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A Transgenerational Study of Exposure to Zeranol, a Dietary Contaminant with Potent Estrogenic Activity

by
Christal April Lewis
B.S. Montclair State University- 2006

Thesis Advisor: Helmut Zarbl, Ph.D.

Graduate Program in Cell & Developmental Biology

EOHSI Conference Room A/B
Piscataway, NJ

Friday, September 25, 2015
11:00 a.m.


Abstract

Zeranol is a potent semi-synthetic derivative of zearalenone, a mycoestrogen that contaminates grain and cereal. Zeranol was originally developed as a substitute for the carcinogen, diethylstilbestrol (DES). Zeranol is currently banned in Europe and Asia but still used in the US as growth promoter in livestock. It is detected in finished food products and is extremely stable at cooking temperatures with a long half-life in humans. Occupational exposures to Zer are associated with precocious puberty, thelarche and gynecomastia. Recently our lab showed that urinary levels of unconjugated Zer were associated with altered onset of puberty, height and weight in girls that primarily consumed beef and corn (Bandera et al., 2011). We evaluated F344 rats to determine whether low dose perinatal exposure to Zer caused transgenerational phenotypic alterations on precocious puberty, feminization of males, and tumorigenesis aided by N-nitroso-N-methylurea (NMU). Dose finding studies indicated perinatal exposure to 25 g/kg/day increased dam body weight in week 3 of gestation. Litter size and pup body weight were decreased in 1.25 and 25 g/kg/day Zer exposed groups demonstrating a non-monotonic dose response. Our studies in F-344 rats indicated that developmental dietary exposure to Zer (between postnatal day 7 (PND7) to weaning), at doses below the human allowable daily intake (ADI, 1.25 gg/kg/day) resulted in decreased male offspring, precocious puberty (defined as a 3 day decrease in age at vaginal opening) in F1 progeny, increased reproductive organ weight and abnormally prolonged estrous cycle. The F1 male progeny demonstrated decreased anogenital distance and lowered sperm count in the cauda epididymis. The F2 female offspring had advanced vaginal opening if both the dam and sire had been treated with perinatal Zer. Zeranol exposure prolonged estrus phase in both the TFxCM and TFxTM groups. Male F2 progeny showed feminization assessed by both decreased anogenital distance and sperm count when exposed to perinatal Zer. Studies on the F3 generation demonstrated a significant decrease in fecundity, male offspring and delayed vaginal opening in F3 female progeny coupled with prolonged proestrus phase. F3 males had decreased anogenital distance, lower corpus/caput epididymis and decreased Sry mRNA expression levels. Lastly, F1 females treated with a single carcinogenic dose of NMU showed decreased latency, increased incidence of mammary tumors, tumor multiplicity and larger tumor volume. Similar effects on carcinogenesis were also observed in the F2 progeny; the female offspring showed decreased latency, increased incidence of mammary tumors, tumor multiplicity and larger tumor volume when both the dam and sire were exposed to perinatal Zer. Together, these studies suggest that perinatal exposure to Zer produces transgenerational effects on sexual maturation, fertility and susceptibility to chemical-induced carcinogenesis.


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