Effects of butylated hydroxyanisole on the development and functions of reproductive system in rats

Butylated hydroxyanisol (BHA) is a widely used antioxidant for long preservation of food products, cosmetics and pharmaceuticals. Although BHA is generally recognized as safe, it is classified as a suspected endocrine-disrupting compound. We investigated the effects of BHA on reproductive function and development by the treatment of mature male and female SD rats (F0) through pre-gestation, gestation and lactation period and of their offspring (F1) until 13 weeks old via gavage with BHA 0 (corn oil, vehicle control), 10, 100 and 500 mg/kg bw/day. Organ weights of liver, adrenal gland and thyroid gland of F0 rats were increased by BHA 500 mg/kg but those of spleen and ventral prostate were decreased without significant difference in terminal body weight. Reduced serum testosterone and thyroxine (T4) were observed with dose-dependent manner in F0 male rats. Mating rate was decreased and cohabitation duration for conception was longer without differences in the number, motility and morphology of sperm by BHA 500 mg/kg. Body weight of F1 offspring was significantly decreased with change of relative weight of liver and brain by BHA 500 mg/kg at PND21. Sexual maturation indicated by vaginal opening and preputial separation was delayed by BHA 500 mg/kg. The weights of liver and adrenal gland were increased while those of spleen, vagina, testes and ventral prostate were decreased in F1 rats exposed to BHA 100 or 500 mg/kg for 13 weeks. Also, BHA 500 mg/kg reduced the velocity of sperm motion and number with smaller-sized sperm head in F1 male rats and slightly shortened estrous cycle length with higher frequency of estrus and lower frequency of diestrus stages in F1 female rats. Lower serum T4 and testosterone contents with higher serum cholesterol levels were also observed by BHA 500 mg/kg. Increased follicular cell height, and exfoliated and vacuolated follicular epithelial cells were observed in thyroids of F1 female and males rats exposed to BHA 500 mg/kg. This study elucidates that high dose of BHA induce weak dysfunction and underdevelopment of reproductive system of male and female rats with the change of T4 and testosterone levels, sex organ weights and sexual maturation and histological lesions of thyroid gland.