Developmental exposure to 50 parts-per-billion arsenic influences histone modifications and associated epigenetic machinery in a region- and sex-specific manner in the adult mouse brain

Abstract

Epidemiological studies report that arsenic exposure via drinking water adversely impacts cognitive development in children and, in adults, can lead to greater psychiatric disease susceptibility, among other conditions. While it is known that arsenic toxicity alters the epigenome, very few studies have investigated its effects on chromatin architecture in the brain. We have previously demonstrated that exposure to a low level of arsenic (50 ppb) during all three trimesters of fetal/neonatal development induces deficits in adult hippocampal neurogenesis in the dentate gyrus (DG), depressive-like symptoms, and alterations in gene expression in the adult mouse brain. As epigenetic processes control these outcomes, here we assess the impact of our developmental arsenic exposure (DAE) paradigm on global histone posttranslational modifications and expression of associated chromatin-modifying proteins in the dentate gyrus and frontal cortex (FC) of adult male and female mice. DAE influenced histone 3 K4 trimethylation with increased levels in the male DG and FC and decreased levels in the female DG (no change in female FC). The histone methyltransferase MLL exhibited a similar sex- and region- specific expression profile as H3K4me3 levels, while histone demethylase KDM5B expression trended in the opposite direction. DAE increased histone 3 K9 acetylation levels in the male DG along with histone acetyltransferase (HAT) expression of GCN5 and decreased H3K9ac levels in the male FC along with decreased HAT expression of GCN5 and PCAF. DAE decreased expression of histone deacetylase enzymes HDAC1 and HDAC2, which were concurrent with increased H3K9ac levels but only in the female DG. Levels of H3 and H3K9me3 were not influenced by DAE in either brain region of either sex. These findings suggest that exposure to a low, environmentally relevant level of arsenic during development induces alterations in the adult brain via histone modifications and chromatin modifiers a sex- and region-specific manner.

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

“…The catalytic domain RD2 of the protein REST interacts with CoREST, the main co-repressor of the REST/NRSF complex, that binds to the RE-1 element in neuron-specific genes; additionally, CoREST requires chromatin modifying proteins that we found are impacted by perinatal arsenic exposure in the adult brain [59]. We assessed mRNA expression of Rcor1 , the CoREST gene.…”

“…Previously, we have shown that perinatal arsenic exposure alters the epigenetic programs that control the highly orchestrated processes of adult neurogenesis leading to deficits in differentiation of adult NSCs and aberrant stress responses in the hippocampus [59–61]. However, while we have determined dysregulation of glucocorticoid signaling in the embryonic brain in response to prenatal arsenic [7], its effect on regulation of embryonic neurogenesis has not been characterized.…”

“…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].…”

“…In response to the requirements of the embryonic niche, REST interacts with the microRNAs, miR-9 and miR-124 to control switching from self-renewal of NSCs to differentiation [41,64,67]. We have previously demonstrated that our arsenic exposure paradigm alters the expression of chromatin modifications, histone-modifying proteins that associate with REST, and epigenetic regulation of genes with RE-1 motifs, in the adult brain [59,61]. Whether these epigenetic effects that occur in the adult are induced by altered developmental programming of transcriptional regulation, including REST/NRSF regulatory loops, has not been determined.…”

Epigenomic reprogramming in inorganic arsenic-mediated gene expression patterns during carcinogenesis

“…This shift in the global H3K4 methylation status occurs quickly; exposing cells to 1 μM iAs led to the changes in H3K4 methylation states in as little as 24 h (50). Furthermore, Tyler et al found that perinatal arsenic exposure resulted in changes to H3K9Ac and H3K4me3 levels in the brains of adult mice (56,57).…”