding the potential adverse health effects of the ubiquitous herbicide glyphosate. Here, we investigated long-term effects of developmental exposure to a glyphosate-based herbicide (GBH) by analyzing serum melatonin levels and cellular changes in the striatum of adult male rats (90 days old). Pregnant and lactating rats were exposed to 3% GBH (0.36% glyphosate) through drinking water from gestational day 5 to postnatal day 15. The offspring showed reduced serum melatonin levels (43%) at the adult age compared with the control group. The perinatal exposure to GBH also induced long-term oxidative stress-related changes in the striatum demonstrated by increased lipid peroxidation (45%) and DNA/RNA oxidation (39%) together with increased protein levels of the antioxidant enzymes, superoxide dismutase (SOD1, 24%), glutamate–cysteine ligase (GCLC, 58%), and glutathione peroxidase 1 (GPx1, 31%). Moreover, perinatal GBH exposure significantly increased the total number of neurons (20%) and tyrosine hydroxylase (TH)-positive neurons (38%) in the adult striatum. Mechanistic in vitro studies with primary rat pinealocytes exposed to 50 µM glyphosate demonstrated a decreased melatonin secretion partially through activation of metabotropic glutamate receptor 3 (mGluR3), while higher glyphosate levels (100 or 500 µM) also reduced the pinealocyte viability. Since decreased levels of the important antioxidant and neuroprotector melatonin have been associated with an increased risk of developing neurodegenerative disorders, this demonstrates the need to consider the melatonin hormone system as a central endocrine-related target of glyphosate and other environmental contaminants.

Triphenyl phosphate (TPhP) is a flame retardant additive frequently found in consumer products and household dust. We administered 170μg of TPhP in maternal food from gestational day 8.5 to weaning and evaluated metabolic phenotypes of 3.5 month old male and female rats, and weight-matched males up to 6 months, to assess the development of obesity and type 2 diabetes mellitus (T2DM), respectively. Perinatal TPhP exposure increased body and fat mass in 3.5 month old male and female rats, while leptin and cumulative energy intake were elevated in males and females, respectively. Independent of body mass, perinatal TPhP exposure accelerated T2DM onset in males and increased plasma non-esterified- fasting fatty acids. These observations suggest that perinatal exposure to TPhP exacerbates the development of obesity in male and female UCDavis-T2DM rats and accelerates T2DM onset in male UCD-T2DM rats.

We have previously reported that the valproic acid (VPA)‐induced disruption pattern of hippocampal adult neurogenesis differs between developmental and 28‐day postpubertal exposure. In the present study, we performed brain region‐specific global gene expression profiling to compare the profiles of VPA‐induced neurotoxicity between developmental and postpubertal exposure. Offspring exposed to VPA at 0, 667, and 2000 parts per million (ppm) via maternal drinking water from gestational day 6 until weaning (postnatal day 21) were examined, along with male rats orally administered VPA at 0, 200, and 900 mg/kg body weight for 28 days starting at 5 weeks old. Four brain regions—the hippocampal dentate gyrus, corpus callosum, cerebral cortex, and cerebellar vermis—were subjected to expression microarray analysis. Profiled data suggested a region‐specific pattern of effects after developmental VPA exposure, and a common pattern of effects among brain regions after postpubertal VPA exposure. Developmental VPA exposure typically led to the altered expression of genes related to nervous system development (Msx1, Xcl1, Foxj1, Prdm16, C3, and Kif11) in the hippocampus, and those related to nervous system development (Neurod1) and gliogenesis (Notch1 and Sox9) in the corpus callosum. Postpubertal VPA exposure led to the altered expression of genes related to neuronal differentiation and projection (Cd47, Cyr61, Dbi, Adamts1, and Btg2) in multiple brain regions. These findings suggested that neurotoxic patterns of VPA might be different between developmental and postpubertal exposure, which was consistent with our previous study. Of note, the hippocampal dentate gyrus might be a sensitive target of developmental neurotoxicants after puberty. Global gene expression profiling was performed in four different brain regions in rats after developmental or postpubertal 28‐day valproic acid (VPA) exposure. Developmental VPA exposure had specific effects on each of the four brain regions, while postpubertal VPA exposure had common effects among multiple brain regions. Our results suggested that the neurotoxic pattern of VPA might differ between developmental and postpubertal exposure. They also suggested that the hippocampal dentate gyrus might be particularly vulnerable to postpubertal exposure to developmental neurotoxicants. [ABSTRACT FROM AUTHOR]

