Abstract 1477: Acrylamide exposure in obesity enhances mammary epithelial DNA damage via the activity of its metabolite, glycidamide, and increased oxidative stress

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Abstract Obesity is a world-wide epidemic, with 39% of adults considered overweight and 13% obese, and rates are rising. Obese women are at greater risk for developing breast cancer than lean women, however the mechanisms of how obesity increases breast cancer risk are not well understood. There is also limited knowledge on how environmental toxins may interact with obesity to promote breast cancer. Acrylamide, a probable carcinogen, is a biproduct in starchy foods cooked at high temperatures, which are prevalent in the obesity-inducing Western diet. Acrylamide is metabolized by the CYP2E1 enzyme into the epoxide, glycidamide, which is known to induce DNA damage. CYP2E1 activity is elevated in obesity, which could enhance DNA damage in obese individuals. Acrylamide exposure is associated with an increased risk of breast cancer in epidemiologic studies, but the evidence has been contradictory. To investigate how acrylamide impacts DNA damage in the obese mammary gland, three-week-old FVB female mice were randomized to receive a low-fat (LFD; 16% kcal from fat) or high-fat diet (HFD; 60% kcal from fat) and either 0.7 mM acrylamide water or control water. HFD-fed mice gained significantly more weight than LFD-fed mice, and exposure to acrylamide did not impact weight gain compared to respective controls. Mammary epithelial cells from acrylamide-treated mice had increased DNA damage compared to controls measured by COMET assays, with the highest DNA damage present in epithelial cells from obese acrylamide-treated mice. Mammary epithelial cells from acrylamide-treated mice also had enhanced oxidative DNA damage, measured by 8-OHdG adducts, and an additive effect was observed between acrylamide exposure and obesity. To investigate the impact of acrylamide in vitro, COMMA-D mammary epithelial cells were treated with vehicle, 9.8 µM acrylamide, or 0.5 mM glycidamide for 24 hours, then COMET assays and immunohistochemistry for markers of DNA damage were performed. COMMA-D cells treated with acrylamide-metabolite glycidamide showed significantly increased double strand DNA breaks compared to vehicle-treated cells, however acrylamide-treated cells did not. Interestingly, acrylamide-treated cells demonstrated significantly higher levels of intracellular reactive oxygen species compared to both glycidamide and vehicle-treated cells. These studies suggest acrylamide exposure enhances DNA damage in mammary epithelial cells via conversion to the genotoxic metabolite glycidamide and through generation of oxidative stress, which is exacerbated by obese conditions. These studies suggest that long-term acrylamide exposure through foods common in the Western diet may enhance DNA damage in mammary epithelial cells, potentially enhancing obesity-induced breast cancer risk. Citation Format: Brenna Walton, Lisa Arendt. Acrylamide exposure in obesity enhances mammary epithelial DNA damage via the activity of its metabolite, glycidamide, and increased oxidative stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1477.

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