article · Environment International
This research examines how exposure to bisphenol A (BPA) affects pregnant sheep and placental cells. In live trials, pregnant Hu ewes receiving daily doses of BPA exhibited placental insufficiency, foetal growth restriction, oxidative stress, mitochondrial dysfunction, and elevated cellular stress and cell death in placental tissue. Laboratory tests on primary ovine trophoblasts confirmed that BPA increased markers of autophagy, endoplasmic reticulum stress, and apoptosis while reducing antioxidant defences. Inhibiting autophagy with chloroquine intensified the cellular damage caused by BPA. Conversely, stimulating autophagy with rapamycin mitigated these detrimental effects, reducing cell death, mitochondrial impairment, and oxidative stress. These findings demonstrate that autophagy acts as a protective response that helps alleviate BPA-induced placental dysfunction and foetal growth restriction.
Bisphenol A is a widespread environmental pollutant that poses risks to reproductive and developmental health. By demonstrating that autophagy serves as a natural cellular defence against BPA toxicity in placental tissue, this work deepens the understanding of how environmental contaminants disrupt pregnancy. It highlights cellular pathways that could be targeted to protect maternal and foetal wellbeing from chemical exposures.
This work represents early-stage basic research in animal and cell models. It suggests that autophagy-modulating agents could potentially serve as a basis for therapeutic interventions or veterinary supplements designed to counteract chemical toxicity during pregnancy. However, practical applications remain far from market, requiring extensive preclinical development, safety testing, and validation in targeted species before any commercial use can be realised.
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Bisphenol A (BPA)-induced oxidative stress (OS) and its potentially associated autophagy and apoptosis have not been studied previously in pregnant ewes. Accordingly, this study investigated the underlying mechanisms of BPA-induced autophagy and apoptosis in the placenta and primary trophoblasts of pregnant ewes exposed to BPA both in vivo and in vitro. In vivo experiment, pregnant Hu ewes (n = 8) were exposed to 5 mg/kg/d of BPA compared to control ewes (n = 8) receiving only corn oil from day 40 through day 110 of gestation. Exposure to BPA during gestation resulted in placental insufficiency, fetal growth restriction (FGR), autophagy, endoplasmic reticulum stress (ERS), mitochondrial dysfunction, OS, and apoptosis in type A placentomes. Regarding in vitro model, primary ovine trophoblasts were exposed to BPA, BPA plus chloroquine (CQ; an autophagy inhibitor) or BPA plus rapamycin (RAP; an autophagy activator) for 12 h. Data illustrated that exposure to BPA enhanced autophagy (ULK1, Beclin-1, LC3, Parkin, and PINK1), ERS (GRP78, CHOP10, ATF4, and ATF6) and apoptosis (Caspase 3, Bcl-2, Bax, P53) but decreased the antioxidant (CAT, Nrf2, HO-1, and NQO1)-related mRNA and protein expressions as well as impaired the mitochondrial function. Moreover, treatment with CQ exacerbated the BPA-mediated OS, mitochondrial dysfunction, apoptosis, and ERS. On the contrary, RAP treatment counteracted the BPA-induced trophoblast dysfunctions mentioned above. Overall, the findings illustrated that BPA exposure could contribute to autophagy in the ovine placenta and trophoblasts and that autophagy, in turn, could alleviate BPA-induced apoptosis, mitochondrial dysfunction, ERS, and OS. These results offer new mechanistic insights into the role of autophagy in mitigating BPA-induced placental dysfunctions and FGR.
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DOI: 10.1016/j.envint.2023.107806
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