Analysis Tools
mortality/aging
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• all pups (if any) delivered by 12-mo-old heterozygous females die within 18-48 hrs after birth
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• success at first weaning (number of surviving pups by P21) in crosses between 3-mo-old heterozygous females and wild-type males is reduced by 25% relative to age-matched wild-type females
• in crosses between 7-mo-old heterozygous females and wild-type males the index of weaning success declines to ~43% versus ~71% in age-matched wild-type controls
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• at 3-4 months of age, female heterozygotes begin to exhibit several features that are consistent with an accelerated aging process, including premature reproductive senescence by about 7 months, skeletal deformity, and late onset of obesity
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• female heterozygotes display premature reproductive senescence by about 7 months
(J:65577)
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reproductive system
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• at 3 months of age, the oocyte diameters within primordial (stage I) follicles, primary (stage II) follicles, secondary (stage III) follicles and antral follicles of heterozygous ovaries are greater than in wild-type control follicles
• notably, at 7- and 12 months, heterozygous oocyte diameters within all types of follicles are reduced relative to wild-type; however, these differences are significant only within antral follicles of 7-mo-old ovaries and within primordial follicles of 12-mo-old ovaries
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• by 12 months of age, the heterozygous ovary is virtually depleted of all oocytes
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• heterozygous females exhibit accelerated oocyte loss due to atresia and increased follicular cell death in the ovary
• at 7 months of age, heterozygous ovaries have lost 75% of the oocyte pool
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• by 12 months, the corpus luteum is absent
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• at 3 months, heterozygous mutant ovaries display large numbers of atretic follicles indicating disruption of the cellular layers and pyknotic nuclei, which is typical of atretic granulosa cells
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• female heterozygotes a significant decrease in the numbers of growing follicles in their ovary
• by 12 months of age, all heterozygous ovaries are barren while wild-type ovaries retain 30% of values noted at 3 months with active folliculogenesis and hundreds of different types of follicles and corpora lutea
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• female heterozygotes show a 50% reduction in the number of primary follicles
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• at 7 months, heterozygous ovaries display pyknotic nuclei and cellular debris in the antrum of some large follicles, many of which appear abnormal
• at 7 months, some follicles contain aberrant or double oocytes while the corpus luteum is sparse
• by 12 months, very few follicles are found, the corpus luteum is absent, and most of the heterozygous ovary consists of fibroid interstitial tissue and cystic follicles
• at 3 months, apoptotic changes in the heterozygous ovary occur predominantly in preantral medium-sized follicles while in wild-type ovaries apoptosis is mostly confined to some granulosa cells of large, antral-size follicles
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• by 7 months of age, heterozygous ovaries show an accelerated rate of follicle recruitment from the resting pool as indicated by increased numbers of developing or growing follicles
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• at 7 months, some follicles contain double oocytes
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• at >12 months of age, females heterozygotes exhibit ovarian tumors
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• by 15 months of age, female heterozygotes exhibit large ovarian cysts, not present in wild-type females
(J:70933)
• by 12 months, cysts form the greater part of the ovarian space in some cases
(J:140008)
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• female heterozygotes exhibit premature ovarian failure accompanied by degenerative changes, including atresia, apoptosis, and profound loss of oocytes evident by 7 months of age
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• female heterozygotes display premature reproductive senescence by about 7 months
(J:65577)
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• in female heterozygotes the age of pubertal onset occurs ~1.8 days earlier than in wild-type siblings
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• F2 heterozygous females conceive later than wild-type females (at 10-12 weeks versus at 7-8 weeks, respectively)
• the interval between mating and conception gets progressively longer with each pregnancy
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• in 1-yr-old heterozygous females the interval between establishing the vaginal plug and delivery ranges between 45 and 60 days while age-matched wild-type controls give healthy pups within 24-28 days
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• at 7 months long estrus cycles are interspersed with short ones, and intermittent ovulatory cycles are intermingled with acyclic periods
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• at 7 months, only 8 of 75 heterozygous females exhibit some cyclicity; the remaining are either acyclic with only leukocytes in the smears or with smears showing persistent vaginal cornification
• cycle frequency drops steadily with age from 4.5 cycles per month at 3 months and 2.5 cycles per month at 7 months and is lost altogether by 1 yr of age
• female heterozygotes show an increased number of cycles with extended cornification at a much earlier age relative to wild-type controls
• the percentage of virgin heterozygotes cycling at 3 months (84%) is reduced to 49% at 7 months and to 0% at 12 months versus 92%, 78%, and 62%, respectively, in virgin wild-type controls
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• heterozygotes display prolonged estrous cycles due to extended diestrus and irregular estrus patterns albeit with normal vaginal cytology
(J:65577)
• notably, all heterozygous females show normal signs of estrogen stimulation (full vaginal cornification) during estrus
(J:65577)
• at 3 months of age, all heterozygous females show prolonged cycles (~6.2 days) due to extended diestrus versus ~4.9 day cycles in wild-type females
(J:140008)
• at 7 months, the mean length of estrous cycle for heterozygous females is ~11.6 days with a range of 4-15 days versus ~5.6 day cycles with a range of 4-7 days in wild-type controls
(J:140008)
• at 7 months long estrus cycles are interspersed with short ones, and intermittent ovulatory cycles are intermingled with acyclic periods
(J:140008)
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• following ~6-8 births, heterozygous females undergo early reproductive senescence and can no longer conceive, whereas wild-type controls continue to breed for >14 months
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• at 3 months of age, the percentage of mated heterozygous females that deliver litters is 85% relative to 96% in wild-type controls
