Analysis Tools
mortality/aging
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• despite normal complements of oocytes/ovarian follicles at birth and P21, females show a significantly faster rate of decline in healthy ovarian follicles than wild-type females, driven by an accelerated age-related decline in primordial follicles
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• 4 of 5 mice died following treatment with 800 mg/kg acetaminophen and N-acetylcysteine while no wild-type mice died from the same treatment and no mouse receiving N-acetylcysteine alone demonstrated toxicity
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homeostasis/metabolism
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• at 2 months of age, females exhibit normal serum LH and FSH concentrations on the day of proestrus
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• at 2 and 6 months of age, ovarian total glutathione (GSH) concentrations are 23% of wild-type levels
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• alanine aminotransferase levels are elevated in response to 500 mg/kg acetaminophen in both males and females whereas only wild-type males are similarly affected and the increase is not mitigated by treatment with N-acetylcysteine or glutathione ethyl ester
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• 4 of 5 mice died following treatment with 800 mg/kg acetaminophen and N-acetylcysteine while no wild-type mice died from the same treatment and no mouse receiving N-acetylcysteine alone demonstrated toxicity
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• liver toxicity induced by 500 mg/kg acetaminophen is more severe than in wild-type mice and heterozygotes, and treatment with N-acetylcysteine or glutathione ethyl ester does not offer any protection against acetaminophen-induced hepatotoxicity
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reproductive system
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• total number of ovarian follicles (primordial plus primary plus secondary plus antral) is 46% less than in wild-type females by 3 months, 54% less by 7.5 months, 74% less by 9 months and 64% less by 12 months
• adult ovaries exhibit lower numbers of healthy follicles of all classes from 3 months of age
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• at P21, very few antral follicles are present, unlike in wild-type ovaries where multiple antral follicles are observed
• number of healthy antral follicles is significantly reduced at 3 months while the number of atretic antral follicles is reduced at 7 months of age; however, the % of atretic antral follicles is not significantly altered
• no significant differences in immunostaining for 4-hydroxynonenal (4-HNE, a product of lipid peroxidation) or nitrotyrosine (NTY, an oxidative protein damage marker) are observed in healthy antral follicles at P21 or at 9 months of age
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• although total counts of healthy ovarian follicles and naked oocytes are normal at P2 and P21, very few antral follicles are observed at P21, suggesting a delay in follicular development
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• at P21, the % of PCNA-positive primary follicles is significantly increased, indicating increased recruitment of primordial follicles into the growing pool
• mean % of healthy primary follicles out of total healthy follicles is significantly increased at 7.5 months and approaches significance at 3 months of age, supporting that ovarian follicular activation increased
• increased recruitment of primordial follicles precedes the decline in ovarian follicle numbers seen at 3 months
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• at P21 and 9 months of age, healthy primary follicles show significantly increased NTY immunostaining in granulosa cells
• however, no significant differences in 4-HNE immunostaining are observed in healthy primary follicles at P21 or at 9 months of age
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• at 9 months of age, healthy primordial follicles show significantly increased NTY immunostaining in granulosa cells
• however, no significant differences in 4-HNE immunostaining are observed in healthy primordial follicles at P21 or at 9 months of age
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• at 3, 7.5 and 9 months of age, the number of healthy primordial follicles is significantly lower than in wild-type females, indicating accelerated depletion of the ovarian reserve
• mean % of healthy primordial follicles out of total healthy follicles is significantly reduced at 7.5 and 9 months of age
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• at P21, healthy secondary follicles show significantly increased 4-HNE immunostaining in granulosa cells and theca cells
• at 2 months, the % of secondary follicles with 4-HNE-positive granulosa cells is significantly higher than in wild-type ovaries
• however, no significant differences in NTY immunostaining are observed at P21 or at 9 months of age
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• females show chronic ovarian oxidative stress with significantly reduced ovarian GSH concentrations and oxidized GSH/oxidized glutathione redox potential
• furthermore, ovaries show increased lipid peroxidation and protein oxidation by immunostaining for 4-HNE and NTY, respectively
• increased oxidative stress-induced damage is observed at P21, prior to any difference in follicle numbers
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• at 2 months of age, the % of antral follicles with cleaved caspase-3-positive granulosa cells is significantly higher than in wild-type ovaries, with a nonsignificant increase seen in the % of cleaved caspase 3-positive secondary follicles
• also at 2 months, the % of secondary follicles with TUNEL-positive granulosa cells is significantly higher than in wild-type ovaries, with no significant difference in the % of TUNEL-positive antral follicles
• no genotype-related differences are seen in the %s of TUNEL-positive secondary or antral follicles at P21 or at 9 months of age
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• at P21, the % of PCNA-positive primary follicles (including both transitional or activated follicles) is significantly higher than in wild-type ovaries, indicating increased granulosa cell proliferation
• at 2 months of age, the % of primary follicles with PCNA-positive proliferating granulosa cells is significantly higher than in wild-type ovaries
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• despite normal complements of oocytes/ovarian follicles at birth and P21, females show a significantly faster rate of decline in healthy ovarian follicles than wild-type females, driven by an accelerated age-related decline in primordial follicles
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• at 2 months of age, females show a significantly greater % of days with cornified vaginal cytology (typical of estrus) than wild-type females
