Pulmonary toxicity, genotoxicity, and carcinogenicity evaluation of molybdenum, lithium, and tungsten: A review.

Molybdenum, lithium, and tungsten are constituents of many products, and exposure to these elements potentially occurs at work. Therefore it is important to determine at what levels they are toxic, and thus we set out to review their pulmonary toxicity, genotoxicity, and carcinogenicity. After pulmonary exposure, molybdenum and tungsten are increased in multiple tissues; data on the distribution of lithium are limited. Excretion of all three elements is both via faeces and urine. Molybdenum trioxide exerted pulmonary toxicity in a 2-year inhalation study in rats and mice with a lowest-observed-adverse-effect concentration (LOAEC) of 6.6 mg Mo/m3. Lithium chloride had a LOAEC of 1.9 mg Li/m3 after subacute inhalation in rabbits. Tungsten oxide nanoparticles resulted in a no-observed-adverse-effect concentration (NOAEC) of 5 mg/m3 after inhalation in hamsters. In another study, tungsten blue oxide had a LOAEC of 63 mg W/m3 in rats. Concerning genotoxicity, for molybdenum, the in vivo genotoxicity after inhalation remains unknown; however, there was some evidence of carcinogenicity of molybdenum trioxide. The data on the genotoxicity of lithium are equivocal, and one carcinogenicity study was negative. Tungsten seems to have a genotoxic potential, but the data on carcinogenicity are equivocal. In conclusion, for all three elements, dose descriptors for inhalation toxicity were identified, and the potential for genotoxicity and carcinogenicity was assessed.

Effect of Experimental Fanconi Syndrome on Tubular Reabsorption of Lithium in Rats.

Lithium, administered to patients of bipolar disorders, is mainly excreted into urine, and tubular reabsorption at the proximal tubule is involved in the renal handling of lithium. In this study, we examined the renal excretion of lithium in rats with Fanconi syndrome, characterized by defects of transports of various compounds at the proximal tubules, induced by maleic acid. After maleic acid was intravenously injected, mannitol and lithium chloride were infused in turn. Using samples of plasma and bladder urine during the mannitol infusion, renal parameters were determined. Pharmacokinetic parameters of lithium were obtained using samples during the lithium chloride infusion. Maleic acid decreased creatinine clearance and increased the fractional excretion of glucose and phosphate, suggesting the induction of Fanconi syndrome. In rats with Fanconi syndrome, plasma concentration of lithium was increased, and its renal clearance was decreased. No effect on the fractional excretion of lithium was exhibited. This study represents that the tubular reabsorption of lithium was impaired to the same degree with glomerular filtration in rats with experimental Fanconi syndrome and that the dysfunction of the tubular reabsorption of glucose and phosphate was more severe. It is possible that Fanconi syndrome inhibited the reabsorption of lithium at the proximal tubule and facilitated the reabsorption of lithium from the loop of Henle to the collecting duct.

Effect of renal ischemia on urinary excretion of lithium in rats.

Lithium, administered to patients with bipolar disorders, is mainly excreted in the urine, and tubular reabsorption is involved. This study characterized the renal excretion of lithium in rats subjected to renal ischemia for 60 min or 90 min. After intravenous injection of lithium chloride at 25 mg/kg, the pharmacokinetic parameters of lithium were determined. In sham-operated rats, the renal clearance of lithium was calculated to be 1.49 ml/min/kg, and its ratio to creatinine clearance (fractional excretion) was 43.4%. Renal ischemia inhibited the renal excretion of lithium, and did not affect its fractional excretion. The urinary pH of rats with renal ischemia for 90 min was significantly higher than those of the other groups, and the linear regression with the fractional excretion of lithium in rats with renal ischemia showed a moderate correlation (r = 0.650, p = 0.00193). This study demonstrated the effect of renal ischemia on the renal excretion of lithium in rats. It was suggested that not only glomerular filtration but also the reabsorption of lithium was impaired by renal ischemia.

Lithium decreases VEGF mRNA expression in leukocytes of healthy subjects and patients with bipolar disorder.

