Donoghue Lauren J, Neufeld Thomas I, Li Yin, Arao Yukitomo, Coons Laurel A, Korach Kenneth S
Receptor Biology Section, Reproductive and Developmental Biology Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
Environ Health Perspect. 2017 Apr;125(4):634-642. doi: 10.1289/EHP396. Epub 2016 Sep 16.
Endocrine-disrupting chemicals (EDCs) are suspected of altering estrogenic signaling through estrogen receptor (ER) α or β (mERβ1 in mice). Several EDC effects have been reported in animal studies and extrapolated to human studies. Unlike humans, rodents express a novel isoform of ERβ (mERβ2) with a modified ligand-binding domain sequence. EDC activity through this isoform remains uncharacterized.
We identified the expression pattern of mERβ2 in mouse tissues and assessed the estrogenic activity of EDCs through mERβ2.
mERβ2 mRNA expression was measured in mouse tissues. HepG2 cells were used to assess the transactivation activity of mERβ isoforms with EDCs and ER co-activators. 293A cells transiently transfected with mER isoforms were used to detect EDC-mediated changes in endogenous ER target gene expression.
Expression of mERβ2 mRNA was detected in mouse reproductive tissues (ovary, testis, and prostate) and lung and colon tissues from both female and male mice. Five (E2, DES, DPN, BPAF, Coum, 1-BP) of 16 compounds tested by reporter assay had estrogenic activity through mERβ2. mERβ2 had a compound-specific negative effect on ERβ/ligand-mediated activity and ER target genes when co-expressed with mERβ1. mERβ2 recruited coactivators SRC2 or SRC3 in the presence of EDCs, but showed less recruitment than mERβ1.
mERβ2 showed weaker estrogenic activity than mERβ1 in our system, and can dampen mERβ1 activity. models of EDC activity and ER-mediated toxicity should consider the role of mERβ2, as rodent tissue responses involving mERβ2 may not be reproduced in human biology.
内分泌干扰化学物（EDCs）被怀疑通过雌激素受体（ER）α或β（小鼠中的mERβ1）改变雌激素信号传导。在动物研究中已报道了几种EDC的作用，并外推至人体研究。与人类不同，啮齿动物表达一种具有修饰配体结合域序列的新型ERβ亚型（mERβ2）。通过这种亚型的EDC活性仍未得到表征。
我们确定了mERβ2在小鼠组织中的表达模式，并评估了EDC通过mERβ2的雌激素活性。
检测小鼠组织中mERβ2 mRNA的表达。使用HepG2细胞评估mERβ亚型与EDC和ER共激活剂的反式激活活性。用mER亚型瞬时转染的293A细胞用于检测EDC介导的内源性ER靶基因表达变化。
在小鼠生殖组织（卵巢、睾丸和前列腺）以及雌性和雄性小鼠的肺和结肠组织中检测到mERβ2 mRNA的表达。通过报告基因检测法测试的16种化合物中有5种（E2、DES、DPN、BPAF、香豆素、1-BP）通过mERβ2具有雌激素活性。当与mERβ1共表达时，mERβ2对ERβ/配体介导的活性和ER靶基因具有化合物特异性的负面影响。在存在EDC的情况下，mERβ2募集共激活剂SRC2或SRC3，但募集量比mERβ1少。
在我们的系统中，mERβ2显示出比mERβ1弱的雌激素活性，并且可以抑制mERβ1的活性。EDC活性和ER介导的毒性模型应考虑mERβ2的作用，因为涉及mERβ2的啮齿动物组织反应可能无法在人体生物学中重现。
