BACKGROUND: Endocrine disruptors (EDs) constitute a class of chemicals that can interfere with the endocrine system, possibly influencing breast cancer risk. EDs exposure has been associated with changes in the epigenome such as methylation; their ability to modify other epigenetic processes, such as microRNA, has not been thoroughly investigated, especially in the context of mammary development.

METHODS: We investigated the influence on microRNA of three EDs widely used in personal care products: diethyl phthalate (DEP), methyl paraben (MPB) and triclosan (TCS). Sprague-Dawley rats were treated with these EDs at six windows of susceptibility (prenatal, neonatal, prepubertal and pubertal, parous, and nulliparous) from in utero to young adulthood. Oral treatment doses were selected to produce urinary metabolite levels comparable to those found in the US population. MicroRNAs were profiled using the NanoString platform.

RESULTS: Of 420 microRNAs analyzed, 90 were stably detected in >90% samples across all windows, with let-7 family members showing the highest expression. In the meantime, 132 microRNA species were expressed below the detection level in >90% of the samples; other miRNAs were expressed at different levels in some but not all samples. Principal component analysis revealed that different developmental windows displayed markedly different microRNA profiles. Importantly, we found that ED exposure, TCS in particular, resulted in measurable difference in rat mammary microRNAs, and the changes were window-specific. More specifically, the TCS-related changes were mainly present in prenatal, neonatal and pubertal windows; among these the neonatal period appeared to be the most susceptible window to EDs with the largest number of differentially expressed microRNAs (7 microRNA species with adjusted p<0.05).

CONCLUSIONS: Low-dose ED exposure, even at levels comparable to human exposure, was able to modify microRNA expression in rat mammary tissues in a window-specific fashion. The study also demonstrates dynamic changes of microRNA profiles in developing mammary glands and highlights the importance of taking the normal developmental gene signal into account when searching for environment-induced gene signatures.

Citation Format: Vasily N. Aushev, Maya Kappil, Kalpana Gopalakrishnan, Qian Li, Yula Ma, Luca Lambertini, Fabiana Manservisi, Laura Falcioni, Luciano Bua, Fiorella Belpoggi, Susan L. Teitelbaum, Jia Chen. Defining windows of susceptibility for low-dose exposure to endocrine disruptors in rat mammary development by microRNA profiling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-089. doi:10.1158/1538-7445.AM2015-LB-089