Fischer Catha, Mamillapalli Ramanaiah, Goetz Laura G, Jorgenson Elisa, Ilagan Ysabel, Taylor Hugh S
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, P.O. Box 208063, New Haven, CT, 06510, USA.
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, 06520, USA.
Horm Cancer. 2016 Aug;7(4):241-51. doi: 10.1007/s12672-016-0254-5. Epub 2016 Feb 24.
Bisphenol-A (BPA) is a ubiquitous estrogen-like endocrine disrupting compound (EDC). BPA exposure in utero has been linked to breast cancer and abnormal mammary gland development in mice. The recent rise in incidence of human breast cancer and decreased age of first detection suggests a possible environmental etiology. We hypothesized that developmental programming of carcinogenesis may involve an aberrant immune response. Both innate and adaptive immunity play a role in tumor suppression through cytolytic CD8, NK, and Th1 T-cells. We hypothesized that BPA exposure in utero would lead to dysregulation of both innate and adaptive immunity in the mammary gland. CD1 mice were exposed to BPA in utero during gestation (days 9-21) via osmotic minipump. At 6 weeks, the female offspring were ovariectomized and estradiol was given at 8 weeks. RNA and protein were extracted from the posterior mammary glands, and the mRNA and protein levels were measured by PCR array, qRT-PCR, and western blot. In mouse mammary tissue, BPA exposure in utero significantly decreased the expression of members of the chemokine CXC family (Cxcl2, Cxcl4, Cxcl14, and Ccl20), interleukin 1 (Il1) gene family (Il1β and Il1rn), interleukin 2 gene family (Il7 receptor), and interferon gene family (interferon regulatory factor 9 (Irf9), as well as immune response gene 1 (Irg1). Additionally, BPA exposure in utero decreased Esr1 receptor gene expression and increased Esr2 receptor gene expression. In utero exposure of BPA resulted in significant changes to inflammatory modulators within mammary tissue. We suggest that dysregulation of inflammatory cytokines, both pro-inflammatory and anti-inflammatory, leads to a microenvironment that may promote disordered cell growth through inhibition of the immune response that targets cancer cells.
双酚A（BPA）是一种普遍存在的类雌激素内分泌干扰化合物（EDC）。子宫内暴露于双酚A与小鼠乳腺癌及乳腺异常发育有关。近期人类乳腺癌发病率上升且首次发现年龄降低，提示可能存在环境病因。我们推测致癌作用的发育编程可能涉及异常免疫反应。先天性免疫和适应性免疫均通过细胞毒性CD8、NK和Th1 T细胞在肿瘤抑制中发挥作用。我们假设子宫内暴露于双酚A会导致乳腺中先天性免疫和适应性免疫失调。在妊娠期（第9 - 21天），通过渗透微型泵使CD1小鼠子宫内暴露于双酚A。6周时，对雌性后代进行卵巢切除，并在8周时给予雌二醇。从乳腺后部提取RNA和蛋白质，通过PCR阵列、qRT - PCR和蛋白质印迹法测量mRNA和蛋白质水平。在小鼠乳腺组织中，子宫内暴露于双酚A显著降低了趋化因子CXC家族成员（Cxcl2、Cxcl4、Cxcl14和Ccl20）、白细胞介素1（Il1）基因家族（Il1β和Il1rn）、白细胞介素2基因家族（Il7受体）以及干扰素基因家族（干扰素调节因子9（Irf9））和免疫反应基因1（Irg1）的表达。此外，子宫内暴露于双酚A降低了Esr1受体基因表达并增加了Esr2受体基因表达。子宫内暴露于双酚A导致乳腺组织内炎症调节因子发生显著变化。我们认为，促炎和抗炎细胞因子的失调导致了一种微环境，该微环境可能通过抑制针对癌细胞的免疫反应来促进细胞生长紊乱。
