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

M Bellingham, P. A. Fowler, E. S. MacDonald, B. Mandon-Pepin, C. Cotinot, S. Rhind, R. M. Sharpe, N. P. Evans

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)
6 Downloads (Pure)


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.

This article is protected by copyright. All rights reserved.
Original languageEnglish
Article number12444
JournalJournal of Neuroendocrinology
Issue number12
Early online date21 Nov 2016
Publication statusPublished - Dec 2016

Bibliographical note

We are grateful to Mrs Carol Kyle (James Hutton Institute) for providing excellent technical assistance and to the staff of the James Hutton Research Institute for their assistance in the management of experimental animals. We are also grateful to Dr Alan Law for his statistical guidance and input. This work was funded by the Wellcome Trust (080388 to PAF, SMR, CC, NPE and RMS).


  • GnRH
  • kisspeptin
  • oestrogen receptor
  • hypothalamus
  • endocrine receptors
  • fetal


Dive into the research topics of 'Timing of Maternal Exposure and Foetal Sex Determine the Effects of Low-level Chemical Mixture Exposure on the Foetal Neuroendocrine System in Sheep'. Together they form a unique fingerprint.

Cite this