Instituto de Salud y Ambiente del Litoral (ISAL, UNL-CONICET), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, 3000, Argentina; Cátedra de Patología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina.
Instituto de Salud y Ambiente del Litoral (ISAL, UNL-CONICET), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, 3000, Argentina.
Mol Cell Endocrinol. 2019 Feb 5;481:14-25. doi: 10.1016/j.mce.2018.11.005. Epub 2018 Nov 14.
Postnatal treatment with glyphosate-based herbicides (GBHs) induces endocrine-disrupting effects on the male rat mammary gland. In this study, the effects of developmental exposure to GBH on mammary gland growth and development, and the possible molecular mechanisms involved, were evaluated in pre- and post-pubertal male rats. To this end, pregnant rats were orally exposed through the food to 0, 3.5 or 350 mg GBH/kg bw/day from gestational day 9 until weaning. Mammary gland development and estradiol (E2) and testosterone (T) serum levels of male offspring were evaluated on postnatal day (PND)21 and PND60. Besides, prolactin (PRL) serum levels, proliferation index, androgen (AR) and estrogen receptor alpha (ESR1) expression, ESR1 alternative transcript mRNA levels, and DNA methylation status of ESR1 promoters were assessed on PND60. No differences between groups were observed in mammary gland development at PND21 or in E2 and T levels on both PNDs studied. On PND60, GBH3.5-exposed animals presented similar mammary gland histology but higher AR protein expression than controls, whereas GBH350-exposed males presented a less developed mammary gland, accompanied by a lower proliferation index, similar AR levels, and slightly increased PRL serum levels than controls. In both exposed groups, ESR1 expression was lower than in control rats, being lower in GBH350-exposed rats. GBH also altered the abundance of ESR1 transcript variants by hypermethylation of ESR1 promoters. GHB3.5 decreased only ESR1-OS expression, whereas GBH350 affected ESR1-O, OT and E1 expression. Our results show that developmental exposure to GBH induces epigenetic changes in ESR1, which could be responsible for the altered male mammary gland development observed in GBH350-exposed animals.
草甘膦基除草剂（GBH）的产后处理对雄性大鼠乳腺产生内分泌干扰作用。在这项研究中，评估了发育过程中暴露于 GBH 对雄性大鼠乳腺生长和发育的影响，以及涉及的可能分子机制。为此，从妊娠第 9 天到断奶，将怀孕的大鼠通过食物经口暴露于 0、3.5 或 350mg GBH/kg bw/天。在产后第 21 天（PND21）和第 60 天（PND60）评估雄性后代的乳腺发育和雌二醇（E2）和睾酮（T）血清水平。此外，在 PND60 时评估催乳素（PRL）血清水平、增殖指数、雄激素（AR）和雌激素受体 alpha（ESR1）表达、ESR1 替代转录本 mRNA 水平以及 ESR1 启动子的 DNA 甲基化状态。在 PND21 时，各组之间的乳腺发育没有差异，在两个研究的 PND 时，E2 和 T 水平也没有差异。在 PND60 时，GBH3.5 暴露的动物呈现出相似的乳腺组织学，但比对照组具有更高的 AR 蛋白表达，而 GBH350 暴露的雄性大鼠表现出发育不良的乳腺，伴随着较低的增殖指数、相似的 AR 水平和稍高的 PRL 血清水平比对照组。在两个暴露组中，ESR1 的表达均低于对照组，而 GBH350 暴露组的表达更低。GBH 还通过 ESR1 启动子的超甲基化改变了 ESR1 转录变体的丰度。GBH3.5 仅降低 ESR1-OS 的表达，而 GBH350 影响 ESR1-O、OT 和 E1 的表达。我们的研究结果表明，发育过程中暴露于 GBH 会导致 ESR1 发生表观遗传变化，这可能是导致 GBH350 暴露动物雄性乳腺发育异常的原因。
