Identification of Transmembrane Protease Serine 2 and Forkhead Box A1 As the Potential Bisphenol A Responsive Genes in the Neonatal Male Rat Brain.

Takayoshi Ubuka,Tomoko Soga,Shogo Moriya,Ishwar Parhar

doi:10.3389/fendo.2018.00139

Abstract

Perinatal exposure of Bisphenol A (BPA) to rodents modifies their behavior in later life. To understand how BPA modifies their neurodevelopmental process, we first searched for BPA responsive genes from androgen and estrogen receptor signaling target genes by polymerase chain reaction array in the neonatal male rat brain. We used a transgenic strain of Wistar rats carrying enhanced green fluorescent protein tagged to gonadotropin-inhibitory hormone (GnIH) promoter to investigate the possible interaction of BPA responsive genes and GnIH neurons. We found upregulation of transmembrane protease serine 2 (Tmprss2), an androgen receptor signaling target gene, and downregulation of Forkhead box A1 (Foxa1), an ER signaling target gene, in the medial amygdala of male rats that were subcutaneously administered with BPA from day 1 to 3. Tmprss2-immunoreactive (ir) cells were distributed in the olfactory bulb, cerebral cortex, hippocampus, amygdala, and hypothalamus in 3 days old but not in 1-month-old male rats. Density of Tmprss2-ir cells in the medial amygdala was increased by daily administration of BPA from day 1 to 3. Tmprss2 immunoreactivity was observed in 26.5% of GnIH neurons clustered from the ventral region of the ventromedial hypothalamic nucleus to the dorsal region of the arcuate nucleus of 3-day-old male rat hypothalamus. However, Tmprss2 mRNA expression significantly decreased in the amygdala and hypothalamus of 1-month-old male rats. Foxa1 mRNA expression was higher in the hypothalamus than the amygdala in 3 days old male rats. Intense Foxa1-ir cells were only found in the peduncular part of lateral hypothalamus of 3-day-old male rats. Density of Foxa1-ir cells in the hypothalamus was decreased by daily administration of BPA from day 1 to 3. Foxa1 mRNA expression in the hypothalamus also significantly decreased at 1 month. These results suggest that BPA disturbs the neurodevelopmental process and behavior of rats later in their life by modifying Tmprss2 and Foxa1 expressions in the brain.

Highlights

Bisphenol A (BPA) is an organic synthetic compound widely used to make polycarbonate plastics and epoxy resins utilized in reusable food and drink containers and inner lining of cans and bottles [1]
Differential expression of androgen receptor (AR) and estrogen receptor (ER) signaling target genes in the medial amygdala by BPA administration was analyzed in neonatal male rats
An AR signaling target gene, transmembrane protease serine 2 (Tmprss2) (NM_130424) was the only gene that was significantly increased in the medial amygdala of neonatal male rats by BPA treatment

Summary

Introduction

Bisphenol A (BPA) is an organic synthetic compound widely used to make polycarbonate plastics and epoxy resins utilized in reusable food and drink containers and inner lining of cans and bottles [1]. The estrogenic effect of BPA is 10,000 times less potent than estradiol-17β shown by uterine vascular permeability assay in ovariectomized mice [5]. Similar level of agonistic activity of BPA to estrogen receptor (ER) was shown in yeast expressing human estrogen or androgen receptor (AR) [6]. Stronger antagonistic activity of BPA to human AR was shown in an African monkey kidney cell line [9]. Perera et al [11] examined the association between prenatal BPA exposure and child behavior. There are numerous studies showing the effect of perinatally administered BPA on social behavior of rodents. BPA exposed males during gestation and lactation showed persistent deficits in sexual behavior in adulthood [14]

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Conclusion