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

Author:

Xiong Yong-WeiORCID,Zhu Hua-Long,Zhang Jin,Geng Hao,Tan Lu-Lu,Zheng Xin-Mei,Li Hao,Fan Long-Long,Wang Xin-Run,Zhang Xu-Dong,Wang Kai-Wen,Chang Wei,Zhang Yu-Feng,Yuan Zhi,Duan Zong-Liu,Cao Yun-Xia,He Xiao-JinORCID,Xu De-XiangORCID,Wang HuaORCID

Abstract

AbstractThere 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.

Funder

National Natural Science Foundation of China

Publisher

Springer Science and Business Media LLC

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