Developmental consequences of prenatal drug exposure have been reported in many human cohorts and animal studies. The long-lasting impact on the offspring—including motor and cognitive impairments, cranial and cardiac anomalies and increased prevalence of ADHD—is a socioeconomic burden worldwide. Identifying the molecular changes leading to developmental consequences could help ameliorate the deficits and limit the impact. In this study, we have used zebrafish, a well-established behavioral and genetic model with conserved drug response and reward pathways, to identify changes in behavior and cellular pathways in response to developmental exposure to amphetamine, nicotine or oxycodone. In the presence of the drug, exposed animals showed altered behavior, consistent with effects seen in mammalian systems, including impaired locomotion and altered habituation to acoustic startle. Differences in responses seen following acute and chronic exposure suggest adaptation to the presence of the drug. Transcriptomic analysis of exposed larvae revealed differential expression of numerous genes and alterations in many pathways, including those related to cell death, immunity and circadian rhythm regulation. Differential expression of circadian rhythm genes did not correlate with behavioral changes in the larvae, however, two of the circadian genes, arntl2 and per2, were also differentially expressed at later stages of development, suggesting a long-lasting impact of developmental exposures on circadian gene expression. The immediate-early genes, egr1, egr4, fosab, and junbb, which are associated with synaptic plasticity, were downregulated by all three drugs and in situ hybridization showed that the expression for all four genes was reduced across all neuroanatomical regions, including brain regions implicated in reward processing, addiction and other psychiatric conditions. We anticipate that these early changes in gene expression in response to drug exposure are likely to contribute to the consequences of prenatal exposure and their discovery might pave the way to therapeutic intervention to ameliorate the long-lasting deficits.

Developmental consequences of prenatal drug exposure have been reported in many human cohorts and animal studies. The long-lasting impact on the offspring—including motor and cognitive impairments, cranial and cardiac anomalies and increased prevalence of ADHD—is a socioeconomic burden worldwide. Identifying the molecular changes leading to developmental consequences could help ameliorate the deficits and limit the impact. In this study, we have used zebrafish, a well-established behavioral and genetic model with conserved drug response and reward pathways, to identify changes in behavior and cellular pathways in response to developmental exposure to amphetamine, nicotine or oxycodone. In the presence of the drug, exposed animals showed altered behavior, consistent with effects seen in mammalian systems, including impaired locomotion and altered habituation to acoustic startle. Differences in responses seen following acute and chronic exposure suggest adaptation to the presence of the drug. Transcriptomic analysis of exposed larvae revealed differential expression of numerous genes and alterations in many pathways, including those related to cell death, immunity and circadian rhythm regulation. Differential expression of circadian rhythm genes did not correlate with behavioral changes in the larvae, however, two of the circadian genes, arntl2 and per2 , were also differentially expressed at later stages of development, suggesting a long-lasting impact of developmental exposures on circadian gene expression. The immediate-early genes, egr1, egr4, fosab , and junbb , which are associated with synaptic plasticity, were downregulated by all three drugs and in situ hybridization showed that the expression for all four genes was reduced across all neuroanatomical regions, including brain regions implicated in reward processing, addiction and other psychiatric conditions. We anticipate that these early changes in gene expression in response to drug exposure are likely to contribute to the consequences of prenatal exposure and their discovery might pave the way to therapeutic intervention to ameliorate the long-lasting deficits. [ABSTRACT FROM AUTHOR]

