Nonalcoholic fatty liver disease (
NAFLD) is a major global public health concern affecting more than 25% of the world's population. Although
obesity and diabetes are major risk factors for
NAFLD, they cannot account for all cases, indicating the importance of other factors such as environmental exposures.
Cadmium (Cd) exposure is implicated in the development of
NAFLD; however, the influence of early life, in utero Cd 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 Cd exposure on high fat diet (HFD)-induced
NAFLD. Adult male and female C57BL/6 J mice fed normal diets (ND) were exposed to 0, 0.5 or 5 ppm Cd-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 for 24 weeks. Cd exposure at different concentrations differentially altered HFD-associated adverse health effects, including liver injury. HFD-induced increased
body weight, decreased
glucose tolerance. Liver injury and
lipid deposition were exacerbated by 5 ppm Cd exposure but attenuated by 0.5 ppm Cd exposure. Further, HFD blunted the response of
metallothionein, a major Cd detoxification
protein, in mice exposed to 5 ppm Cd but enhanced the response in mice exposed to 0.5 ppm Cd, suggesting a possible mechanism for Cd alteration of HFD-induced
NAFLD. These results confirm the multi-hit nature of
NAFLD and show whole life, low dose Cd exposure alters HFD-induced
NAFLD with outcomes dependent on Cd concentration.