INSERM U965, UFR Médecine, Hôpital Lariboisière; Université Paris 7, 41 Bd de la chapelle, F-75475 Paris Cedex 10, France Laboratoire d'Oncogénétique, Institut Curie Hôpital René Huguenin, St-Cloud F-92210, France.
J Endocrinol. 2013 Jan 18;216(2):245-63. doi: 10.1530/JOE-12-0395. Print 2013 Feb.
Exposure to low doses of environmental estrogens such as bisphenol A and genistein (G) alters mammary gland development. The effects of environmental anti-androgens, such as the fungicide vinclozolin (V), on mammary gland morphogenesis are unknown. We previously reported that perinatal exposure to G, V, and the GV combination causes histological changes in the mammary gland during the peripubertal period, suggesting alterations to the peripubertal hormone response. We now investigate whether perinatal exposure to these compounds alters the gene expression profiles of the developing glands to identify the dysregulated signaling pathways and the underlying mechanisms. G, V, or GV (1 mg/kg body weight per day) was added to diet of Wistar rats, from conception to weaning; female offspring mammary glands were collected at postnatal days (PNDs) 35 and 50. Genes displaying differential expression and belonging to different functional categories were validated by quantitative PCR and immunocytochemistry. At PND35, G had little effect; the slight changes noted were in genes related to morphogenesis. The changes following exposure to V concerned the functional categories associated with development (Cldn1, Krt17, and Sprr1a), carbohydrate metabolism, and steroidogenesis. The GV mixture upregulated genes (Krt17, Pvalb, and Tnni2) involved in muscle development, indicating effects on myoepithelial cells during mammary gland morphogenesis. Importantly, at PND50, cycling females exposed to GV showed an increase in the expression of genes (Csn2, Wap, and Elf5) related to differentiation, consistent with the previously reported abnormal lobuloalveolar development previously described. Thus, perinatal exposure to GV alters the mammary gland hormone response differently at PND35 (puberty) and in animals with established cycles.
暴露于低剂量的环境雌激素，如双酚 A 和染料木黄酮（G），会改变乳腺的发育。环境抗雄激素如杀真菌剂伏马菌素（V）对乳腺形态发生的影响尚不清楚。我们之前的研究报道，围产期暴露于 G、V 和 GV 组合会导致青春期前乳腺在青春期期间发生组织学变化，提示青春期前激素反应发生改变。我们现在研究围产期暴露于这些化合物是否会改变发育中腺体的基因表达谱，以确定失调的信号通路和潜在机制。从受孕到断奶，将 G、V 或 GV（1mg/kg 体重/天）添加到 Wistar 大鼠的饮食中；在产后第 35 天和第 50 天收集雌性后代的乳腺。通过定量 PCR 和免疫细胞化学验证显示差异表达并属于不同功能类别的基因。在 PND35 时，G 的影响较小；注意到的微小变化与形态发生有关的基因有关。暴露于 V 后发生的变化涉及与发育相关的功能类别（Cldn1、Krt17 和 Sprr1a）、碳水化合物代谢和类固醇生成。GV 混合物上调了参与肌肉发育的基因（Krt17、Pvalb 和 Tnni2），表明对乳腺形态发生过程中的肌上皮细胞有影响。重要的是，在 PND50，暴露于 GV 的循环雌性动物显示与分化相关的基因（Csn2、Wap 和 Elf5）表达增加，与之前报道的异常小叶泡发育一致。因此，围产期暴露于 GV 在 PND35（青春期）和具有既定周期的动物中不同地改变乳腺的激素反应。
