Prenatal exposure to bisphenol A, genistein and indole-3-carbinol on early mammary gland development and carcinogenesis in female Sprague-Dawley offspring

Rodent studies have indicated that gestational and perinatal bisphenol A (BPA) exposure increase the risk of developing breast cancer during adulthood. In contrast, some dietary compounds such as genistein (GEN) and indole 3-carbinol (I3C) present potential protective effects against inducing hormone-dependent cancers, including that of the mammary gland. Thus, we aimed to evaluate the role of these dietary compounds on early mammary gland development and carcinogenesis in female Sprague-Dawley offspring. Pregnant Sprague-Dawley (SD) rats were treated with BPA at 25 or 250µg/kg b.w./day by gavage from gestational day (GD) 10 to 21 with or without dietary GEN (250 mg/kg chow, ~5.5 mg/kg b.w./day) or I3C (2000 mg/kg chow, ~45.0 mg/kg b.w./day). At post-natal day (PND) 21, some female offspring from different litters were euthanized for mammary gland development and gene expression analyses while other female offspring received a single dose of N-methyl-N-nitrosourea (MNU) for mammary carcinogenesis initiation. The findings this study indicated the prenatal exposure to BPA, GEN and I3C did not significantly alter ductal elongation, number of terminal end buds (TEB) or cell proliferation, and estrogen receptor alpha (ER-α) immunostaining expression in epithelial mammary cells at PND 21. BPA treatment modulated the expression of several genes, but these changes were not associated with a dose dependent response. Dietary GEN and I3C treatment causally and consistent with the mammary gland structures outcomes. Besides, maternal BPA exposure associated with dietary GEN and I3C did not alter the susceptibility to the mammary cancer development in adulthood when the carcinogen was administered in a window of immature mammary gland development. Pregnant Sprague-Dawley (SD) rats were treated with BPA at 25 or 250µg/kg b.w./day by gavage from gestational day (GD) 10 to 21 with or without dietary GEN (250 mg/kg chow, ~5.5 mg/kg b.w./day) or I3C (2000 mg/kg chow, ~45.0 mg/kg b.w./day). At post-natal day (PND) 21, some female offspring from different litters were euthanized for mammary gland development and gene expression analyses while other female offspring received a single dose of N-methyl-N-nitrosourea (MNU) for mammary carcinogenesis initiation.

啮齿类动物研究表明，妊娠期与围产期双酚A（bisphenol A, BPA）暴露会提升子代成年期罹患乳腺癌的风险。与之相对，部分膳食化合物如染料木黄酮（genistein, GEN）与吲哚-3-甲醇（indole 3-carbinol, I3C）对包括乳腺癌在内的激素依赖性癌症具有潜在的预防作用。为此，本研究旨在评估上述膳食化合物对雌性斯普拉格-道利（Sprague-Dawley, SD）子代乳腺早期发育及癌变进程的调控作用。实验选取妊娠斯普拉格-道利（SD）大鼠，自妊娠第10天至第21天，以灌胃方式给予25 μg/kg体重/天或250 μg/kg体重/天的BPA，同时辅以或不辅以膳食型染料木黄酮（250 mg/kg饲料，约5.5 mg/kg体重/天）或吲哚-3-甲醇（2000 mg/kg饲料，约45.0 mg/kg体重/天）。在出生后第21天（post-natal day, PND 21），处死不同窝别的部分雌性子代，用于乳腺发育与基因表达分析；剩余雌性子代则单次给予N-甲基-N-亚硝基脲（N-methyl-N-nitrosourea, MNU）以启动乳腺癌变过程。本研究结果显示，产前暴露于BPA、GEN及I3C，并未显著改变出生后第21天乳腺上皮细胞的导管延伸长度、末端芽泡（terminal end buds, TEB）数量、细胞增殖活性以及雌激素受体α（estrogen receptor alpha, ER-α）免疫染色表达水平。BPA处理可调控部分基因的表达，但上述变化未呈现剂量依赖性。膳食型GEN与I3C的处理效应与乳腺结构观测结果相符。此外，当致癌物于乳腺未成熟发育阶段给予时，母体BPA暴露联合膳食GEN或I3C，并未改变子代成年期罹患乳腺癌的易感性。实验选取妊娠斯普拉格-道利（SD）大鼠，自妊娠第10天至第21天，以灌胃方式给予25 μg/kg体重/天或250 μg/kg体重/天的BPA，同时辅以或不辅以膳食型染料木黄酮（250 mg/kg饲料，约5.5 mg/kg体重/天）或吲哚-3-甲醇（2000 mg/kg饲料，约45.0 mg/kg体重/天）。在出生后第21天（post-natal day, PND 21），处死不同窝别的部分雌性子代，用于乳腺发育与基因表达分析；剩余雌性子代则单次给予N-甲基-N-亚硝基脲（N-methyl-N-nitrosourea, MNU）以启动乳腺癌变过程。