• Developmental exposure to corn and soybean oils alters body weight in offspring mice. • It impaired locomotor activity, motor coordination and spatial memory. • It induced depression-like and anxiety-like behavior in exposed mice. • It disrupted brain antioxidant enzyme activities in both sexes. Corn and soybean oils are among the most frequently used vehicles for water-insoluble compounds in toxicological studies. These two vegetable oils are nutrients and may induce some biological effects on animals that might interfere with the experimental results. However, their chronic effects on a developing brain have not been reported. This study aims to evaluate the neurobehavioral and brain biochemical effects of both oils on male and female Swiss albino mice. Pregnant female mice were exposed to 1 µl/g/d of either tap water, corn oil (CO), or soybean oil (SO) from early gestation (GD1) until weaning then offspring mice were exposed to the same treatment regimen until adulthood (PND70). Our results showed that developmental exposure to both oils induced body weight changes in offspring mice. In addition, we detected some behavioral abnormalities where both oil-treated groups showed a significant decrease in locomotor activity and greater levels of anxiety behavior. Moreover, our results suggest that continuous exposure to these oils may alter motor coordination, spatial memory and induce depression-like behavior in adult mice. These alterations were accompanied by increased malondialdehyde, superoxide dismutase, and glutathione peroxidase activities in specific brain regions. Together, these data suggest that exposure to CO and SO as vehicles in developmental studies may interfere with the behavioral response and brain redox homeostasis in offspring mice. [ABSTRACT FROM AUTHOR]

Environmental and genetic risk factors, and their interactions, contribute significantly to the etiology of neurodevelopmental disorders (NDDs). Recent epidemiology studies have implicated pyrethroid pesticides as an environmental risk factor for autism and developmental delay. Our previous research showed that low-dose developmental exposure to the pyrethroid pesticide deltamethrin in mice caused male-biased changes in the brain and in NDD-relevant behaviors in adulthood. Here, we used a metabolomics approach to determine the broadest possible set of metabolic changes in the adult male mouse brain caused by low-dose pyrethroid exposure during development. Using a litter-based design, we exposed mouse dams during pregnancy and lactation to deltamethrin (3 mg/kg or vehicle every 3 days) at a concentration well below the EPA-determined benchmark dose used for regulatory guidance. We raised male offspring to adulthood and collected whole brain samples for untargeted high-resolution metabolomics analysis. Developmentally exposed mice had disruptions in 116 metabolites which clustered into pathways for folate biosynthesis, retinol metabolism, and tryptophan metabolism. As a cross-validation, we integrated metabolomics and transcriptomics data from the same samples, which confirmed previous findings of altered dopamine signaling. These results suggest that pyrethroid exposure during development leads to disruptions in metabolism in the adult brain, which may inform both prevention and therapeutic strategies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: James P. Burkett reports financial support was provided by National Institute of Environmental Health Sciences. Gary W. Miller reports financial support was provided by National Institute of Environmental Health Sciences. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Developmental toxicity and its affiliation to long-term health, particularly neurodegenerative disease (ND) has attracted significant attentions in recent years. There is, however, a significant gap in current models to track longitudinal changes arising from developmental toxicity. The advent of induced pluripotent stem cell (iPSC) derived neuronal culture has allowed for more complex and functionally active in vitro neuronal models. Coupled with recent progress in the detection of ND biomarkers, we are equipped with promising new tools to understand neurotoxicity arising from developmental exposure. This review provides a brief overview of current progress in neuronal culture derived from iPSC and in ND markers.

