Grant Abstract: Developmental Gene-Environment Interactions and Premature Ovarian Failure

Grant Number: 5R01ES020454-04
PI Name: Luderer
Project Title: Developmental Gene-Environment Interactions and Premature Ovarian Failure

Abstract: About 90% of cases of premature ovarian failure (POF) occur in women who have normal menarche, cycle normally for some years, and then undergo early onset of ovarian senescence (Nelson 2009). A large number of genetically modified mouse models with POF have POF onset prior to puberty, while many more have a very short fertile window, giving birth to perhaps one or two litters. We have discovered that mice deficient in the modifier subunit of glutamate cysteine ligase (Gclm-/- mice), the rate-limiting enzyme in synthesis of the antioxidant GSH, have a normal complement of oocytes at birth and weaning, but subsequently show an accelerated age-related decline in ovarian follicle numbers compared to wild type littermates. Women with POF also have poor oocyte quality even before the onset of ovarian senescence, and our Gclm-/- mice similarly show poor oocyte quality resulting in preimplantation embryonic mortality due to abnormal development already at the zygote stage. The Gclm-/- mouse model thus recapitulates the key characteristics of the majority of cases of idiopathic POF. The hypothesis of this supplement proposal is that dietary supplementation with the dithiol ?-lipoic acid (LA) beginning at the time of weaning will rescue both the accelerated follicle depletion and the poor oocyte quality of the POF phenotype of the Gclm-/- mice.
Specific Aim 1: Test the ability of ?-lipoic acid (LA) supplemented diet to prevent the accelerated age-related decline in ovarian follicles in Gclm null females and to prevent the early embryonic mortality observed in pregnant Gclm null females.
Specific Aim 2: Test the ability of LA supplemented diets to increase ovarian GSH concentrations in Gclm null and wild type females.

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