Hypothalamic transcriptomic alterations in male and female California mice (Peromyscus californicus) developmentally exposed to bisphenol A or ethinyl estradiol.

Sarah A Johnson,Nathan J Bivens,Scott A Givan,Lindsey K Manshack,Cheryl S Rosenfeld,William G Spollen

doi:10.14814/phy2.13133

Abstract

Bisphenol A (BPA) is an endocrine‐disrupting chemical (EDC) prevalent in many household items. Rodent models and human epidemiological studies have linked this chemical to neurobehavior impairments. In California mice, developmental exposure to BPA results in sociosexual disorders at adulthood, including communication and biparental care deficits, behaviors that are primarily regulated by the hypothalamus. Thus, we sought to examine the transcriptomic profile in this brain region of juvenile male and female California mice offspring exposed from periconception through lactation to BPA or ethinyl estradiol (EE, estrogen present in birth control pills and considered a positive estrogen control for BPA studies). Two weeks prior to breeding, P0 females were fed a control diet, or this diet supplemented with 50 mg BPA/kg feed weight or 0.1 ppb EE, and continued on the diets through lactation. At weaning, brains from male and female offspring were collected, hypothalamic RNA isolated, and RNA‐seq analysis performed. Results indicate that BPA and EE groups clustered separately from controls with BPA and EE exposure leading to unique set of signature gene profiles. Kcnd3 was downregulated in the hypothalamus of BPA‐ and EE‐exposed females, whereas Tbl2, Topors, Kif3a, and Phactr2 were upregulated in these groups. Comparison of transcripts differentially expressed in BPA and EE groups revealed significant enrichment of gene ontology terms associated with microtubule‐based processes. Current results show that perinatal exposure to BPA or EE can result in several transcriptomic alterations, including those associated with microtubule functions, in the hypothalamus of California mice. It remains to be determined whether these genes mediate BPA‐induced behavioral disruptions.

Highlights

Exposure to endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA), may increase the risk of neurobehavioral disorders typified by social impairments, such as autism spectrum disorders
Two weeks prior to breeding, virgin females, 8–12 weeks of age were randomly assigned to receive one of three diets: (1) a low phytoestrogen AIN 93G diet supplemented with 7% by weight corn oil to minimize potential phytoestrogenic contamination that would otherwise be present with inclusion of soybean oil in the diet, (2) the same diet supplemented with 50 mg Bisphenol A (BPA)/kg feed weight, which we have documented to lead to internal serum concentrations close to those measured in pregnant women unknowingly exposed to this chemical (Jasarevic et al 2011; Sieli et al 2011), or (3) AIN93G diet supplemented with 0.1 parts per billion of EE, as the U.S Food and Drug Administration (FDA) required estrogen-positive control for BPA studies
The goals of the current study were to determine if developmental exposure through the maternal diet to BPA or EE induces global gene expression changes in the hypothalamus of juvenile California mice

Summary

Introduction

Exposure to endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA), may increase the risk of neurobehavioral disorders typified by social impairments, such as autism spectrum disorders Its stability and pervasiveness (Environment Canada, 2008) has ensured continual exposure (Vandenberg et al 2009) This chemical is detectable in the urine of 93% of the U.S population (Calafat et al 2008), as well as in fetal plasma, placenta (vom Saal et al 2007), and breast milk (Vandenberg et al 2007). This restriction fails to address transfer of BPA across the placenta and through the milk (Ikezuki et al 2002; Kawamoto et al 2007; Balakrishnan et al 2010; Nishikawa et al 2010; Vandenberg et al 2010). Fetuses and neonates lack many enzymes needed to metabolize BPA and may experience greater levels of active BPA than the mother (Ikezuki et al 2002; Kawamoto et al 2007; Nishikawa et al 2010)

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