title: Compound- and sex-specific effects on programming of energy and immune homeostasis in adult C57BL/6JxFVB mice after perinatal TCDD and PCB 153.
abstract: Early life exposure to endocrine disrupting compounds has been linked to chronic diseases later in life, like obesity and related metabolic disorders. We exposed C57BL/6JxFVB hybrid mice to the aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the constitutive androstane receptor/pregnane X receptor agonist polychlorinated biphenyl 153 (PCB 153) in an experimental design relevant for human exposure. Exposure occurred during gestation and lactation via maternal feed to a wide dose range (TCDD: 10-10,000 pg/kg body weight/day; PCB 153: 0.09-1406 μg/kg body weight/d). Then exposure was ceased and offspring were followed up to 1 year of age. Metabolic parameters like body weight, fat pad weights, glucose tolerance, endocrine serum profile, and neurobehavioral and immunological parameters were determined. Body weight was transiently affected by both compounds throughout the follow-up. TCDD-exposed males showed decreased fat pad and spleen weights and an increase in IL-4 production of splenic immune cells. In contrast, females showed increased fat pad weights and production of IFNγ. PCB 153-exposed males showed an increase in glucose, whereas females showed an increase in glucagon, a decrease in pancreas weight, and an increase in thymus weight. In conclusion, early life exposure to TCDD appears to affect programming of energy and immune homeostasis in offspring, whereas the effects of perinatal PCB 153 were mainly on programming of glucose homeostasis. Both compounds act sex-specifically. Lowest derived BMDLs (lower bounds of the (two sided) 90%-confidence interval for the benchmark dose) for both compounds are not lower than current tolerable daily intakes.
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: henny.verharen@rivm.nl.
authors.forename: H W
authors.initials: HW
authors.lastname: Verharen
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: hennie.hodemaekers@rivm.nl.
authors.forename: H M
authors.initials: HM
authors.lastname: Hodemaekers
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: eric.gremmer@rivm.nl.
authors.forename: E R
authors.initials: ER
authors.lastname: Gremmer
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: bhawani.nagarajah@rivm.nl.
authors.forename: B
authors.initials: B
authors.lastname: Nagarajah
authors.affiliation: Department of Chemistry and Biology, Institute for Environmental Studies (IVM), VU University, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands. Electronic address: jorke.kamstra@vu.nl.
authors.forename: J H
authors.initials: JH
authors.lastname: Kamstra
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: 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: D050154:Adiposity / Q000187:drug effects; D000367:Age Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity*; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D005865:Gestational Age; D006706:Homeostasis; D007107:Immune System / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007774:Lactation; D008297:Male; D018811:Maternal Exposure; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011247:Pregnancy; D000077297:Pregnane X Receptor; D011297:Prenatal Exposure Delayed Effects; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists / Q000378:metabolism; D012737:Sex Factors; D015430:Weight Gain / Q000187:drug effects
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D001786:Blood Glucose; D052244:Endocrine Disruptors; D007371:Interferon-gamma; D015847:Interleukin-4; D011078:Polychlorinated Biphenyls; D000072317:Polychlorinated Dibenzodioxins; D000077297:Pregnane X Receptor; D018336:Receptors, Aryl Hydrocarbon; D011987:Receptors, Steroid; C484722:Ahr protein, mouse; C014024:2,4,5,2',4',5'-hexachlorobiphenyl
keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin; Endocrine disrupting compounds; Energy homeostasis; Immune homeostasis; Polychlorinated biphenyl 153; Programming