Inorganic arsenic and its methylated metabolites as endocrine disruptors in the placenta: Mechanisms underpinning glucocorticoid receptor (GR) pathway perturbations

Exposure to inorganic arsenic (iAs) is a significant public health concern with individuals around the globe exposed to harmful levels through contaminated drinking water. Exposure to iAs during pregnancy is of particular concern and has been associated with pregnancy complications and adverse child health later in life. Effects of in utero exposure may be mediated through alterations in key signaling pathways in the placenta that regulate fetal growth and development. A pathway of interest is the glucocorticoid receptor (GR)- signaling pathway, which is known to regulate fetal and placental development. While prior research has shown that iAs alters GR-associated gene expression in trophoblasts, the mechanisms that underlie these perturbations remain unknown. In the present study, we set out to elucidate the molecular mechanisms that underpin observed alterations in GR-associated gene expression. We also aimed to determine whether the methylated metabolites of iAs, namely monomethyl‑arsenic (MMA) and dimethyl‑arsenic (DMA), also influence GR-associated signaling in the placenta. The data indicate that iAs alters GR activation in a dose-dependent manner, reduces nuclear translocation, and reduces DNA binding. Additionally, the results demonstrate that MMA and DMA alter the expression of eight GR-associated genes, modulate GR activation, and alter DNA binding. These data are significant as they highlight the role of iAs as an endocrine disruptor and for the first time explore the effects of MMA and DMA on endocrine signaling in the placenta. •Arenite (iAs) significantly alters glucocorticoid receptor (GR) activity dosedose•iAs reduces nuclear translocation and DNA binding of the GR•Monomethylarsenic and dimethylarsenic are more toxic in trophoblasts vs. iAs•MMA3+ and DMA3+ alter the expression of eight GR-associated genes