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

  • Nat Commun. 2024 Feb 14;15(1):1353. doi: 10.1038/s41467-024-45675-4.
Yong-Wei Xiong  #  1  2 ,  Hua-Long Zhu  #  1  2 ,  Jin Zhang  #  1  2 ,  Hao Geng  #  3  4  5 ,  Lu-Lu Tan  1  2 ,  Xin-Mei Zheng  1  2 ,  Hao Li  1  2 ,  Long-Long Fan  1  2 ,  Xin-Run Wang  1  2 ,  Xu-Dong Zhang  1  2 ,  Kai-Wen Wang  1  2 ,  Wei Chang  1  2 ,  Yu-Feng Zhang  1  2 ,  Zhi Yuan  1  2 ,  Zong-Liu Duan  3  4  5 ,  Yun-Xia Cao  3  4  5 ,  Xiao-Jin He  6  7 ,  De-Xiang Xu  8  9  10 ,  Hua Wang  11  12  13
Affiliations
  • 1. Department of Toxicology, School of Public Health, Anhui Medical University, Hefei, China.
  • 2. Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, China.
  • 3. Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 4. NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China.
  • 5. Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, China.
  • 6. NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China. [email protected].
  • 7. Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 8. Department of Toxicology, School of Public Health, Anhui Medical University, Hefei, China. [email protected].
  • 9. Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, China. [email protected].
  • 10. Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, China. [email protected].
  • 11. Department of Toxicology, School of Public Health, Anhui Medical University, Hefei, China. [email protected].
  • 12. Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, China. [email protected].
  • 13. Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, China. [email protected].
  • # Contributed equally.
PMID: 38355624 DOI: 10.1038/s41467-024-45675-4
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.

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