Environmental cadmium disrupts placental angiogenesis and fetal growth via enhancing m6A modification in Wwp2.

Authors

Cheng-Fang Sun, Ye-Xin Luo, Xin-Xin Zhang, Rui Pan, Yu-Xi Wu, Jia-Ying Chen, Xin-Run Wang, Lan-Lan Wu, Si-Ting Liu, Wei Chang, Zhi Yuan, Da-Min Zhu, Yong-Wei Xiong, Ling-Li Zhao, De-Xiang Xu, Ya-Ling Feng, Hua-Long Zhu

Published in

Environmental pollution (Barking, Essex : 1987). Pages 129085. Sep 04, 2026. Epub Sep 04, 2026.

Abstract

Gestational exposure to cadmium (Cd), a widespread environmental toxicant, disrupted placental angiogenesis to induce fetal growth restriction (FGR). This study aimed to clarify the mechanism by which Cd disrupts placental angiogenesis. Human and mouse studies indicated that Cd exposure reduced VEGF-A to disrupt placental angiogenesis. Further data confirmed that gestational Cd exposure promoted estrogen receptor ESR1-specific degradation via ubiquitin-proteasome system (UPS), thereby decreasing placental VEGF-A. Bortezomib, the only clinically approved protease inhibitor, blocked ESR1 degradation to alleviate Cd-impaired placental angiogenesis. Based on mouse and human transcriptomics, WWP2 was identified as an unreported ubiquitin E3 ligase targeting placental ESR1. Specifically, both WWP2 knockdown and its inhibitor NSC2805 treatment consistently reversed environmental Cd-induced placental angiogenesis disorders and FGR. Furthermore, the m6A modification in Wwp2 mRNA was increased in Cd-exposed placentae. METTL3 and ELAVL1 knockdown verified that m6A modification enhanced the stability of Wwp2 mRNA. SAH, an inhibitor for METTL3, not only decreased WWP2 but also alleviated Cd-impaired placental angiogenesis and fetal growth. Based on a human case-control study, m6A-methylated Wwp2 was positively correlated with placental angiogenesis inhibition and all-cause FGR. In conclusion, gestational Cd exposure enhanced m6A modification in Wwp2 mRNA to drive ESR1 degradation, thereby inhibiting placental angiogenesis and fetal growth.

PMID:
42697459
Bibliographic data and abstract were imported from PubMed on 05 Sep 2026.

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