Marilyn C. Reid

Nickel induction of microsomal heme oxygenase activity in rodents

Heme oxygenase activity was measured in tissues of rats killed after administration of NiCl2 or Ni3S2. Induction of renal heme oxygenase activity occurred 6 hr after NiCl2 injection (0.25 mmol/kg, sc), reached a maximum of five to six times the baseline activity at 17 hr, and remained significantly increased at 72 hr. Heme oxygenase activities were also increased in liver, lung, and brain at 17 hr after the NiCl2 injection; heme oxygenase activities in spleen and intestinal mucosa were unchanged. The effects of NiCl2 on heme oxygenase activities in kidney and liver were dose-related from 0.06 to 0.75 mmol/kg, sc. Three Ni chelators were administered (1 mmol/kg, im) prior to injection of NiCl2 (0.25 mmol/kg, sc); d-penicillamine partially prevented Ni induction of renal heme oxygenase activity; triethylenetetramine had no effect; sodium diethyldithiocarbamate enhanced the Ni induction of renal heme oxygenase activity (three times greater than NiCl2 alone). Intrarenal injection of Ni3S2 (10 mg/rat) caused induction of renal heme oxygenase activity at 1 week but not at 2, 3, or 4 weeks; no correlation was observed between induction of renal heme oxygenase activity and erythropoietin-mediated erythrocytosis. Hypoxia (10% O2, 12 hr/day, 7 days) did not affect renal heme oxygenase activity. Induction of renal heme oxygenase activity was observed in mice, hamsters, and guinea pigs killed 17 hr after injection of NiCl2 (0.25 mmol/kg, sc). These studies established (a) the time course, dose-effect, organ selectivity, and species susceptibility relationships for Ni induction of microsomal heme oxygenase activity, (b) the effects of Ni chelators, and (c) the lack of relationship between induction of renal heme oxygenase activity and the erythrocytosis that develops after intrarenal injection of Ni3S2.

Embryotoxicity and Teratogenicity of Nickel Compounds

Three experiments are described that illustrate the effects of nickel compounds upon the progeny of Fischer rats. In the first experiment, administration of Ni(C0)4 to pregnant dams by intravenous injection (11 mg Ni/kg) on day 7 of gestation caused increased fetal mortality, diminished body weight of live pups, and 16 percent incidence of fetal malformations, including anophthalmia, microphthalmia, cystic lungs, and hydronephrosis. In the second experiment, a dominant lethal mutation test in male rats, administration of Ni (CO)4 by inhalation (0.05 mg Ni/litre/15 min) 2 to 6 weeks prior to breeding did not impair fertilization rates or reproductive yields; under the same conditions, administration of Ni(CO)4 by intravenous injection (22 mg Ni/kg) diminished the number of live pups in litters sired during the fifth week, consistent with chromosomal damage during the meiotic stage of spermatogenesis. In the third experiment, administration of Ni3S2 to female rats by intrarenal injection (30 mg Ni/kg) one week prior to breeding produced intense erythrocytosis in the dams but did not cause erythrocytosis in the pups; on the contrary, pups from Ni3S2-treated dams had diminished blood hematocrits at two weeks postpartum. In light of previous reports that Ni3S2-induced erythrocytosis is mediated by increased renal production of erythropoietin, the present observations suggest that increased erythropoietin activity in maternal serum does not stimulate erythropoiesis in the fetus. The discussion section of this paper presents comprehensive tabulations of the literature on embryotoxicity and teratogenicity of nickel compounds.

Synergistic induction of microsomal heme oxygenase activity in rat liver and kidney by diethyldithiocarbamate and nickel chloride

Microsomal heme oxygenase activity was measured in liver and kidney of rats killed after administration of sodium diethyldithiocarbamate (DDC) and nickel chloride (NiCl2), singly and in combinations (DDC dosages: 0.33 to 1.33 mmol/kg, im, 17 hr before death; NiCl2 dosages: 0.125 and 0.25 mmol/kg, sc, 17 hr before death). Synergistic induction was observed at all dosage combinations. At the highest dosages of DDC and NiCl2, the dual treatments induced heme oxygenase activity 11-fold in liver and 16-fold in kidney; at the same dosages given individually, DDC induction of heme oxygenase activity was 3-fold in liver and 2-fold in kidney, and NiCl2-induction was 1.3-fold in liver and 6-fold in kidney. Synergistic induction of heme oxygenase activity in liver occurred when DDC was injected 6 hr before to 6 hr after NiCl2; synergistic induction in kidney occurred when DDC was injected 6 hr before to 3 hr after NiCl2. Actinomycin D prevented the induction of heme oxygenase activity by DDC or NiCl2, given individually; the effect of actinomycin D on synergistic induction could not be measured, since the rats all died following treatment with DDC, NiCl2, and actinomycin D. Administration of cysteine to rats, po, 18 hr before death, partially suppressed the induction of hepatic heme oxygenase activity by DDC, singly or in combination with NiCl2. Synergistic induction of hepatic heme oxygenase activity also occurred in rats that received dual injections of DDC (1.33 mmol/kg, im) and hemoglobin (0.3 g/kg, iv); the synergism of DDC and hemoglobin, although statistically significant, was small in comparison to the striking synergistic effect of DDC and NiCl2.

Effects of unilateral nephrectomy on erythrocytosis and arteriosclerosis induced in rats by intrarenal injection of nickel subsulfide.

Administration of Ni3S2 to rats by unilateral inrarenal (ir) injection (5 mg/rat) caused erythrocytosis, arteriosclerosis, and abnormal plasma concentrations of asparagine, glycine, histidine, and lysine. Resection of the ipsilateral (Ni3S2-treated) kidney on the fourth day after the ir injection prevented erythrocytosis, amino acid disturbances, and severe arteriosclerotic lesions (fibrous intimal plaques and focal medial necrosis), but did not prevent early arteriosclerotic lesions (subintimal oedema with splitting of elastica). The early arteriosclerotic lesions appear to be initiated by vascular dissemination of Ni3S2 particles immediately post-injection, whereas the erythrocytosis, amino acid disturbances, and advanced arteriosclerotic lesions depend upon continued presence of the Ni3S2-injected kidney. Resection of the contralateral (non-injected) kidney has no effect upon Ni3S2-induced erythrocytosis, arteriosclerosis, or amino acid disturbances. Glomerulomegaly and mesangial hyperplasia developed in control rats following unilateral nephrectomy, owing to compensatory renal hypertrophy. Glomerulomegaly was more pronounced in Ni3S2-treated rats following contralateral nephrectomy than following ipsilateral nephrectomy, suggesting that erythrocytosis and compensatory renal hypertrophy act synergistically to enhance glomerulomegaly.