title: Progressive obesity alters ovarian insulin, phosphatidylinositol-3 kinase, and chemical metabolism signaling pathways and potentiates ovotoxicity induced by phosphoramide mustard in mice.
abstract: Mechanisms underlying obesity-associated reproductive impairment are ill defined. Hyperinsulinemia is a metabolic perturbation often observed in obese subjects. Insulin activates phosphatidylinositol 3-kinase (PI3K) signaling, which regulates ovarian folliculogenesis, steroidogenesis, and xenobiotic metabolism. The impact of progressive obesity on ovarian genes encoding mRNA involved in insulin-mediated PI3K signaling and xenobiotic biotransformation [insulin receptor (Insr), insulin receptor substrate 1 (Irs1), 2 (Irs2), and 3 (Irs3); kit ligand (Kitlg), stem cell growth factor receptor (Kit), protein kinase B (AKT) alpha (Akt1), beta (Akt2), forkhead transcription factor (FOXO) subfamily 1 (Foxo1), and subfamily 3 (Foxo3a), microsomal epoxide hydrolase (Ephx1), cytochrome P450 family 2, subfamily E, polypeptide 1 (Cyp2e1), glutathione S-transferase (GST) class Pi (Gstp1) and class mu 1 (Gstm1)] was determined in normal wild-type nonagouti (a/a; lean) and lethal yellow mice (KK.CG-Ay/J; obese) at 6, 12, 18, or 24 weeks of age. At 6 weeks, ovaries from obese mice had increased (P < 0.05) Insr and Irs3 but decreased (P < 0.05) Kitlg, Foxo1, and Cyp2e1 mRNA levels. Interestingly, at 12 weeks, an increase (P < 0.05) in Kitlg and Kit mRNA, pIRS1Ser302, pAKTThr308, EPHX1, and GSTP1 protein level was observed due to obesity, while Cyp2e1 mRNA and protein were reduced. A phosphoramide mustard (PM) challenge increased (P < 0.05) ovarian EPHX1 protein abundance in lean but not obese females. In addition, lung tissue from PM-exposed animals had increased (P < 0.05) EPHX1 protein with no impact of obesity thereon. Taken together, progressive obesity affected ovarian signaling pathways potentially involved in obesity-associated reproductive disorders.
authors.affiliation: Department of Animal Science, 2356 Kildee Hall, Iowa State University, Ames, IA, USA.
authors.forename: Jackson
authors.initials: J
authors.lastname: Nteeba
authors.affiliation: Department of Animal Science, 2356 Kildee Hall, Iowa State University, Ames, IA, USA.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Ganesan
authors.affiliation: Department of Animal Science, 2356 Kildee Hall, Iowa State University, Ames, IA, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Madden
authors.affiliation: Department of Animal Science, 2356 Kildee Hall, Iowa State University, Ames, IA, USA.
authors.forename: Mackenzie J
authors.initials: MJ
authors.lastname: Dickson
authors.affiliation: Department of Animal Science, 2356 Kildee Hall, Iowa State University, Ames, IA, USA.
authors.forename: Aileen F
authors.initials: AF
authors.lastname: Keating
mesh_terms: D000818:Animals; D005260:Female; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D009765:Obesity; D010053:Ovary / Q000187:drug effects / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D010752:Phosphoramide Mustards / Q000633:toxicity*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D007328:Insulin; D010752:Phosphoramide Mustards; C030090:phosphoramide mustard; D058539:Phosphatidylinositol 3-Kinase
keywords: ovary; obesity; phosphatidylinositol-3 kinase; ovotoxicant