Analysis Tools
reproductive system
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• at 7 months of age, rounded germ cells that have lost their intercellular attachments are observed
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• by 4 months of age, the number of apoptotic germ cells per seminiferous tubule cross section is 1.7-fold greater, the fraction of tubule cross sections with any apoptotic germ cells is 1.4-fold greater, and the fraction of tubule cross sections with >3 apoptotic germ cells is 2.3-fold greater than in wild-type males
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• at 6 months of age, cauda epididymal sperm motility was 66% lower than in wild-type males
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• middle-aged (10- to 12-month-old) females have significantly fewer healthy primordial follicles than age-matched wild-type controls, consistent with accelerated ovarian aging
• however, peripubertal (35-day-old) females exhibit normal ovarian follicle numbers
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• ovaries show significantly fewer healthy antral follicles than wild-type ovaries, regardless of benzo[a]pyrene (BaP) dose
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• at 35 days of age, ovaries show significantly greater numbers of multiovular follicles than wild-type ovaries, regardless of benzo[a]pyrene (BaP) dose
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• males develop age-related seminiferous tubule pathology
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• at 7 months of age, 5 of 8 males show moderate to severe vacuolization of seminiferous tubules, with >10% vacuolated tubules per cross section
• severe intracytoplasmic vacuolization begins in the tubular epithelium more centrally within the tubule and progresses to the periphery, sparing the Sertoli cells
• severely affected males show numerous seminiferous tubules that are completely devoid of germ cells, containing only Sertoli cells
• less affected tubules show spermatid heads near the basement membrane and meiotic stages interspersed with haploid germ cell stages
• however, no inflammation is observed in testis sections at 35 days, and 4 or 7 months of age
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• testes weigh 44% less at 35 days of age, 5% less at 2 months of age, 34% less at 3 months of age, 36% less at 4 months of age, and 41% less at 6 months of age relative to control testes
• however, serum testosterone levels are relatively normal at 2 and 6 months of age
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• ovaries show lower protein levels of the catalytic and modifier subunits of glutamate-cysteine ligase (GCL) as well as a ~15% reduction in total ovarian glutathione (GSH) concentrations
• mRNA levels of several GSTs and of Ephx1, which are involved in benzo[a]pyrene (BaP) metabolism, are also reduced
• however, ovaries exhibit normal sensitivity to DNA damage, apoptosis and follicle destruction in response to BaP treatment, with no increase in ovarian BaP-related DNA adduct formation relative to wild-type controls
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• middle-aged females have significantly fewer remaining primordial ovarian follicles, indicating accelerated age-related depletion of the ovarian reserve
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• males show an age-related decline in spermatogenesis caused by chronic oxidative stress and progressive accumulation of oxidative damage to seminiferous tubules due to reduced testicular antioxidant activities
• a moderately high vitamin E-supplemented diet fails to prevent the age-related spermatogenic defects
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• males show an age-related decline in both testicular sperm head counts and epididymal sperm counts
• at 4 months of age, males show significantly fewer sperm heads per testis, sperm per epididymis, and sperm per milligram of epididymis than wild-type males
• by 6 months of age, males have 65% fewer epididymal sperm per cauda and 63% fewer sperm per milligram cauda than wild-type males
• 6-month-old males have 44% fewer sperm heads per testis; however, sperm heads per milligram testis are only slightly lower than in wild-type males
• by 7 months of age, few epididymal sperm are found within the epididymal lumen
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• epididymal weights are significantly reduced at 4 but not at 6 months of age
• however, epididymal epithelium remains normal in severely affected males up to 7 months of age
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• during a 20-week continuous breeding study, male mice sire fewer litters and a lower cumulative number of offspring than wild-type or heterozygous males
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cellular
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N |
• 7 days after i.p. injection with 50 mg/kg benzo[a]pyrene (BaP), ovaries show no significant increase in BaP DNA adduct formation or in ovarian surface epithelial cell
proliferation and apoptosis relative to BaP-treated wild-type ovaries
• no genotype- or BaP treatment-related differences in the percentages of TUNEL-positive, apoptotic ovarian secondary or antral follicles are observed
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• at 7 months of age, rounded germ cells that have lost their intercellular attachments are observed
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• males show an age-related decline in both testicular sperm head counts and epididymal sperm counts
• at 4 months of age, males show significantly fewer sperm heads per testis, sperm per epididymis, and sperm per milligram of epididymis than wild-type males
• by 6 months of age, males have 65% fewer epididymal sperm per cauda and 63% fewer sperm per milligram cauda than wild-type males
• 6-month-old males have 44% fewer sperm heads per testis; however, sperm heads per milligram testis are only slightly lower than in wild-type males
• by 7 months of age, few epididymal sperm are found within the epididymal lumen
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• by 4 months of age, the number of apoptotic germ cells per seminiferous tubule cross section is 1.7-fold greater, the fraction of tubule cross sections with any apoptotic germ cells is 1.4-fold greater, and the fraction of tubule cross sections with >3 apoptotic germ cells is 2.3-fold greater than in wild-type males
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• at 6 months of age, cauda epididymal sperm motility was 66% lower than in wild-type males
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• at 3 months of age, testicular levels of lipid hydroperoxides malondialdehyde (MDA) and 4-hydroxyalkenals (HAE) are ~23% higher than in wild-type testes when expressed per milligram of protein
• epididymal MDA and HAE levels are also 59% higher when expressed per milligram of protein
