Hedgehog signal disruption, gonadal dysgenesis and reproductive disorders: Is there a link to endocrine disrupting chemicals?

Developmental exposure to chemicals that can disrupt sex hormone signaling may cause a broad spectrum of reproductive disorders. This is because reproductive development is tightly regulated by steroid sex hormones. Consequently, non-animal screening methods currently used to test chemicals for potential endocrine disrupting activities typically include steroidogenesis and nuclear receptor assays. In many cases there is a correlation between in vitro and in vivo data examining endocrine disruption, for example between blocked androgen receptor activity and feminized male genitals. However, there are many examples where there is poor, or no, correlation between in vitro data and in vivo effect outcomes in rodent studies, for various reasons. One possible, and less studied, reason for discordance between in vitro and in vivo data is that the mechanisms causing the in vivo effects are not covered by those typically tested for in vitro. This knowledge gap must be addressed if we are to elaborate robust testing strategies that do not rely on animal experimentation. In this review, we highlight the Hedgehog (HH) signaling pathway as a target for environmental chemicals and its potential implications for reproductive disorders originating from early life exposure. A central proposition is that, by disrupting HH signal transduction during critical stages of mammalian development, the endocrine cells of the testes or ovaries fail to develop normally, which ultimately will lead to disrupted sex hormone synthesis and sexual development in both sexes. If this is the case, then such mechanism must also be included in future test strategies aimed at eliminating chemicals that may cause reproductive disorders in humans.