Bisphenol A Exposure in utero Disrupts Hypothalamic Gene Expression Particularly Genes Suspected in Autism Spectrum Disorders and Neuron and Hormone Signaling

Abstract

Bisphenol A (BPA) is an endocrine-disrupting compound detected in the urine of more than 92% of humans, easily crosses the placental barrier, and has been shown to influence gene expression during fetal brain development. The purpose of this study was to investigate the effect of in utero BPA exposure on gene expression in the anterior hypothalamus, the basal nucleus of the stria terminalis (BNST), and hippocampus in C57BL/6 mice. Mice were exposed in utero to human-relevant doses of BPA, and then RNA sequencing was performed on male PND 28 tissue from whole hypothalamus (n = 3/group) that included the medial preoptic area (mPOA) and BNST to determine whether any genes were differentially expressed between BPA-exposed and control mice. A subset of genes was selected for further study using RT-qPCR on adult tissue from hippocampus to determine whether any differentially expressed genes (DEGs) persisted into adulthood. Two different RNA-Seq workflows indicated a total of 259 genes that were differentially expressed between BPA-exposed and control mice. Gene ontology analysis indicated that those DEGs were overrepresented in categories relating to mating, cell–cell signaling, behavior, neurodevelopment, neurogenesis, synapse formation, cognition, learning behaviors, hormone activity, and signaling receptor activity, among others. Ingenuity Pathway Analysis was used to interrogate novel gene networks and upstream regulators, indicating the top five upstream regulators as huntingtin, beta-estradiol, alpha-synuclein, Creb1, and estrogen receptor (ER)-alpha. In addition, 15 DE genes were identified that are suspected in autism spectrum disorders.