Developmental toxicity and its affiliation to long-term health, particularly neurodegenerative disease (ND) has attracted significant attentions in recent years. There is, however, a significant gap in current models to track longitudinal changes arising from developmental toxicity. The advent of induced pluripotent stem cell (iPSC) derived neuronal culture has allowed for more complex and functionally active in vitro neuronal models. Coupled with recent progress in the detection of ND biomarkers, we are equipped with promising new tools to understand neurotoxicity arising from developmental exposure. This review provides a brief overview of current progress in neuronal culture derived from iPSC and in ND markers. [ABSTRACT FROM AUTHOR]

• Perinatal SSRIs alter activity, stress coping, and sensory processing in rodents. • Fewer females than males are studied in regards to early SSRI exposure. • Females appear less affected by perinatal SSRIs than males. • SSRIs have the largest effects in rodents after early postnatal exposure. • More animal models of perinatal depression and SSRI use are needed. In the Western world, 2–5 % of pregnant women use selective serotonin reuptake inhibitor (SSRI) antidepressants. There is no consensus on the potential long-term neurodevelopmental outcomes of early SSRI exposure. Our aim was to determine whether there is an overall effect of perinatal SSRI exposure in animals on a spectrum of behavioral domains. After a comprehensive database search in PubMed, PsycINFO, and Web of Science, we included 99 publications. We performed nine meta-analyses and two qualitative syntheses corresponding to different behavioral categories, aggregating data from thousands of animals. We found evidence for reduced activity and exploration behavior (standardized mean difference (SMD) −0.28 [−0.38, −0.18]), more passive stress coping (SMD −0.37 [−0.52, −0.23]), and less efficient sensory processing (SMD −0.37 [−0.69, −0.06]) in SSRI- versus vehicle-exposed animals. No differences were found for anxiety (p = 0.06), social behavior, learning and memory, ingestive- and reward behavior, motoric behavior, or reflex and pain sensitivity. Exposure in the period equivalent to the human third trimester was associated with the strongest effects. [ABSTRACT FROM AUTHOR]

The development and maintenance of prostate function depend on a fine balance between oestrogen and androgen levels. Finasteride inhibits 5α‐reductase, which is responsible for the conversion of testosterone into its most active form, dihydrotestosterone. Enzymes that metabolize these hormones have a highly relevant role in both the normal prostate metabolism and in the occurrence of pathological conditions. There are few studies on the impact of finasteride on male prostate development and fewer studies on the female prostate and possible intersexual differences. Therefore, we treated male and female gerbils from 7 to 14 days in postnatal life with a high dose of finasteride (500 μg/kg/day); the prostate complexes were then removed and submitted to immunohistochemistry, immunofluorescence and three‐dimensional reconstruction. In addition, hormonal serum dosages were administered. Treatment with finasteride resulted in an increased thickness of the periductal smooth musculature in the prostate of both male and female gerbils, such as well as a reduction in the thickness of developing prostate alveoli in both sexes. In addition, intersexual differences were observed as increased epithelial proliferation and decreases in the number of developing alveoli in females. Together, the data indicate that postnatal exposure to finasteride causes greater changes in the female gerbil prostate than in the male. [ABSTRACT FROM AUTHOR]

Polystyrene nanoplastic(PS-NP) can originate from sources such as plastic waste and industrial wastewater and have been shown to have deleterious effects on abnormal neurobehaviors. However, evidence regarding the health impacts, biological mechanisms, and treatment strategies underlying developmental exposure to low dose PS-NP is still lacking. This study aimed to fill this knowledge gap by administering low doses of PS-NP(50 and 100 μg/L) to weaning rats for 4 consecutive weeks. Behavioral and morphological experiments were performed to evaluate hippocampal damage, and transcriptomics and Assay for Transposase Accessible Chromatin with hight-throughput sequencing(ATAC) analyses were conducted to identify potential key targets. Additionally, Connectivity Map(CMap) database, Limited proteolysis-mass spectrometry(LiP-SMap), and molecular-protein docking were used to examine potential phytochemicals with therapeutic effects on key targets. The results indicated that developmental exposure to PS-NP can induce hippocampal impairment and aberrant neurobehaviors in adulthood. Multi-omics analyses consistently showed that apoptosis-related signaling pathways were sensitive to PS-NP exposure, and mitogen-activated protein kinase 3(Mapk3) was identified as the core gene by the gene network, which was further validated in vitro experiments. The CMap database provided a series of phytochemicals that might regulate Mapk3 expression, and trihydroxy-phenolacetone(THP) was found to have directly binding sites with Mapk3 through LiP-SMap and molecular docking analysis. Furthermore, THP administration could significantly alleviate apoptosis induced by PS-NP exposure in primary hippocampal cells through down-regulation of Mapk3. These findings suggested that developmental exposure to PS-NP has adverse effects on cognitive function and that THP can alleviate these effects by directly binding to Mapk3. [Display omitted] • Early-life exposed to PS-NPs could deteriorate cognitive function. • CMap and LiP-Map were used to identify potential therapeutic compound, phloretin. • Mapk3 was a therapeutic target for PS-NPs-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

