Diethylstilbestrol (DES): Carcinogenic Potential in Xpa^−/−, Xpa^−/−/p53^+/−, and Wild-Type Mice During 9 Months’ Dietary Exposure

Abstract

DES carcinogenicity has been investigated in 2 mouse knockout models, the Xpa homozygous knockout, and the combined Xpa homozygous and p53 heterozygous knockout. Wild-type (WT) mice were also included. Xpa mice received diets containing DES at concentrations of 0, 100, 300, and 1500 ppb for 39 weeks; Xpa/p53 and WT mice received diets containing 0 or 1500 ppb. There were 15 of each sex per group. Both Xpa and WT mice had a similar incidence of tumors at the high dosage of 1500 ppb, including pituitary adenomas in 4 WT mice and 7 Xpa mice, and single incidences of osteosarcoma (Xpa), T-cell lymphoma (WT and Xpa), and testicular interstitial cell adenoma (WT and Xpa). The incidence of tumors was higher in the Xpa/p53 mice at 1500 ppb, mainly attributable to 5 osteosarcomas in males and 2 in females, but also 4 pituitary adenomas, testicular interstitial cell adenomas in 4 males, and single incidences of cerebral glioma, phaeochromocytoma, and cervical fibrosarcoma. The incidence of osteosarcomas was related to the severity of fibro-osseous lesions in the bone marrow. It was concluded that for carcinogenicity screening, Xpa mice were no more sensitive than wild-type mice for compounds like DES, but the Xpa/p53 model showed an increased sensitivity.

The Pathology of Aging 129S6/SvEvTac Mice

“…2,70,72 Experimental evidence supporting these mechanisms were provided by the observation that synthetic compounds with hormonal activity like diethylstilbestrol and misoprostol also induce a high incidence of FOL in female mice, while males are only marginally affected. 32 A causal association has been proposed between other age-related lesions of female reproductive tract (eg, ovarian atrophy, ovarian cysts, cystic endometrial hyperplasia) and development FOL. 2,9,70 A similar correlation could not be confirmed in our study, since all the examined females were ultimately affected by multiple and often concurrent uterine and ovarian lesions.…”

Exposure to endocrine disruptors during adulthood: consequences for female fertility

“…A common result seen from DES exposure (5 μg/g body weight and 50 – 2000 ppb) was a complete loss, degeneration, or a decrease in the number of corpora lutea in the adult ovary, suggesting that DES impaired ovulation (Hong et al 2010; McAnulty and Skydsgaard 2005; Zhao et al 2014). Additionally, DES exposure (200 μg/kg body weight/ day) decreased the numbers of primary, secondary, and pre-ovulatory follicles and increased atretic antral follicles in mice (Jaroenporn et al 2007).…”

“…Additionally, DES exposure (200 μg/kg body weight/ day) decreased the numbers of primary, secondary, and pre-ovulatory follicles and increased atretic antral follicles in mice (Jaroenporn et al 2007). DES (5 μg/g body weight and 250 – 2000 ppb) also caused atrophy of the ovary as well as the thickening and scarring of ovarian connective tissues in mice (Hong et al 2010; McAnulty and Skydsgaard 2005). Further, DES (5 μg/g body weight) impaired reproductive activity in females by decreasing the maturation of ovarian follicles in mice (Hong et al 2010).…”

“…Further, adult exposure to DES (200 μg/kg body weight/ day) increased the thickening of the uterine endometrium, increased dilatation of uterine glands, and increased secretory proteins in mice (Jaroenporn et al 2007). Additionally, DES exposure (250 – 2000 ppb) increased endometrial glandular hyperplasia and caused accumulation of hyaline cartilage in the endometrium of mice (McAnulty and Skydsgaard 2005). Finally, DES exposure (50 ppb) caused mouse uterine horns to become distended (Zhao et al 2014).…”

“…Specifically, daily DES treatment (200 μg/kg body weight/ day) caused cornification of the vaginal epithelium (Jaroenporn et al 2007) and it (250 – 2000 ppb) caused keratinization of the vagina (McAnulty and Skydsgaard 2005). Further, it (200 μg/kg body weight/day, 5μg/g body weight, and 50 ppb) decreased female fertility in mice by interfering with embryo transport, implantation, uterine receptivity, and preimplantation embryo development (Hong et al 2010; Jaroenporn et al 2007; Zhao et al 2014).…”