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Folic acid intake during juvenile/peri-pubertal development modulates the mammary tissue transcriptome of female C56BL/6 mice

ABSTRACT: We tested the hypothesis that high FA (HFA) intake alters the juvenile/peri-pubertal mammary transcriptome in a manner consistent with increased potential for breast cancer, detectable beyond the period of intake. C57BL/6 mice were fed control FA (CFA) (1 mg/kg diet) or HFA (5 mg/kg diet) diets for 4 weeks, followed by AIN93M maintenance diet for 4 weeks. RNA sequencing of the mammary transcriptome (~83 million reads) showed 18 transcripts (17 downregulated) differentially expressed between groups. Gene Set Enrichment showed downregulated genes significantly enriched in oxidative phosphorylation, adipogenesis, fatty acid metabolism and epithelial mesenchymal transition. Cancer and developmental disorder were the most altered Disease and Disorder pathways, with top upstream regulators identified as DNA methyltransferases. This study demonstrates HFA intake during juvenile/peri-pubertal mammary development induces changes in the mammary transcriptome associated with altered energy metabolism, cell neoplasia and epigenetic regulation of gene.

ORGANISM(S): Mus musculus

PROVIDER: GSE191160 | GEO | 2024/12/01

REPOSITORIES: GEO

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Project description:A rexinoid, targretin (TRG) and two retinoids, 9-cis retinoic acid (9cRA) and 4-hydroxyphenylretinamide (4HPR) were examined for their effects on gene expression in rat mammary gland, liver, and lung tissues. The chemopreventive effects of these agents have largely been attributed to their ability to interact with retinoic acid receptors (RAR) and/or retinoid X-receptors (RXR). TRG interacts with the RXR receptors. 9cRA interacts with both the RAR and RXR receptors, while 4HPR has a moderate affinity primarily for RAR gamma. Based on previously performed mammary chemoprevention studies, TRG (150mg/Kg diet), 9cRA (100 mg/Kg diet), and 4HPR (792 mg/Kg diet), were administrated to rats continually in their diet for 7 days. Tissue - and agent - specific expression differences were determined by comparing tissues from treated rats with those form rats administered a control diet. There were significantly more changes seen associated with TRG than 9cRA or 4HPR. Only a limited number of expression changes were found with 4HPR treatment. For each organ, TRG and 9cRA treated tissues clustered closely together, whereas 4HPR treated tissues clustered with the tissues from the control diet group. In contrast to 9cRA treatment, TRG treatment altered genes that involved fatty acid metabolism and modulation of various cytochromes P450 in the liver clearly demonstrating the very disparate nature of these two retinoids. These expression signatures could provide useful pharmacodynamic biomarkers for retinoidsâ treatment and chemoprevention. Experiment Overall Design: Agent : The 3 agents were obtained from NCI Chemical Repository (Bethesda, MD), Targretin, 9-cis retinoic acid, and 4-hydroxyphenylretinamide. Experiment Overall Design: Rat :Female Sprague-Dawley rats were used (Harlan Sprague-Dawley, Inc. Indianapolis, IN) Experiment Overall Design: Treatment: Starting at 100 days of age, the rats received treatment of TRG (60 mg/kg BW, gavage), 9cRA (100 mg/kg diet), or 4HPR (782 mg/kg diet) for 7 days. At the end of the 7-day treatment, normal mammary gland, liver and lung tissues were collected.

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Folic acid intake during juvenile/peri-pubertal development modulates the mammary tissue transcriptome of female C56BL/6 mice

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