Oxygen is an essential micronutrient. Unlike many internal tissues, human epidermis obtains much of its oxygen supply from the atmosphere (21% oxygen), and it ordinarily experiences higher oxygen levels than internal tissues (estimated approximately 5%). To test whether epidermal cell growth and differentiation depend upon this higher oxygen level, keratinocyte cultures were studied at 21, 5, and 2% oxygen concentrations. Compared to 21% oxygen, culture in 5% had little effect on growth but led to profound suppression of the differentiation program as assessed by expression of differentiation markers and formation of squames in the superficial layers. Culture in 2% oxygen reduced the growth rate as well as stratification and differentiation. In low-oxygen conditions, the cells exhibited increased colony-forming ability, consistent with a lower proportion of differentiated cells, and increased expression of vascular endothelial growth factor and cyclooxygenase-2. Growth in 21% oxygen led to higher levels of glutathione and expression of oxidant-responsive genes. Electrophoretic mobility supershift assay using an involucrin activator protein 1 (AP1) response element sequence revealed altered binding by proteins of the Jun and Fos families in nuclear extracts. The present data thus demonstrate oxygen-dependent differentiation in human keratinocytes, to which altered utilization of AP1 transcriptional response elements may contribute.

Dermal exposure to a diverse range of chemicals may result from various uses. In order to assess exposure and estimate potential risks, accurate quantitative data on absorption are required. Various factors will influence the final results and interpretations of studies designed to assess the ability of compounds to penetrate the skin. This overview will discuss skin penetration by pesticides, emphasizing key parameters to be considered from the perspective of exposure assessment.

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Sodium arsenite is much more potent than sodium arsenate in producing adverse effects in animals and in cultured cells. Although arsenate may exhibit toxicity as a phosphate analogue, its potency in vivo appears to be enhanced by reduction to arsenite. To understand the relative importance of this reduction, which is critical in evaluating the responsiveness of cell culture models to the different oxidation states and thus to elucidating the mechanism of arsenic action, present work has correlated the extent of reduction with biological activity in human keratinocytes. The results show that at biologically relevant concentrations, arsenate reduction to appreciable levels required several days, helping rationalize a previous empirical observation that it was approximately one-third as potent as arsenite. The relatively low conversion rate also emphasizes a limitation of culture; arsenate was nearly as efficacious as arsenite, but the time required for it to reach maximal effect exceeded ordinary medium change intervals. In keratinocytes, an important role for purine nucleoside phosphorylase in the reduction could not be demonstrated, indicating that another pathway is dominant in this cell type. Methylation of inorganic arsenic, uptake of methylated forms, and their reduction were all very slow. These findings suggest that the reduced methylated forms have only a small contribution to skin carcinogenesis unless they are supplied through the circulation. In parallel experiments, trivalent antimony was similar to arsenite in potency and efficacy, whereas pentavalent antimony was virtually without biological effect. Conversion of antimony in the pentavalent to the trivalent oxidation state was not detectable in keratinocytes. These findings emphasize the importance of intracellular reduction of the metalloids for biological effects.