Abstract
In utero exposure to bisphenol A (BPA) increases mammary cancer susceptibility in offspring. High-fat diet is widely believed to be a risk factor of breast cancer. The objective of this study was to determine whether maternal exposure to BPA in addition to high-butterfat (HBF) intake during pregnancy further influences carcinogen-induced mammary cancer risk in offspring, and its dose–response curve. In this study, we found that gestational HBF intake in addition to a low-dose BPA (25 µg/kg BW/day) exposure increased mammary tumor incidence in a 50-day-of-age chemical carcinogen administration model and altered mammary gland morphology in offspring in a non-monotonic manner, while shortening tumor-free survival time compared with the HBF-alone group. In utero HBF and BPA exposure elicited differential effects at the gene level in PND21 mammary glands through DNA methylation, compared with HBF intake in the absence of BPA. Top HBF + BPA-dysregulated genes (ALDH1B1, ASTL, CA7, CPLX4, KCNV2, MAGEE2 and TUBA3E) are associated with poor overall survival in The Cancer Genomic Atlas (TCGA) human breast cancer cohort (n = 1082). Furthermore, the prognostic power of the identified genes was further enhanced in the survival analysis of Caucasian patients with estrogen receptor-positive tumors. In conclusion, concurrent HBF dietary and a low-dose BPA exposure during pregnancy increases mammary tumor incidence in offspring, accompanied by alterations in mammary gland development and gene expression, and possibly through epigenetic reprogramming.
Highlights
Breast cancer is a major global public health problem and effective prevention strategies are needed to combat the disease, most desirably at the primary prevention level (Hanf & Gonder 2005, Fabian et al 2015)
The primary aim of this study was to determine if maternal exposure to low doses of bisphenol A (BPA) (2.5–2500 μg/kg body weight (BW)/day) in combination with a HBF diet modifies mammary gland development and increases the risk of mammary tumorigenesis in first-generation offspring
Our major findings were that as a result of gestational intake of a diet containing 39% kcal from butterfat, exposure to BPA at 25 μg/kg BW/day was most effective in increasing mammary tumor incidence to 90% compared with 45.5% when BPA was not present in the diet
Summary
Breast cancer is a major global public health problem and effective prevention strategies are needed to combat the disease, most desirably at the primary prevention level (Hanf & Gonder 2005, Fabian et al 2015). Exposure to Western lifestyles dramatically increases breast cancer incidence in Asian immigrants in the United States (US) during their lifetime and in their offspring over several generations (Buell 1973, Ziegler et al 1993). Cohort and human case–control studies have generated conflicting reports regarding the effect of high-fat intake on adult breast cancer risk (Hulka 1989, Willett et al 1992, Hunter et al 1996, Martin et al 2011), partly due to differences in fat/dietary composition, and study design, including exposure window. The development of rodent models have proved critical to assess the effects of single and/or multiple exposures on susceptible windows of mammary gland development and in the subsequent identification of factors relevant for breast cancer prevention in humans
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