Development of infertility at young adult age in a mouse model of human Sandhoff disease

Abstract

Sandhoff disease is a human lysosomal storage disease. In a knockout mouse model of Sandhoff disease, which lacks the β-subunit of β-hexosaminidase A (Hex A, αβ subunits) and B (Hex B, ββ subunits), the mutant homozygous mice (Hexb^–/–) are healthy until 15 weeks of age when they develop neurodegenerative symptoms. This study was designed to analyse the fertility profile of male and female Hexb^–/– mice. Mating behaviour of Hexb^–/– mice was assessed at different ages. The ovarian function of Hexb^–/– females was determined by superovulation studies. The quality of spermatozoa and ova was assessed by an in vitro fertilization (IVF) procedure. Hexb^–/– mice were fertile at a young age. Males were fertile up to the age of 69.3 ± 6.3 days (mean ± SD) and females were fertile up to the age of 56–63 days. Since both the Hexb^–/– sexes showed fertility, the results indicate that Hex A and Hex B (major isozymes of β-hexosaminidase) may not be required for sperm–ovum interactions, in contrast to the widely accepted belief. On the other hand, young adult Hexb^–/– males showed a reduction in mating behaviour at the age of 84.8 ± 2.2 days and an absence of mating behaviour at 94.2 ± 2.0 days. Spermatozoa from Hexb^–/– mice (aged 109.2 ± 1.8 days) showed a lower IVF rate. Among Hexb^–/– females aged 85.6 ± 2.1 days, no mice became pregnant although they were positive for a vaginal plug when caged with fertile males. The number of ova recovered from Hexb^–/– females (aged 111.0 ± 3.1 days) and the IVF rate of ova were lower than those of controls. In conclusion, Hex A and Hex B may not be required for sperm–ovum interactions. Mice lacking Hex A and Hex B activities develop infertility at a young adult age in an age-dependent manner.