Perinatal Exposure to Bisphenol A or Diethylstilbestrol Increases the Susceptibility to Develop Mammary Gland Lesions After Estrogen Replacement Therapy in Middle-Aged Rats

Abstract

The development of the mammary gland is a hormone-regulated event. Several factors can dysregulate its growth and make the gland more susceptible to cellular transformation. Among these factors, perinatal exposure to xenoestrogens and hormone replacement therapy has been associated with increased risk of developing breast cancer. Here, we assessed the effects induced by estrogen replacement therapy (ERT) in ovariectomized (OVX) middle-aged rats and whether perinatal exposure to diethylstilbestrol (DES) or bisphenol A (BPA) modified these effects in the mammary gland. Pregnant rats were orally exposed to vehicle, 5 μg DES/kg/day, or 0.5 or 50 μg BPA/kg/day from gestational day 9 until weaning. Then, 12-month-old offspring were OVX and treated with 17β-estradiol for 3 months. Morphological changes and the percentage of epithelial cells that proliferated or expressed estrogen receptor alpha (ESR1) and progesterone receptor (PR) were analyzed in mammary gland samples of 15-month-old animals. ERT induced lobuloalveolar hyperplasia and ductal cysts in the mammary gland of middle-aged rats, associated with a higher proliferation index of epithelial cells. Perinatal exposure to DES followed by ERT increased the number of cysts and induced the formation of fibroadenoma and ductal carcinoma in situ, without modifying the expression of ESR1 or PR. Also, after 3 months of ERT, BPA-exposed rats had a higher incidence of ductal hyperplasia and atypical lobular hyperplasia than animals under ERT alone. In conclusion, perinatal exposure to xenoestrogens increases the susceptibility of the mammary gland to develop cysts and hyperplastic lesions when confronted with ERT later in life.

Bisphenol S and Bisphenol A disrupt morphogenesis of MCF-12A human mammary epithelial cells

“…The mammary gland is one of the targets for endocrine disruption. Studies in mice have shown that gestational exposure of female mice to BPA resulted in alterations in the reproductive organs of the animals altered mammary gland development and subsequent susceptibility to mammary tumour formation later in life 3,8 . Since BPA is being replaced with other analogues, such as BPS, it is important to determine whether these analogues have the potential to disrupt mammary gland development and/or have a potential to increase breast cancer incidence.…”

“…However, an increasing body of evidence suggests that the aetiology for breast cancer may be in part related to chemical exposure. Evidence from epidemiological studies suggests that exposure to chemicals with endocrine disruptor activity, or endocrine disruptors (EDCs), may be positively correlated to the development of breast cancer especially if the exposure occurred during critical developmental stages 3 . Numerous studies have examined the correlation between exposure to environmental pollutants and development of breast cancer, in a variety of in vitro and in vivo models.…”

“…It has been reported that prenatal and perinatal exposures of rats to diethylstilboestrol (DES) or BPA altered mammary gland development and induced precancerous and cancerous lesions in the mammary gland 7,8 . Further, a study showed that perinatal exposure of rats to BPA increased the incidence of cancerous lesions in rats who also received hormone replacement therapy when they reached middle age 3 . Several studies have linked BPA exposure to increased breast cancer risk in epidemiological studies 9 .…”

Genome-Wide Analysis of Low Dose Bisphenol-A (BPA) Exposure in Human Prostate Cells

“…Three biological replicate cultures exposed to BPA or EE2 were used in the analyses. Expression level data from the Illumina Bead Studio software were normalized using a loess algorithm [42]. Probes, whose expression level that exceeded a threshold value in at least one sample, are called detected.…”

“…In the United States, BPA has been detected in 93% of 2,517 urine samples collected from both adults and children, indicating pervasive exposure to this contaminant [3,28,29]. Data from multiple sources indicate that its ubiquitous presence and thereby continuous exposure in humans cause adverse health effects including premature puberty [30], reduced fertility [31][32][33], obesity [34][35][36][37], metabolic diseases [38] and cancer [39][40][41][42]. The initial study to assess BPA's estrogenic effects demonstrated that it increased the growth rate of MCF-7 cells [43].…”