Sex-dependent effects of developmental arsenic exposure on methylation capacity and methylation regulation of the glucocorticoid receptor system in the embryonic mouse brain

Allan, Andrea M.; Hafez, Alexander; Labrecque, Matthew T.; Solomon, Elizabeth R.; Shaikh, Nabil; Zheng, Xianyun; Ali, Abdul-Mehdi S.

doi:10.1016/j.toxrep.2015.10.003

Cited by 30 publications

(21 citation statements)

References 52 publications

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“…Epidemiological studies on the impact of arsenic on cognitive development in children demonstrate a significant sex difference, with females protected against arsenic’s effects ( Rosado et al, 2007 ; Tyler and Allan, 2014 ). Indeed, we have observed a resilience to arsenic exposure in the female brain counter to findings in the male brain, especially with regard to epigenetic mechanisms of action ( Allan et al, 2015 ; Tyler et al, 2015a , 2017 ). However, it is unclear if this arsenic-induced sex difference manifests as differences in behavioral flexibility, which, in part, underlies neurodegeneration.…”

Section: Introductioncontrasting

confidence: 75%

“…We have demonstrated arsenic’s impact on development of the brain, including effects on molecular pathways controlling neural stem cell differentiation that may propagate into aberrant hippocampal functioning in adulthood. We have proposed that the toxic mechanism of action of this heavy metal, particularly in the brain and among the sexes, is initiated via altered epigenetic processes ( Allan et al, 2015 ; Tyler et al, 2015b , 2017 ) and thus has the potential to be corrected using epigenetic modifiers. In the present study, we tested the hypothesis that aberrant executive functioning induced by DAE is ameliorated by administration of an epigenetic modifier and that these deficits are apparent in male but not female mice.…”

Section: Discussionmentioning

confidence: 99%

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Sex-Dependent Effects of the Histone Deacetylase Inhibitor, Sodium Valproate, on Reversal Learning After Developmental Arsenic Exposure

et al. 2018

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Several studies have demonstrated that exposure to arsenic in drinking water adversely affects brain development and cognitive function in adulthood. While the mechanism by which arsenic induces adverse neurological outcomes remains elusive, studies suggest a link between reduced levels of histone acetylation and impaired performance on a variety of behavioral tasks following arsenic exposure. Using our developmental arsenic exposure (DAE) paradigm, we have previously reported reduced histone acetylation and associated histone acetyltransferase enzyme expression in the frontal cortex of C57BL/6J adult male mice, with no changes observed in the female frontal cortex. In the present study, we sought to determine if DAE produced sex-dependent deficits in frontal cortical executive function using the Y-maze acquisition and reversal learning tasks, which are specific for assessing cognitive flexibility. Further, we tested whether the administration of valproic acid, a class I–IIa histone deacetylase inhibitor, was able to mitigate behavioral and biochemical changes resulting from DAE. As anticipated, DAE inhibited acquisition and reversal learning performance in adult male, but not female, mice. Valproate treatment for 2 weeks restored reversal performance in the male arsenic-exposed offspring, while not affecting female performance. Protein levels of HDACs 1, 2, and 5 were elevated following behavioral assessment but only in DAE male mice; restoration of appropriate HDAC levels occurred after valproate treatment and was concurrent with improved behavioral performance, particularly during reversal learning. Female frontal cortical levels of HDAC enzymes were not impacted by DAE or valproate treatment. Finally, mRNA expression levels of brain-derived neurotrophic factor, Bdnf, which has been implicated in the control of frontal cortical flexibility and is regulated by HDAC5, were elevated in DAE male mice and restored to normal levels following HDACi treatment. Levels of mRNA encoding glutamate receptor ionotropic NMDA type subunits, which have been linked to cognitive flexibility, were not related to the reversal learning deficit in the DAE mice and were not altered by HDACi treatments. These findings demonstrate that DAE alters frontal cortical HDAC levels and Bdnf expression in males, but not females, and that these molecular changes are associated with sex-dependent differences in cognitive flexibility in a reversal-learning task.

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Section: Introductioncontrasting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Sex-Dependent Effects of the Histone Deacetylase Inhibitor, Sodium Valproate, on Reversal Learning After Developmental Arsenic Exposure

et al. 2018

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“…No sex patterning in methylation was observed for As, Cd, or Hg. Previous work has shown some epigenetic patterning by sex in relation to prenatal As, Cd, and Pb exposures and DNA methylation, 26,40,50,51 though these studies reflect a heterogeneous mix of epigenome wide association studies, candidate gene examinations, and mouse models, rendering it difficult to compare our findings with published research. Thus, we suggest cautious interpretation of our sex-specific analysis and advise replication of these results.…”

Section: Discussionmentioning

confidence: 77%

“…No human studies have considered the role of neurotoxic metals as similarly disrupting NR3C1, despite the evidence linking prenatal metals exposure to a similar set of at-risk neurobehavioral phenotypes. Emerging animal work finds that prenatal arsenic exposure is associated with less Nr3c1 expression, 39 and lower levels of Nr3c1 methylation in mouse brains, 40 suggesting prenatal programming to the glucocorticoid system may be attributable in part to arsenic exposure. Among humans, 2 recent studies of pregnant women found that lead, 41 and mercury in association with psychosocial stress, 42 were concurrently associated with dysregulated maternal salivary cortisol, suggesting heavy metals may disrupt HPA function during pregnancy.…”

