title: Dietary exposure to the endocrine disruptor tolylfluanid promotes global metabolic dysfunction in male mice.
abstract: Environmental endocrine disruptors are implicated as putative contributors to the burgeoning metabolic disease epidemic. Tolylfluanid (TF) is a commonly detected fungicide in Europe, and previous in vitro and ex vivo work has identified it as a potent endocrine disruptor with the capacity to promote adipocyte differentiation and induce adipocytic insulin resistance, effects likely resulting from activation of glucocorticoid receptor signaling. The present study extends these findings to an in vivo mouse model of dietary TF exposure. After 12 weeks of consumption of a normal chow diet supplemented with 100 parts per million TF, mice exhibited increased body weight gain and an increase in total fat mass, with a specific augmentation in visceral adipose depots. This increased adipose accumulation is proposed to occur through a reduction in lipolytic and fatty acid oxidation gene expression. Dietary TF exposure induced glucose intolerance, insulin resistance, and metabolic inflexibility, while also disrupting diurnal rhythms of energy expenditure and food consumption. Adipose tissue endocrine function was also impaired with a reduction in serum adiponectin levels. Moreover, adipocytes from TF-exposed mice exhibited reduced insulin sensitivity, an effect likely mediated through a specific down-regulation of insulin receptor substrate-1 expression, mirroring effects of ex vivo TF exposure. Finally, gene set enrichment analysis revealed an increase in adipose glucocorticoid receptor signaling with TF treatment. Taken together, these findings identify TF as a novel in vivo endocrine disruptor and obesogen in mice, with dietary exposure leading to alterations in energy homeostasis that recapitulate many features of the metabolic syndrome.
authors.affiliation: Committee on Molecular Metabolism and Nutrition (S.M.R., R.M.S.), Pritzker School of Medicine (S.M.R., R.M.S.), Kovler Diabetes Center (H.Y., E.E.-H., X.Z., C.C.T., N.L.M., R.M.S.), Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Committee on Molecular Pathogenesis and Molecular Medicine (A.G.K., B.A.N.), Department of Pathology (D.N.J.), Center for Research Informatics (L.H., C.Z.), and University of Chicago (S.M.R., A.G.K., H.Y., E.E.-H., X.Z., B.A.N., W.K., C.C.T., N.L.M., D.N.J., L.H., C.Z., R.M.S.), Chicago, Illinois 60637; Kennedy-King College (A.K.W.), Chicago, Illinois 60621; and Walter Payton College Preparatory High School (E.T.H.), Chicago, Illinois 60610.
authors.forename: Shane M
authors.initials: SM
authors.lastname: Regnier
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Kirkley
authors.forename: Honggang
authors.initials: H
authors.lastname: Ye
authors.forename: Essam
authors.initials: E
authors.lastname: El-Hashani
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Zhang
authors.forename: Brian A
authors.initials: BA
authors.lastname: Neel
authors.forename: Wakanene
authors.initials: W
authors.lastname: Kamau
authors.forename: Celeste C
authors.initials: CC
authors.lastname: Thomas
authors.forename: Ayanna K
authors.initials: AK
authors.lastname: Williams
authors.forename: Emily T
authors.initials: ET
authors.lastname: Hayes
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Massad
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Johnson
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.forename: Chunling
authors.initials: C
authors.lastname: Zhang
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sargis
mesh_terms: D052242:Adiponectin; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D002940:Circadian Rhythm; D004435:Eating; D052244:Endocrine Disruptors / Q000633:toxicity*; D004734:Energy Metabolism / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D020738:Leptin; D008297:Male; D008659:Metabolic Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000633:toxicity*; D014052:Toluidines / Q000633:toxicity*; D015430:Weight Gain / Q000187:drug effects
chemical_list: D052242:Adiponectin; D052244:Endocrine Disruptors; D007328:Insulin; D020738:Leptin; D013449:Sulfonamides; D014052:Toluidines; C070021:N-dichlorofluoromethylthio-N',N'-dimethyl-N-p-tolylsulfamide; D012313:RNA