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Molecular Effects of 1-Naphthyl-Methylcarbamate and Solar Radiation Exposures on Human Melanocytes

Bianca Ferrucio, Manoela Tiago, Richard D. Fannin, Liwen Liu, Kevin Gerrish, Silvya Stuchi Maria-Engler, Richard S. Paules, and Silvia Berlanga de Moraes Barros.
Toxicology in Vitro (2017) DOI: https://doi.org/10.1016/j.tiv.2016.11.005 PMID: 27829164


Publication


Abstract

Carbaryl (1-naphthyl-methylcarbamate), a broad-spectrum insecticide, has recently been associated with the development of cutaneous melanoma in an epidemiological cohort study with U.S. farm workers also exposed to ultraviolet radiation, the main etiologic factor for skin carcinogenesis. We hypothesized that carbaryl exposure may increase deleterious effects of UV solar radiation on skin melanocytes. This study aimed to characterize human melanocytes after individual or combined exposure to carbaryl (100μM) and solar radiation (375mJ/cm2). In a microarray analysis, carbaryl, but not solar radiation, induced an oxidative stress response, evidenced by the upregulation of antioxidant genes, such as Hemeoxygenase-1 (HMOX1), and downregulation of Microphtalmia-associated Transcription Factor (MITF), the main regulator of melanocytic activity; results were confirmed by qRT-PCR. Carbaryl and solar radiation induced a gene response suggestive of DNA damage and cell cycle alteration. The expression of CDKN1A, BRCA1/2 and MDM2 genes was notably more intense in the combined treatment group, in a synergistic manner. Flow cytometry assays demonstrated S-phase cell cycle arrest, reduced apoptosis levels and faster induction of cyclobutane pyrimidine dimers (CPD) lesions in carbaryl treated groups. Our data suggests that carbaryl is genotoxic to human melanocytes, especially when associated with solar radiation.

Figures


Figure 1. Relative gene expression validation by qRT-PCR.

Relative gene expression validation by qRT-PCR – comparison between microarray and qRT-PCR data. Data generated in experimental triplicate, analyzed by ANOVA followed by Dunnett's test to evaluate differences between treated groups and the control group, and ANOVA followed by Tukey's test to verify which groups differ from one another (*p < 0.05, **p < 0.001). Results are expressed as fold change (mean ± standard deviation) relative to DMSO treatment (vehicle control). Groups identified by the same letter do not differ significantly. Circled asterisks indicate a synergistic response evaluated by Student t-test for the non-orthogonal contrast (p < 0.001), between Carbaryl and UV radiation treatments. UV – treated with DMSO 0.07% and 375 mJ/cm2 solar radiation; Carb UV – treated with carbaryl 100 μM and 375 mJ/cm2 solar radiation; Carb – treated with carbaryl 100 μM; DMSO – treated with DMSO 0.07%.

Figure 2. Cell growth evaluation - cell counting after 24, 48 and 72 h of treatment.

Data was generated in triplicate, analyzed by Data generated in experimental triplicate, analyzed by ANOVA followed by Dunnett's test to evaluate differences between treated groups and the control group (*p < 0.05; **p < 0.005; ***p < 0.0005). DMSO UV – treated with DMSO 0.07% and irradiated with solar radiation 375 mJ/cm2; Carb UV – treated with carbaryl 100 μM and irradiated with solar radiation 375 mJ/cm2; Carb – treated with carbaryl 100 μM; DMSO – treated with DMSO 0.07%; and Ctrl – non-treated group.

Figure 3. Evaluation of cell death mechanisms by flow cytometry analysis – human melanocytes.

Evaluation of cell death mechanisms by flow cytometry analysis – human melanocytes treated for 24 h. Data was generated in triplicate, analyzed by ANOVA followed by Tukey's test, and compared to the DMSO control group (*p < 0.05, **p < 0.001). DMSO UV – treated with DMSO 0.07% and irradiated with solar radiation 375 mJ/cm2; Carb UV – treated with carbaryl 100 μM and irradiated with solar radiation 375 mJ/cm2; Carb – treated with carbaryl 100 μM; DMSO – treated with DMSO 0.07%; and Ctrl – non-treated group.

Figure 4. Quantification of cyclobutane pyrimidine dimers (CPDs).

