Date on Master's Thesis/Doctoral Dissertation

12-2020

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Cai, Lu

Committee Co-Chair (if applicable)

States, J. Christopher

Committee Member

States, J. Christopher

Committee Member

Merchant, Michael L.

Committee Member

Kong, Maiying

Committee Member

Chen, ShaoYu

Author's Keywords

Cadmium; zinc; sexual-dimorphism; NAFLD

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major global public health concern affecting more than 25% of the world’s population. Although obesity is a major risk factor for NAFLD, it cannot account for many cases, indicating the importance of other factors such as sex and environmental exposures. Cadmium exposure is implicated in the development of NAFLD; however, the influence of early-life, in utero cadmium exposure on the development of diet-induced NAFLD is poorly understood. Therefore, we developed an in vivo, multiple-hit model to study the effect of whole-life, low-dose cadmium exposure on high fat diet (HFD)-induced NAFLD. Additionally, we investigated the impact of dietary zinc supplementation on disease outcome as both obesity and cadmium disrupt zinc homeostasis and zinc deficiency is common in NAFLD patients. Adult male and female C57BL/6J mice fed normal diets (ND) were exposed to 0, 0.5 or 5 ppm cadmium-containing drinking water for 14 weeks before breeding. At weaning, offspring were fed ND or HFD and continued on the same drinking water regimen as their parents. Male offspring were further subdivided into diets containing 30 or 90 mg zinc/4057 kcal, representing normal and zinc supplemented diet, respectively. Cadmium exposure altered HFD-associated weight gain and insulin resistance in males, but not females. In males only, cadmium exposure altered HFD-induced liver injury and NAFLD. Specifically, 0.5 ppm cadmium exposure rescued the adverse health effects of HFD while 5 ppm cadmium exposure exacerbated outcomes. Further, HFD blunted the response of metallothionein in mice exposed to 5 ppm cadmium but enhanced the response in male mice exposed to 0.5 ppm cadmium, suggesting a possible mechanism for cadmium altering HFD-induced NAFLD. Zinc supplementation rescued the adverse effects cause by HFD and 5 ppm cadmium exposure. Interestingly, in 5 ppm cadmium-exposed, HFD-fed female mice hepatic zinc levels were similar to levels in males after zinc supplementation. Overall, results from this study confirm the multi-hit nature of NAFLD, show whole life, low dose cadmium exposure alters HFD-induced NAFLD, and suggest a potential therapeutic role for zinc. Furthermore, this study highlights the importance of sex as a risk factor in disease development.

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