In utero exposure of rats to high-fat diets perturbs gene-expression profiles and cancer susceptibility of prepubertal mammary glands

Human studies suggest that high-fat diets (HFD) increase the risk of breast cancer. The 7,12 dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis rat model is commonly used to evaluate the effects of lifestyle factors such as HFD on mammary-tumor risk. Past studies focused primarily on the effects of continuous maternal exposure on the risk of offspring at the end of puberty (PND50). We assessed the effects of prenatal HFD exposure on cancer susceptibility in prepubertal mammary glands and identified key gene networks associated with such disruption. During pregnancy, dams were fed AIN93G-based diets with high (39% Kcal) olive oil, butterfat, or safflower oil. The control group received AIN-93G with 10% Kcal soy oil. Female offspring were treated with DMBA on PND21. However, a significant increase in tumor volume and a trend of shortened tumor latency were observed in rates with HFD exposure against the controls (p=0.067 and 0.048 respectively). Large-volume tumors harbored carcinoma in situ. Transcriptome profiling identified 43 differentially expressed genes in the mammary glands of the HFD group as compared with control. Rapid hormone signaling was the most dysregulated pathway. The diet also induced aberrant expression of Dnmt3a, Mbd1, and Mbd3, suggesting potential epigenetic disruption. Collectively, these findings provide the first evidence supporting susceptibility of prepubertal mammary glands to DMBA-induced tumorigenesis that can be modulated by dietary fat that involves aberrant gene expression and epigenetic dysregulation. Overall design: Rats were treated prenatally with control (AIN) or high fat butter (HFB) diet from gestation day 1 to PND 23. The newborns were exposed only to AIN from postnatal day 0 and day 21. One snap frozen mammary gland from each litter and six from each group (CTL vs HFB) were collected for RNAseq analyses.