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

Abstract

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 isocaloric high olive oil, butterfat, or safflower oil. The control group received AIN-93G. 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 rats with HFD exposure against the controls (p=0.048 and p=0.067 respectively). Large-volume tumors harbored carcinoma in situ. Transcriptome profiling identified 43 differentially expressed genes in the mammary glands of the HFBUTTER group as compared with control. Rapid hormone signaling was the most dysregulated pathway. The diet also induced aberrant expression of Dnmt3a, Mbd1, and Mbd3, consistent with 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 likely epigenetic dysregulation.

Effect of high-fat diet feeding and associated transcriptome changes in the peak lactation mammary gland in C57BL/6 dams

“…Also identified in the top 50 most DEGs, butyrophilin 2 member A2 (Btn2a2) was significantly decreased in dams consuming an HFD. Its homolog, Btn1a1, was also identified with significant downregulation in a both our study and the Chen et al (14) study, in addition to the similar finding reported in the rat mammary gland fed an HFD (17). Both Btn1a1 and Btn2a2 are implicated in modulation of leukocyte activation.…”

Selenium and Selenoproteins in Adipose Tissue Physiology and Obesity

“…HFD-feeding resulted in obesity and insulin resistance, as well as significantly reduced muscle selenoprotein W (Selenow) content, although Selenow deficiency was not associated with antioxidant levels, being indicative of lack of protective effect of Selenow in obesity [224]. Prenatal HFD exposure also resulted in a significant increase in Selenow and Selenom expression in mammary glands in prepubertal rats [225]. HFD significantly reduced lymphocyte selenoprotein expression (except Gpx1, Gpx2, Selenot, and Selenom) and this effect was aggravated by low-Se intake.…”

DNA methylation of angiotensin II receptor gene in nonalcoholic steatohepatitis-related liver fibrosis

“…Agtr1a methylation was first demonstrated in the liver of rats born to mothers fed a methyl donor-deficient diet during gestation and lactation, and it was reported that rat pups with Agtr1a methylation have a high risk of developing NAFLD[ 12 ]. Epigenetics derived from mother-pup interaction is a prominent research field, and epigenetic susceptibility to phenotypes and diseases, such as yellow coat color, stress response, and breast cancer in offspring, has been identified[ 19 - 21 ]. However, few studies have focused on whether these epigenetic changes responsible for susceptibility to particular diseases occur when the diseases actually develop in adults.…”