title: 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 (HFDs) 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 AIN-93G-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=.048 and P=.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.
authors.affiliation: Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, Ohio.
authors.forename: Vinothini
authors.initials: V
authors.lastname: Govindarajah
authors.affiliation: Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, Ohio.|Center of Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio.|Department of Pharmacology and Cell Biophysics Pharmacology, University of Cincinnati Medical Center, Cincinnati, Ohio.
authors.forename: Yuet-Kin
authors.initials: YK
authors.lastname: Leung
authors.affiliation: Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, Ohio.
authors.forename: Jun
authors.initials: J
authors.lastname: Ying
authors.affiliation: Department of Pharmacology and Cell Biophysics Pharmacology, University of Cincinnati Medical Center, Cincinnati, Ohio.
authors.forename: Robin
authors.initials: R
authors.lastname: Gear
authors.affiliation: Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, Ohio.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bornschein
authors.affiliation: Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, Ohio.
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.affiliation: Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, Ohio.|Center of Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio.|Cincinnati Cancer Center, Cincinnati, Ohio.|Cincinnati Veteran Affairs Medical Center, Cincinnati, Ohio.
authors.forename: Shuk-Mei
authors.initials: SM
authors.lastname: Ho
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000008:administration & dosage; D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage; D059305:Diet, High-Fat; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012741:Sexual Maturation
chemical_list: D002273:Carcinogens; D015127:9,10-Dimethyl-1,2-benzanthracene
keywords: Breast cancer; DNA methyl transferases; DNA methylation; Developmental origin of health and disease; Epigenetics; Methylated DNA binding domain