The impact of realistic environmental chemical exposure on male gonadal development and reproductive health

Continuing declines in human male reproductive health are of increasing concern. Many believe low-dose exposure to vast numbers of chemicals through the environment, particularly during fetal development, are a contributary factor in this decline. To address limitations with traditional, component-based methodologies of assessing chemical mixtures, this research utilised a unique, ovine based, whole-mixture exposure model. This model was used to investigate the impact of gestational exposure to realistic numbers of chemicals, at appropriately low doses, on male reproductive development. The research detailed herein characterises exposure-induced changes to the testes of neonatal, pre-pubertal, and adult male offspring of mothers exposed to an environmental chemical mixture prior to and during pregnancy. A testicular dysgenesis syndrome (TDS)-like phenotype was described in neonatal and prepubertal testes. This TDS-like phenotype was complemented by transcriptomic analyses which showed an extremely high degree of similarity between the testicular transcriptome of the affected pre-pubertal male offspring and those of human TDS patients. While this phenotype was not apparent in the same manner by adulthood, morphological and transcriptomic alterations were still apparent. This both exemplifies the potential for xenobiotic exposure during fetal development to impact reproductive health in later life, despite the cessation of exposure at birth, and indicates periods of post-partum vulnerability to xenobiotic exposure crucial to the persistence of or recovery from the TDS-like phenotype. Further investigations following transcriptomic analyses identified perturbations in the transcription, activation, and/or nuclear localisation of various transcription factors. Of these, there is supporting evidence that one (HIF1α) may have an important role in the pathogenesis of the TDS-like phenotype, while another (CREB1) may facilitate an amount of post-exposure recovery and might also be important in determining susceptibility or resistance to developing the TDS-phenotype. Overall, these findings strengthen the increasing evidence that gestational exposure to realistic levels and mixtures of environmental chemicals can have a negative impact on male reproductive health and provides leads for future investigations into the pathogenesis of TDS

Sexually dimorphic impact of preconceptional and gestational exposure to a real-life environmental chemical mixture (biosolids) on offspring growth dynamics and puberty in sheep

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