CHRONIC ADMINISTRATION OF SODIUM VALPROIC ACID SLOWS PUBERTAL MATURATION IN INBRED DBA 2J MICE - SKELETAL, HISTOLOGICAL, AND ENDOCRINOLOGICEVIDENCE/

Sodium valproic acid (VPA) has been reported to occasionally delay pub ertal maturation in children. In the current study, we sought to estab lish a valid animal model with which to further investigate the neuroe ndocrinological sequelae of VPA administration. Male and female DBA/2J mice were weaned at 2 weeks of age and administered either VPA (17-20 mg/kg/day) or control solution via drinking water. Animals were weigh ed and sacrificed via decapitation at 4, 6, or 8 weeks of age. Testes and ovaries were prepared for histological analyses. In addition, the length of the left humerus bone from each animal was obtained as an in dex of skeletal growth, and trunk blood was assayed for circulating fo llicle-stimulating hormone (FSH) and prolactin (PRL). For males, testi cular weights of the animals receiving VPA were significantly lower th an those of control animals at all three sampling ages. No between-gro up differences were found for body weight at any sampling age, and yet the rate of skeletal maturation (as indexed by humerus length) was de creased significantly for the VPA-treated males at an three sampling p eriods. Additionally, while hormone levels did not consistently differ , histological analyses of the gonadal tissue demonstrated significant ly decreased rates of spermatogenesis at all sampling points for WA-tr eated animals. For females, chronic VPA administration led to a signif icant reduction in uterine weight at the 4 and 6 week sampling periods , and yet by 8 weeks of age the uterine weights for the two groups did not differ. Histological analyses of the ovarian tissue revealed that both the density of atrial follicles and corpora lutea were significa ntly less in VPA-treated animals after 4 weeks of treatment, but not a fter 2 or 6 weeks of treatment. However, these results were not corrob orated by differences in circulating FSH or PRL levels. Finally, altho ugh body weight did not differ between the two groups at any sampling period, humerus length was significantly less for the VPA-treated fema les at the 4 week sampling period. These data indicate that chronic ad ministration of VPA delays reproductive and skeletal maturation in gen etically epilepsy-prone mice.