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Combined exposure to low levels of Pb2 + and 1-nitropyrene induces damage to the hypothalamic–pituitary–ovarian axis in mice via the hippo pathway and pyroptosis

Year: 2025

Type: article

Abstract: High concentrations of divalent lead (Pb 2+ ) in the environment induce damage to the hypothalamic–pituitary–ovarian axis (HPOA) axis, whereas 1-nitropyrene (1-NP) not only damages the brain but also leads to female reproductive toxicity. However, the effects of combined exposure to low levels of Pb 2+ and 1-NP on the HPOA damage remain unexplored. In this study, mice were simultaneously exposed to both environmental chemicals for 21 days through free water ingestion of Pb 2+ and intraperitoneal administration of 1-NP. Additionally, HPOA was exposed to low levels of Pb 2+ and 1-NP for 7 days in vitro using a multi-organ co-culture approach. The results showed that the combined exposure to 0.008 mg/L Pb 2+ (which complies with some hygiene standards) and ≥ 0.02 mg/kg 1-NP caused tissue damage and decreased the function of HPOA in vivo . In vitro , the same changes were induced by 0.008 mg/L Pb 2+ combined with 0.3 μM 1-NP in the culture medium. Both in vivo and in vitro , the damaged HPO exhibited decreased levels of YAP and increased levels of LATS1, pYAP, NLRP3, ASC, cleaved CASPASE-1, and GSDMD. These findings suggest that simultaneous exposure to low levels of Pb 2+ and 1-NP can induce HPOA damage in mice. The potential molecular mechanism may be that low levels of Pb 2+ and 1-NP synergistically activate the Hippo signaling pathway, leading to the upregulation of the NLRP3/GSDMD axis. This, in turn, regulates inflammation-mediated pyroptosis, ultimately triggering organ damage.

Source: Ecotoxicology and Environmental Safety

DOI: 10.1016/j.ecoenv.2025.118588