Workshop Report 30

Effects on rat reproductive development produced by antiandrogens: upstream indicators of downstream effects

Paul Foster
Chief of Toxicology,
Dr Foster briefly described the normal development of the male reproductive system in the rat and the phenotypic changes produced in the developing Wolffian duct (WD)/ foetal epididymis, following in utero exposure to two antiandrogens with different modes of action: di-n-butyl phthalate (DBP) which produces effects on the concentration of the androgen ligand and Linuron (Lin) which is predominantly a competitive inhibitor of the androgen receptor.
Both agents produced very similar phenotypic effects on the failure of the developing WD to undergo coiling ― an essential component of its normal development. Exposure only during the period of sexual differentiation in utero produced profound effects in the offspring as they reach adulthood, with the occurrence of a high incidence of epididymal maldevelopment and consequent infertility.
A number of approaches have been taken to explore the early molecular events in the developing WD that resulted in the endocrine disruption of epididymal development. In the main these focused on the role of the androgen receptor, since androgens are required to prevent degeneration of the WD and that we know testosterone (T) induces coiling of the WD in vitro. Further, we know that T can act directly and indirectly via mesenchymal and epithelial interactions involving paracrine factors including EGF, IGF-1, and FGF (and/or their receptors) that have been shown to be altered following either DBP or Lin exposure.
However, Dr Foster emphasised that there is a ‘disconnect’ in the critical windows of exposure and development for the induction of epididymal malformations in rats (GD 15-17, the male programming window) ― and when we can see changes in either WD phenotype, or in WD gene expression for the above growth factors (at GD 21 and not noted at earlier times). One could speculate that the adverse events in the WD/ epididymis are ‘programmed’ to occur later in development, and that a potential mechanism that could be explored for such programming could be via epigenetic changes induced by chemical exposure. However, it seems unlikely that such effects could be inherited, since the phenotype of interest leads to infertility and that this would argue that selection would be against this trait / phenotype of interest.