title: DHEA-mediated inhibition of the pentose phosphate pathway alters oocyte lipid metabolism in mice.
abstract: Women with polycystic ovary syndrome (PCOS) and hyperandrogenism have altered hormone levels and suffer from ovarian dysfunction leading to subfertility. We have attempted to generate a model of hyperandrogenism by feeding mice chow supplemented with dehydroepiandrosterone (DHEA), an androgen precursor that is often elevated in women with PCOS. Treated mice had polycystic ovaries, low ovulation rates, disrupted estrous cycles, and altered hormone levels. Because DHEA is an inhibitor of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the pentose phosphate pathway, we tested the hypothesis that oocytes from DHEA-exposed mice would have metabolic disruptions. Citrate levels, glucose-6-phosphate dehydrogenase activity, and lipid content in denuded oocytes from these mice were significantly lower than controls, suggesting abnormal tricarboxylic acid and pentose phosphate pathway metabolism. The lipid and citrate effects were reversible by supplementation with nicotinic acid, a precursor for reduced nicotinamide adenine dinucleotide phosphate. These findings suggest that elevations in systemic DHEA can have a negative impact on oocyte metabolism and may contribute to poor pregnancy outcomes in women with hyperandrogenism and PCOS.
authors.affiliation: 425 South Euclid Avenue, BJC Institute of Health, Box 8064, St Louis, MO 63110. moleyk@wustl.edu.
authors.forename: Patricia T
authors.initials: PT
authors.lastname: Jimenez
authors.forename: Antonina I
authors.initials: AI
authors.lastname: Frolova
authors.forename: Maggie M
authors.initials: MM
authors.lastname: Chi
authors.forename: Natalia M
authors.initials: NM
authors.lastname: Grindler
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Willcockson
authors.forename: Kasey A
authors.initials: KA
authors.lastname: Reynolds
authors.forename: Quihong
authors.initials: Q
authors.lastname: Zhao
authors.forename: Kelle H
authors.initials: KH
authors.lastname: Moley
mesh_terms: D000818:Animals; D003687:Dehydroepiandrosterone / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005298:Fertility; D005947:Glucose / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism; D010053:Ovary / Q000187:drug effects; D010427:Pentose Phosphate Pathway / Q000187:drug effects* / Q000502:physiology; D011247:Pregnancy
chemical_list: D003687:Dehydroepiandrosterone; D005947:Glucose
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