GENOME-LINKED TOXIC RESPONSES TO DIETARY IRON OVERLOAD

Genome-related differences to Fe overload between and within rodent sp ecies were evaluated in the present study. Male B6C3F(1) mice, yellow and black C5YSF(1) mice, and Fischer 344 (F344) rats were fed AIN-76A diets containing 35 (control), 1,500, 3,500, 5,000, or 10,000 mu g car bonyl Fe/g for 12 wk. No effects on body weight gain were observed in the B6C3F(1) and black C5YSF(1) mice, whereas at all doses of Fe above the control, weight gain was reduced in yellow C5YSF(1) mice and F344 rats. At the 10,000 mu g 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 pre dominantly in the periportal region. There was significant hypertrophy of the hepatocytes in both B6C3F(1) mice and F344 rats fed the 10,000 mu g Fe/g diet. PCNA assays showed significant stimulatory effects of the high dose of Fe on hepatocyte proliferation in the F344 rats and the C5YSF(1) mice but not in the B6C3F(1) mice. In the rat, there was pancreatic atrophy with loss of both endocrine and exocrine tissue. Mo rphometric evaluation of pancreas showed fewer beta cells in B6C3F(1) and yellow C5YSF(1) mice but not in the black C5YSF(1) mice. There wer e fewer islets in the yellow C5YSF(1) mice, and total and mean islet a reas were smaller than in the control mice. Rats in the 10,000 mu g Fe /g dose group had markedly exacerbated dose-dependent nephropathy and changes in glomerular and tubular epithelium associated with Fe accumu lation. The rats also showed degeneration of the germinal epithelium o f the testis, formation of multinucleated giant cells, and lack of mat ure sperm.