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.