Exposure to paraben in early gestational period: Impact on placental estrogen biosynthesis and fetal growth restriction

Parabens (PBs) are associated with altered fetal growth parameters, but the underlying mechanisms-particularly those involving placental function-remain unclear. To elucidate the mechanisms through PB exposure impairs placental steroidogenic function, thereby contributing to the pathogenesis of fetal growth restriction (FGR). Metabolic profiles in maternal serum samples from FGR cases (n = 20) and the matched controls (n = 20) within a Maternal-Child Health Cohort (Obstetrics & Gynecology Hospital of Fudan University), which were prospectively collected in the first-trimester, were analyzed using UPLC-MS/MS. Trophoblast-derived JEG-3 cells were exposed to butylparaben (BuPB; 1-100 μM, 6-24 h) to assess steroidogenic pathway disruption. Pregnant C57BL/6 mice received subcutaneous BuPB (0, 100 and 400 mg/kg/day, GD 0-13.5) for longitudinal evaluation of exposure effects on placental and fetal development. Pregnancies complicated by FGR exhibited elevated PBs burdens in first-trimester, along with steroidogenic metabolomes significantly disrupted. In vitro exposure of JEG-3 cells to BuPB further confirmed that the estrogen biosynthesis pathway was preferential impaired, as demonstrated by dose-dependent upregulation of HSD3B1 and HSD17B1 expression (1.40-1.42-fold; p < 0.05), while suppression of CYP19A1 expression (35 %-68 % reduction; p < 0.01). In vivo, gestational BuP exposure (GD 0.5-G13.5) induced FGR phenotypes in mice, characterized by reduced fetal weight (28 % decrease; p < 0.01), placental damage. At GD13.5, placental Hsd17b1 was upregulated, while Cyp19a1 was suppressed (p < 0.05) with concomitant estrogen deficiency. Our findings indicate that early gestational BuPB exposure may disrupt placental steroidogenesis, specifically through placental steroidogenesis homeostasis, resulting in placental estrogen deficiency and impaired placenta and fetal development. Our study provided integrated evidences of developmental toxicity of PBs in the pathogenesis of FGR.