Office of Research and Development, Oak Ridge Institute for Science and Education (ORISE).
Integrated Systems Toxicology Division.
Toxicol Sci. 2017 Nov 1;160(1):15-29. doi: 10.1093/toxsci/kfx153.
Current strategies for predicting carcinogenic mode of action for nongenotoxic chemicals are based on identification of early key events in toxicity pathways. The goal of this study was to evaluate short-term key event indicators resulting from exposure to androstenedione (A4), an androgen receptor agonist and known liver carcinogen in mice. Liver cancer is more prevalent in men compared with women, but androgen-related pathways underlying this sex difference have not been clearly identified. Short-term hepatic effects of A4 were compared with reference agonists of the estrogen receptor (ethinyl estradiol, EE) and glucocorticoid receptor (prednisone, PRED). Male B6C3F1 mice were exposed for 7 or 28 days to A4, EE, or PRED. EE increased and PRED suppressed hepatocyte proliferation, while A4 had no detectable effects. In a microarray analysis, EE and PRED altered >3000 and >670 genes, respectively, in a dose-dependent manner, whereas A4 did not significantly alter any genes. Gene expression was subsequently examined in archival liver samples from male and female B6C3F1 mice exposed to A4 for 90 days. A4 altered more genes in females than males and did not alter expression of genes linked to activation of the mitogenic xenobiotic receptors AhR, CAR, and PPARα in either sex. A gene expression biomarker was used to show that in female mice, the high dose of A4 activated the growth hormone-regulated transcription factor STAT5b, which controls sexually dimorphic gene expression in the liver. These findings suggest that A4 induces subtle age-related effects on STAT5b signaling that may contribute to the higher risk of liver cancer in males compared with females.
目前用于预测非遗传毒性化学物质致癌作用模式的策略基于识别毒性途径中的早期关键事件。本研究的目的是评估暴露于雄烯二酮（A4）后产生的短期关键事件指标，A4 是一种雄激素受体激动剂，也是已知的小鼠肝脏致癌物。与女性相比，男性的肝癌更为普遍，但导致这种性别差异的雄激素相关途径尚未明确确定。将 A4 的短期肝效应与雌激素受体（乙炔雌二醇，EE）和糖皮质激素受体（泼尼松，PRED）的参考激动剂进行了比较。雄性 B6C3F1 小鼠分别用 A4、EE 或 PRED 暴露 7 或 28 天。EE 增加和 PRED 抑制肝细胞增殖，而 A4 没有可检测到的作用。在微阵列分析中，EE 和 PRED 分别以剂量依赖的方式改变了 >3000 和 >670 个基因，而 A4 没有显著改变任何基因。随后在暴露于 A4 90 天的雄性和雌性 B6C3F1 小鼠的存档肝样本中检查了基因表达。A4 在雌性中改变的基因多于雄性，并且在两性中均未改变与激活致瘤性外源性受体 AhR、CAR 和 PPARα相关的基因表达。使用基因表达生物标志物表明，在雌性小鼠中，A4 的高剂量激活了生长激素调节的转录因子 STAT5b，该因子控制肝脏中性别二态性基因表达。这些发现表明，A4 对 STAT5b 信号转导产生微妙的与年龄相关的影响，这可能导致与女性相比，男性患肝癌的风险更高。
