Multigenerational paternal obesity enhances the susceptibility to male subfertility in offspring via Wt1 N6-methyladenosine modification

Yong-Wei Xiong, Hua-Long Zhu, Jin Zhang, Hao Geng, Lu-Lu Tan, Xin-Mei Zheng, Hao Li, Long-Long Fan, Xin-Run Wang, Xu-Dong Zhang, Kai-Wen Wang, Wei Chang, Yu-Feng Zhang, Zhi Yuan, Zong-Liu Duan, Yun-Xia Cao, Xiao-Jin He (), Xu De-Xiang () and Hua Wang ()
Additional contact information
Yong-Wei Xiong: Anhui Medical University
Hua-Long Zhu: Anhui Medical University
Jin Zhang: Anhui Medical University
Hao Geng: The First Affiliated Hospital of Anhui Medical University
Lu-Lu Tan: Anhui Medical University
Xin-Mei Zheng: Anhui Medical University
Hao Li: Anhui Medical University
Long-Long Fan: Anhui Medical University
Xin-Run Wang: Anhui Medical University
Xu-Dong Zhang: Anhui Medical University
Kai-Wen Wang: Anhui Medical University
Wei Chang: Anhui Medical University
Yu-Feng Zhang: Anhui Medical University
Zhi Yuan: Anhui Medical University
Zong-Liu Duan: The First Affiliated Hospital of Anhui Medical University
Yun-Xia Cao: The First Affiliated Hospital of Anhui Medical University
Xiao-Jin He: NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University)
Xu De-Xiang: Anhui Medical University
Hua Wang: Anhui Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract There is strong evidence that obesity is a risk factor for poor semen quality. However, the effects of multigenerational paternal obesity on the susceptibility to cadmium (a reproductive toxicant)-induced spermatogenesis disorders in offspring remain unknown. Here, we show that, in mice, spermatogenesis and retinoic acid levels become progressively lower as the number of generations exposed to a high-fat diet increase. Furthermore, exposing several generations of mice to a high fat diet results in a decrease in the expression of Wt1, a transcription factor upstream of the enzymes that synthesize retinoic acid. These effects can be rescued by injecting adeno-associated virus 9-Wt1 into the mouse testes of the offspring. Additionally, multigenerational paternal high-fat diet progressively increases METTL3 and Wt1 N6-methyladenosine levels in the testes of offspring mice. Mechanistically, treating the fathers with STM2457, a METTL3 inhibitor, restores obesity-reduced sperm count, and decreases Wt1 N6-methyladenosine level in the mouse testes of the offspring. A case-controlled study shows that human donors who are overweight or obese exhibit elevated N6-methyladenosine levels in sperm and decreased sperm concentration. Collectively, these results indicate that multigenerational paternal obesity enhances the susceptibility of the offspring to spermatogenesis disorders by increasing METTL3-mediated Wt1 N6-methyladenosine modification.

Date: 2024
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DOI: 10.1038/s41467-024-45675-4

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