title: In utero growth restriction and catch-up adipogenesis after developmental di (2-ethylhexyl) phthalate exposure cause glucose intolerance in adult male rats following a high-fat dietary challenge.
abstract: Phthalates impact adipocyte morphology in vitro, but the sex-specific adipogenic signature immediately after perinatal di(2-ethylhexyl) phthalate (DEHP) exposure and adulthood physiology following a high-fat (HF) dietary challenge are unknown. In the current study, pregnant and lactating dams received DEHP (300 mg/kg body weight) or oil. At weaning [postnatal day (PND) 21], adipose tissue was sampled for real-time polymerase chain reaction. The remaining offspring consumed a control or HF diet. DEHP decreased % fat in males at birth from 13.9%±0.2 to 11.8%±0.6 (mean±S.E.M.), representing a 15.1% decrease in fat by DEHP, and these males caught up in adiposity to controls by PND21. Adult DEHP-exposed males had a 27.5% increase in fat (12.5%±0.9% in controls vs. 15.9%±1.5% in the DEHP group); adipocyte perimeter was increased as well, with fewer small/medium-sized adipocytes, and decreased cell number compared to oil controls. HF diet intake in DEHP-exposed males further increased male energy intake and body weight and led to glucose intolerance. In PND21 males, DEHP increased the expression of adipogenic markers (Pparg1, Cebpa, Adipoq, Ppard, Fabp4, Fasn, Igf1), decreased Lep, and decreased markers of mesenchymal stem cell commitment to the adipogenic lineage (Bmp2, Bmp4, Stat1, Stat5a) compared to oil controls. These data suggest that DEHP may decrease the adipocyte pool at birth, which initially increases adaptive adipocyte maturation and lipid accumulation, but leads to adipose tissue dysfunction in adulthood, decreasing the capacity to adapt to a HF diet, and leading to systemic glucose intolerance.
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, Illinois.
authors.forename: Rita S
authors.initials: RS
authors.lastname: Strakovsky
authors.affiliation: Department of Pathobiology, University of Illinois, Urbana-Champaign, Urbana, Illinois.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Lezmi
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, Illinois.
authors.forename: Ielyzaveta
authors.initials: I
authors.lastname: Shkoda
authors.affiliation: Department of Comparative Biosciences, University of Illinois, Urbana-Champaign, Urbana, Illinois.
authors.forename: Jodi A
authors.initials: JA
authors.lastname: Flaws
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, Illinois.
authors.forename: William G
authors.initials: WG
authors.lastname: Helferich
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, Illinois; Division of Nutritional Sciences, University of Illinois, Urbana-Champaign, Urbana, Illinois. Electronic address: yxpan@illinois.edu.
authors.forename: Yuan-Xiang
authors.initials: YX
authors.lastname: Pan
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000473:pathology; D050156:Adipogenesis / Q000187:drug effects* / Q000235:genetics; D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D001724:Birth Weight / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects*; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018149:Glucose Intolerance; D008099:Liver / Q000187:drug effects; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D013739:Testosterone / Q000378:metabolism
chemical_list: D013739:Testosterone; D004051:Diethylhexyl Phthalate
keywords: Adipose; Diabetes; Obesity; Phthalates; Pparg; Programming