Bisphenol a Exposure in Utero Disrupts Hypothalamic Gene Expression Particularly Genes Suspected in Autism Spectrum Disorders and Neuron and Hormone Signaling.

Anne D Henriksen,Emilie F Rissman,Erin P Harris,Jennifer T Wolstenholme,Alejandro Andrade

doi:10.3390/ijms21093129

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.

Highlights

Bisphenol A (BPA) is an endocrine-disrupting compound used in the manufacture of everyday products such as plastic water bottles, canned food linings and thermal receipts
We tested putative signaling pathways to determine whether any were persistently altered in adults following gestational BPA exposure. These studies were designed to investigate gene expression changes in the hypothalamus following gestational exposure to low-dose BPA. Since many of these gene expression changes were found to be overrepresented in categories relating to neurodevelopment, neurogenesis, synapse formation, and learning behaviors, we extended these findings to determine whether candidate gene expression effects persisted into adulthood in a brain region, the hippocampus, known for playing a role in learning and memory
RNA-Sequencing and Analysis In Experiment 1, tissue from male PND 28 offspring of dams exposed to human-relevant levels of BPA during gestation was used for RNA-sequencing analysis

Summary

Introduction

Bisphenol A (BPA) is an endocrine-disrupting compound used in the manufacture of everyday products such as plastic water bottles, canned food linings and thermal receipts. Due to its ability to leach from these products, BPA is found ubiquitously in the environment and has been detected in the urine of more than 92% of people tested [1]. BPA acts at several steroid receptors and has weak estrogenic activity at the estrogen receptor (ER)-alpha, ER-beta, and G-protein-coupled ER-1 (GPER1). It antagonizes the androgen receptor and blocks aromatase enzyme activity [2]. BPA can disrupt endocrine signaling—important for many biological functions such as growth, metabolism and reproduction—and can impact social behaviors

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