Eric Ditzel

Pharmacology and Toxicology

Exploring Early Life and In Utero Cardiometabolic Effects of As (III) Exposure

Arsenic exposure through drinking water is an ongoing health concern that has been increasingly linked to the development of many pathologies including, but not limited to, cardiovascular disease and the metabolic syndrome. Previous work in our lab found evidence of low-dose early life As (III) exposure resulting in the development of hypertension as well as in utero As (III) exposure resulting in metabolic alterations and fatty liver disease. The role of low-dose As (III) exposure on the development of the metabolic syndrome remains inconclusive, and our study aims to explore possible mechanisms of early life and in utero low-dose As (III) toxicity on the development of the cardiometabolic syndrome. In order to approach this problem, Swiss Webster mice were treated with 100ppb As (III) starting at embryonic day 5 (IU), after weaning (PN), or from embryonic day 5 through the end of the study (IU+). After weaning all mice were fed a high fat, high cholesterol, western diet. Blood pressure measurements, echocardiography, and fasted blood plasma collection were performed regularly. There was increased mortality and body weight among treated males. Metabolomic analysis of male blood plasma found changes in arsenic exposed animals in plasma global metabolic profiles that support an influence on energy metabolism- with effects evident in glycolysis, TCA cycle, and lipid metabolism- and on liver and kidney function as reflected by levels of circulating glycine-conjugates and sulfated forms of amino acid and fatty acid metabolites. In males there were indicators of fatty liver disease including: fibrosis, increased liver weight, microvesicular steatosis and hepatocellular ballooning in treated animals. Measurement of insulin resistance and glucose homeostasis, histology, and resolution of metabolic changes at a tissue level are ongoing. When complete this work will help resolve the mechanistic basis of As (III) contribution to the cardiometabolic syndrome so that therapeutic interventions can be developed.