Timing of maternal exposure and fetal sex determine the effects of low-level chemical mixture exposure on the fetal neuroendocrine system in sheep

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 hypothalamo-pituitary gonadal (HPG) function in sheep. This 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 fetal neuroendocrine system in a sex-specific manner. Maternal exposure prior to conception or during pregnancy only, altered the expression of key fetal neuroendocrine regulatory systems such as GnRH 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 fetuses 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 fetal 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