The anti-androgenic fungicide triticonazole induces region-specific transcriptional changes in the developing rat perineum and phallus

Intrauterine exposure to endocrine disrupting chemicals can interfere with male reproductive development. This can lead to male reproductive disorders such as hypospadias, cryptorchidism and reduced fertility, as well as shorter anogenital distance (AGD) - a biomarker for incomplete androgen-dependent fetal masculinization. However, it remains challenging to predict adverse in vivo outcomes based on in vitro effect patterns for many chemicals. This is a challenge for modern toxicology, which aims to reduce animal testing for chemical safety assessments. To enable the transition towards higher reliance on alternative test methods, we need to better map underlying mechanisms leading to adverse effects. Herein, we have analyzed the transcriptome of the perineum and phallus of male fetal rats and defined the impacts of exposure to an anti-androgenic fungicide, triticonazole. Previously we have shown that developmental exposure to triticonazole can induce short male AGD, but without a marked effect on the transcriptome of the fetal testes. In contrast, we report here significant changes to the transcriptional landscape of the perineum and phallus, including regional differences between these adjacent tissues. This highlights the importance of analyzing the correct tissue when characterizing mechanisms of complex in vivo effect outcomes. Our results provide a rich resource for the spatiotemporal gene networks that are involved in the development of male external genitalia, and that can be disrupted upon exposure to chemicals that prevent normal masculinization of the perineum and phallus. Such data will be critical in the development of novel alternative test methods to determine the endocrine disrupting potential of existing and emerging chemicals.

Automated summary

Intrauterine exposure to endocrine disrupting chemicals can affect male reproductive development and lead to disorders. Predicting adverse effects in vivo based on in vitro effects is challenging. Understanding the underlying mechanisms of adverse effects is key to reducing animal testing for chemical safety assessments. This study analyzed the transcriptome of male fetal rats and the impact of an anti-androgenic fungicide, triticonazole, on the perineum and phallus. The findings highlight the importance of analyzing the correct tissue and provide valuable information for developing alternative test methods for assessing endocrine disrupting potential of chemicals.