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• by 12 months of age, all females show absence of estrus cycling versus only half of wild-type females
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• at 2 months of age, females show significantly longer estrous cycles than wild-type females
• however, no genotype-related differences are observed at 6 or 9 months of age
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cellular
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• at 2 months of age, the % of antral follicles with cleaved caspase-3-positive granulosa cells is significantly higher than in wild-type ovaries, with a nonsignificant increase seen in the % of cleaved caspase 3-positive secondary follicles
• also at 2 months, the % of secondary follicles with TUNEL-positive granulosa cells is significantly higher than in wild-type ovaries, with no significant difference in the % of TUNEL-positive antral follicles
• no genotype-related differences are seen in the %s of TUNEL-positive secondary or antral follicles at P21 or at 9 months of age
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• at P21, the % of PCNA-positive primary follicles (including both transitional or activated follicles) is significantly higher than in wild-type ovaries, indicating increased granulosa cell proliferation
• at 2 months of age, the % of primary follicles with PCNA-positive proliferating granulosa cells is significantly higher than in wild-type ovaries
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• ovarian oxidized glutathione (GSSG) concentrations are 69% at 2 months and 40% at 6 months, respectively, of wild-type levels
• ratio of reduced GSH to GSSG is reduced by approximately half in ovaries at 2 and 6 months of age, and the Nernst potential (Eh) for the GSH/GSSG redox couple is significantly oxidized by ~30 mV at both ages
• ovaries show increased lipid peroxidation and protein oxidation by immunostaining for 4-HNE and NTY, respectively
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endocrine/exocrine glands
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• total number of ovarian follicles (primordial plus primary plus secondary plus antral) is 46% less than in wild-type females by 3 months, 54% less by 7.5 months, 74% less by 9 months and 64% less by 12 months
• adult ovaries exhibit lower numbers of healthy follicles of all classes from 3 months of age
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• at P21, very few antral follicles are present, unlike in wild-type ovaries where multiple antral follicles are observed
• number of healthy antral follicles is significantly reduced at 3 months while the number of atretic antral follicles is reduced at 7 months of age; however, the % of atretic antral follicles is not significantly altered
• no significant differences in immunostaining for 4-hydroxynonenal (4-HNE, a product of lipid peroxidation) or nitrotyrosine (NTY, an oxidative protein damage marker) are observed in healthy antral follicles at P21 or at 9 months of age
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• although total counts of healthy ovarian follicles and naked oocytes are normal at P2 and P21, very few antral follicles are observed at P21, suggesting a delay in follicular development
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• at P21, the % of PCNA-positive primary follicles is significantly increased, indicating increased recruitment of primordial follicles into the growing pool
• mean % of healthy primary follicles out of total healthy follicles is significantly increased at 7.5 months and approaches significance at 3 months of age, supporting that ovarian follicular activation increased
• increased recruitment of primordial follicles precedes the decline in ovarian follicle numbers seen at 3 months
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• at P21 and 9 months of age, healthy primary follicles show significantly increased NTY immunostaining in granulosa cells
• however, no significant differences in 4-HNE immunostaining are observed in healthy primary follicles at P21 or at 9 months of age
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• at 9 months of age, healthy primordial follicles show significantly increased NTY immunostaining in granulosa cells
• however, no significant differences in 4-HNE immunostaining are observed in healthy primordial follicles at P21 or at 9 months of age
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• at 3, 7.5 and 9 months of age, the number of healthy primordial follicles is significantly lower than in wild-type females, indicating accelerated depletion of the ovarian reserve
• mean % of healthy primordial follicles out of total healthy follicles is significantly reduced at 7.5 and 9 months of age
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• at P21, healthy secondary follicles show significantly increased 4-HNE immunostaining in granulosa cells and theca cells
• at 2 months, the % of secondary follicles with 4-HNE-positive granulosa cells is significantly higher than in wild-type ovaries
• however, no significant differences in NTY immunostaining are observed at P21 or at 9 months of age
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• females show chronic ovarian oxidative stress with significantly reduced ovarian GSH concentrations and oxidized GSH/oxidized glutathione redox potential
• furthermore, ovaries show increased lipid peroxidation and protein oxidation by immunostaining for 4-HNE and NTY, respectively
• increased oxidative stress-induced damage is observed at P21, prior to any difference in follicle numbers
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• at 2 months of age, the % of antral follicles with cleaved caspase-3-positive granulosa cells is significantly higher than in wild-type ovaries, with a nonsignificant increase seen in the % of cleaved caspase 3-positive secondary follicles
• also at 2 months, the % of secondary follicles with TUNEL-positive granulosa cells is significantly higher than in wild-type ovaries, with no significant difference in the % of TUNEL-positive antral follicles
• no genotype-related differences are seen in the %s of TUNEL-positive secondary or antral follicles at P21 or at 9 months of age
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• at P21, the % of PCNA-positive primary follicles (including both transitional or activated follicles) is significantly higher than in wild-type ovaries, indicating increased granulosa cell proliferation
• at 2 months of age, the % of primary follicles with PCNA-positive proliferating granulosa cells is significantly higher than in wild-type ovaries
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• despite normal complements of oocytes/ovarian follicles at birth and P21, females show a significantly faster rate of decline in healthy ovarian follicles than wild-type females, driven by an accelerated age-related decline in primordial follicles
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