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.
Highlights
It is evident from human and animal studies that many factors, including maternal nutrition and stress during pregnancy, can alter normal foetal development and programme risk of disease in later life [1,2]
There was no effect of biosolids exposure on aryl hydrocarbon receptor (AhR) mRNA expression in male foetal pituitary glands (Fig. 4C). This is the first study to address the effects of the timing of maternal exposure to environmentally relevant chemical mixtures on the foetal reproductive neuroendocrine system
The findings from this ovine model are significant for the following reasons. They show that: (i) the effects of maternal exposure to mixtures of environmental chemicals (ECs) in biosolids on the foetal neuroendocrine system are sexually dimorphic; (ii) the timing and duration of maternal EC exposure is critical in determining its effects on the foetal neuroendocrine system; in particular EC exposure prior to conception, but not during pregnancy, can affect development of the foetal reproductive neuroendocrine system; (iii) the effect of maternal exposure to EC mixtures during pregnancy alone on the foetal neuroendocrine system can be different compared to those seen when maternal exposure has been life-long; and (iv) life-long maternal exposure to chemical mixtures does not necessarily mean greater/more effects on gene expression in the foetal neuroendocrine system
Summary
It is evident from human and animal studies that many factors, including maternal nutrition and stress during pregnancy, can alter normal foetal development and programme risk of disease in later life [1,2]. When considering the factors that might influence the effects of ECs on foetal development, it is important to remember that humans are rarely exposed to high levels of individual chemicals but rather to mixtures of different chemicals. We have previously shown that life-long maternal exposure to biosolids is associated with behavioural changes [28] and reduced bone density [29] in adult offspring, altered foetal testis and ovary development [24,30,31] and altered mRNA expression of regulatory systems within the foetal reproductive neuroendocrine axis [32,33], whereas more recent studies have reported that the timing of maternal exposure has significant effects on foetal ovarian development [24,34].
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