Quantification of cyclobutane pyrimidine dimers (CPDs): fluorescence absorbance median analyzed by flow cytometry after 1 and 6 h of treatment. Data was generated in triplicate, analyzed by ANOVA followed by the Tukey's test, and compared to the DMSO control group (*p < 0.05, **p < 0.005).
DMSO UV – treated with DMSO 0.07% and irradiated with solar radiation 375 mJ/cm2; Carb UV – treated with carbaryl 100 μM and irradiated with solar radiation 375 mJ/cm2; Carb – treated with carbaryl 100 μM; DMSO – treated with DMSO 0.07%; and Ctrl – non-treated group.

Figure 5. Quantification of 8-oxo-dG: fluorescence median absorbance analyzed by flow cytometry.

Quantification of 8-oxo-dG: fluorescence median absorbance analyzed by flow cytometry after 1 and 24 h of treatment. Data was generated in triplicate, analyzed by ANOVA followed by the Tukey's test, and compared to the DMSO control group.
DMSO UV – treated with DMSO 0.07% and irradiated with solar radiation 375 mJ/cm2; Carb UV – treated with carbaryl 100 μM and irradiated with solar radiation 375 mJ/cm2; Carb – treated with carbaryl 100 μM; DMSO – treated with DMSO 0.07%; and Ctrl – non-treated group.

Tables


Table 1. Significantly altered canonical pathways and the related altered genes.

Significantly altered canonical pathways and the related altered genes in the different treatment groups.

Table 2. Evaluation of cell cycle phase at different time-points.

