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Sunscreens containing ZnO and TiO(2) nanoparticles (NPs) are increasingly applied to skin over long time periods to reduce the risk of skin cancer. However, long-term toxicological studies of NPs are very sparse. The in vitro toxicity of ZnO and TiO(2) NPs on keratinocytes over short- and long-term applications is reported. The effects studied are intracellular formation of radicals, alterations in cell morphology, mitochondrial activity, and cell-cycle distribution. Cellular response depends on the type of NP, concentration, and exposure time. ZnO NPs have more pronounced adverse effects on keratinocytes than TiO(2). TiO(2) has no effect on cell viability up to 100 μg mL(-1), whereas ZnO reduces viability above 15 μg mL(-1) after short-term exposure. Prolonged exposure to ZnO NPs at 10 μg mL(-1) results in decreased mitochondrial activity, loss of normal cell morphology, and disturbances in cell-cycle distribution. From this point of view TiO(2) has no harmful effect. More nanotubular intercellular structures are observed in keratinocytes exposed to either type of NP than in untreated cells. This observation may indicate cellular transformation from normal to tumor cells due to NP treatment. Transmission electron microscopy images show NPs in vesicles within the cell cytoplasm, particularly in early and late endosomes and amphisomes. Contrary to insoluble TiO(2), partially soluble ZnO stimulates generation of reactive oxygen species to swamp the cell redox defense system thus initiating the death processes, seen also in cell-cycle distribution and fluorescence imaging. Long-term exposure to NPs has adverse effects on human keratinocytes in vitro, which indicates a potential health risk.

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1a,25-dihydroxyvitamin D 3 upregulates tumour necrosis factor superfamily member 11 (TNFSF11) that codes for the receptor activator of nuclear factor kB ligand (RANKL), and downregulates osteoprotegerin (OPG) expression. We have analyzed the individual effects of polymorphisms in the vitamin D receptor gene (VDR), OPG and TNFSF11, and searched for interactions between them. Six hundred and forty one subjects were evaluated: 239 osteoporotic and 228 non-osteoporotic post-menopausal, 57 pre-menopausal women and 117 elderly men. The subjects were genotyped for BsmI, FokI and Cdx2 in VDR, K3N in OPG and K290COT, K643COT and K693GOC in TNFSF11 gene. Bone mineral density (BMD) and biochemical markers were measured. In the osteoporotic women, femoral neck BMD (BMD-fn)showed associations with BsmI(VDR) and Cdx2(VDR) (PZ0 . 015 and 0 . 047 respectively), and lumbar spine BMD (BMDls) with K3N(OPG) and K290COT(TNFSF11) (PZ0 . 021 and 0 . 017). No association with BMD was found in the nonosteoporotic women. In the pre-menopausal women, the Cdx2(VDR) polymorphism was associated with BMD-fn and total hip BMD (PZ0 . 011 and 0 . 011). In elderly men, FokI(VDR) was associated with BMD-fn and BMD-ls (PZ0 . 040 and 0 . 036). Interestingly, the K290COT(TNFSF11)-K3N(OPG) combination was associated with BMD-th (PZ0 . 041) in the osteoporotic women. In the non-osteoporotic women, the combination K3N(OPG)-Cdx2(VDR) was associated with BMD-ls, BMD-th and BMD-fn (PZ0 . 032, 0 . 049 and 0 . 022), and the combination K290COT(TNFSF11)-K3N(OPG) with BMD-fn (PZ0 . 029). For the first time, the presence of gene-gene interactions between VDR, OPG and TNFSF11 genes was studied. Our results strongly suggest further confirmation of their combined influence on larger cohorts.

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