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Humans are ubiquitously exposed to complex mixtures of environmental chemicals (ECs). This study characterised changes in post-natal and peripubertal growth, and the activation of the reproductive axis, in male and female offspring of sheep exposed to a translationally relevant EC mixture (in biosolids), during pregnancy. Birthweight in both sexes was unaffected by gestational biosolids exposure. In contrast to females (unaffected), bodyweight in biosolids males was significantly lower than controls across the peripubertal period, however, they exhibited catch-up growth eventually surpassing controls. Despite weighing less, testosterone concentrations were elevated earlier, indicative of early puberty in the biosolids males. This contrasted with females in which the mean date of puberty (first progesterone cycle) was delayed. These results demonstrate that developmental EC-mixture exposure has sexually dimorphic effects on growth, puberty and the relationship between body size and puberty. Such programmed metabolic/reproductive effects could have significant impacts on human health and wellbeing. • Puberty was delayed in female offspring of gestational biosolids exposed sheep. • Testicular activation was advanced in male offspring of biosolids exposed sheep. • Maternal biosolid exposure did not affect birthweight of male and female lambs. • Male offspring of biosolids exposed mothers weighed less prior to adulthood. • Maternal biosolid exposure had no impact on bodyweight of female lambs. [ABSTRACT FROM AUTHOR]

Environmental chemical (EC) exposure may be impacting male reproductive health. The translationally relevant biosolids treated pasture (BTP) sheep model was used to investigate gestational low-level EC mixture exposure on the testes of F1 male offspring. Adult rams from ewes exposed to BTP 1 month before and throughout pregnancy had more seminiferous tubules with degeneration and depletion of elongating spermatids, indicating possible "recovery" from previously reported testicular dysgenesis syndrome-like phenotype in neonatal and pre-pubertal BTP lambs. Expression of transcription factors CREB1 (neonatal) and BCL11A and FOXP2 (pre-pubertal) were significantly higher in the BTP exposed testes, with no changes seen in adults. Increased CREB1 , which is crucial for testes development and regulation of steroidogenic enzymes, could be an adaptive response to gestational EC exposure to facilitate the phenotypic recovery. Overall, this demonstrates that testicular effects from gestational exposure to low-level mixtures of ECs can last into adulthood, potentially impacting fertility and fecundity. • Testis development affected by gestational environmental chemical mixture exposure. • Adult phenotypic "recovery" from TDS-like phenotype in neonatal and pre-pubertal. • mTOR signalling a repeat finding in foetal, neonatal, pre-pubertal and adult testes. • HIF1α activation highest in neonatal, then pre-pubertal, but absent in adult testes. • Higher testes expression of CREB1 (neonatal) and BCL11A and FOXP2 (pre-pubertal). [ABSTRACT FROM AUTHOR]

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. • 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 FROM AUTHOR]