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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

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


Authors

Chris S. Elcombe

Ana Monteiro

Matthew R. Elcombe

Mohammad Ghasemzadeh-Hasankolaei

KEVIN SINCLAIR kevin.sinclair@nottingham.ac.uk
Professor of Developmental Biology

RICHARD LEA richard.lea@nottingham.ac.uk
Professor of Reproductive Biology

Vasantha Padmanabhan

Neil P. Evans

Michelle Bellingham



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.

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

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