The rapidly growing increase in prevalence of adult chronic diseases poses a significant long term threat to health and well being of humans. While the etiology of chronic diseases is complex, a growing body of evidence indicates the in utero environment can determine susceptibility of offspring to adult chronic diseases. For the last decade, much emphasis has been placed on impact of nutritional insults. Less attention has been placed on in utero developmental programming effects of exposure to environmental contaminants such as the heavy metals, cadmium (Cd) and mercury (Hg). Cadmium and Hg are widely used in various industries with limited understanding of their developmental programming effects. Available data suggest that individual exposure to Cd or Hg throughout pregnancy can impact birth weight, glucose homeostasis and behavior of offspring. Moreover, accumulating evidence suggests that developmental programming effects of adverse in utero conditions are not limited to offspring directly exposed to relevant insults and effects can persist in subsequent generations even in the absence of original insult. However, developmental programming effects of combinational exposure to Cd and Hg in the context of administration during early life, even before conception, and their persistent transgenerational effects have not been studied. Therefore, it was hypothesized that periconception co-administration of Cd and Hg increase indices of chronic diseases in offspring at adulthood in subsequent generations. This hypothesis was tested by a) subcutaneously administering Cd and Hg at 0, 0.125, 0.5 and 2 mg/kg body weight doses of each compound to adult naïve female CD1 mice four days before and four days after conception b) determined anxiety-like behavior, glucose homeostasis, insulin sensitivity, body weight gain and abdominal adiposity, and serum and molecular markers of metabolic syndrome in offspring of control females and females treated with Cd and Hg and c) determined persistent transgenerational effects in F2-F4 generation offspring in the absence of additional heavy metal exposure. Results indicate anxiety-like behavior was increased in male offspring and glucose tolerance was impaired in male and female offspring of Cd plus Hg-treated females. Male offspring of treated females in the F1 generation displayed molecular and endocrine markers of insulin resistance, including significantly higher serum concentrations of insulin and leptin, higher glucose concentrations in response to insulin administration, as well as increased mRNA abundance for genes associated with glucose and lipid homeostasis in liver and decreased mRNA abundance in abdominal adipose tissue. Increased anxiety-like behavior persisted in the F2 generation male offspring descended from the female germ line but not in subsequent generations. Glucose homeostasis was altered in male offspring descended from the maternal germ line through four generations, including impaired glucose tolerance and increased phosphorylation of insulin receptor substrate 1 (IRS1) at serine residue 307, a biochemical indicator of insulin resistance. Increased body weight gain and abdominal adiposity was observed in male but not female offspring through the F4 generation who were descendants of periconception Cd plus Hg-treated females (F0 generation). Based on these results, it is concluded that periconception heavy metal administration to female mice impacts developmental programming of offspring susceptibility to chronic diseases later on adulthood and the effects persist transgenerationally in male offspring and are inherited through the maternal germ line.
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