• at 7 months, the percentage of mated heterozygous females that deliver pups is reduced to 49% versus 83% in wild-type controls
• by 12 months, this percentage is further reduced to 12% while 73% of wild-type controls continue to produce live offspring
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• heterozygous females show a >50% reduction in litter size relative to wild-type controls
(J:65577)
• heterozygous females mated with wild-type males show a significantly longer time lag between mating and first litter while the number of pups in first litter is reduced by 43% and success at first weaning (pups surviving on P21) is decreased by 25%
(J:65577)
• overall breeding performance is more profoundly affected in crosses among heterozygous breeders
(J:65577)
• starting at 3 months of age, heterozygous females show a 33% reduction in litter size relative to wild-type littermates
(J:140008)
• litter size is further reduced at 7 months (54% less), and by 12 months heterozygous females deliver an average of only 0.5 0.3 offspring that die within 18-48 hrs after birth while 73% of wild-type controls continue to produce viable offspring
(J:140008)
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homeostasis/metabolism
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• heterozygous females show slightly increased serum testosterone levels relative to wild-type controls
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• heterozygous females show a 30% reduction in serum progesterone levels relative to wild-type controls
• plasma levels of estradiol also display a decreasing trend but this difference is not significant due to variations among animals
• in the heterozygous uterus, the A form of the progesterone receptor (PR-A) (-64%) is reduced more than PR-B (-44%) relative to wild-type controls
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growth/size/body
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• by 15 months of age, female heterozygotes exhibit large ovarian cysts, not present in wild-type females
(J:70933)
• by 12 months, cysts form the greater part of the ovarian space in some cases
(J:140008)
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• at 3-4 months of age, the body weights of heterozygous females are increased by 9.6% relative to wild-type controls
(J:65577)
• although at weaning the average body weight of immature heterozygous females is reduced by 9%, by 7 months their average body weight (~28.3 g) is significantly higher than that of age-matched wild-type females
(J:140008)
• by 12 months, the average body weight of female heterozygotes is increased by ~25% relative to wild-type controls
(J:140008)
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• by 10-12 months of age, all heterozygous females become obese
(J:65577)
• at 12 months, female heterozygotes are pear-shaped and show clear signs of obesity
(J:140008)
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skeleton
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• at 1 year of age, female heterozygotes that show early reproductive senescence also exhibit skeletal abnormalities characterized by a severe stooped posture-kyphosis
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behavior/neurological
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• at 1 year of age, female heterozygotes that show early reproductive senescence also exhibit skeletal abnormalities characterized by a severe stooped posture
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endocrine/exocrine glands
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• by 12 months, the corpus luteum is absent
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• at 3 months, heterozygous mutant ovaries display large numbers of atretic follicles indicating disruption of the cellular layers and pyknotic nuclei, which is typical of atretic granulosa cells
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• female heterozygotes a significant decrease in the numbers of growing follicles in their ovary
• by 12 months of age, all heterozygous ovaries are barren while wild-type ovaries retain 30% of values noted at 3 months with active folliculogenesis and hundreds of different types of follicles and corpora lutea
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• female heterozygotes show a 50% reduction in the number of primary follicles
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• at 7 months, heterozygous ovaries display pyknotic nuclei and cellular debris in the antrum of some large follicles, many of which appear abnormal
• at 7 months, some follicles contain aberrant or double oocytes while the corpus luteum is sparse
• by 12 months, very few follicles are found, the corpus luteum is absent, and most of the heterozygous ovary consists of fibroid interstitial tissue and cystic follicles
• at 3 months, apoptotic changes in the heterozygous ovary occur predominantly in preantral medium-sized follicles while in wild-type ovaries apoptosis is mostly confined to some granulosa cells of large, antral-size follicles
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• by 7 months of age, heterozygous ovaries show an accelerated rate of follicle recruitment from the resting pool as indicated by increased numbers of developing or growing follicles
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• at 7 months, some follicles contain double oocytes
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• at >12 months of age, females heterozygotes exhibit ovarian tumors
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• by 15 months of age, female heterozygotes exhibit large ovarian cysts, not present in wild-type females
(J:70933)
• by 12 months, cysts form the greater part of the ovarian space in some cases
(J:140008)
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• female heterozygotes exhibit premature ovarian failure accompanied by degenerative changes, including atresia, apoptosis, and profound loss of oocytes evident by 7 months of age
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neoplasm
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• at >12 months of age, females heterozygotes exhibit ovarian tumors
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cellular
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• at 3 months of age, the oocyte diameters within primordial (stage I) follicles, primary (stage II) follicles, secondary (stage III) follicles and antral follicles of heterozygous ovaries are greater than in wild-type control follicles
• notably, at 7- and 12 months, heterozygous oocyte diameters within all types of follicles are reduced relative to wild-type; however, these differences are significant only within antral follicles of 7-mo-old ovaries and within primordial follicles of 12-mo-old ovaries
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• by 12 months of age, the heterozygous ovary is virtually depleted of all oocytes
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• heterozygous females exhibit accelerated oocyte loss due to atresia and increased follicular cell death in the ovary
• at 7 months of age, heterozygous ovaries have lost 75% of the oocyte pool
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• as early as 3 months of age, TUNEL staining indicates that antral and many preantral ovarian follicles undergo apoptosis
• the percentage of degenerating preantral follicles is significantly higher in heterozygous females relative to wild-type controls (15% versus 4.3%, respectively)
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