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homeostasis/metabolism
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N |
• in response to benzo[a]pyrene (BaP) treatment, females show a similar BaP dose-dependent reduction in the number of total healthy ovarian follicles and healthy primordial and primary ovarian follicles relative to BaP-treated wild-type controls, indicating normal sensitivity to BaP-induced ovarian toxicity
(J:310044)
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N |
• males do not exhibit facial edema up to 7 months of age
(J:165602)
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• total ovarian glutathione (GSH) concentrations are ~15% lower than in wild-type females
(J:310044)
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• total glutathione (GSH) concentrations in epididymides are 34% lower when expressed per milligram of protein and 35% lower when expressed per milligram of tissue, respectively, whereas epididymal oxidized glutathione (GSSG) levels are normal
(J:165602)
• no differences in total GSH or GSSG concentrations are observed in testes
(J:165602)
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• ovaries show reduced protein levels of the catalytic and modifier subunits of glutamate-cysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis, with 36% lower protein levels of GCLC and 45% lower protein levels of GCLM
(J:310044)
• ovarian mRNA levels of Gstm1 (glutathione S-transferase, mu 1) and Ephx1 (epoxide hydrolase 1, microsomal) are 67% and 91% lower than in wild-type controls
(J:310044)
• however, ovarian SOD2 (superoxide dismutase 2, mitochondrial) protein levels are normal
(J:310044)
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• testicular and epididymal mRNA levels of antioxidant genes are reduced at 2 months of age
(J:165602)
• mRNA levels of Gclc (glutamate-cysteine ligase, catalytic subunit), Gsta3 (glutathione S-transferase, alpha 3) and Gstm1 (glutathione S-transferase, mu 1) are significantly lower in testes, while Gclc, Gclm (glutamate-cysteine ligase, modifier subunit), Gstm1, Gstm2 (glutathione S-transferase, mu 2), and Sod2 (superoxide dismutase 2, mitochondrial) mRNA levels are significantly lower in the epididymides
(J:165602)
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• 2- to 4-month-old males show increased levels of testicular and epididymal lipid peroxidation
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• glutathione reductase activity is 31% lower in epididymides when expressed as milliunits per milligram of tissue
• glutathione S-transferase (GST) activity is 24% lower when expressed as milliunits per milligram of tissue and 14% lower when expressed as milliunits per milligram of protein in testes
• epididymal GST activity is 8% lower when expressed as milliunits per milligram of tissue
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• glutathione peroxidase activity is 16% lower in epididymides when expressed as milliunits per milligram of tissue
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mortality/aging
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N |
• males do not show increased mortality or clinical signs of illness up to 7 months of age
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• middle-aged females have significantly fewer remaining primordial ovarian follicles, indicating accelerated age-related depletion of the ovarian reserve
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endocrine/exocrine glands
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• middle-aged (10- to 12-month-old) females have significantly fewer healthy primordial follicles than age-matched wild-type controls, consistent with accelerated ovarian aging
• however, peripubertal (35-day-old) females exhibit normal ovarian follicle numbers
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• ovaries show significantly fewer healthy antral follicles than wild-type ovaries, regardless of benzo[a]pyrene (BaP) dose
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• at 35 days of age, ovaries show significantly greater numbers of multiovular follicles than wild-type ovaries, regardless of benzo[a]pyrene (BaP) dose
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• males develop age-related seminiferous tubule pathology
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• at 7 months of age, 5 of 8 males show moderate to severe vacuolization of seminiferous tubules, with >10% vacuolated tubules per cross section
• severe intracytoplasmic vacuolization begins in the tubular epithelium more centrally within the tubule and progresses to the periphery, sparing the Sertoli cells
• severely affected males show numerous seminiferous tubules that are completely devoid of germ cells, containing only Sertoli cells
• less affected tubules show spermatid heads near the basement membrane and meiotic stages interspersed with haploid germ cell stages
• however, no inflammation is observed in testis sections at 35 days, and 4 or 7 months of age
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• testes weigh 44% less at 35 days of age, 5% less at 2 months of age, 34% less at 3 months of age, 36% less at 4 months of age, and 41% less at 6 months of age relative to control testes
• however, serum testosterone levels are relatively normal at 2 and 6 months of age
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• ovaries show lower protein levels of the catalytic and modifier subunits of glutamate-cysteine ligase (GCL) as well as a ~15% reduction in total ovarian glutathione (GSH) concentrations
• mRNA levels of several GSTs and of Ephx1, which are involved in benzo[a]pyrene (BaP) metabolism, are also reduced
• however, ovaries exhibit normal sensitivity to DNA damage, apoptosis and follicle destruction in response to BaP treatment, with no increase in ovarian BaP-related DNA adduct formation relative to wild-type controls
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immune system
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• 4 of 12 males (2 each in the high and low vitamin E diet groups) show elevated dsDNA antibodies relative to 0 of 10 wild-type controls
• however, no correlation between dsDNA antibody level and testicular weight, testicular sperm count, or epididymal sperm count is observed
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limbs/digits/tail
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N |
• males do not exhibit any tail lesions up to 7 months of age
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behavior/neurological
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N |
• males do not exhibit decreased grooming up to 7 months of age
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renal/urinary system
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N |
• males show normal kidney weights with no histological evidence of glomerulonephritis at 4 months of age
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