Vitamin D receptor genotypes, ultraviolet radiation exposure, and risk of non-Hodgkin lymphoma.

Ultraviolet radiation (UVR) exposure may influence risk of non-Hodgkin lymphoma (NHL) through vitamin D, with antineoplastic effects mediated through the vitamin D receptor (VDR). To explore the role of vitamin D in NHL risk and the potential interaction with UVR, the authors genotyped 10 VDR polymorphisms in 2,448 NHL patients and 1,981 controls from Denmark and Sweden who were recruited in 1999-2002. Odds ratios and 95% confidence intervals were computed with logistic regression. P values were 2-sided. Most VDR variants (e.g., rs731236/TaqI, rs15444410/BsmI) were not associated with overall risk of NHL, but there was some evidence of a positive association between rs4760655 and follicular lymphoma risk (nominal P(trend) = 0.004, corrected P(trend) = 0.24). There was no support for an effect of interaction between VDR variants and UVR exposure on risk of overall NHL or B-cell lymphoma subtypes. However, there was some evidence that rs731236 altered associations between UVR and T-cell NHL risk; while increasing UVR frequency lowered T-cell NHL risk among rs731236 TT carriers, an elevated risk was observed among rs731236 CC carriers (nominal P(interaction) ≤ 0.008, corrected P(interaction) ≥ 0.12). VDR does not appear to harbor major determinants of NHL risk, except perhaps for follicular lymphoma. Possible heterogeneity in effects of UVR exposure on T-cell lymphoma risk by VDR rs731236 genotype merits further investigation.

The effect of melanism and vitamin D synthesis on the incidence of autoimmune disease.

Melanin has several physiological roles in maintaining health, but, notably, it affects the synthesis of vitamin D. Melanin is the primary determinant of the degree of skin pigmentation and protects the body from harmful ultraviolet radiation. Synthesis of 1,25-dihydroxyvitamin D(3) (1,25[OH](2)D(3)) in the skin, however, is dependent on ultraviolet B light. Highly pigmented skin, to the level found in people of African origin, abrogates almost all ultraviolet-induced 1,25(OH)(2)D(3) synthesis. Numerous animal models and clinical studies have underlined the essential role of vitamin D as a modulator of the different processes of the immune system. Evidence indicates that serum concentrations of 1,25(OH)(2)D(3) and the prevalence of autoimmune diseases in a certain population are associated with the latitude at which that population resides. This article explores the relationship between skin pigmentation, vitamin D and the prevalence of autoimmune disease.

Vitamin D receptor-dependent inhibition of mammary tumor growth by EB1089 and ultraviolet radiation in vivo.

1,25-Dihydroxyvitamin D(3) (1,25D), the biologically active form of vitamin D(3), exerts antiproliferative and proapoptotic effects in multiple transformed cell types, and thus, the vitamin D signaling pathway represents a potential anticancer target. Although chronic treatment with 1,25D induces hypercalcemia, synthetic vitamin D analogs have been developed that inhibit tumor growth in vivo with minimal elevation of serum calcium. Furthermore, vitamin D is synthesized in skin exposed to UV light, and this route of vitamin D elevation is not associated with hypercalcemia. In this study, we examined whether enhancement of vitamin D status via exogenous (EB1089, a 1,25D analog) or endogenous (UV exposure) approaches could exert antitumor effects without hypercalcemia. We used mammary xenografts with differential vitamin D receptor (VDR) expression to examine whether the antitumor effects of either therapy are receptor mediated. We present evidence that both EB1089 and UV exposure inhibit tumor growth via induction of growth arrest and apoptosis. These antitumor effects were observed only in xenografts containing VDR-positive tumor cells; heterogeneous tumors containing VDR-negative tumor cells and VDR-positive stromal and endothelial cells were unresponsive to both therapies. No evidence for antiangiogenic effects of EB1089 were detected in this model system. Neither EB1089 nor UV was associated with overt toxicity, but keratinocyte proliferation was increased in UV-exposed skin. These data provide proof of principle that UV exposure modulates tumor growth via elevation of vitamin D signaling and that therapeutic approaches designed to target the vitamin D pathway will be effective only if tumor cells express functional VDR.

In vivo effects of chronic contamination with depleted uranium on vitamin D3 metabolism in rat.

The extensive use of depleted uranium (DU) in today's society results in the increase of the number of human population exposed to this radionuclide. The aim of this work was to investigate in vivo the effects of a chronic exposure to DU on vitamin D(3) metabolism, a hormone essential in mineral and bone homeostasis. The experiments were carried out in rats after a chronic contamination for 9 months by DU through drinking water at 40 mg/L (1 mg/rat/day). This dose corresponds to the double of highest concentration found naturally in Finland. In DU-exposed rats, the active vitamin D (1,25(OH)(2)D(3)) plasma level was significantly decreased. In kidney, a decreased gene expression was observed for cyp24a1, as well as for vdr and rxralpha, the principal regulators of CYP24A1. Similarly, mRNA levels of vitamin D target genes ecac1, cabp-d28k and ncx-1, involved in renal calcium transport were decreased in kidney. In the brain lower levels of messengers were observed for cyp27a1 as well as for lxrbeta, involved in its regulation. In conclusion, this study showed for the first time that DU affects both the vitamin D active form (1,25(OH)(2)D(3)) level and the vitamin D receptor expression, and consequently could modulate the expression of cyp24a1 and vitamin D target genes involved in calcium homeostasis.