Trichloroethylene (TCE) is an industrial solvent and drinking water pollutant associated with CD4+ T cell-mediated autoimmunity. In our mouse model, discontinuation of TCE exposure during adulthood after developmental exposure did not prevent immunotoxicity. To determine whether persistent effects were linked to epigenetic changes we conducted whole genome reduced representation bisulfite sequencing (RRBS) to evaluate methylation of CpG sites in autosomal chromosomes in activated effector/memory CD4+ T cells. Female MRL+/+ mice were exposed to vehicle control or TCE in the drinking water from gestation until ~37 weeks of age [postnatal day (PND) 259]. In a subset of mice, TCE exposure was discontinued at ~22 weeks of age (PND 154). At PND 259, RRBS assessment revealed more global methylation changes in the continuous exposure group vs. the discontinuous exposure group. A majority of the differentially methylated CpG regions (DMRs) across promoters, islands, and regulatory elements were hypermethylated (~90%). However, continuous developmental TCE exposure altered the methylation of 274 CpG sites in promoters and CpG islands. In contrast, only 4 CpG island regions were differentially methylated (hypermethylated) in the discontinuous group. Interestingly, 2 of these 4 sites were also hypermethylated in the continuous exposure group, and both of these island regions are associated with lysine 27 on histone H3 (H3K27) involved in polycomb complex-dependent transcriptional repression via H3K27 tri-methylation. CpG sites were overlapped with the Open Regulatory Annotation database. Unlike the discontinuous group, continuous TCE treatment resulted in 129 DMRs including 12 unique transcription factors and regulatory elements; 80% of which were enriched for one or more polycomb group (PcG) protein binding regions (i.e., SUZ12, EZH2, JARID2, and MTF2). Pathway analysis of the DMRs indicated that TCE primarily altered the methylation of genes associated with regulation of cellular metabolism and cell signaling. The results demonstrated that continuous developmental exposure to TCE differentially methylated binding sites of PcG proteins in effector/memory CD4+ cells. There were minimal yet potentially biologically significant effects that occurred when exposure was discontinued. These results point toward a novel mechanism by which chronic developmental TCE exposure may alter terminally differentiated CD4+ T cell function in adulthood.

Trichloroethylene (TCE) is an industrial solvent and drinking water pollutant associated with CD4+ T cell-mediated autoimmunity. In our mouse model, discontinuation of TCE exposure during adulthood after developmental exposure did not prevent immunotoxicity. To determine whether persistent effects were linked to epigenetic changes we conducted whole genome reduced representation bisulfite sequencing (RRBS) to evaluate methylation of CpG sites in autosomal chromosomes in activated effector/memory CD4+ T cells. Female MRL+/+ mice were exposed to vehicle control or TCE in the drinking water from gestation until ~37 weeks of age [postnatal day (PND) 259]. In a subset of mice, TCE exposure was discontinued at ~22 weeks of age (PND 154). At PND 259, RRBS assessment revealed more global methylation changes in the continuous exposure group vs. the discontinuous exposure group. A majority of the differentially methylated CpG regions (DMRs) across promoters, islands, and regulatory elements were hypermethylated (~90%). However, continuous developmental TCE exposure altered the methylation of 274 CpG sites in promoters and CpG islands. In contrast, only 4 CpG island regions were differentially methylated (hypermethylated) in the discontinuous group. Interestingly, 2 of these 4 sites were also hypermethylated in the continuous exposure group, and both of these island regions are associated with lysine 27 on histone H3 (H3K27) involved in polycomb complex-dependent transcriptional repression via H3K27 tri-methylation. CpG sites were overlapped with the Open Regulatory Annotation database. Unlike the discontinuous group, continuous TCE treatment resulted in 129 DMRs including 12 unique transcription factors and regulatory elements; 80% of which were enriched for one or more polycomb group (PcG) protein binding regions (i.e., SUZ12, EZH2, JARID2, and MTF2). Pathway analysis of the DMRs indicated that TCE primarily altered the methylation of genes associated with regulation of cellular metabolism and cell signaling. The results demonstrated that continuous developmental exposure to TCE differentially methylated binding sites of PcG proteins in effector/memory CD4+ cells. There were minimal yet potentially biologically significant effects that occurred when exposure was discontinued. These results point toward a novel mechanism by which chronic developmental TCE exposure may alter terminally differentiated CD4+ T cell function in adulthood. [ABSTRACT FROM AUTHOR]

