Reduced expression of MAPK/ERK genes in perinatal arsenic-exposed offspring induced by glucocorticoid receptor deficits

Abstract

Changes within the glucocorticoid receptor (GR) cellular signaling pathway were evaluated in adolescent mice exposed to 50 ppb arsenic during gestation. Previously, we reported increased basal plasma corticosterone levels, decreased hippocampal GR levels and deficits in learning and memory performance in perinatal arsenic-exposed mice. The biosynthesis of members of the mitogen-activated protein kinase (MAPK) signaling pathway, known to be involved in learning and memory, is modulated by the binding of GR to glucocorticoid response elements (GREs) in the gene promoters. Two genes of the MAPK pathway, Ras and Raf, contain GREs which are activated upon binding of GRs. We evaluated the activity of GRs at Ras and Raf promoters using chromatin immunoprecipitation and real-time PCR and report decreased binding of the GR at these promoters. An ELISA-based GR binding assay was used to explore whether this decreased binding was restricted to in vivo promoters and revealed no differences in binding of native GR to synthetic GREs. The decreased in vivo GR binding coincides with significantly decreased mRNA levels and slight reductions of protein of both H-Ras and Raf-1 in perinatally arsenic-exposed mice. Nuclear activated extracellular-signal regulated kinase (ERK), a downstream target of Ras and Raf, whose transcriptional targets also play an important role in learning and memory, was decreased in the hippocampus of arsenic-exposed animals when compared to controls. GR-mediated transcriptional deficits in the MAPK/ERK pathway could be an underlying cause of previously reported learning deficits and provide the link to arsenic-induced deficiencies in cognitive development.

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

“…In utero arsenic exposure alters global DNA methylation profiles in cord blood with a greater influence in males than females (Broberg et al, 2014). Indeed, many of the changes that we observed using our developmental arsenic exposure paradigm have been demonstrated in males (Martinez-Finley et al, 2011, Goggin et al, 2012). Finally, several sex-dependent alterations in cognition and intelligence measures have been observed among males and females, suggesting that arsenic may disrupt endocrine function, possibly mediating differences observed in these studies (Vahter, 2009, Hughes et al, 2011, Kundakovic et al, 2013).…”

Inhibition of phosphodiesterase 2 reverses impaired cognition and neuronal remodeling caused by chronic stress

“…An increase of ERK1/2 phosphorylation (pERK1/2) was found after chronic stress, but it was reversed by treatment with Bay 60-7550. Phospho-ERK1/2 may mediate cellular stress by interacting with nuclear targets involved in neuronal survival and plasticity, which includes cAMP responsive element-binding protein (CREB) and other transcription factors, such as TORC1 and Elk-1 (Finkbeiner et al, 1997; Martinez-Finley et al, 2011; Kleppisch and Feil, 2009). Some transcription factors drive the expression of key plasticity-related genes, such as c-fos and Egr-1 (Flavell and Greenberg, 2008).…”

Perinatal exposure to 50 ppb sodium arsenate induces hypothalamic-pituitary-adrenal axis dysregulation in male C57BL/6 mice

“…All western blotting procedures were performed according to our established protocols (Martinez-Finley et al, 2011) with the following changes implemented: a 7 μg aliquot of total protein was separated and probed with either rabbit anti-GR (1:3,000 Santa Cruz Biotechnology, Santa Cruz, CA; #sc-1004) and a mouse anti-β-Actin (1:2,000 Sigma; #A5441-.2ML) antibody to serve as a loading control. Values are expressed as GR normalized to β-Actin.…”