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

https://doi.org/10.1016/j.etap.2022.103913Get rights and content
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Highlights

  • Developmental exposure to environmental chemical mixture affects testis development.

  • Adverse outcome phenotypically resembles mixed testicular atrophy seen in TDS patients.

  • Transcriptome positively correlates with testicular transcriptomes of human TDS patients.

  • Analysis of correlating genes indicates changes in the mTOR signalling pathway.

  • Investigation of mTOR targets identified increased HIF1α activation and nuclear localisation.

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.

Abbreviations

B
Biosolids
BTP
Biosolids treated pasture
BPA
Bisphenol A
BTB
Blood-testes barrier
C
Control
DGE
Differential gene expression
DEGs
Differentially expressed genes
EDCs
Endocrine disrupting chemicals
ECs
Environmental chemicals
FDR
False discovery rate
GO
Gene ontology
GD
Gestation Day
HIF1α
Hypoxia Inducible Factor 1 Alpha
PPCPs
Pharmaceuticals and personal care products
PBDEs
Polybrominated diphenyl ethers
PCBs
Polychlorinated biphenyls
PAHs
Polycyclic aromatic hydrocarbons
SCO
Sertoli-cell-only
TDS
Testicular dysgenesis syndrome
TDI
Tolerable daily intake

Keywords

Developmental toxicity
Reproductive toxicity
Environmental chemicals
Testicular dysgenesis syndrome
Hypoxia inducible factor 1 alpha

Cited by (0)

1

(0000-0002-7869-0123)

2

(0000-0003-2349-9716)

3

(0000-0003-3512-5025)

4

(0000-0003-2053-5566)

5

(0000-0002-6375-215X)

6

(0000-0002-6793-3601)

7

(0000-0002-8443-7212)

8

(0000-0001-7395-3222)

9

(0000-0002-3646-8989)