Genome-Linked Toxic Responses to Dietary Iron Overload

Abstract

Genome-related differences to Fe overload between and within rodent species were evaluated in the present study. Male B6C3F1 mice, yellow and black C5YSF1 mice, and Fischer 344 (F344) rats were fed AIN-76A diets containing 35 (control), 1,500, 3,500, 5,000, or 10,000 micrograms carbonyl Fe/g for 12 wk. No effects on body weight gain were observed in the B6C3F1 and black C5YSF1 mice, whereas at all doses of Fe above the control, weight gain was reduced in yellow C5YSF1 mice and F344 rats. At the 10,000 micrograms Fe/g dose, 9 of 12 rats died, but there was no mortality among the mice. In all animals, there was a dose-related increase in liver nonheme Fe, and the Fe was stored in hepatocytes predominantly in the periportal region. There was significant hypertrophy of the hepatocytes in both B6C3F1 mice and F344 rats fed the 10,000 micrograms Fe/g diet. PCNA assays showed significant stimulatory effects of the high dose of Fe on hepatocyte proliferation in the F344 rats and the C5YSF1 mice but not in the B6C3F1 mice. In the rat, there was pancreatic atrophy with loss of both endocrine and exocrine tissue. Morphometric evaluation of pancreas showed fewer beta cells in B6C3F1 and yellow C5YSF1 mice but not in the black C5YSF1 mice. There were fewer islets in the yellow C5YSF1 mice, and total and mean islet areas were smaller than in the control mice. Rats in the 10,000 micrograms Fe/g dose group had markedly exacerbated dose-dependent nephropathy and changes in glomerular and tubular epithelium associated with Fe accumulation. The rats also showed degeneration of the germinal epithelium of the testis, formation of multinucleated giant cells, and lack of mature sperm.

Iron Lactate-Induced Osteopenia in Male Sprague-Dawley Rats

“…The effect of iron overloading on bone resorption has not been subjected to biochemical or histomorphometrical study, although much effort has been expended in trying to clarify the mechanism of toxic or carcinogenic effects of iron on the liver, kidney, and other organs by detailed histopathology of iron toxicity (4,8,9,12,17,18,20,32,36,37,40). We observed bone loss of the secondary spongiosa in rats in a preliminary 3-month toxicity study of iron-lactate and conducted the present study to induce bone lesions and clarify the early changes using histomorphometry and biochemical markers of bone turnover.…”

Increased hepatic telomerase activity in a rat model of iron overload: A role for altered thiol redox state?

“…Given that we and others have demonstrated that iron overload is associated with increased hepatocyte proliferation [20][21][22], which would be expected to cause telomere shortening, the finding that telomere lengths were not dramatically altered by iron loading suggested that telomerase activity might be increased in the iron loaded livers. Indeed, telomerase activity in the iron-loaded livers was increased 3-fold relative to control livers (p<0.05), in which there were detectable but rather low levels of telomerase activity, consistent with previous reports (Fig.…”

Dose- and Time-Dependent In Vitro Effects of Divalent and Trivalent Iron on the Activity of Bovine Spermatozoa

“…The data were obtained from five independent experiments. The level of significance was set at ***P<0.001, **P<0.01, and * P<0.05 impaired spermatogenesis, epididymal lesions, and impaired reproductive performance [8,25,26]. Iron overload often leads to testicular and seminal oxidative stress (OS) contributing to infertility [25].…”