Abstract

H-Tx rats have fetal-onset inherited hydrocephalus. Linkage analysis has determined the genetics is complex, with at least three loci associated with hydrocephalus. In addition, maternal and/or intrauterine factors influence the frequency of expression. The aim of this study was to characterize nongenetic (epigenetic) factors that affect hydrocephalus in this strain. Groups of primiparous and multiparous females were used to breed fetuses for examination in utero. Multiparous females were manipulated to have either gestation with lactation or, by removal of pups at birth, gestation without lactation. In addition, hydrocephalus expression in postnatal rats from the breeding colony was analyzed for primiparous and multiparous females. The latter were subdivided according to the interval between the litter examined and the previous litter. There was no particular uterine position or horn that favored hydrocephalus and hydrocephalic fetuses were the same weight as normal littermates. The frequency of hydrocephalus was 16-20% in primiparous females and twofold higher in multiparous females that were lactating during pregnancy. Removal of the suckling pups prevented this increase. The severity of hydrocephalus was measured on 1-mm-thick fixed brain slices. Fetuses from lactating females had hydrocephalus that was significantly more severe than the nonlactating groups. However, all fetus groups had hydrocephalus that was very much less severe than the postnatal pups, suggesting that severity increases after birth. It is concluded that there is an epigenetic factor that increases the frequency of inherited hydrocephalus in fetuses if suckling pups are present during gestation. Future experiments will examine possible mechanisms for this genotype-environment interaction.