Exposure to environmental chemicals, including those commonly found in personal care products has been linked to mammary cancer at high doses using animal models. Their effects at low doses comparable to human exposure, especially during critical windows of development remain poorly understood. We investigated the effects of three prevalent environmental chemicals - diethyl phthalate (DEP), methyl paraben (MPB), triclosan (TCS) - and their mixture (MIX) on the transcriptome of normally developing mammary at low doses mimicking human exposure. Using a female Sprague-Dawley rat model, we targeted four early developmental exposure windows - prenatal, neonatal, prepubertal and pubertal, as well as continuous exposure from birth to adulthood (both parous and nulliparous). Control rats were exposed to vehicle only. All exposures were by oral gavage. Whole-transcriptomes of mammary glands were profiled by Affymetrix rat gene arrays. Differentially expressed genes were identified by linear models. Despite dynamic transcriptome changes in the normal developing mammary, exposure to environmental chemicals induced detectable gene expression changes in a window-specific fashion. We discovered that puberty represented a window of heightened sensitivity to MPB and DEP exposure with 341 and 175 altered genes relative to controls, respectively (false discovery rate (FDR) < 0.25, fold change (FC) ≥ 1.5). Chronic DEP exposure from birth to adulthood resulted in changes in 1151 and 427 genes in parous and nulliparous rats, respectively, compared to corresponding controls (FDR < 0.25, FC ≥ 1.5). Importantly, the number of differentially expressed genes across development in exposed rats was significantly reduced compared to control rats, suggesting possible alteration in developmental pace by environmental chemicals. We used a joint random forest algorithm to construct co-expression networks and identified gene modules with distinct connectivity patterns between treatments and controls. Results indicated a loss of correlation structure in exposed rats compared to controls. For example, genes such as Ntn4, Tmcc3, Lalba and Lcn2 showed fewer connected edges in the co-expression network of the DEP, MPB and TCS groups compared to controls. These results highlight critical windows of exposure and implicate the potential health effects of these ubiquitous environmental chemicals in human populations.

Citation Format: Kalpana Gopalakrishnan, Francesca Petralia, Pei Wang, Fabiana Manservisi, Laura Falcioni, Luciano Bua, Fiorella Belpoggi, Luca Lambertini, James Wetmur, Susan Teitelbaum, Jia Chen, Vasily Aushev. Effects of low-dose environmental chemicals on the mammary transcriptome at critical windows of development in a rodent model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 798.