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
Open accessAbstract
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 has a profound effect on the epigenetic landscape, 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 (50ppb) 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 associated chromatin-modifying proteins in the dentate gyrus and frontal cortex (FC) of adult male and female mice. DAE influenced histone 3K4 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 3K9 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 leads to long-lasting changes in histone methylation and acetylation in the adult brain due to aberrant expression of epigenetic machinery based on region and sex.
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Male animals display increased H3K4me3 and H3K9ac, along with MLL upregulation and KDM5B reduction, whereas females exhibit the opposite pattern, including reduced H3K4me3 and H3K9ac and increased HDAC1/2 expression.
“Male animals display increased H3K4me3 and H3K9ac, along with MLL upregulation and KDM5B reduction, whereas females exhibit the opposite pattern, including reduced H3K4me3 and H3K9ac and increased HDAC1/2 expression (Tyler et al., 2015).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Tyler et al., 2015
The Results sections on the dentate gyrus report the claimed male increases in H3K4me3, H3K9ac, and MLL, reduced KDM5B, and female decreases in H3K4me3 and H3K9ac with increased HDAC1/2. The claim omits the brain-region qualifier: in the frontal cortex, male H3K9ac decreased, while female H3K4me3 and H3K9ac did not change. (LLM, conf=0.88)
Experimental — accuracy not yet measuredFemales exhibit minimal chromatin alterations in the prefrontal cortex.
“Females, however, exhibit minimal chromatin alterations.”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Tyler et al., 2015
Male prefrontal cortex shows increased H3K4me3 but reduced H3K9ac, accompanied by reduced expression of acetyltransferases GCN5 and PCAF, indicating impaired transcriptional activation.
“Male PFC shows increased H3K4me3 but reduced H3K9ac (Tyler et al., 2015), accompanied by reduced expression of acetyltransferases such as GCN5 and PCAF, indicating impaired transcriptional activation.”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Tyler et al., 2015
The prefrontal cortex displays a distinct and more selective pattern of chromatin alterations.
“In contrast, the prefrontal cortex (PFC) displays a distinct and more selective pattern.”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Tyler et al., 2015
Environmental exposures during development induce robust and sex-dependent chromatin alterations in the dentate gyrus.
“Environmental exposures during development similarly induce robust and sex-dependent chromatin alterations in the DG.”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Tyler et al., 2015
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- Authors
- Tyler, C. R., Hafez, A. K., Solomon, E. R., & Allan, A. M.
- Affiliations
- University of New Mexico Health Sciences Center (US)
- University of New Mexico (US)
- Corresponding author
- Allan, Andrea M.
- Venue
- Toxicology and Applied Pharmacology
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 288
- Issue
- 1
- Pages
- 40-51
- ISSN
- 0041-008X (ISSN-L)
- PMC
- PMC4579037
- OpenAlex
- W899590184
- Cited by
- 60
- References
- 64
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 4 · 2023: 2 · 2022: 7 · 2021: 4 · 2020: 7 · 2019: 6 · 2018: 2 · 2017: 9 · 2016: 8 · 2015: 3
- FWCI
- 3.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Toxicology and Applied Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Environmental Health Sciences (R01ES019583)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Physical Sciences › Environmental Science › Environmental Chemistry › Arsenic contamination and mitigation
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
- Keywords
- arsenic exposure, histone modifications, epigenetic machinery, histone H3 lysine 4 trimethylation, histone H3K9 acetylation, histone H3K9 trimethylation, MLL, KDM5B, GCN5, PCAF, HDAC1, HDAC2, dentate gyrus, frontal cortex, sex differences, brain region specificity, chromatin structure
- MeSH terms
- p300-CBP-Associated Factor, Acetylation, Age Factors, Animals, Animals, Newborn, Arsenates, Dealkylation, DNA-Binding Proteins, Female, Frontal Lobe, Gene Expression Regulation, Gestational Age, Histones, Male, Methylation, Mice, Inbred C57BL, Pregnancy, Prenatal Exposure Delayed Effects, Histone-Lysine N-Methyltransferase, Sex Factors, Water Pollutants, Chemical, Dentate Gyrus, Chromatin Assembly and Disassembly, Epigenesis, Genetic, p300-CBP Transcription Factors, Myeloid-Lymphoid Leukemia Protein, Histone Deacetylase 1, Histone Deacetylase 2, Jumonji Domain-Containing Histone Demethylases
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