Elmelund Emilie, Draskau Monica K, Berg Marie, Strand Ida W, Black Jay R, Axelstad Marta, Pask Andrew J, Svingen Terje
National Food Institute, Technical University of Denmark, Kongens Lyngby, Denmark.
School of Geography, Earth and Atmospheric Sciences, The University of Melbourne, Melbourne, VIC, Australia.
Front Endocrinol (Lausanne). 2025 Sep 12;16:1654965. doi: 10.3389/fendo.2025.1654965. eCollection 2025.
Intrauterine exposure to endocrine disrupting chemicals (EDCs), particularly anti-androgens, has been implicated in hypospadias by disrupting fetal masculinization of the genital tubercle (GT). Other pathways, including estrogen signaling, may also contribute but remain poorly characterized, especially in rats - a key model in chemical toxicity testing. Estrogen signaling has also been linked to hypospadias in mice, raising questions about androgen-estrogen interactions in guiding GT differentiation.
We induced hypospadias in male rat offspring via intrauterine exposure to the antiandrogenic drug flutamide and characterized androgen and estrogen receptor expression.
We observed key structural and transcriptional changes in the developing penis, including altered estrogen receptor a (ERa, Esr1) expression. Notably, beyond this established androgen-estrogen relationship in hormone-sensitive tissues, anti-androgenic exposure also induced spatial changes in Esr1 expression in specific regions of the GT.
Future toxicological testing using new approach methodologies (NAMs) should consider androgen-estrogen balance and crosstalk in reproductive tissues as a mechanism of action.
子宫内暴露于内分泌干扰化学物质（EDCs），尤其是抗雄激素物质，已被认为通过破坏生殖器结节（GT）的胎儿男性化过程而导致尿道下裂。其他途径，包括雌激素信号通路，可能也起作用，但仍缺乏充分的特征描述，特别是在大鼠中——化学毒性测试的关键模型。雌激素信号通路也与小鼠的尿道下裂有关，这引发了关于雄激素 - 雌激素相互作用在引导GT分化中作用的疑问。
我们通过子宫内暴露于抗雄激素药物氟他胺诱导雄性大鼠后代出现尿道下裂，并对雄激素和雌激素受体表达进行了特征分析。
我们观察到发育中的阴茎出现关键的结构和转录变化，包括雌激素受体α（ERα，Esr1）表达改变。值得注意的是，除了激素敏感组织中已确定的雄激素 - 雌激素关系外，抗雄激素暴露还诱导了GT特定区域Esr1表达的空间变化。
未来使用新方法学（NAMs）进行的毒理学测试应将生殖组织中的雄激素 - 雌激素平衡和相互作用视为一种作用机制。
