INORGANIC ARSENIC AS AN ENDOCRINE DISRUPTOR IN THE PLACENTA: IMPLICATIONS FOR THE GLUCOCORTICOID RECEPTOR SIGNALING PATHWAY

Exposure to inorganic arsenic (iAs) is a worldwide public health concern as millions of individuals may be exposed to harmful levels of inorganic arsenic through contaminated drinking water. Prenatal exposures to iAs are associated with adverse cognitive functioning, cancer, low birthweight, spontaneous abortion, and infant mortality, among others. Many of the health outcomes may be due to the fact that iAs alters key pathway that regulate fetal and placental development as posited by the Developmental Origins of Health and Disease (DOHAD). Many of these adverse health effects may be tied to altered glucocorticoid receptor (GR) signaling in the placenta as GR signaling in the placenta regulates both placental and fetal development, and dysregulation of this pathway is associated with adverse neonatal health outcomes. Previous research in non-placental cells has shown that iAs acts as a potent endocrine disruptor and dysregulates the glucocorticoid receptor (GR) pathway, while the effects of arsenic metabolites on the GR pathway have not been investigated. In this dissertation, we set out to determine if iAs induces genomic alterations of the GR pathway in cytotrophoblasts and to elucidate the molecular mechanisms by which iAs alters the GR pathway. In addition, we also explored the effects of iAs metabolites (MMA and DMA) on placental GR signaling. To investigate this, JEG-3 cytotrophoblasts were treated with non-cytotoxic, environmentally-relevant doses of iAs (0.5-3 µM), MMA, and DMA (0.05-0.25µM), for 24 hours and assessed for various molecular endpoints related to GR signaling. The findings from this study are supported by previous literature that implicates iAs acts as an endocrine disruptor and provides evidence of a novel mechanism by which prenatal iAs exposure may induce adverse birth outcomes.Doctor of Philosoph