Receptor and Nonreceptor-Mediated Organ-Specific Toxicity of Di(2-ethylhexyl)phthalate (DEHP) in Peroxisome Proliferator-Activated Receptorα-Null Mice
| Autor: | Jeffrey M. Peters, Jerrold M. Ward, Frank J. Gonzalez, Christine M. Perella |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Male
0301 basic medicine endocrine system medicine.medical_specialty Ratón Receptors Cytoplasmic and Nuclear Biology Testicle Kidney Toxicology Pathology and Forensic Medicine Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Plasticizers Diethylhexyl Phthalate Internal medicine Testis medicine Animals Receptor Molecular Biology Mice Knockout Cystic kidney 030102 biochemistry & molecular biology Body Weight Phthalate Cell Biology Endocrinology medicine.anatomical_structure Liver chemistry 030220 oncology & carcinogenesis Toxicity Knockout mouse Transcription Factors |
| Zdroj: | Toxicologic Pathology. 26:240-246 |
| ISSN: | 1533-1601 0192-6233 |
| DOI: | 10.1177/019262339802600208 |
| Popis: | The peroxisome proliferator-activated receptor alpha (PPAR alpha) is the mediator of the biological effects of peroxisome proliferators through control of gene transcription. To determine if the toxic effects of di(2-ethylhexyl)phthalate (DEHP) are mediated by PPAR alpha, we examined its effect in PPAR alpha-null mice. Male Sv/129 mice, PPAR alpha-null (-/-) or wild-type (+/+) were fed ad libitum either a control diet or one containing 12,000 ppm DEHP for up to 24 wk. Significant body weight loss and high mortality was observed in (+/+) mice fed DEHP. By 16 wk, all DEHP-fed (+/+) mice had died of cystic renal tubular disease. In contrast, the (-/-) mice fed DEHP had no changes in body weight until later in the study nor increased mortality. Histologically, (+/+) mice fed DEHP had typical toxic lesions in liver, kidney, and testis while (-/-) mice fed DEHP had no toxic liver lesions but did show evidence of toxicity in kidney and testis after 4-8 wk of feeding, which progressed into moderate lesions by 24 wk. Analysis of hepatic and renal mRNAs showed a typical pleiotropic response in gene expression in the DEHP-fed (+/+) mice that was absent in the DEHP-fed (-/-) mice. These results provide evidence that PPAR alpha mediates the subacute-chronic toxicity of DEHP in liver, kidney, and testis. However, because (-/-) mice did develop toxic lesions in kidney and testis, DEHP can also act through PPAR alpha-independent pathways in mediating renal and testicular toxicity. |
| Databáze: | OpenAIRE |
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