title: Dynamic Metabolic Disruption in Rats Perinatally Exposed to Low Doses of Bisphenol-A.
abstract: Along with the well-established effects on fertility and fecundity, perinatal exposure to endocrine disrupting chemicals, and notably to xeno-estrogens, is strongly suspected of modulating general metabolism. The metabolism of a perinatally exposed individual may be durably altered leading to a higher susceptibility of developing metabolic disorders such as obesity and diabetes; however, experimental designs involving the long term study of these dynamic changes in the metabolome raise novel challenges. 1H-NMR-based metabolomics was applied to study the effects of bisphenol-A (BPA, 0; 0.25; 2.5, 25 and 250 μg/kg BW/day) in rats exposed perinatally. Serum and liver samples of exposed animals were analyzed on days 21, 50, 90, 140 and 200 in order to explore whether maternal exposure to BPA alters metabolism. Partial Least Squares-Discriminant Analysis (PLS-DA) was independently applied to each time point, demonstrating a significant pair-wise discrimination for liver as well as serum samples at all time-points, and highlighting unequivocal metabolic shifts in rats perinatally exposed to BPA, including those exposed to lower doses. In BPA exposed animals, metabolism of glucose, lactate and fatty acids was modified over time. To further explore dynamic variation, ANOVA-Simultaneous Component Analysis (A-SCA) was used to separate data into blocks corresponding to the different sources of variation (Time, Dose and Time*Dose interaction). A-SCA enabled the demonstration of a dynamic, time/age dependent shift of serum metabolome throughout the rats' lifetimes. Variables responsible for the discrimination between groups clearly indicate that BPA modulates energy metabolism, and suggest alterations of neurotransmitter signaling, the latter finding being compatible with the neurodevelopmental effect of this xenoestrogen. In conclusion, long lasting metabolic effects of BPA could be characterized over 200 days, despite physiological (and thus metabolic) changes connected with sexual maturation and aging.
authors.affiliation: UMR1331, TOXALIM, Research Centre in Food Toxicology, Institut National de la Recherche Agronomique, INRA, Université de Toulouse, Toulouse, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Tremblay-Franco
authors.affiliation: UMR1331, TOXALIM, Research Centre in Food Toxicology, Institut National de la Recherche Agronomique, INRA, Université de Toulouse, Toulouse, France.
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Cabaton
authors.affiliation: UMR1331, TOXALIM, Research Centre in Food Toxicology, Institut National de la Recherche Agronomique, INRA, Université de Toulouse, Toulouse, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Canlet
authors.affiliation: UMR1331, TOXALIM, Research Centre in Food Toxicology, Institut National de la Recherche Agronomique, INRA, Université de Toulouse, Toulouse, France.
authors.forename: Roselyne
authors.initials: R
authors.lastname: Gautier
authors.affiliation: Department of Integrative Physiology & Pathobiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Schaeberle
authors.affiliation: UMR1331, TOXALIM, Research Centre in Food Toxicology, Institut National de la Recherche Agronomique, INRA, Université de Toulouse, Toulouse, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Jourdan
authors.affiliation: Department of Integrative Physiology & Pathobiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Carlos
authors.initials: C
authors.lastname: Sonnenschein
authors.affiliation: UMR1331, TOXALIM, Research Centre in Food Toxicology, Institut National de la Recherche Agronomique, INRA, Université de Toulouse, Toulouse, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Vinson
authors.affiliation: Department of Integrative Physiology & Pathobiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Soto
authors.affiliation: UMR1331, TOXALIM, Research Centre in Food Toxicology, Institut National de la Recherche Agronomique, INRA, Université de Toulouse, Toulouse, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zalko
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D004968:Estrogens, Non-Steroidal / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D055442:Metabolome / Q000187:drug effects*; D010636:Phenols / Q000008:administration & dosage* / Q000494:pharmacology; D011247:Pregnancy; D066244:Proton Magnetic Resonance Spectroscopy / Q000379:methods*; D051381:Rats; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D004968:Estrogens, Non-Steroidal; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds