Effects of Fetal Exposure to Diethylstilbestrol on Mammary Tumorigenesis in Rats

Abstract

ABSTRACT. The aim of this study was to investigate the effect of fetal exposure to diethylstilbestrol (DES) on the induction of mammary tumors induced by 7,12-dimethylbenz [a]anthracene (DMBA) in female rats. Pregnant rats were fed only normal diet, diet mixed with 0.1 ppm DES throughout pregnancy period or diet mixed with 0.1, 1 or 10 ppm DES from day 13 of pregnancy till the end of pregnancy. Delivered pups were given 10 mg DMBA by gastric intubation at 50 days after birth and observed till 336 days after birth. Some rats exposed to DES throughout pregnancy and those from day 13 till the end of pregnancy showed endocrine disrupting effects such as absence of CL and active lactation in mammary glands at necropsy, while no abnormal estrus cycle such as persistent estrus was seen during the observation period until 88 days after birth. Fetal exposure to 0.1 ppm DES throughout pregnancy period, 0.1 and 1 ppm DES from day 13 of pregnancy increased the incidence and number of mammary carcinomas (MCs) at the earlier period while exposure to 0.1 ppm DES throughout pregnancy period enhanced the incidence and number of benign proliferative lesions (PLs) at the later period. MCs appeared earlier than benign PLs. These results suggest that exposure to DES throughout pregnancy and from day 13 of pregnancy could induce endocrine disrupting conditions and enhance the induction of MCs and that exposure to DES throughout pregnancy enhance PLs. There is evidence that many environmental endocrine disruptors act as sex hormones, particularly during the perinatal or neonatal period, directly or indirectly affecting reproduction in human and rats [13,23,27]. Endogenous hormone mimics are proposed for a number of adverse human health effects, including infertility, abnormal prenatal and childhood development, and reproductive cancers [18].We have reported that the neonatal administration of diethylstilbestrol (DES) [12,14,33], 4-n-octylphenol [10], 17-estradiol (E 2 ) [4] and testosterone propionate [9,[28][29][30] affected mammary tumorigenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female rats.In humans, women exposed to diethylstilbestrol (DES), a synthetic estrogen with strong estrogenic activity, during pregnancy have a moderately increased risk of breast cancer [17,27]. It is also known that the frequency of vaginal clear cell adenocarcinoma was increased in young women whose mothers used DES to prevent or lower the risk of abortion, while DES was ineffective to prevent miscarriages and premature births [3,27].Huggins et al. previously showed that a single administration of 20 mg DMBA at 50 days after birth induced visible mammary cancer in rats by 110 days after birth [6]. This animal has since been a useful model for studying the carcinogenesis of human breast cancer. DMBA is known to be a polycyclic hydrocarbon carcinogen forming DNA adducts [24]. The presence of estrogen and progesterone receptors in DMBA-induced mammary carcinomas (MCs) has been well documented in rats [31,32]. DMBA-transformed cells (intrad...

Endocrine-active chemicals in mammary cancer causation and prevention

“…Similar findings were reported through the use of a dimethylbenz[a]anthracene (DMBA) model of rodent mammary carcinogenesis, with female ACI rats treated in utero with DES (0.8 or 8 g DES) on gestational days 15 and 18 exhibiting increased tumor incidence and multiplicity [15]. Kawaguchi et al found that fetal exposure (from gestational day 13 until birth) to dietary DES (0.1, 1, or 10 ppm DES) followed by DMBA at postnatal day (PND) 50 increased tumor incidence and multiplicity when compared to controls [16].…”

Emerging Estrogenic Pollutants in the Aquatic Environment and Breast Cancer

“…However, a parallel experiment with 45 mg/kg/day showed an increase of mammary cancer formation in MMTVneu mice that expressed an unactivated Erbb2 under the control of the mouse mammary tumor virus promoter that gave an increase in cancer susceptibility [ 69 ]. Concerning octylphenol, a study using 100 to 1000 ppm of octylphenol mixed into the diet during pregnancy showed an increase of early incidence and number of mammary cancers induced by DMBA [ 76 ]. Nevertheless, as for triclosan, the carcinogenic effects of octylphenol remain controversial.…”

Prenatal exposure to diethylstilbestrol and long-term impact on the breast and reproductive tract in humans and mice

“…Fetal DES exposure increases mammary tumorigenesis and tumor multiplicity. [40][41][42][43][44][45][46][47][48] In addition, neonatal DES exposure of rodents (a time that corresponds to prenatal development in humans) also increases the incidence of cancer in experimental mammary tumor models [49][50][51][52][53][54] (for review see Fenton and Newbold 72 ). Recently, altered gene expression was demonstrated in rat TEBs exposed neonatally to DES, thus showing that differentiation-and development-related genes are involved in altered TEB structural and cellular abnormalities in DES-exposed mammary tissue and its increased propensity to develop cancer.…”