Developmental exposure to real-life environmental chemical mixture programs a testicular dysgenesis syndrome-like phenotype in prepubertal lambs

Elcombe, Chris S.; Monteiro, Ana; Elcombe, Matthew R.; Ghasemzadeh-Hasankolaei, Mohammad; Sinclair, Kevin D.; Lea, Richard; Padmanabhan, Vasantha; Evans, Neil P.; Bellingham, Michelle

Abstract

Current declines in male reproductive health may, in part, be driven by anthropogenic environmental chemical (EC) exposure. Using a biosolids treated pasture (BTP) sheep model, this study examined the effects of gestational exposure to a translationally relevant EC mixture. Testes of 8-week-old ram lambs from mothers exposed to BTP during pregnancy contained fewer germ cells and had a greater proportion of Sertoli-cell-only seminiferous tubules. This concurs with previous published data from fetuses and neonatal lambs from mothers exposed to BTP. Comparison between the testicular transcriptome of biosolids lambs and human testicular dysgenesis syndrome (TDS) patients indicated common changes in genes involved in apoptotic and mTOR signalling. Gene expression data and immunohistochemistry indicated increased HIF1α activation and nuclear localisation in Leydig cells of BTP exposed animals. As HIF1α is reported to disrupt testosterone synthesis, these results provide a potential mechanism for the pathogenesis of this testicular phenotype, and TDS in humans.

Citation

Elcombe, C. S., Monteiro, A., Elcombe, M. R., Ghasemzadeh-Hasankolaei, M., Sinclair, K. D., Lea, R., …Bellingham, M. (2022). Developmental exposure to real-life environmental chemical mixture programs a testicular dysgenesis syndrome-like phenotype in prepubertal lambs. Environmental Toxicology and Pharmacology, 94, Article 103913. https://doi.org/10.1016/j.etap.2022.103913

• Journal Article Type: Article
• Acceptance Date: Jun 17, 2022
• Online Publication Date: Jun 20, 2022
• Publication Date: Aug 1, 2022
• Deposit Date: Dec 22, 2022
• Publicly Available Date: Jan 3, 2023
• Journal: Environmental Toxicology and Pharmacology
• Print ISSN: 1382-6689
• Electronic ISSN: 1872-7077
• Peer Reviewed: Peer Reviewed
• Volume: 94
• Article Number: 103913
• DOI: https://doi.org/10.1016/j.etap.2022.103913
• Public URL: https://nottingham-repository.worktribe.com/output/8956135
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S1382668922001065?via%3Dihub