title: Programming of metabolic effects in C57BL/6JxFVB mice by exposure to bisphenol A during gestation and lactation.
abstract: The global rise in prevalence of obesity is not fully explained by genetics or life style factors. The developmental origins of health and disease paradigm suggests that environmental factors during early life could play a role. In this perspective, perinatal exposure to bisphenol A (BPA) has been indicated as a programming factor for obesity and related metabolic disorders later in life. Here we study early life programming by BPA using an experimental design that is relevant for human exposure. C57BL/6JxFVB hybrid mice were exposed during gestation and lactation via maternal feed to 8 non-toxic doses (0-3000 μg/kg body weight/day (μg/kg bw/d)) of BPA. After weaning, offspring were followed for 20 weeks without further exposure. Adult male offspring showed dose-dependent increases of body and liver weights, no effects on fat pad weights and a dose-dependent decrease in circulating glucagon. Female offspring showed a dose-dependent decrease in body weight, liver, muscle and fat pad weights, adipocyte size, serum lipids, serum leptin and adiponectin. Physical activity was decreased in exposed males and suggested to be increased in exposed females. Brown adipose tissue showed slightly increased lipid accumulation in males and lipid depletion in females, and ucp1 expression was dose-dependently increased in females. The effects in females were more reliable and robust than in males due to wide confidence intervals and potential confounding by litter size for male data. The lowest derived BMDL (lower bound of the (two-sided) 90%-confidence interval for the benchmark dose) of 233 μg/kg bw/d (for interscapular weight in females) was below the proposed BMDL of 3633 μg/kg bw/d as a basis for tolerable daily intake. Although these results suggest that BPA can program for an altered metabolic phenotype, the sexual dimorphism of effects and diversity of outcomes among studies similar in design as the present study do not mark BPA as a specific obesogen. The consistency within the complex of observed metabolic effects suggests that upstream key element(s) in energy homeostasis are modified. Sex-dependent factors contribute to the final phenotypic outcome.
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands; Department of Chemistry and Biology, Institute for Environmental Studies (IVM), VU University, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands. Electronic address: joantine.van.esterik@rivm.nl.
authors.forename: J C J
authors.initials: JC
authors.lastname: van Esterik
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands. Electronic address: martijn.dolle@rivm.nl.
authors.forename: M E T
authors.initials: ME
authors.lastname: Dollé
authors.affiliation: Department of Chemistry and Biology, Institute for Environmental Studies (IVM), VU University, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands. Electronic address: marja.lamoree@vu.nl.
authors.forename: M H
authors.initials: MH
authors.lastname: Lamoree
authors.affiliation: Department of Chemistry and Biology, Institute for Environmental Studies (IVM), VU University, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands. Electronic address: stefan.vanleeuwen@wur.nl.
authors.forename: S P J
authors.initials: SP
authors.lastname: van Leeuwen
authors.affiliation: Department of Chemistry and Biology, Institute for Environmental Studies (IVM), VU University, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands. Electronic address: timo.hamers@vu.nl.
authors.forename: T
authors.initials: T
authors.lastname: Hamers
authors.affiliation: Department of Chemistry and Biology, Institute for Environmental Studies (IVM), VU University, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands. Electronic address: juliette.legler@vu.nl.
authors.forename: J
authors.initials: J
authors.lastname: Legler
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands. Electronic address: leo.van.der.ven@rivm.nl.
authors.forename: L T M
authors.initials: LT
authors.lastname: van der Ven
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D001774:Blood Chemical Analysis; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004032:Diet; D004968:Estrogens, Non-Steroidal / Q000633:toxicity*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects; D007473:Ion Channels / Q000096:biosynthesis / Q000235:genetics; D007774:Lactation / Q000502:physiology*; D008297:Male; D008660:Metabolism / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D009043:Motor Activity / Q000187:drug effects; D009765:Obesity / Q000139:chemically induced / Q000235:genetics; D009929:Organ Size / Q000187:drug effects; D010636:Phenols / Q000633:toxicity*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D011297:Prenatal Exposure Delayed Effects / Q000473:pathology; D012098:Reproduction / Q000187:drug effects; D012727:Sex Characteristics; D000071256:Uncoupling Protein 1; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D018076:DNA, Complementary; D004968:Estrogens, Non-Steroidal; D007473:Ion Channels; D024101:Mitochondrial Proteins; D010636:Phenols; D000071256:Uncoupling Protein 1; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: Bisphenol A; Developmental programming; Early life exposure; Endocrine disrupting compounds; Metabolic impairment; Obesogen