National Food Institute, Technical University of Denmark, Kemitorvet Building 202, Kongens Lyngby DK-2800, Denmark.
Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, F-35000 Rennes, France.
Chemosphere. 2022 Dec;308(Pt 2):136346. doi: 10.1016/j.chemosphere.2022.136346. Epub 2022 Sep 6.
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.
子宫内暴露于内分泌干扰化学物质会干扰男性生殖发育。这可能导致男性生殖障碍，如尿道下裂、隐睾和生育能力下降，以及较短的肛生殖器距离（AGD） - 一种不完全雄激素依赖胎儿男性化的生物标志物。然而，对于许多化学物质，根据体外效应模式预测不利的体内结果仍然具有挑战性。这是现代毒理学的一个挑战，其目的是减少化学安全性评估中的动物测试。为了能够更多地依赖替代测试方法，我们需要更好地映射导致不良影响的潜在机制。在此，我们分析了雄性胎儿大鼠会阴和阴茎的转录组，并定义了暴露于抗雄激素杀真菌剂三氯苯唑的影响。此前我们已经表明，发育暴露于三氯苯唑会导致男性 AGD 缩短，但对胎儿睾丸的转录组没有明显影响。相比之下，我们在这里报告了会阴和阴茎转录谱的显著变化，包括这些相邻组织之间的区域差异。这突出了在描述复杂体内效应结果的机制时分析正确组织的重要性。我们的结果为涉及男性外生殖器发育的时空基因网络提供了丰富的资源，并且当暴露于阻止会阴和阴茎正常男性化的化学物质时，这些网络可能会被破坏。这些数据对于开发新的替代测试方法以确定现有和新兴化学物质的内分泌干扰潜力至关重要。
