title: Triflumizole is an obesogen in mice that acts through peroxisome proliferator activated receptor gamma (PPARγ).
abstract: BACKGROUND
  Triflumizole (TFZ) is an imidazole fungicide used on many food and ornamental crops. TFZ is not thought to be particularly toxic or carcinogenic, but little is known about its effect on development. TFZ is identified as a peroxisome proliferator activated receptor gamma (PPARγ) activator in ToxCast. Because PPARγ is a master regulator of adipogenesis, we hypothesized that TFZ would activate PPARγ, thereby inducing adipogenesis and weight gain in vivo.
  
  
  OBJECTIVE
  We sought to test the ability of TFZ to activate PPARγ and promote adipogenesis in vitro and in vivo.
  
  
  METHODS
  We used transient transfection to test the ability of TFZ to activate PPARγ, and we used 3T3-L1 preadipocytes and human multipotent mesenchymal stromal stem cells (MSCs) to study the adipogenic capacity of TFZ in culture. We treated pregnant mice with three doses of TFZ and evaluated the effects on body weight, adipose depot weight, and MSC programming in the prenatally exposed offspring.
  
  
  CONCLUSIONS
  TFZ induced adipogenesis in MSCs and in mouse 3T3-L1 preadipocytes. Prenatal exposure to levels of TFZ at approximately 400-fold below the reported no observed adverse effect level increased adipose depot weight. All doses of TFZ tested increased adipogenic gene expression in MSCs while inhibiting expression of osteogenic genes.
  
  
  CONCLUSIONS
  TFZ acts through a PPARγ-dependent mechanism to induce adipogenic differentiation in MSCs and preadipocytes at low nanomolar concentrations. Prenatal TFZ exposure increases adipose depot weight and diverts MSC fate toward the adipocyte lineage; therefore, we conclude that TFZ is an obesogen in vivo.
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California 92697-2300, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.forename: Hang T
authors.initials: HT
authors.lastname: Pham
authors.forename: Amanda S
authors.initials: AS
authors.lastname: Janesick
authors.forename: Bruce
authors.initials: B
authors.lastname: Blumberg
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007093:Imidazoles / Q000633:toxicity*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects*; D051379:Mice; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism
chemical_list: D004785:Environmental Pollutants; D007093:Imidazoles; D047495:PPAR gamma; D045162:Thiazolidinediones; D014280:Triglycerides; D000077154:Rosiglitazone; C053549:triflumizol; D004121:Dimethyl Sulfoxide