Intrauterine combined exposure to bisphenol A and benzophenone-3 affects implantation, fetal growth and impacts on uterine innate immune cells supporting pregnancy

KRETSCHMER, TOBIAS; FISCHER, FLORENCE; SEIFERT, PAULINA; SCHUMACHER A; KASS, LAURA; RODRÍGUEZ HORACIO ADOLFO; ZENCLUSSEN, MARÍA LAURA; ZENCLUSSEN AC

Santa Fe

Congreso; 42nd Annual Meeting American Society for Reproductive Immunology; 2023

American Society for Reproductive Immunology

ProblemEndocrine disrupting chemicals (EDCs) found in consumer products constitute a significant risk for fertility, pregnancy and fetal development due to their hormone-mimicking mechanisms of action. EDC exposure at environmentally relevant levels has been suggested to promote pregnancy complications and increase the prevalence of intrauterine growth restriction (IUGR) by mechanisms also involving innate immune cells. However, insights into physiological and molecular changes during implantation and fetal development caused by exposure to ubiquitous EDCs and especially mixtures are still scarce. Therefore, we applied high frequency ultrasound and Doppler, histological and flow cytometry analyses to determine fetal growth in utero, spiral artery remodeling and uterine immune cell populations.Method of StudyIn this study, pregnant C57BL/6 mice were exposure to two prominent EDCs bisphenol A (BPA), benzophenone-3 (BP-3) and a BPA/BP-3 mixture at concentrations considered appropriate for daily intake by the European Food Safety Authority (EFSA) to investigate effects on implantation and fetal development as well as changes in uterine immune cell populations. Using high frequency ultrasound and Doppler measurements, we aimed to determine intrauterine development and hemodynamics between gestation day (GD) 5 and 14. Furthermore, uterine spiral artery remodeling and changes in gene expression of the placenta were studied. ResultsWe found that litter size, resorption rate and placenta weights were not affected by maternal treatment with EDCs compared to controls. Moreover, ultrasound and Doppler measurements revealed no significant differences in pulsatility or resistance index between EDC treated dams and controls. However, fetuses of BP-3 exposed mothers were small for gestational age (below the 10th weight percentile) and suffered from IUGR (below the 5th weight percentile). Flow cytometry analyses revealed an altered innate immune cell profile in uterine tissue with an increase in CD3+ and NK cells in BPA and BPA/BP-3 treated dams at GD14 compared to controls. Spiral artery wall-to-lumen ratio and wall thickness were similar among treatment groups.ConclusionsIn conclusion, offspring of BP-3 exposed dams showed reduced weight at GD14 and were affected by IUGR indicating an effect of BP-3 on fetal growth. Moreover, exposure to BPA and BPA/BP-3 mixture appear to increase CD3+ and NK cells in the uterus at mid-gestation. Spiral artery remodeling was not affected by exposure to BPA, BP-3 or BPA/BP-3 mixture. Our work unravels the consequences of intrauterine exposure to these EDCs for offspring health.