Abstract
Fetal and neonatal exposure to long-chain alkylphenols has been suspected to promote breast developmental disorders and consequently to increase breast cancer risk. However, disease predisposition from developmental exposures remains unclear. In this work, human MCF-10A mammary epithelial cells were exposed in vitro to a low dose of a realistic (4-nonylphenol + 4-tert-octylphenol) mixture. Transcriptome and cell-phenotype analyses combined to functional and signaling network modeling indicated that long-chain alkylphenols triggered enhanced proliferation, migration ability, and apoptosis resistance and shed light on the underlying molecular mechanisms which involved the human estrogen receptor alpha 36 (ERα36) variant. A male mouse-inherited transgenerational model of exposure to three environmentally relevant doses of the alkylphenol mix was set up in order to determine whether and how it would impact on mammary gland architecture. Mammary glands from F3 progeny obtained after intrabuccal chronic exposure of C57BL/6J P0 pregnant mice followed by F1–F3 male inheritance displayed an altered histology which correlated with the phenotypes observed in vitro in human mammary epithelial cells. Since cellular phenotypes are similar in vivo and in vitro and involve the unique ERα36 human variant, such consequences of alkylphenol exposure could be extrapolated from mouse model to human. However, transient alkylphenol treatments combined to ERα36 overexpression in mammary epithelial cells were not sufficient to trigger tumorigenesis in xenografted Nude mice. Therefore, it remains to be determined if low-dose alkylphenol transgenerational exposure and subsequent abnormal mammary gland development could account for an increased breast cancer susceptibility.
Highlights
Mammary duct network development initiates during fetal life and continues until first lactation in adulthood
We demonstrated that the alkylphenol mix acts through a rapid, estrogen receptor alpha 36 (ERα36) dependent non-genomic pathway [13]
The results strongly suggest that a low-dose alkylphenol exposure could promote a mammary gland abnormal development
Summary
Mammary duct network development initiates during fetal life and continues until first lactation in adulthood. Recent works indicate that fetal and/or neonatal exposure to xenoestrogens––such as bisphenol A (BPA)––alters the mammary gland development and subsequently drives an increased long-term risk of breast cancer [3, 4]. Previous studies by Chapin et al [7] confirmed by Tyl et al [8] demonstrated a lack of any transgenerational reproductive toxicity of dietary 4-nonylphenol (4NP) exposure during late gestation in Sprague–Dawley rats at doses ranging from 15 to 150 mg/kg/day. Prenatal exposure to high doses of 4NP (25 mg/kg/day in MMTV-neu mice and 100 mg/kg/day in rats) causes altered development of the mammary gland, changes in steroid-receptor activation as well as increased synthesis of liver estriol [9, 10] in F1 pups. The authors concluded that the infant intake of this mix ranges from 0.23 to 0.65 μg/kg/day, which is about 1,000 times less than the doses previously experimented before
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
