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

Ying Li; Xuning Wang; Fan Li; Xiaohui Li; Hu Fu; Xin Huang; Yongfei Zhu

doi:10.1016/j.ecoenv.2025.118588

Combined exposure to low levels of Pb^{2 +} and 1-nitropyrene induces damage to the hypothalamic-pituitary-ovarian axis in mice via the hippo pathway and pyroptosis

Ecotoxicol Environ Saf. 2025 Jun 27:302:118588. doi: 10.1016/j.ecoenv.2025.118588. Online ahead of print.

Authors

Ying Li¹, Xuning Wang², Fan Li³, Xiaohui Li⁴, Hu Fu³, Xin Huang⁵, Yongfei Zhu⁶

Affiliations

¹ Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
² Administration Department of Nosocomial Infection, Jinnan Hospital, Jinnan District, Tianjin City 300350, China; Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Public Health, Hunan Normal University, Changsha, Hunan 410013, China.
³ Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Public Health, Hunan Normal University, Changsha, Hunan 410013, China.
⁴ Department of Pharmacology, Xiangya School of Pharmaceutical Science, Central South University, Changsha, Hunan 410013, China; Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha, Hunan 410221, China.
⁵ Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Public Health, Hunan Normal University, Changsha, Hunan 410013, China. Electronic address: xin.huang@hunnu.edu.cn.
⁶ Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Public Health, Hunan Normal University, Changsha, Hunan 410013, China. Electronic address: njzhu70@126.com.

PMID: 40580634
DOI: 10.1016/j.ecoenv.2025.118588

Abstract

High concentrations of divalent lead (Pb²⁺) 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 Pb²⁺ 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 Pb²⁺ and intraperitoneal administration of 1-NP. Additionally, HPOA was exposed to low levels of Pb²⁺ 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 Pb²⁺ (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 Pb²⁺ 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 Pb²⁺ and 1-NP can induce HPOA damage in mice. The potential molecular mechanism may be that low levels of Pb²⁺ 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.

Keywords: 1-nitropyrene; Hippo pathway; Hypothalamic–pituitary–ovarian axis; Pb(2+); Pyroptosis.