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

Andrea M. Allan; Alexander K. Hafez; Matthew T. Labrecque; Elizabeth R. Solomon; M. Nabil Shaikh; Xianyun Zheng; Abdulmehdi Ali

doi:10.1016/j.toxrep.2015.10.003

Toxicology Reports (Jan 2015)

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

Andrea M. Allan,
Alexander K. Hafez,
Matthew T. Labrecque,
Elizabeth R. Solomon,
M. Nabil Shaikh,
Xianyun Zheng,
Abdulmehdi Ali

Affiliations

Andrea M. Allan: Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Alexander K. Hafez: Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Matthew T. Labrecque: Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Elizabeth R. Solomon: Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
M. Nabil Shaikh: Department of Civil Engineering, University of New Mexico, Albuquerque, NM 87131, USA
Xianyun Zheng: Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Abdulmehdi Ali: Department of Earth and Planetary Sciences, University of New Mexico, Albuquerque, NM 87131, USA

DOI: https://doi.org/10.1016/j.toxrep.2015.10.003
Journal volume & issue: Vol. 2, no. C
pp. 1376 – 1390

Abstract

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Previously we have shown that prenatal moderate arsenic exposure (50 ppb) disrupts glucocorticoid receptor (GR) programming and that these changes continue into adolescence in males. However, it was not clear what the molecular mechanisms were promoting these GR programming changes or if these changes occurred in arsenic-exposed females. In the present studies, we assessed the effects of arsenic on protein and mRNA of the glucocorticoid receptor (GR) and 11β-hydroxysteroid dehydrogenase (Hsd) isozymes and compared the levels of methylation within the promoters of the Nr3c1 and Hsd11b1 genes in female fetal brain at embryonic days (E) 14 and 18. Prenatal arsenate exposure produced sex specific effects on the glucocorticoid system. Compared to males, females were resistant to arsenic induced changes in GR, 11β-Hsd-1 and 11β-Hsd-2 protein levels despite observed elevations in Nr3c1 and Hsd11b2 mRNA. This sex-specific effect was not due to differences in the methylation of the GR promoter as methylation of the Nr3c1 gene was either unchanged (region containing the egr-1 binding site) or similarly reduced (region containing the SP-1 transcription factor binding site) in both males and females exposed to arsenic. Arsenic did produce sex and age-specific changes in the methylation of Hsd11b1 gene, producing increased methylation in females at E14 and decreased methylation at E18.These changes were not attributed to changes in DNMT levels. Since arsenate metabolism could interfere with the generation of methyl donor groups, we assessed glutathione (GSH), S-adenosylmethionine (SAM) and As 3 methyltransferase (As3MT). Exposed males and females had similar levels of As3MT and SAM; however, females had higher levels of GSH/GSSH. It is possible that this greater anti-oxidative capacity within the females provides protection against low to moderate arsenate. Our data suggest that the GR signaling system in female offspring was not as affected by prenatal arsenic and predicts that female arsenic-exposed mice should have normal GR feedback regulation.

Published in Toxicology Reports

ISSN: 2214-7500 (Online)
Publisher: Elsevier
Country of publisher: Ireland
LCC subjects: Medicine: Public aspects of medicine: Toxicology. Poisons
Website: http://www.journals.elsevier.com/toxicology-reports/

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