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The application of transcriptional benchmark dose modeling for deriving thresholds of effects associated with solar-simulated ultraviolet radiation exposure.

ABSTRACT: Considerable data has been generated to elucidate the transcriptional response of cells to ultraviolet radiation (UVR) exposure providing a mechanistic understanding of UVR-induced cellular responses. However, using these data to support standards development has been challenging. In this study, we apply benchmark dose (BMD) modeling of transcriptional data to derive thresholds of gene responsiveness following exposure to solar-simulated UVR. Human epidermal keratinocytes were exposed to three doses (10, 20, 150 kJ/m2 ) of solar simulated UVR and assessed for gene expression changes 6 and 24 hr postexposure. The dose-response curves for genes with p-fit values (? 0.1) were used to derive BMD values for genes and pathways. Gene BMDs were bi-modally distributed, with a peak at ?16 kJ/m2 and ?108 kJ/m2 UVR exposure. Genes/pathways within Mode 1 were involved in cell signaling and DNA damage response, while genes/pathways in the higher Mode 2 were associated with immune response and cancer development. The median value of each Mode coincides with the current human exposure limits for UVR and for the minimal erythemal dose, respectively. Such concordance implies that the use of transcriptional BMD data may represent a promising new approach for deriving thresholds of actinic effects. Environ. Mol. Mutagen. 59:502-515, 2018. © 2018 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.

SUBMITTER: Qutob SS

PROVIDER: S-EPMC6099464 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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The application of transcriptional benchmark dose modeling for deriving thresholds of effects associated with solar-simulated ultraviolet radiation exposure.

Qutob Sami S SS Chauhan Vinita V Kuo Byron B Williams Andrew A Yauk Carole L CL McNamee James P JP Gollapudi B B

Environmental and molecular mutagenesis 20180515 6

Considerable data has been generated to elucidate the transcriptional response of cells to ultraviolet radiation (UVR) exposure providing a mechanistic understanding of UVR-induced cellular responses. However, using these data to support standards development has been challenging. In this study, we apply benchmark dose (BMD) modeling of transcriptional data to derive thresholds of gene responsiveness following exposure to solar-simulated UVR. Human epidermal keratinocytes were exposed to three d ...[more]

PMID: 29761935

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Project description:BackgroundTerrestrial ultraviolet (UV) radiation causes erythema, oxidative stress, DNA mutations and skin cancer. Skin can adapt to these adverse effects by DNA repair, apoptosis, keratinization and tanning.ObjectivesTo investigate the transcriptional response to fluorescent solar-simulated radiation (FSSR) in sun-sensitive human skin in vivo.MethodsSeven healthy male volunteers were exposed to 0, 3 and 6 standard erythemal doses (SED). Skin biopsies were taken at 6 h and 24 h after exposure. Gene and microRNA expression were quantified with next generation sequencing. A set of candidate genes was validated by quantitative polymerase chain reaction (qPCR); and wavelength dependence was examined in other volunteers through microarrays.ResultsThe number of differentially expressed genes increased with FSSR dose and decreased between 6 and 24 h. Six hours after 6 SED, 4071 genes were differentially expressed, but only 16 genes were affected at 24 h after 3 SED. Genes for apoptosis and keratinization were prominent at 6 h, whereas inflammation and immunoregulation genes were predominant at 24 h. Validation by qPCR confirmed the altered expression of nine genes detected under all conditions; genes related to DNA repair and apoptosis; immunity and inflammation; pigmentation; and vitamin D synthesis. In general, candidate genes also responded to UVA1 (340-400 nm) and/or UVB (300 nm), but with variations in wavelength dependence and peak expression time. Only four microRNAs were differentially expressed by FSSR.ConclusionsThe UV radiation doses of this acute study are readily achieved daily during holidays in the sun, suggesting that the skin transcriptional profile of 'typical' holiday makers is markedly deregulated. What's already known about this topic? The skin's transcriptional profile underpins its adverse (i.e. inflammation) and adaptive molecular, cellular and clinical responses (i.e. tanning, hyperkeratosis) to solar ultraviolet radiation. Few studies have assessed microRNA and gene expression in vivo in humans, and there is a lack of information on dose, time and waveband effects. What does this study add? Acute doses of fluorescent solar-simulated radiation (FSSR), of similar magnitude to those received daily in holiday situations, markedly altered the skin's transcriptional profiles. The number of differentially expressed genes was FSSR-dose-dependent, reached a peak at 6 h and returned to baseline at 24 h. The initial transcriptional response involved apoptosis and keratinization, followed by inflammation and immune modulation. In these conditions, microRNA expression was less affected than gene expression.

