Division of Biochemical Toxicology, National Center for Toxicological Research (NCTR), U.S Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
Toxicologic Pathology Associates, Inc., National Center for Toxicological Research (NCTR), U.S Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
Arch Toxicol. 2018 Nov;92(11):3391-3402. doi: 10.1007/s00204-018-2308-7. Epub 2018 Sep 20.
Triclosan, a widely used broad spectrum anti-bacterial agent, is hepatotoxic in rodents and exhibits differential effects on mouse and human peroxisome proliferator-activated receptor alpha (PPARα) in vitro; however, the mechanism underlying triclosan-induced liver toxicity has not been elucidated. This study examined the role of mouse and human PPARα in triclosan-induced liver toxicity by comparing the effects between wild-type and PPARα-humanized mice. Female mice of each genotype received dermal applications of 0, 58, or 125 mg triclosan/kg body weight daily for 13 weeks. Following the treatment, triclosan caused an increase in liver weight and relative liver weight only in wild-type mice. The expression levels of PPARα target genes cytochrome P450 4A and acyl-coenzyme A oxidase 1 were increased in livers of both wild-type and PPARα-humanized mice, indicating that triclosan activated PPARα. Triclosan also elevated the expression levels of peroxisomal membrane protein PMP70 and catalase in the livers of both genotypes, suggesting that triclosan promoted the production of hepatocyte peroxisomes. There was an enhanced expression of cyclin D1, c-myc, proliferating cell nuclear antigen, and Ki67, and a higher percentage of BrdU-labeled hepatocytes in wild-type mice, but not in PPARα-humanized mice, demonstrating triclosan-activated PPARα had differential effects on the hepatocyte proliferation. These findings imply that the differential effects of triclosan-activated PPARα on cell proliferation may play a role in the species differences in triclosan-induced liver toxicity.
三氯生是一种广泛使用的广谱抗菌剂，在啮齿动物中具有肝毒性，并在体外表现出对小鼠和人过氧化物酶体增殖物激活受体α（PPARα）的差异作用；然而，三氯生诱导肝毒性的机制尚未阐明。本研究通过比较野生型和 PPARα 人源化小鼠的作用，研究了小鼠和人 PPARα 在三氯生诱导肝毒性中的作用。每种基因型的雌性小鼠每天接受 0、58 或 125 mg/kg 体重的三氯生经皮应用，共 13 周。治疗后，只有野生型小鼠的肝重和相对肝重增加。野生型和 PPARα 人源化小鼠的肝脏中，PPARα 靶基因细胞色素 P450 4A 和酰基辅酶 A 氧化酶 1 的表达水平增加，表明三氯生激活了 PPARα。三氯生还增加了两种基因型肝脏中过氧化物酶体膜蛋白 PMP70 和过氧化氢酶的表达水平，表明三氯生促进了肝细胞过氧化物酶体的产生。野生型小鼠 cyclin D1、c-myc、增殖细胞核抗原和 Ki67 的表达增强，BrdU 标记的肝细胞比例更高，但 PPARα 人源化小鼠没有，表明三氯生激活的 PPARα 对肝细胞增殖有差异作用。这些发现表明，三氯生激活的 PPARα 对细胞增殖的差异作用可能在三氯生诱导肝毒性的种间差异中起作用。
