title: Adverse effects of long-term exposure to bisphenol A during adulthood leading to hyperglycaemia and hypercholesterolemia in mice.
abstract: Bisphenol A (BPA) is a suspected endocrine disruptor highly prevalent in our environment since it is used as monomer of polycarbonate plastics and epoxy resins. Recent epidemiological and animal studies have suggested that BPA exposure may influence the development of obesity and related pathologies such as type 2 diabetes, and cardiovascular diseases. However, experimental studies have often focused on short-term exposures. In this study, we investigated the effect of several months of BPA exposure on hepatic and plasma metabolic markers in adult mice. Male CD1 mice were exposed during 8 months to five different BPA doses below or equivalent to the current no observed adverse effect level (NOAEL: 5000 μg/kg/day) through drinking water. Plasma lipid profiles and liver transcriptomic analysis were performed in control and BPA-treated animals. We report a specific impact of BPA exposure on glycaemia, glucose tolerance and cholesterolemia. Consistent with the hypercholesterolemia in BPA-treated animals, RT-qPCR performed on hepatic mRNA from same animals demonstrated an overexpression of key genes involved in cholesterol biosynthesis, namely, Mvd, Lss Hmgcr, and Sqle. BPA also induced the expression of the sterol regulatory element-binding proteins 2, a master regulator of hepatic cholesterol biosynthesis. As shown by the plasma lathosterol to cholesterol ratio, a surrogate marker for cholesterol biosynthesis, whole body cholesterol de novo synthesis was also increased in BPA-exposed animals. These original results are consistent with many epidemiological studies reporting on a link between BPA exposure and the onset of cardiovascular diseases.
authors.affiliation: INRA, ToxAlim (Research Centre in Food Toxicology), 180 chemin de Tournefeuille, BP 93173, F-31027 Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, 31027 Toulouse, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Marmugi
authors.affiliation: INRA, ToxAlim (Research Centre in Food Toxicology), 180 chemin de Tournefeuille, BP 93173, F-31027 Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, 31027 Toulouse, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Lasserre
authors.affiliation: Inserm UMR1048, Institute of Metabolic and Cardiovascular Diseases, Obesity Research Laboratory, CHU Rangueil, 1 Avenue Jean Poulhes, BP 84225, 31432 Toulouse Cedex 4, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Beuzelin
authors.affiliation: INRA, ToxAlim (Research Centre in Food Toxicology), 180 chemin de Tournefeuille, BP 93173, F-31027 Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, 31027 Toulouse, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Ducheix
authors.affiliation: INRA, ToxAlim (Research Centre in Food Toxicology), 180 chemin de Tournefeuille, BP 93173, F-31027 Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, 31027 Toulouse, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Huc
authors.affiliation: INRA, ToxAlim (Research Centre in Food Toxicology), 180 chemin de Tournefeuille, BP 93173, F-31027 Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, 31027 Toulouse, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Polizzi
authors.affiliation: Inserm UMR1087/CNRS UMR 6291, L'Institut du Thorax, IRS-UN, 8 quai Moncousu, BP 70721, 44007 Nantes Cedex 1, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Chetivaux
authors.affiliation: INRA, ToxAlim (Research Centre in Food Toxicology), 180 chemin de Tournefeuille, BP 93173, F-31027 Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, 31027 Toulouse, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Pineau
authors.affiliation: INRA, ToxAlim (Research Centre in Food Toxicology), 180 chemin de Tournefeuille, BP 93173, F-31027 Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, 31027 Toulouse, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Martin
authors.affiliation: INRA, ToxAlim (Research Centre in Food Toxicology), 180 chemin de Tournefeuille, BP 93173, F-31027 Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, 31027 Toulouse, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Guillou
authors.affiliation: INRA, ToxAlim (Research Centre in Food Toxicology), 180 chemin de Tournefeuille, BP 93173, F-31027 Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, 31027 Toulouse, France. Electronic address: Laila.lakhal@toulouse.inra.fr.
authors.forename: Laila
authors.initials: L
authors.lastname: Mselli-Lakhal
mesh_terms: D000367:Age Factors; D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D052244:Endocrine Disruptors / Q000633:toxicity*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006937:Hypercholesterolemia / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis; D006943:Hyperglycemia / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010636:Phenols / Q000633:toxicity*; D018570:Risk Assessment; D013997:Time Factors; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D015415:Biomarkers; D001786:Blood Glucose; D002784:Cholesterol; D052244:Endocrine Disruptors; D007328:Insulin; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: Bisphenol A; Cholesterol metabolism; Glucose metabolism; Lipogenesis; Liver