Effects of Benzophenone-3 and Propylparaben on Estrogen Receptor-Dependent R-Loops and DNA Damage in Breast Epithelial Cells and Mice
Author Department
PVLSI
Document Type
Article, Peer-reviewed
Publication Date
1-2020
Abstract
BACKGROUND:
Endocrine-disrupting chemicals have been shown to have broad effects on development, but their mutagenic actions that can lead to cancer have been less clearly demonstrated. Physiological levels of estrogen have been shown to stimulate DNA damage in breast epithelial cells through mechanisms mediated by estrogen-receptor alpha (ERα ). Benzophenone-3 (BP-3) and propylparaben (PP) are xenoestrogens found in the urine of>96% of U.S.
POPULATION:
OBJECTIVES:
We investigated the effect of BP-3 and PP on estrogen receptor-dependent transactivation and DNA damage at concentrations relevant to exposures in humans.
METHODS:
In human breast epithelial cells, DNA damage following treatment with 17β-estradiol (E 2 ), BP-3, and PP was determined by immunostaining with antibodies against γ-H2AX and 53BP1. Estrogenic responses were determined using luciferase reporter assays and gene expression. Formation of R-loops was determined with DNA: RNA hybrid-specific S9.6 antibody. Short-term exposure to the chemicals was also studied in ovariectomized mice. Immunostaining of mouse mammary epithelium was performed to quantify R-loops and DNA damage in vivo.
RESULTS:
Concentrations of1μM and5μM BP-3 or PP increased DNA damage similar to that ofE 2 treatment in aERα-dependent manner. However, BP-3 and PP had limited transactivation of target genes at1μM and5μM concentrations. BP-3 and PP exposure caused R-loop formation in a normal human breast epithelial cell line whenERα was introduced. R-loops and DNA damage were also detected in mammary epithelial cells of mice treated with BP-3 and PP.
CONCLUSIONS:
Acute exposure to xenoestrogens (PP and BP-3) in mice induce DNA damage mediated by formation ofERα-dependent R-loops at concentrations 10-fold lower than those required for transactivation. Exposure to these xenoestrogens may cause deleterious estrogenic responses, such as DNA damage, in susceptible individuals. https://doi.org/10.1289/EHP5221.
Recommended Citation
Majhi PD1,2, Sharma A1, Roberts AL1, Daniele E1, Majewski AR1, Chuong LM1, Black AL1, Vandenberg LN3, Schneider SS4,5, Dunphy KA1, Jerry DJ1,5. Effects of Benzophenone-3 and Propylparaben on Estrogen Receptor-Dependent R-Loops and DNA Damage in Breast Epithelial Cells and Mice. Environ Health Perspect. 2020 Jan;128(1):17002.
PMID
31939680