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Funds"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,8,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Evidence suggests that species differences exist between rodents and humans in their biological responses to ligand activation of PPAR\u03b1. Moreover, neonatal\/postnatal rodents may be more sensitive to the effects of activating PPAR\u03b1. Thus, the present studies examined the effects of chronic ligand activation of PPAR\u03b1 initiated during early neonatal development and continued into adulthood on hepatocarcinogenesis in mice. Wild-type, Ppara-null, or PPARA-humanized mice were administered a potent, high-affinity human PPAR\u03b1 agonist GW7647, and cohorts of mice were examined over time. Activation of PPAR\u03b1 with GW7647 increased expression of known PPAR\u03b1 target genes in liver and was associated with hepatomegaly, increased hepatic cytotoxicity and necrosis, increased expression of hepatic MYC, and a high incidence of hepatocarcinogenesis in wild-type mice. These effects did not occur or were largely diminished in Ppara-null and PPARA-humanized mice, although background levels of hepatocarcinogenesis were also noted in both Ppara-null and PPARA-humanized mice. More fatty change (steatosis) was also observed in both Ppara-null and PPARA-humanized mice independent of GW7647 administration. Results from these studies indicate that the mouse PPAR\u03b1 is required to mediate hepatocarcinogenesis induced by GW7647 in mice and that activation of the human PPAR\u03b1 with GW7647 in PPARA-humanized mice are diminished compared with wild-type mice. Ppara-null and PPARA-humanized mice are valuable tools for examining species differences in the mechanisms of PPAR\u03b1-induced hepatocarcinogenesis, but background levels of liver cancer observed in aged Ppara-null and PPARA-humanized mice must be considered when interpreting results from studies that use these models. These results also demonstrate that early life exposure to a potent human PPAR\u03b1 agonist does not enhance sensitivity to hepatocarcinogenesis.<\/jats:p>","DOI":"10.1093\/toxsci\/kfab068","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T20:30:27Z","timestamp":1622665827000},"page":"81-92","source":"Crossref","is-referenced-by-count":26,"title":["Species Differences between Mouse and Human PPAR\u03b1 in Modulating the Hepatocarcinogenic Effects of Perinatal Exposure to a High-Affinity Human PPAR\u03b1 Agonist in Mice"],"prefix":"10.1093","volume":"183","author":[{"given":"Jennifer E","family":"Foreman","sequence":"first","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Koga","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oksana","family":"Kosyk","sequence":"additional","affiliation":[{"name":"Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boo-Hyon","family":"Kang","sequence":"additional","affiliation":[{"name":"Non-clinical Research Institute, Chemon, Gyeonggi-Do 17162, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5047-0962","authenticated-orcid":false,"given":"Samuel M","family":"Cohen","sequence":"additional","affiliation":[{"name":"Havlik-Wall Professor of Oncology, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, 68198-3135, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura J","family":"Billy","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun K","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, The Pennsylvania State University, Hershey, Pennsylvania, 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shantu","family":"Amin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, The Pennsylvania State University, Hershey, Pennsylvania, 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank J","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland, 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Rusyn","sequence":"additional","affiliation":[{"name":"Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M","family":"Peters","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,6,3]]},"reference":[{"key":"2021083017303289900_kfab068-B1","doi-asserted-by":"crossref","first-page":"39088","DOI":"10.1074\/jbc.M107073200","article-title":"Peroxisome proliferator-activated receptor-\u03b1 regulates lipid homeostasis, but is not associated with obesity: Studies with congenic mouse lines","volume":"276","author":"Akiyama","year":"2001","journal-title":"J. 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