Exposure of the developing fetus to Zika virus (ZIKV) results in a set of brain abnormalities described as the congenital Zika syndrome. Although microcephaly is the most obvious outcome, neuropathologies, such as intracranial calcifications and polymicrogyria, can occur in the absence of microcephaly. Moreover, the full impact of exposure on motor, social, and cognitive skills during development remains uncharacterized. We examined the long-term neurobehavioral consequences of neonatal ZIKV exposure in four genetically divergent inbred mouse strains (C57BL/6J, 129Sl/SvImJ, FVB/NJ, and DBA/2J). Male and female mice were infected on postnatal day 1, considered comparable with exposure late in the second trimester of humans. We demonstrate strain differences in early susceptibility to the virus and the time course of glial reaction in the brain. These changes were associated with strain- and sex-dependent differences in long-term behavioral abnormalities that include hyperactivity, impulsiveness, and motor incoordination. In addition, the adult brains of susceptible mice exhibited widespread calcifications that may underlie the behavioral deficits observed. Characterization of the neuropathological sequelae of developmental exposure to the Zika virus in different immunocompetent mouse strains provides a foundation for identifying genetic and immune factors that contribute to long-term neurobehavioral consequences in susceptible individuals. [ABSTRACT FROM AUTHOR]

This study was aimed to predict bisphenol-A (BPA)-responsive miRNA's using an in silico approach and to study their expression in granulosa cells of animals exposed prenatally to BPA. Pregnant Wistar rats were exposed to BPA through water (25 µg/L, 250 µg/L, and 2.5 mg/L) during gestation. The expression of miRNA-133b, miRNA-378 and miRNA-224 were analyzed in ovarian granulosa cells. BPA affected the postnatal developmental landmarks such as weight of the pups at birth and reduced anogenital distance. BPA exposed animals showed elevated serum estradiol (E2) levels, while follicle-stimulating hormone levels were reduced. The expression of miRNA-224 and aromatase protein levels were found to be increased. This preliminary finding reveals the impact of early life exposure to BPA on the long-term ovarian functions that may be mediated through miRNA-based granulosa cell response. Besides, it is also a compelling indicator for the subclinical response that could have important consequences on female fertility. [ABSTRACT FROM AUTHOR]

Recent advances in neuroepigenetics have revealed its essential role in governing body function and disease. Epigenetics regulates an array of mechanisms that are susceptible to undergoing alteration by intracellular or extracellular factors. DNA methylation, one of the most extensively studied epigenetic markers is involved in the regulation of gene expression and also plays a vital role in neuronal development. The epigenome is most vulnerable during early the embryonic stage and perturbation in DNA methylation during this period can result in a latent outcome which can persist during the entire lifespan. Accumulating evidence suggests that environmental insults during the developmental phase can impart changes in the DNA methylation landscape. Based on reports on human subjects and animal models this review will explore the evidence on how developmental exposure of the known environmental pollutant, lead (Pb), can induce changes in the DNA methylation of genes which later can induce development of neurodegenerative disorders like Alzheimer's disease (AD). [ABSTRACT FROM AUTHOR]

