Sex differences in the effects of whole-life, low-dose cadmium exposure on postweaning high-fat diet-induced cardiac pathogeneses.

We previously showed the development of cardiac remodeling (hypertrophy or fibrosis) in mice with either post-weaning high-fat diet (HFD, 60% kcal fat) feeding or exposure to chronic low-dose cadmium. Here, we determined whether whole-life exposure to environmentally relevant, low-dose cadmium affects the susceptibility of offspring to post-weaning HFD-induced cardiac pathologies and function. Besides, we also determined whether these effects are sex-dependent. Male and female mice were exposed to cadmium-containing (0, 0.5, or 5 parts per million [ppm]) drinking water before breeding; the pregnant mice and dams with offspring continually drank the same cadmium-containing water. After weaning, the offspring were continued on the same regime as their parents and fed either a HFD or normal fat diet for 24 weeks. Cardiac function was examined with echocardiography. Cardiac tissues were used for the histopathological and biochemical (gene and protein expression by real-time PCR and Western blotting) assays. Results showed a dose-dependent cadmium accumulation in the hearts of male and female mice along with decreased cardiac zinc and copper levels only in female offspring. Exposure to 5 ppm, but not 0.5 ppm, cadmium significantly enhanced HFD cardiac effects only in female mice, shown by worsened cardiac systolic and diastolic dysfunction (ejection fraction, mitral E-to-annular e' ratio), increased fibrosis (collagen, fibronectin, collagen1A1), hypertrophy (cardiomyocyte size, atrial natriuretic peptide, β-myosin heavy chain), and inflammation (intercellular adhesion molecule-1, tumor necrosis factor-α, plasminogen activator inhibitor type 1), compared to the HFD group. These synergistic effects were associated with activation of the p38 mitogen-activated protein kinases (MAPK) signaling pathway and increased oxidative stress, shown by 3-nitrotyrosine and malondialdehyde, along with decreased metallothionein expression. These results suggest that whole-life 5 ppm cadmium exposure significantly increases the susceptibility of female offspring to HFD-induced cardiac remodeling and dysfunction. The underlying mechanism and potential intervention will be further explored in the future.