Timing of Maternal Exposure and Foetal Sex Determine the Effects of Low‐level Chemical Mixture Exposure on the Foetal Neuroendocrine System in Sheep

Abstract

We have shown that continuous maternal exposure to the complex mixture of environmental chemicals (ECs) found in human biosolids (sewage sludge), disrupts mRNA expression of genes crucial for development and long-term regulation of hypothalamic-pituitary gonadal (HPG) function in sheep. The present study investigated whether exposure to ECs only during preconceptional period or only during pregnancy perturbed key regulatory genes within the hypothalamus and pituitary gland and whether these effects were different from chronic (life-long) exposure to biosolid ECs. The findings demonstrate that the timing and duration of maternal EC exposure influences the subsequent effects on the foetal neuroendocrine system in a sex-specific manner. Maternal exposure prior to conception, or during pregnancy only, altered the expression of key foetal neuroendocrine regulatory systems such as gonadotrophin-releasing hormone and kisspeptin to a greater extent than when maternal exposure was 'life-long'. Furthermore, hypothalamic gene expression was affected to a greater extent in males than in females and, following EC exposure, male foetuses expressed more 'female-like' mRNA levels for some key neuroendocrine genes. This is the first study to show that 'real-life' maternal exposure to low levels of a complex cocktail of chemicals prior to conception can subsequently affect the developing foetal neuroendocrine system. These findings demonstrate that the developing neuroendocrine system is sensitive to EC mixtures in a sex-dimorphic manner likely to predispose to reproductive dysfunction in later life.

Female Fertility and Environmental Pollution

“…In fact, recent reports highlighted that environmental pollution and climate change are significantly increasing the risk of birth defects, especially after prolonged exposure [147,148]. Indeed, it has been proposed that timing and duration of maternal exposure to a complex mixture of environmental chemicals impairs the fetal neuroendocrine system in a sex-specific manner, as expression of some genes involved in neuroendocrine development is altered in male fetus in comparison with control [149].…”

Windows of sensitivity to toxic chemicals in the development of reproductive effects: an analysis of ATSDR’s toxicological profile database

“…While ATSDR includes studies in other laboratory mammal species, the vast majority of the toxicological database is focused on these two species. Studies utilizing sheep have shown that exposure to environmental chemicals prior to conception only, during pregnancy only, or throughout life can affect the developing fetus differently (Bellingham et al 2009, 2016; Lea et al 2016). These results support findings in rodents.…”

Preconceptional and in utero exposure of sheep to a real‐life environmental chemical mixture disrupts key markers of energy metabolism in male offspring

“…Specific hypothalamic areas were isolated for RNA extraction as described previously. 52 Briefly, the hemi-hypothalamic block was cut into 2 mm coronal slices, and relative to visible anatomical landmarks (the anterior commissure, the mammillary body, etc. ), 2 mm diameter punches representative of specific hypothalamic areas collected into TRIzol ® reagent (Invitrogen, Carlsbad, CA, USA).…”