Boucher Jonathan G, Boudreau Adèle, Ahmed Shaimaa, Atlas Ella
Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada.
Environ Health Perspect. 2015 Dec;123(12):1287-93. doi: 10.1289/ehp.1409143. Epub 2015 May 27.
Exposure to common environmental substances, such as bisphenol A (BPA), has been associated with a number of negative health outcomes. In vivo, BPA is rapidly converted to its predominant metabolite, BPA-glucuronide (BPA-G), which has long been believed to be biologically inactive because it lacks estrogenic activity. However, the effects of BPA-G on cellular metabolism have not been characterized. In the present study we examined the effect of BPA-G on adipogenesis.
The effect of BPA-G on the differentiation of human and 3T3L1 murine preadipocytes was evaluated in vitro by quantifying lipid accumulation and the expression of adipogenic markers.
Treatment of 3T3L1 preadipocytes with 10 μM BPA-G induced a significant increase in lipid accumulation, mRNA expression of the adipogenic markers sterol regulatory element binding factor 1 (SREBF1) and lipoprotein lipase (LPL), and protein levels of LPL, aP2, and adipsin. Treatment of primary human preadipocytes with BPA-G also induced adipogenesis as determined by aP2 levels. Co-treatment of cells with the estrogen receptor (ER) antagonist fulvestrant (ICI) significantly inhibited the BPA-G-induced increase in LPL and aP2 levels, whereas treatment with ICI alone had no effect. Moreover, BPA-G did not display any significant estrogenic activity.
To our knowledge, this study is the first to report that BPA-G induces adipocyte differentiation and is not simply an inactive metabolite. The fact that BPA-G induced adipogenesis and was inhibited by an ER antagonist yet showed no estrogenic activity suggests that it has no classical ER transcriptional activation function and acts through a pathway that remains to be determined.
接触常见环境物质，如双酚A（BPA），已与多种负面健康结果相关联。在体内，BPA迅速转化为其主要代谢产物BPA-葡萄糖醛酸苷（BPA-G），长期以来人们一直认为它没有生物活性，因为它缺乏雌激素活性。然而，BPA-G对细胞代谢的影响尚未得到表征。在本研究中，我们检测了BPA-G对脂肪生成的影响。
通过定量脂质积累和脂肪生成标志物的表达，在体外评估BPA-G对人和3T3L1小鼠前脂肪细胞分化的影响。
用10μM BPA-G处理3T3L1前脂肪细胞可导致脂质积累、脂肪生成标志物固醇调节元件结合因子1（SREBF1）和脂蛋白脂肪酶（LPL）的mRNA表达以及LPL、aP2和脂肪酶蛋白水平显著增加。用BPA-G处理原代人前脂肪细胞也可诱导脂肪生成，这由aP2水平确定。用雌激素受体（ER）拮抗剂氟维司群（ICI）共同处理细胞可显著抑制BPA-G诱导的LPL和aP2水平升高，而单独用ICI处理则无效果。此外，BPA-G未显示出任何显著的雌激素活性。
据我们所知，本研究首次报道BPA-G可诱导脂肪细胞分化，并非仅仅是一种无活性的代谢产物。BPA-G诱导脂肪生成且被ER拮抗剂抑制但未显示雌激素活性这一事实表明，它没有经典的ER转录激活功能，而是通过一条有待确定的途径发挥作用。
