Division of Diet, Disease Prevention and Toxicology, National Food Institute, Technical University of Denmark, Kgs. Lyngby, Denmark.
INSERM, Université de Rennes, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) - UMR_S1085, Rennes, France.
Toxicol Sci. 2019 May 1;169(1):303-311. doi: 10.1093/toxsci/kfz046.
A short anogenital distance (AGD) in males is a marker for incomplete masculinization and a predictor of adverse effects on male reproductive health. For this reason, AGD is used to assess the endocrine disrupting potential of chemicals for risk assessment purposes. The molecular mechanisms underpinning this chemically induced shortening of the AGD, however, remains unclear. Although it is clear that androgen receptor-mediated signaling is essential, evidence also suggest the involvement of other signaling pathways. This study presents the first global transcriptional profile of the anogenital tissue in male rat fetuses with chemically induced short AGD, also including comparison to normal male and female control animals. The antiandrogenic drug finasteride (10 mg/kg bw/day) was used to induce short AGD by exposing time-mated Sprague Dawley rats at gestation days 7-21. The AGD was 37% shorter in exposed male fetuses compared with control males at gestation day 21. Transcriptomics analysis on anogenital tissues revealed a sexually dimorphic transcriptional profile. More than 350 genes were found to be differentially expressed between the 3 groups. The expression pattern of 4 genes of particular interest (Esr1, Padi2, Wnt2, and Sfrp4) was also tested by RT-qPCR analyses, indicating that estrogen and Wnt2 signaling play a role in the sexually dimorphic development of the anogenital region. Our transcriptomics profiles provide a stepping-stone for future studies aimed at characterizing the molecular events governing development of the anogenital tissues, as well as describing the detailed Adverse Outcome Pathways for short AGD; an accepted biomarker of endocrine effects for chemical risk assessment.
男性的阴肛距离（AGD）较短是不完全男性化的标志，也是男性生殖健康不良影响的预测因子。出于这个原因，AGD 被用于评估化学物质对内分泌干扰的潜在风险，以进行风险评估。然而，导致 AGD 这种化学诱导缩短的分子机制尚不清楚。虽然雄激素受体介导的信号传导是必不可少的，但有证据表明其他信号通路也参与其中。本研究首次呈现了具有化学诱导的短 AGD 的雄性大鼠胎儿的肛生殖器组织的全转录组图谱，还包括与正常雄性和雌性对照动物的比较。抗雄激素药物非那雄胺（10mg/kg bw/day）用于通过在妊娠第 7-21 天暴露时间匹配的 Sprague Dawley 大鼠来诱导短 AGD。与对照组雄性相比，暴露组雄性胎儿的 AGD 在妊娠第 21 天短 37%。肛生殖器组织的转录组分析显示出性别二态性的转录谱。在这 3 组之间发现了 350 多个差异表达的基因。特别关注的 4 个基因（Esr1、Padi2、Wnt2 和 Sfrp4）的表达模式也通过 RT-qPCR 分析进行了测试，表明雌激素和 Wnt2 信号在肛生殖器区域的性别二态性发育中起作用。我们的转录组图谱为未来的研究提供了一个基础，旨在描述控制肛生殖器组织发育的分子事件，并描述短 AGD 的详细不良结局途径；短 AGD 是化学风险评估中内分泌效应的公认生物标志物。
