Role of peroxisome proliferator-activated receptor alpha (PPARα) and PPARα-mediated species differences in triclosan-induced liver toxicity
| Autor: | Yangshun Tang, Yuanfeng Wu, Jia-Long Fang, Greg R. Olson, Michelle Vanlandingham, Frederick A. Beland |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Health Toxicology and Mutagenesis Alpha (ethology) 010501 environmental sciences Toxicology 01 natural sciences Mice 03 medical and health sciences Species Specificity Internal medicine Peroxisomes medicine Animals Humans PPAR alpha Receptor Cell Proliferation 0105 earth and related environmental sciences Oxidase test biology Cell growth Chemistry Cytochrome P450 General Medicine Peroxisome Triclosan Mice Inbred C57BL Ki-67 Antigen 030104 developmental biology medicine.anatomical_structure Endocrinology Liver Hepatocyte Hepatocytes biology.protein Female Peroxisome proliferator-activated receptor alpha |
| Zdroj: | Archives of Toxicology. 92:3391-3402 |
| ISSN: | 1432-0738 0340-5761 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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