Developmental exposure to inorganic arsenic has been associated with several adverse health effects, including reduction in cognitive performance and increased rates of psychiatric disorders. Altered programming of the glucocorticoid receptor (GR) could account for many of the long-lasting consequences of arsenic. While the impact of arsenic exposure on the epigenome has been studied in the context of cancer research, the influence of this toxicant in the developing brain, particularly as it relates to epigenetics, is not well understood. In our previous work, we found that male offspring exposed to 50 ppb arsenic prenatally (PAE) had decreased expression of both GR protein and mRNA in brain. Female PAE mice were resistant to arsenic induced changes in GR protein despite elevations in GR (Nr3c1) mRNA. In assessing epigenetic mechanisms, we found PAE affected levels of histone3 lysine4 trimethylation (H3K4me3) as well as several noncoding RNAs (miRs and lncRNA) in a sex-dependent manner. The goal of this competing renewal is to demonstrate that changes in transcriptional, posttranscriptional and posttranslational regulation result in PAE sex-dependent effects at a molecular, physiological and behavioral level.
Specific Aim 1 will test the hypothesis that PAE alters histone modifications that control the transcription of stress-related genes during fetal development in a sex-specific manner. We will assess histone posttranslational modifications (HPTMs), H3K4 me3/ H3K27 me3, histone writers and erasers, and associated genes by western and sequential ChIP-qPCR techniques. We will confirm a functional link by pharmacologically altering specific histone marks at embryonic day 12.5 (E12.5).
Specific Aim 2 will test the hypothesis that PAE alters the posttranscriptional regulation of stress-related mRNA levels through micro-RNAs (miRs) during fetal development in a sex- specific manner. These experiments will assess miR expression using qPCR and miR-RIP to target the GR signaling system. We will confirm a functional link using LNA microRNA mimics and LNA-antimiR at E12.5.
Specific Aim 3 will test the hypothesis that PAE alters the posttranslational regulation of stress- related proteins through long noncoding RNA (lncRNA) during fetal development in a sex- specific manner. These experiments will assess growth arrest-specific 5 (Gas-5) expression at E12-18. We will confirm a functional link to the GR system using LNA-GAPmer and LNA?antimir approaches.
Specific Aim 4 will test the mechanistic link between PAE-induced transcriptional, posttranscriptional and/or posttranslational changes and the functional outcomes in the adult animal. These experiments will assess the impact of interventions identified in Aims 1-3 on arsenic-induced deficits: corticosterone response, learning and depression.

Public Health Relevance

Arsenic is one of the most common naturally occurring contaminants found in the environment and studies have shown that it can increase cancer as well as adversely affect human cognitive development. Our studies have found that prenatal exposures to low concentrations of arsenic alter the stress response of the offspring throughout their adult life. This change in stress response may be the cause for lower cognitive performance and increased incidence of mood disorders, like depression. Our recent work has found that this damaging effect of prenatal arsenic occurs in male offspring but not female offspring. Our preliminary work indicates that arsenic mediated changes to the stress system may involve epigenetic changes that occur only in the male offspring. These current studies are designed to help determine the specific epigenetic mechanism through which arsenic produces this sex-specific damage.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Neurotoxicology and Alcohol Study Section (NAL)
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Tyson, Frederick L
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University of New Mexico Health Sciences Center
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Tyler, Christina R Steadman; Smoake, Jane J W; Solomon, Elizabeth R et al. (2018) Sex-Dependent Effects of the Histone Deacetylase Inhibitor, Sodium Valproate, on Reversal Learning After Developmental Arsenic Exposure. Front Genet 9:200
Caldwell, Kevin K; Hafez, Alexander; Solomon, Elizabeth et al. (2018) Arsenic exposure during embryonic development alters the expression of the long noncoding RNA growth arrest specific-5 (Gas5) in a sex-dependent manner. Neurotoxicol Teratol 66:102-112
Tyler, Christina R; Labrecque, Matthew T; Solomon, Elizabeth R et al. (2017) Prenatal arsenic exposure alters REST/NRSF and microRNA regulators of embryonic neural stem cell fate in a sex-dependent manner. Neurotoxicol Teratol 59:1-15
Tyler, Christina R; Hafez, Alexander K; Solomon, Elizabeth R et al. (2015) 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. Toxicol Appl Pharmacol 288:40-51
Allan, Andrea M; Hafez, Alexander K; Labrecque, Matthew T et al. (2015) Sex-Dependent effects of developmental arsenic exposure on methylation capacity and methylation regulation of the glucocorticoid receptor system in the embryonic mouse brain. Toxicol Rep 2:1376-1390
Caldwell, Katharine E; Labrecque, Matthew T; Solomon, Benjamin R et al. (2015) Prenatal arsenic exposure alters the programming of the glucocorticoid signaling system during embryonic development. Neurotoxicol Teratol 47:66-79
Tyler, Christina R; Weber, Jessica A; Labrecque, Matthew et al. (2015) ChIP-Seq analysis of the adult male mouse brain after developmental exposure to arsenic. Data Brief 5:248-54
Tyler, Christina R; Allan, Andrea M (2014) The Effects of Arsenic Exposure on Neurological and Cognitive Dysfunction in Human and Rodent Studies: A Review. Curr Environ Health Rep 1:132-147
Tyler, Christina R; Solomon, Benjamin R; Ulibarri, Adam L et al. (2014) Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism. Neurotoxicology 44:98-109
Tyler, Christina R; Allan, Andrea M (2013) Adult hippocampal neurogenesis and mRNA expression are altered by perinatal arsenic exposure in mice and restored by brief exposure to enrichment. PLoS One 8:e73720

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