Section: Introductionmentioning

confidence: 99%

Prenatal exposure to neurotoxic metals is associated with increased placental glucocorticoid receptor DNA methylation

2017

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Epigenetic alterations related to prenatal neurotoxic metals exposure may be key in understanding the origins of cognitive and neurobehavioral problems in children. Placental glucocorticoid receptor (NR3C1) methylation has been linked to neurobehavioral risk in early life, but has not been examined in response to neurotoxic metals exposure despite parallel lines of research showing metals exposure and NR3C1 methylation each contribute to a similar set of neurobehavioral phenotypes. Thus, we conducted a study of prenatal neurotoxic metals exposure and placental NR3C1 methylation in a cohort of healthy term singleton pregnancies from Rhode Island, USA (n D 222). Concentrations of arsenic (As; median 0.02 ug/g), cadmium (Cd; median 0.03 mg/g), lead (Pb; median 0.40 mg/g), manganese (Mn; median 0.56 mg/g), mercury (Hg; median 0.02 mg/g), and zinc (Zn; 145.18 mg/g) measured in infant toenails were categorized as tertiles. Multivariable linear regression models tested the independent associations for each metal with NR3C1 methylation, as well as the cumulative risk of exposure to multiple metals simultaneously. Compared to the lowest exposure tertiles, higher levels of As, Cd, Pb, Mn, and Hg were each associated with increased placental NR3C1 methylation (all P<0.02). Coefficients for these associations corresponded with a 0.71-1.41 percent increase in NR3C1 methylation per tertile increase in metals concentrations. For Zn, the lowest exposure tertile compared with the highest tertile was associated with 1.26 percent increase in NR3C1 methylation (PD0.01). Higher cumulative metal risk scores were marginally associated with greater NR3C1 methylation. Taken together, these results indicate that prenatal exposure to neurotoxic metals may affect the offspring's NR3C1 activity, which may help explain cognitive and neurodevelopmental risk later in life.

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“…It should be noted that a differential response of females to environmentally-relevant arsenic exposure is not novel and therefore expected [57]. We have previously demonstrated sex-dependent effects of prenatal arsenic exposure in the embryonic and adult brain [3,59]. These data further confirm that while the female brain seems to be susceptible to arsenic exposure during the embryonic period, by adulthood, the female brain is protected, signifying a lack of prenatal programming [59].…”

Section: Discussionmentioning

confidence: 99%

Prenatal arsenic exposure alters REST/NRSF and microRNA regulators of embryonic neural stem cell fate in a sex-dependent manner

Tyler

Labrecque

Solomon

et al. 2017

Neurotoxicology and Teratology

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Exposure to arsenic, a common environmental toxin found in drinking water, leads to a host of neurological pathologies. We have previously demonstrated that developmental exposure to a low level of arsenic (50 ppb) alters epigenetic processes that underlie deficits in adult hippocampal neurogenesis leading to aberrant behavior. It is unclear if arsenic impacts the programming and regulation of embryonic neurogenesis during development when exposure occurs. The master negative regulator of neural-lineage, REST/NRSF, controls the precise timing of fate specification and differentiation of neural stem cells (NSCs). Early in development (embryonic day 14), we observed increased expression of Rest, its co-repressor, CoREST, and the inhibitory RNA binding/splicing protein, Ptbp1, and altered expression of mRNA spliced isoforms of Pbx1 that are directly regulated by these factors in the male brain in response to prenatal 50 ppb arsenic exposure. These increases were concurrent with decreased expression of microRNA-9 (miR-9), miR-9*, and miR-124, all of which are REST/NRSF targets and inversely regulate Rest expression to allow for maturation of NSCs. Exposure to arsenic decreased the formation of neuroblasts in vitro from NSCs derived from male pup brains. The female response to arsenic was limited to increased expression of CoREST and Ptbp2, an RNA binding protein that allows for appropriate splicing of genes involved in the progression of neurogenesis. These changes were accompanied by increased neuroblast formation in vitro from NSCs derived from female pups. Unexposed male mice express transcriptomic factors to induce differentiation earlier in development compared to unexposed females. Thus, arsenic exposure likely delays differentiation of NSCs in males while potentially inducing precocious differentiation in females early in development. These effects are mitigated by embryonic day 18 of development. Arsenic-induced dysregulation of the regulatory loop formed by REST/NRSF, its target microRNAs, miR-9 and miR-124, and RNA splicing proteins, PTBP1 and 2, leads to aberrant programming of NSC function that is perhaps perpetuated into adulthood inducing deficits in differentiation we have previously observed.

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Sex-dependent effects of developmental arsenic exposure on methylation capacity and methylation regulation of the glucocorticoid receptor system in the embryonic mouse brain

Cited by 30 publications

References 52 publications

Sex-Dependent Effects of the Histone Deacetylase Inhibitor, Sodium Valproate, on Reversal Learning After Developmental Arsenic Exposure

Sex-Dependent Effects of the Histone Deacetylase Inhibitor, Sodium Valproate, on Reversal Learning After Developmental Arsenic Exposure

Prenatal exposure to neurotoxic metals is associated with increased placental glucocorticoid receptor DNA methylation

Prenatal arsenic exposure alters REST/NRSF and microRNA regulators of embryonic neural stem cell fate in a sex-dependent manner

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