Lead (Pb) exposure is reported to be unsafe for humans. There have been several studies documenting acute and chronic Pb toxicity on the organ systems. New studies suggest that early-life exposure to such environmental toxins may increase the susceptibility to late-onset degenerative disorders. We aimed to examine the long-term effects of early-life postnatal exposure of Pb on retinal degeneration. Pb exposure (200 ppm) was provided either at postnatal day 1 through lactation (early-life exposure) or at 7th week of age (adulthood exposure) directly through drinking water for 20 days. The Pb-treated mice were followed till 20 weeks of age. At 20th week, ischemia/reperfusion (I/R) injury was induced in these mice by pterygopalatine artery ligation. Further, alpha lipoic acid (ALA) was administered to examine its neuroprotective effects against retinal damage. Histological and molecular analysis revealed that Pb-treated mice had greater retinal damage after I/R injury as compared to untreated or ALA treated mice, suggesting that ALA protects the early-life Pb exposure and its consequent impact on later life. The elevated levels of glial derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) and reduced levels of glial fibrillary acidic protein (GFAP) upon ALA pre-treatment suggest that it probably exerts anti-inflammatory effects via upregulation of neurotrophic factors. [ABSTRACT FROM AUTHOR]

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

Highlights • Non-reproductive behavior was analyzed in fish developmentally exposed to EE 2. • Behavior and sex ratio were altered in exposed fish after remediation. • Induction of intersex in males was induced by 30 ng/L but not by 5 ng/L. Abstract The synthetic estrogen 17α-ethinylestradiol (EE 2), ubiquitous in the aquatic environment and commonly detected in sewage effluents, interferes with the endocrine system in multiple ways. Exposure during sensitive windows of development causes persistent effects on fertility, reproductive and non-reproductive behavior in mammals and fish. In the present study, three-spined stickleback (Gasterosteus aculeatus) were exposed to nominal 0 and 20 ng/L EE 2 from fertilization to 7 weeks post-hatch. After 8 months of remediation in clean water three non-reproductive behaviors, not previously analyzed in developmentally EE 2 -exposed progeny of wild-caught fish, were evaluated. Chemical analysis revealed that the nominal 0 and 20 ng/L exposure contained 5 and 30 ng/L EE 2, respectively. Therefore, the use of control fish from previous experiments was necessary for comparisons. Fish exposed during development showed significant concentration-dependent reduction in anxiety-like behavior in the scototaxis (light/dark preference) test by means of shorter latency to first entrance to the white compartment, more visits in white, and longer total time in white compared to unexposed fish. In the novel tank test, developmental exposure significantly increased the number of transitions to the upper half of the aquaria. Exposure to EE 2 during development did not alter shoal cohesion in the shoaling test compared with unexposed fish but fish exposed to 30 ng/L EE 2 had significantly longer latency to leave the shoal and fewer transitions away from the shoal compared to fish exposed to 5 ng/L EE 2. Skewed sex ratio with more females, sex reversal in genetic males as well as intersex in males was observed after exposure to 30, but not 5 ng/L EE 2. In conclusion, EE 2 exposure during development in three-spined stickleback resulted in persistent effects on anxiety-like behaviors. These long-term effects from developmental exposure are likely to be of higher relevance for natural populations than are short-term effects from adult exposure. [ABSTRACT FROM AUTHOR]

