Ovine fetal testis stage-specific sensitivity to environmental chemical mixtures.

Richard G Lea,Corinne Cotinot,Benoit Loup,Adelle Bowden,Elodie Poumerol,Biola F Egbowon,Beatrice Mandon-Pépin,Luc Jouneau,Paul A Fowler,Laura Purdie,Zulin Zhang,Kevin D Sinclair

doi:10.1530/rep-21-0235

Abstract

Exposure of the fetal testis to numerous individual environmental chemicals (ECs) is frequently associated with dysregulated development, leading to impaired adult reproductive competence. However, ‘real-life’ exposure involves complex mixtures of ECs. Here we test the consequences, for the male fetus, of exposing pregnant ewes to EC mixtures derived from pastures treated with biosolids fertiliser (processed human sewage). Fetal testes from continuously exposed ewes were either unaffected at day 80 or exhibited a reduced area of testis immunostained for CYP17A1 protein at day 140. Fetal testes from day 140 pregnant ewes that were exposed transiently for 80-day periods during early (0–80 days), mid (30–110 days), or late (60–140 days) pregnancy had fewer Sertoli cells and reduced testicular area stained for CYP17A1. Male fetuses from ewes exposed during late pregnancy also exhibited reduced fetal body, adrenal and testis mass, anogenital distance, and lowered testosterone; collectively indicative of an anti-androgenic effect. Exposure limited to early gestation induced more testis transcriptome changes than observed for continuously exposed day 140 fetuses. These data suggest that a short period of EC exposure does not allow sufficient time for the testis to adapt. Consequently, testicular transcriptomic changes induced during the first 80 days of gestation may equate with phenotypic effects observed at day 140. In contrast, relatively fewer changes in the testis transcriptome in fetuses exposed continuously to ECs throughout gestation are associated with less severe consequences. Unless corrected by or during puberty, these differential effects would predictably have adverse outcomes for adult testicular function and fertility.

Highlights

Exposure to environmental pollutants during fetal, neonatal, and/or adult life is associated with adverse effects on male reproductive development and function (Sumner et al 2020)
Day 80: continuous maternal exposure to biosolids had no effect on AMH-positive Sertoli cell numbers per gram of testis (Fig. 2A and Supplementary Fig. 1A)
The data presented in this study demonstrate that the ovine fetal testis exhibits differential and temporal sensitivity to chemical mixtures present in pastures treated with biosolids fertiliser

Summary

Introduction

Exposure to environmental pollutants during fetal, neonatal, and/or adult life is associated with adverse effects on male reproductive development and function (Sumner et al 2020). Meta-analyses confirm that human sperm counts have declined by 50% over 70 years (Carlsen et al 1992, Swan et al 2000, Levine et al 2017). Concomitant with these temporal changes, incidences of testicular cancer in young adults and malformations in male newborns (cryptorchidism and hypospadias) have increased (Skakkebaek et al 2016, Park et al 2018). Since environmental pollutants constitute a complex mixture, extrapolating from single chemical effects to real-life exposure is problematic

Methods

Results

Discussion

Conclusion