Abstract 4366976: Permethrin, a common pyrethroid pesticide, promotes atherosclerotic plaque formation in ApoE null mice

Synthetic pyrethroids, such as permethrin, are commonly used insecticides in crop agriculture, clothing items such as camping and military uniforms, and for treating insect infestations in people and pets. Growing epidemiological evidence supports an association between pyrethroid insecticide exposures and cardiovascular diseases risk, including coronary heart disease. Studies in rats show that pyrethroid insecticides are pro-atherogenic, in part, by increasing circulating total LDL-C and oxidized LDL-C and cholesterol accumulation in the aorta. Here, we used the ApoE Null mouse model to test the hypothesis that chronic exposure to permethrin promotes atherosclerosis. Male and female mice were fed a custom diet based on the "What we eat in America” analysis (NHANES). Cholesterol was included at 296 mg per 1000 kcal (i.e., the 90 th percentile of cholesterol intake in the typical American diet). The mice were exposed to vehicle or 10, 50 and 500 µg/kg/day doses of permethrin delivered in food for 11-12 weeks. By comparison, the Environmental Protection Agency identifies a maximum daily exposure of 50 µg permethrin/kg/day as protective of adverse effects. Using allometric scaling, the approximate human-equivalent doses were 1, 4 and 41 µg/kg/day. For comparison, US military personnel wearing permethrin-treated uniforms have an estimated average daily dose of permethrin of 3-9 µg/kg/day. We observed that at a daily dose as low as 50 μg permethrin/kg for 11-12 weeks, atherosclerotic plaque area was larger in permethrin-exposed compared to vehicle-exposed mice. While the effect of permethrin on plaque area was not different between sexes, we observed a greater reduction in weight gain in female mice and a greater increase in liver lipids in male mice at 500 μg/kg/day. No differences in serum liver enzymes (i.e., AST and ALT) were observed. Given that pyrethroid insecticides have been shown to activate several nuclear receptors in vitro , we analyzed total liver RNA for the expression of target genes of peroxisome proliferator activated receptor α, constitutive androstane receptor and pregnane X receptor, however no significant differences across groups were observed. Our results demonstrate that chronic exposure to pyrethroid insecticides accelerates atherosclerosis in murine models that may represent a mechanism for the clinical epidemiological observations linking pyrethroids to increased cardiovascular disease risk.