title: Liver tumor formation in female rat induced by fluopyram is mediated by CAR/PXR nuclear receptor activation.
abstract: Fluopyram is a broad spectrum fungicide targeting plant pathogenic fungi (eg. white dot, black mold, botrytis). During the general toxicity evaluation of fluopyram in rodents, the liver was identified as a target organ (hepatomegaly and liver hypertrophy were observed in all studies). At the end of the guideline carcinogenicity study, an increased incidence of hepatocellular adenomas and carcinomas was observed in female Wistar rats following exposure to the highest fluopyram dose evaluated (1500ppm). Short-term mechanistic studies (3, 7 or 28days of exposure) were conducted in the female rat to identify the initial key events responsible for the tumor formation and to establish thresholds for each of the early hepatic changes. Increased expression of constitutive androstane receptor (CAR) and pregnane X receptor (PXR) inducible genes was recorded after each exposure period. Further confirmation of CAR/PXR activation was provided by increased activity of specific Phase I enzymes (PROD/BROD respectively). Increased hepatocellular proliferation (measured by Ki67) was observed after each exposure period with the greatest proliferative response occurring after 3days of treatment. In these studies, dose responses and clear thresholds were established for gene expression, enzyme activity and cell proliferation. Furthermore, these early hepatic changes were shown to be reversible following compound withdrawal. Other modes of action for liver tumor formation such as DNA damage, cytotoxicity and peroxisome proliferation were excluded during the investigations. In conclusion, fluopyram is a threshold carcinogen and the resultant hepatocellular carcinomas in the female rat are due to hepatocellular proliferation mediated by CAR/PXR activation.
authors.affiliation: Bayer SAS, 16 Rue Jean-Marie Leclair, 69009 Lyon, France. Electronic address: helen.tinwell@bayer.com.
authors.forename: H
authors.initials: H
authors.lastname: Tinwell
authors.affiliation: Bayer SAS, 16 Rue Jean-Marie Leclair, 69009 Lyon, France.
authors.forename: D
authors.initials: D
authors.lastname: Rouquié
authors.affiliation: Bayer SAS, 16 Rue Jean-Marie Leclair, 69009 Lyon, France.
authors.forename: F
authors.initials: F
authors.lastname: Schorsch
authors.affiliation: Bayer SAS, 16 Rue Jean-Marie Leclair, 69009 Lyon, France.
authors.forename: D
authors.initials: D
authors.lastname: Geter
authors.affiliation: Bayer SAS, 16 Rue Jean-Marie Leclair, 69009 Lyon, France.
authors.forename: S
authors.initials: S
authors.lastname: Wason
authors.affiliation: Bayer SAS, 16 Rue Jean-Marie Leclair, 69009 Lyon, France.
authors.forename: R
authors.initials: R
authors.lastname: Bars
mesh_terms: D018248:Adenoma, Liver Cell / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism*; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D000077297:Pregnane X Receptor; D011725:Pyridines / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*
chemical_list: D001549:Benzamides; D000090702:Constitutive Androstane Receptor; D005659:Fungicides, Industrial; D000077297:Pregnane X Receptor; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System; C572868:N-(2-(3-chloro-5-(trifluoromethyl)-2-pyridyl)ethyl)-alpha,alpha,alpha-trifluoro-o-toluamide
keywords: CAR/PXR nuclear receptors; Mode of action; Rodent liver; Threshold carcinogen