Endocrine Abstracts

Background: Down syndrome (DS) is caused by the triplication of chromosome 21 and is associated with several endocrine abnormalities including reduced fertility. While onset of puberty is unaffected in individuals with DS, fertility and reproductive lifespan are often diminished. We used the Dp1Tyb mouse model to investigate mechanisms underlying reduced fertility and reproductive ageing.

Methods: The Dy1Tyb mouse strain has an extra copy of 63% of Hsa21-orthologous mouse genes and was used as our in vivo model of DS. Breeding performance from Dp1Tyb and wild-type (C57BL/6J) colonies was analysed using in-house facility records and public data from the Mouse Phenome Database (Jackson Laboratory). Animals were sacrificed at the end of reproductive life, defined as >3 months without producing a litter. To evaluate female reproductive ageing, we determined the age of last litter as a proxy for menopause onset and quantified total follicular count at the end of reproductive life.

Results: Male and female Dy1Tyb breeders (crossed with wild-type mice) produced fewer litters per dam, with fewer pups per litter, compared to wild-type breeders, with female mutants producing less than males. Furthermore, female mutants exhibited a significantly earlier age of last litter, indicating premature reproductive decline, compared to wild-type controls. Histological analysis revealed similar ovarian weights but a reduction in total follicular count at the end of reproductive life in female mutants compared to wild-type controls.

Conclusion: Dp1Tyb mice replicate the subfertility observed in individuals with DS and reveal evidence of accelerated reproductive ageing in females, characterised by earlier cessation of reproduction and diminished ovarian reserve. These findings highlight the Dp1Tyb strain as a robust model to investigate mechanisms of infertility and reproductive senescence in DS.