The notion that adverse health effects produced by exposure to environmental contaminants (EC) may be modulated by the presence of non-chemical stressors is gaining attention. Previously, our lab demonstrated that cross-fostering (adoption of a litter at birth) acted as a non-chemical stressor that amplified the influence of developmental exposure to EC on the glucocorticoid stress-response in adult rats. Using liver from the same rats, the aim of the current study was to investigate whether cross-fostering might also modulate EC-induced alterations in hepatic gene expression profiles. During pregnancy and nursing, Sprague-Dawley dams were fed cookies laced with corn oil (control, C) or a chemical mixture (M) composed of polychlorinated biphenyls (PCB), organochlorine pesticides (OCP), and methylmercury (MeHg), at 1 mg/kg/day. This mixture simulated the contaminant profile reported in maternal human blood. At birth, some control and M treated litters were cross-fostered to form two additional groups with different biological/nursing mothers (CC and MM). The hepatic transcriptome was analyzed by DNA microarray in male offspring at postnatal days 21 and 78-86. Mixture exposure altered the expression of detoxification and energy metabolism genes in both age groups, but with different sets of genes affected at day 21 and 78-86. Cross-fostering modulated the effects of M on gene expression pattern (MM vs M), as well as expression of energy metabolism genes between control groups (CC vs C). In conclusion, while describing short and long-term effects of developmental exposure to EC on hepatic transcriptomes, these cross-fostering results further support the consideration of non-chemical stressors in EC risk assessments. [ABSTRACT FROM AUTHOR]

Highlights • No major effects of low doses of BPA on male reproduction in midpubertal or adult rats were observed in the investigated endpoints. • Increased mild inflammatory cell infiltrate in epididymis was seen in adult rats exposed to 50 μg BPA/kg bw/day. • No BPA-related effects on sexual development were detected, but care should be taken due to large morphological variation in midpuberty testis. • Testis morphology was well correlated with testis weight in the 35-day-old rats. Abstract Low doses of Bisphenol A (BPA) during development may affect reproduction. In this study, Fischer 344 rats were exposed to 0.5 or 50 μg BPA/kg bw/day via drinking water from gestational day 3.5 to postnatal day 22. Anogenital distance, organ weight, histopathology of reproductive organs, hormone analysis and sperm morphology were evaluated in male offspring. In this study no major effects of BPA on male reproduction in midpubertal (postnatal day 35) or adult (12-month-old) rats were revealed, apart from a higher prevalence of mild inflammatory cell infiltrate in cauda epididymis in adult rats exposed to 50 μg BPA/kg bw/day. No BPA-related effects on sexual development were seen but care should be taken when evaluating histopathology in midpuberty testis due to large morphological variation. Results from the present study show no major signs of altered male reproduction in rats exposed to low doses of BPA during gestation and lactation. [ABSTRACT FROM AUTHOR]

Abstract: The environmental neurotoxin β‐N‐methylamino‐L‐alanine (BMAA) is a glutamate receptor agonist that can induce oxidative stress and has been implicated as a possible risk factor for neurodegenerative disease. Detection of BMAA in mussels, crustaceans, and fish illustrates that the sources of human exposure to this toxin are more abundant than previously anticipated. The aim of this study was to determine uptake of BMAA in the pineal gland and subsequent effects on melatonin production in primary pinealocyte cultures and a rat model. Autoradiographic imaging of 10‐day‐old male rats revealed a high and selective uptake in the pineal gland at 30 minutes to 24 hours after 14C‐L‐BMAA administration (0.68 mg/kg). Primary pinealocyte cultures exposed to 0.05‐3 mmol/L BMAA showed a 57%‐93% decrease in melatonin synthesis in vitro. Both the metabotropic glutamate receptor 3 (mGluR3) antagonist Ly341495 and the protein kinase C (PKC) activator phorbol‐12‐myristate‐13‐acetate prevented the decrease in melatonin secretion, suggesting that BMAA inhibits melatonin synthesis by mGluR3 activation and PKC inhibition. Serum analysis revealed a 45% decrease in melatonin concentration in neonatal rats assessed 2 weeks after BMAA administration (460 mg/kg) and confirmed an inhibition of melatonin synthesis in vivo. Given that melatonin is a most important neuroprotective molecule in the brain, the etiology of BMAA‐induced neurodegeneration may include mechanisms beyond direct excitotoxicity and oxidative stress. [ABSTRACT FROM AUTHOR]