Transgenerational Effects of Low-Dose, Perinatal Exposure of rats to Zeranol on Sexual Development, Reproduction, and Susceptibility to Mammary Carcinogenesis
Zeranol (Zer) is a semi-synthetic derivative of Zearalenone, a myco-estrogen produced by Fusarium fungi, that is used in livestock to enhance meat production. Zer from implants is detectable in meat, is stable at cooking temperatures and has a long half-life of ~22 hours in humans. Our studies in prepubescent girls indicated that human exposure occurs via the consumption of beef and popcorn, and urinary levels of Zer are associated with altered onset of puberty, height and weight. To determine the effects of perinatal exposure, developing progeny were exposed via the maternal diet between GD-7 to GD21 and every third day PND-7 through weaning. The maternal dose of 0.625 μg/kg/day corresponded half the human ADI (1.25μg/kg/day). Perinatal exposure of F1 progeny resulted in precocious puberty in females F1 progeny, defined by a decrease in mean age at vaginal opening and altered estrus cycling. F1 males showed feminization as assessed by decreased ano-genital distance and decreased sperm counts. F1 females treated with a single dose of carcinogen showed decreased latency and increased incidence of mammary tumors. Similar effects on both male and female sexual development and carcinogenesis were observed in the F2 progeny, but only if both the dam and the sire were perinatally exposed to Zer, suggesting a recessive, epigenetic mode of transmission. F3 progeny showed decreased fecundity and litter sizes, with a significant decrease in the number of males. F3 females also retain an increased susceptibility to mammary carcinogenesis. These studies suggest that perinatal exposure to Zer produces transgenerational effects on sexual development and susceptibility to carcinogenesis.