OBJECTIVES: Vascular endothelial growth factor (VEGF) is thought to be involved in the pathophysiology of mood disorders and the target of antidepressants. The aim of this study was to elucidate molecular effects of lithium on VEGF expression by using leukocytes of healthy subjects and patients with bipolar disorder. METHODS: Eight healthy male subjects participated in the first study. Lithium was prescribed for 2 weeks, enough to reach therapeutic serum concentration. Leukocyte counts and serum lithium concentrations were determined at baseline, at 1- and 2-week medication, and at 2 weeks after stopping medication. VEGF mRNA levels were also examined in nine lithium-treated bipolar patients and healthy controls in the second study. RESULTS: In the first study, leukocyte counts were significantly increased at 2 weeks compared with those at baseline and were normalized after 2 weeks. VEGF mRNA levels were significantly decreased at 2 weeks and after 2 weeks compared with those at baseline. Consistent with the first study, VEGF mRNA levels were significantly decreased in the lithium-treated bipolar patients compared with healthy controls. CONCLUSIONS: Our investigation suggests that VEGF mRNA expression may be useful as a peripheral marker of the effects of lithium.

alphaENaC-mediated lithium absorption promotes nephrogenic diabetes insipidus.

Lithium-induced nephrogenic diabetes insipidus (NDI) is accompanied by polyuria, downregulation of aquaporin 2 (AQP2), and cellular remodeling of the collecting duct (CD). The amiloride-sensitive epithelial sodium channel (ENaC) is a likely candidate for lithium entry. Here, we subjected transgenic mice lacking αENaC specifically in the CD (knockout [KO] mice) and littermate controls to chronic lithium treatment. In contrast to control mice, KO mice did not markedly increase their water intake. Furthermore, KO mice did not demonstrate the polyuria and reduction in urine osmolality induced by lithium treatment in the control mice. Lithium treatment reduced AQP2 protein levels in the cortex/outer medulla and inner medulla (IM) of control mice but only partially reduced AQP2 levels in the IM of KO mice. Furthermore, lithium induced expression of H(+)-ATPase in the IM of control mice but not KO mice. In conclusion, the absence of functional ENaC in the CD protects mice from lithium-induced NDI. These data support the hypothesis that ENaC-mediated lithium entry into the CD principal cells contributes to the pathogenesis of lithium-induced NDI.

Lithium's effect in forced-swim test is blood level dependent but not dependent on weight loss.

The effects of lithium in models of depression are often inconsistent. We aimed to replicate a regimen that induces robust antidepressant effects in the forced-swim test. Mice were treated with three different doses of lithium chloride (LiCl) 0.25, 0.4 or 0.5% in food and the forced-swim test or open field test was performed on day 15. We yoked control mice to food deprivation to test whether lithium-induced food deprivation could cause the lithium effects in the forced-swim test. Treatment with LiCl doses leading to blood levels of 1.3 and 1.4 mmol/l led to highly significant reduction in immobility time in the forced-swim test, but the dose leading to a blood level of 0.8 mmol/l was not different from controls in immobility time. Mice yoked to lithium-induced food deprivation showed no difference in the forced-swim test compared with controls. In conclusion these results suggest that lithium effects in mice in the forced-swim test are dose dependent but not owing to lithium-induced weight loss.

Lithium activates the c-Jun NH2-terminal kinases in vitro and in the CNS in vivo.

The therapeutic efficacy of lithium in the treatment of mood disorders is delayed and only observed after chronic administration, a temporal profile that suggests alterations at the genomic level. Lithium has been demonstrated to modulate AP-1 DNA binding activity as well as the expression of genes regulated by AP-1, but the mechanisms underlying these effects have not been fully elucidated. In the present study, we found that the lithium-induced increases in AP-1 DNA binding activity were accompanied by increases in p-cJun and cJun levels in SH-SY5Y cells. Lithium also increased cJun-mediated reporter gene expression in a dose-dependent manner, with significant effects observed at therapeutically relevant concentrations. Lithium's effects on cJun-mediated reporter gene expression in SH-SY5Y cells were more pronounced in the absence of myo-inositol and were blocked by protein kinase C (PKC) inhibitors and by cotransfection with a PKCalpha dominant-negative mutant. Chronic in vivo lithium administration increased AP-1 DNA binding activity in frontal cortex and hippocampus and also increased the levels of the phosphorylated, active forms of c-Jun NH2-terminal kinases (JNKs) in both brain regions. These results demonstrate that lithium activates the JNK signaling pathway in rat brain during chronic in vivo administration and in human cells of neuronal origin in vitro; in view of the role of JNKs in regulating various aspects of neuronal function and their well-documented role in regulating gene expression, these effects may play a major role in lithium's long-term therapeutic effects.