Project description:BackgroundUltraviolet (UV) radiation modulates secondary metabolism in the skin of Vitis vinifera L. berries, which affects the final composition of both grapes and wines. The expression of several phenylpropanoid biosynthesis-related genes is regulated by UV radiation in grape berries. However, the complete portion of transcriptome and ripening processes influenced by solar UV radiation in grapes remains unknown.ResultsWhole genome arrays were used to identify the berry skin transcriptome modulated by the UV radiation received naturally in a mid-altitude Tempranillo vineyard. UV radiation-blocking and transmitting filters were used to generate the experimental conditions. The expression of 121 genes was significantly altered by solar UV radiation. Functional enrichment analysis of altered transcripts mainly pointed out that secondary metabolism-related transcripts were induced by UV radiation including VvFLS1, VvGT5 and VvGT6 flavonol biosynthetic genes and monoterpenoid biosynthetic genes. Berry skin phenolic composition was also analysed to search for correlation with gene expression changes and UV-increased flavonols accumulation was the most evident impact. Among regulatory genes, novel UV radiation-responsive transcription factors including VvMYB24 and three bHLH, together with known grapevine UV-responsive genes such as VvMYBF1, were identified. A transcriptomic meta-analysis revealed that genes up-regulated by UV radiation in the berry skin were also enriched in homologs of Arabidopsis UVR8 UV-B photoreceptor-dependent UV-B -responsive genes. Indeed, a search of the grapevine reference genomic sequence identified UV-B signalling pathway homologs and among them, VvHY5-1, VvHY5-2 and VvRUP were up-regulated by UV radiation in the berry skin.ConclusionsResults suggest that the UV-B radiation-specific signalling pathway is activated in the skin of grapes grown at mid-altitudes. The biosynthesis and accumulation of secondary metabolites, which are appreciated in winemaking and potentially confer cross-tolerance, were almost specifically triggered. This draws attention to viticultural practices that increase solar UV radiation on vineyards as they may improve grape features.

Project description:UV radiation (UV) alters secondary metabolism in the skin of Vitis vinifera L. berries, which may affect on the final composition of both, grapes and wines. We compared berry skin transcriptome and phenolic composition between Tempranillo berries grown in the presence or absence of solar UV in a mid-altitude Tempranillo vineyard. By analysing two different ripening degrees, expression of 121 genes was significantly altered. Functional enrichment identified that, principally, secondary metabolism-related transcripts were induced by UV, including VvFLS1, VvGT5 and VvGT6 flavonol biosynthetic genes induction. Concurrently, flavonol accumulation was the most evident impact of UV on the berry skin phenolic composition. Monoterpenoid biosynthetic transcripts were also up-regulated by UV, whereas induction of stilbenoid biosynthetic transcripts and stilbenes accumulation was probably induced by the joint action of UV and other condition under the UV-blocking filter, likely higher temperature. Among regulatory genes, VvMYBF1, VvMYB24 and three bHLH transcription factors were up-regulated by UV. Homologs to Arabidopsis UVR8-dependent UV-B-induced genes were also induced, including VvHY5-1, VvHY5-2 and VvRUP UV-B signalling genes. This suggests that the UV-B-specific signalling pathway is activated in the skin of grapes grown at low-medium altitudes. The biosynthesis and accumulation of UV-absorbing compounds that are appreciated for winemaking were almost specifically triggered, which indicates that viticultural practices increasing solar UV incidence may improve grape features important to wine production. A total of 12 samples were hybridized. Grape skin RNA from berries ripening under a UV-transmitting filter (FUV+) and a UV-blocking filter (FUV-) was compared. Berry skin of two different ripening stages was analysed on each UV treatment. All samples were harvested simultaneously and a NaCl series was used to select the ripening degree in a non-invasive way. Three biological replicates were analyzed for each sample.

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The application of transcriptional benchmark dose modeling for deriving thresholds of effects associated with solar-simulated ultraviolet radiation exposure.

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The application of transcriptional benchmark dose modeling for deriving thresholds of effects associated with solar-simulated ultraviolet radiation exposure.

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