Perfluorooctane sulfonic acid impairs spermatogenesis via the liver-gut microbiota-testis axis: a central role of chenodeoxycholic acid metabolism

Wang Yang; Peng Zou; Shijun He; Haonan Cui; Zeyu Yang; Huihui An; Qing Chen; Wei Huang; Hong Guo; Jinyi Liu; Xi Ling; Jia Cao; Lin Ao

doi:10.1016/j.jare.2025.06.037

Perfluorooctane sulfonic acid impairs spermatogenesis via the liver-gut microbiota-testis axis: a central role of chenodeoxycholic acid metabolism

J Adv Res. 2025 Jun 17:S2090-1232(25)00446-1. doi: 10.1016/j.jare.2025.06.037. Online ahead of print.

Authors

Wang Yang¹, Peng Zou², Shijun He², Haonan Cui², Zeyu Yang³, Huihui An², Qing Chen², Wei Huang⁴, Hong Guo⁵, Jinyi Liu², Xi Ling⁶, Jia Cao⁷, Lin Ao⁸

Affiliations

¹ Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing 400038, China; Department of Gastroenterology, Chongqing General Hospital, Chongqing University, Chongqing 401147, China.
² Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing 400038, China.
³ Department of Breast and Thyroid Surgery, Chongqing General Hospital, Chongqing University, Chongqing 401147, China.
⁴ School of Environment, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632 Guangdong, China.
⁵ Department of Gastroenterology, Chongqing General Hospital, Chongqing University, Chongqing 401147, China.
⁶ Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing 400038, China. Electronic address: lingxi@tmmu.edu.cn.
⁷ Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing 400038, China. Electronic address: caojia@tmmu.edu.cn.
⁸ Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing 400038, China. Electronic address: aolin@tmmu.edu.cn.

PMID: 40554061
DOI: 10.1016/j.jare.2025.06.037

Abstract

Introduction: Perfluorooctane sulfonic acid (PFOS) as a global contaminant is ubiquitously presented in the environmental media and human body. The association between PFOS exposure and reduced male fertility has been recently discovered. However, the relevant mechanism remains unexplored.

Objectives: Our study aimed to investigate the effect and mechanism of PFOS exposure on male reproductive function.

Methods: In a murine PFOS exposure model, single-nucleus transcriptome sequencing was performed to delineate the transcriptomic landscape of mouse testes at the single-cell resolution. We examined the serum metabolomic profile and conducted in-depth analysis of hepatic transcriptome datasets to explore the metabolic connections between liver and testis under PFOS exposure. Through integrating chenodeoxycholic acid intervention, fecal microbiota transplantation (FMT), metagenomic sequencing, testicular metabolome, Ligilactobacillus murinus (L. murinus) metabolome, and administration of L. murinus, we confirmed the role of the liver-gut microbiota-testis axis and screened the critical gut microbiota involved in PFOS-mediated spermatogenic disorders.

Results: The results showed that PFOS exposure led to spermatogenic arrest and abnormal spermatogenic microenvironment in the mouse testis. The PFOS-repressed hepatic chenodeoxycholic acid (CDCA) synthesis contributed to the reduced serum/testicular levels of essential fatty acid (linoleic acid) and lipid-soluble vitamins (retinol, vitamin D3), which was responsible for the spermatogenic arrest. Beyond this, PFOS-mediated impaired CDCA production decreased the abundance of gut L. murinus, which affected spermatogenesis through the potential involvement of aspartic acid metabolism. For the first time to our knowledge, we comprehensively assessed the effects of PFOS exposure on the spermatogenic process and elucidated the unrecognized role of liver-gut microbiota-testis axis in PFOS-induced abnormal spermatogenesis.

Conclusions: The unveiled organ crosstalks provide new insights into the metabolism-disrupting properties, hepatotoxicity, and reproductive toxicity of PFOS, which may facilitate the development of molecule-, metabolite-, and microbe-based strategies for PFOS-induced metabolic diseases and reproductive disorders.

Keywords: CDCA; Gut microbiota; Liver; PFAS; Spermatogenic disorder; Testis.