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Cobalt (Co) is an essential element with ubiquitous dietary exposure and possible incremental exposure due to dietary supplements, occupation and medical devices. Adverse health effects, such as cardiomyopathy and vision or hearing impairment, were reported at peak blood Co concentrations typically over 700 µg/L (8-40 weeks), while reversible hypothyroidism and polycythemia were reported in humans at ~300 µg/L and higher (≥2 weeks). Lung cancer risks associated with certain inhalation exposures have not been observed following Co ingestion and Co alloy implants. The mode of action for systemic toxicity relates directly to free Co(II) ion interactions with various receptors, ion channels and biomolecules resulting in generally reversible effects. Certain dose-response anomalies for Co toxicity likely relate to rare disease states known to reduce systemic Co(II)-ion binding to blood proteins. Based on the available information, most people with clearly elevated serum Co, like supplement users and hip implant patients, have >90% of Co as albumin-bound, with considerable excess binding capacity to sequester Co(II) ions. This paper reviews the scientific literature regarding the chemistry, pharmacokinetics and systemic toxicology of Co, and the likely role of free Co(II) ions to explain dose-response relationships. Based on currently available data, it might be useful to monitor implant patients for signs of hypothyroidism and polycythemia starting at blood or serum Co concentrations above 100 µg/L. This concentration is derived by applying an uncertainty factor of 3 to the 300 µg/L point of departure and this should adequately account for the fact that persons in the various studies were exposed for less than one year. A higher uncertainty factor could be warranted but Co has a relatively fast elimination, and many of the populations studied were of children and those with kidney problems. Closer follow-up of patients who also exhibit chronic disease states leading to clinically important hypoalbuminemia and/or severe ischemia modified albumin (IMA) elevations should be considered.

SummaryTo define the mechanisms involved in the molecular response to the carcinogenic metal cadmium, two novel metal-inducible genes from C. elegans were characterized: numr-1 and numr-2 (nuclear localized metal responsive). numr-1 and numr-2 sequences and cellular patterns of expression are identical, indicating that these are functionally equivalent genes. Constitutive transcription of numr-1 and numr-2 is developmentally regulated and occurs in the intestine, in head and tail neurons, and vulva muscles. Exposure to metals induces numr-1 and numr-2 transcription in pharyngeal and intestinal cells. Other environmental stressors do not affect transcription, indicating that these are metal-specific, stress-responsive genes. NUMR-1 and NUMR-2 target to nuclei and colocalize with HSF-1, suggesting that they may be components of nuclear stress granules. Nematodes overexpressing NUMR-1 and NUMR-2 are resistant to stress and live longer than control animals; likewise reducing expression increases sensitivity to metals and decreases neuromuscular functions. Upstream regulatory regions of both genes contain potential binding sites for DAF-16 and SKN-1, which are components of the insulin-IGF-like signaling pathway. This pathway regulates longevity and stress responses in C. elegans. NUMR-1 and NUMR-2 may function to promote resistance to environmental stressors and longevity, which is mediated by the insulin-IGF-like signaling pathway.Key words: C. elegans, Cadmium, Stress response, Lifespan, LongevityJournal of Cell Science increase in the steady-state mRNA level following a 24-hour cadmium exposure (Cui et al., 2007). A second C. elegans gene, originally designated F08F8.1, was subsequently identified based on sequence identity. These genes are now designated numr-1 and numr-2 (nuclear localized metal responsive), respectively.In the present report, the genomic organization, in vivo cellular patterns of expression, effects of transition metals and other stressors on transcription, and phenotypes associated with increased and decreased expression of numr-1 and numr-2 are presented. Phenotypes associated with these genes include changes in neuromuscular activities, as well as increased resistance to metal toxicity and increased lifespan. Results Sequence analysis of numr-1 and numr-2numr-1 and numr-2 were located less than 1 kb apart in a divergent orientation on chromosome III (Fig. 1). numr-1 mRNA was predicted to be encoded by a single exon. By contrast, numr-2 mRNA was predicted to be encoded by five exons, the first of which was ~99% identical to the numr-1 exon. Sequences of the full-length mRNAs and the exon arrangement for numr-1 and numr-2 were determined using 3Ј-and 5Ј-RACE. The sequence of the 3Ј-end of numr-1 was consistent with that reported in WormBase (version WS201). Using 3Ј RACE, however, cDNAs from predicted exons 2-5 of numr-2 were not isolated. This suggested that numr-2 was annotated incorrectly and that it also was a single exon gene. Sequences for the 5Ј-ends of numr-1 and numr-2 were 100% iden...

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