Single and combined exposures to bisphenol A and benzophenone-3 during early mouse pregnancy have differential effects on fetal and placental development

Abstract

Endocrine disrupting chemicals (EDCs) possess the capability to interfere with the endocrine system by binding to hormone receptors, for example on immune cells. Specific effects have already been described for individual substances, but the impact of exposure to chemical mixtures during pregnancy on maternal immune regulation, placentation and fetal development is not known. In this study, we aimed to investigate the combined effects of two widespread EDCs, bisphenol A (BPA) and benzophenone-3 (BP-3), at allowed concentrations on crucial pregnancy processes such as implantation, placentation, uterine immune cell populations and fetal growth. From gestation day (gd) 0 to gd10, female mice were exposed to 4 μg/kg/d BPA, 50 mg/kg/d BP-3 or a BPA/BP-3 mixture. High frequency ultrasound and Doppler measurements were used to determine intrauterine fetal development and hemodynamic parameters. Furthermore, uterine spiral artery remodeling and placental mRNA expression were studied via histology and CHIP-RT-PCR, respectively. Effects of EDC exposure on multiple uterine immune cell populations were investigated using flow cytometry. We found that exposure to BP-3 caused intrauterine growth restriction in offspring at gd14, while BPA and BPA/BP-3 mixture caused varying effects. Moreover, placental morphology at gd12 and placental efficiency at gd14 were altered upon BP-3 exposure. Placental gene transcription was altered particularly in female offspring after in utero exposure to BP-3. Flow cytometry analyses revealed an increase in uterine T cells and NK cells in BPA and BPA/BP-3-treated dams at gd14. Doppler measurements revealed no effect on uterine hemodynamic parameters and spiral artery remodeling was not affected following EDC exposure. Our results provide evidence that exposure to BPA and BP-3 during early gestation affects fetal development in a sex-dependent manner, placental function and immune cell frequencies at the feto-maternal interface. These results call for inclusion of studies addressing pregnancy in the risk assessment of environmental chemicals.

Keywords: Benzophenone-3; Bisphenol A; EDC; Fetal growth restriction; Placenta; Sonography; Spiral arteries; Uterine immune cells.