Supplemental Materials


Supplementary Data

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      • modules/BinViews/Models/Library.php:64
      • view::binviews::layouts.manuscript:54
    • OracleBuilder.php#159CEBSBIN2.46msselect "BIN_FILE".*, "BIN_LIBRARY_FILES"."LIBRARY_ID" as "LARAVEL_THROUGH_KEY" from "BIN_FILE" inner join "BIN_LIBRARY_FILES" on "BIN_LIBRARY_FILES"."FILE_ID" = "BIN_FILE"."FILE_ID" where "BIN_LIBRARY_FILES"."LIBRARY_ID" = 9262 and "IS_DELETED" != 'T'
      Bindings
      • 0: 9262
      • 1: T
      Hints
      • The != operator is not standard. Use the <> operator to test for inequality instead.
      Backtrace
      • vendor/yajra/laravel-oci8/src/Oci8/Query/OracleBuilder.php:159
      • view::binviews::layouts.manuscript:52
      • vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:75
    • OracleBuilder.php#159CEBSBIN5.82msselect * from "BIN_REVIEW" where "BIN_REVIEW"."FILE_ID" = '1de240ff62ed87f901631d02267d0169' and "BIN_REVIEW"."FILE_ID" is not null
      Bindings
      • 0: 1de240ff62ed87f901631d02267d0169
      Hints
      • Use SELECT * only if you need all columns from table
      Backtrace
      • vendor/yajra/laravel-oci8/src/Oci8/Query/OracleBuilder.php:159
      • modules/BinViews/Models/File.php:63
      • modules/BinViews/Models/Library.php:65
      • modules/BinViews/Models/Library.php:64
      • view::binviews::layouts.manuscript:54
    • OracleBuilder.php#159CEBSBIN2.74msselect "BIN_FILE".*, "BIN_LIBRARY_FILES"."LIBRARY_ID" as "LARAVEL_THROUGH_KEY" from "BIN_FILE" inner join "BIN_LIBRARY_FILES" on "BIN_LIBRARY_FILES"."FILE_ID" = "BIN_FILE"."FILE_ID" where "BIN_LIBRARY_FILES"."LIBRARY_ID" = 9263 and "IS_DELETED" != 'T'
      Bindings
      • 0: 9263
      • 1: T
      Hints
      • The != operator is not standard. Use the <> operator to test for inequality instead.
      Backtrace
      • vendor/yajra/laravel-oci8/src/Oci8/Query/OracleBuilder.php:159
      • view::binviews::layouts.manuscript:52
      • vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:75
    • OracleBuilder.php#159CEBSBIN5.75msselect * from "BIN_REVIEW" where "BIN_REVIEW"."FILE_ID" = '1de240ff62ed87f901631d025059016a' and "BIN_REVIEW"."FILE_ID" is not null
      Bindings
      • 0: 1de240ff62ed87f901631d025059016a
      Hints
      • Use SELECT * only if you need all columns from table
      Backtrace
      • vendor/yajra/laravel-oci8/src/Oci8/Query/OracleBuilder.php:159
      • modules/BinViews/Models/File.php:63
      • modules/BinViews/Models/Library.php:65
      • modules/BinViews/Models/Library.php:64
      • view::binviews::layouts.manuscript:54
    • OracleBuilder.php#159CEBSBIN2.4msselect "BIN_FILE".*, "BIN_LIBRARY_FILES"."LIBRARY_ID" as "LARAVEL_THROUGH_KEY" from "BIN_FILE" inner join "BIN_LIBRARY_FILES" on "BIN_LIBRARY_FILES"."FILE_ID" = "BIN_FILE"."FILE_ID" where "BIN_LIBRARY_FILES"."LIBRARY_ID" = 9264 and "IS_DELETED" != 'T'
      Bindings
      • 0: 9264
      • 1: T
      Hints
      • The != operator is not standard. Use the <> operator to test for inequality instead.
      Backtrace
      • vendor/yajra/laravel-oci8/src/Oci8/Query/OracleBuilder.php:159
      • view::binviews::layouts.manuscript:52
      • vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:75
    • OracleBuilder.php#159CEBSBIN5.74msselect * from "BIN_REVIEW" where "BIN_REVIEW"."FILE_ID" = '1de240ff62ed87f901631d0275a6016b' and "BIN_REVIEW"."FILE_ID" is not null
      Bindings
      • 0: 1de240ff62ed87f901631d0275a6016b
      Hints
      • Use SELECT * only if you need all columns from table
      Backtrace
      • vendor/yajra/laravel-oci8/src/Oci8/Query/OracleBuilder.php:159
      • modules/BinViews/Models/File.php:63
      • modules/BinViews/Models/Library.php:65
      • modules/BinViews/Models/Library.php:64
      • view::binviews::layouts.manuscript:54
    • OracleBuilder.php#159CEBSBIN3.1msselect "BIN_FILE".*, "BIN_LIBRARY_FILES"."LIBRARY_ID" as "LARAVEL_THROUGH_KEY" from "BIN_FILE" inner join "BIN_LIBRARY_FILES" on "BIN_LIBRARY_FILES"."FILE_ID" = "BIN_FILE"."FILE_ID" where "BIN_LIBRARY_FILES"."LIBRARY_ID" = 9265 and "IS_DELETED" != 'T'
      Bindings
      • 0: 9265
      • 1: T
      Hints
      • The != operator is not standard. Use the <> operator to test for inequality instead.
      Backtrace
      • vendor/yajra/laravel-oci8/src/Oci8/Query/OracleBuilder.php:159
      • view::binviews::layouts.manuscript:52
      • vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:75
    • OracleBuilder.php#159CEBSBIN5.74msselect * from "BIN_REVIEW" where "BIN_REVIEW"."FILE_ID" = '1de240ff62ed87f901636abf78c303a8' and "BIN_REVIEW"."FILE_ID" is not null
      Bindings
      • 0: 1de240ff62ed87f901636abf78c303a8
      Hints
      • Use SELECT * only if you need all columns from table
      Backtrace
      • vendor/yajra/laravel-oci8/src/Oci8/Query/OracleBuilder.php:159
      • modules/BinViews/Models/File.php:63
      • modules/BinViews/Models/Library.php:65
      • modules/BinViews/Models/Library.php:64
      • view::binviews::layouts.manuscript:54
    • OracleBuilder.php#159CEBSBIN2.07msselect "BIN_FILE".*, "BIN_LIBRARY_FILES"."LIBRARY_ID" as "LARAVEL_THROUGH_KEY" from "BIN_FILE" inner join "BIN_LIBRARY_FILES" on "BIN_LIBRARY_FILES"."FILE_ID" = "BIN_FILE"."FILE_ID" where "BIN_LIBRARY_FILES"."LIBRARY_ID" = 9266 and "IS_DELETED" != 'T'
      Bindings
      • 0: 9266
      • 1: T
      Hints
      • The != operator is not standard. Use the <> operator to test for inequality instead.
      Backtrace
      • vendor/yajra/laravel-oci8/src/Oci8/Query/OracleBuilder.php:159
      • view::binviews::layouts.manuscript:52
      • vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:75
    • OracleBuilder.php#159CEBSBIN6.15msselect * from "BIN_REVIEW" where "BIN_REVIEW"."FILE_ID" = '1de240ff62ed87f901631d02d048016d' and "BIN_REVIEW"."FILE_ID" is not null
      Bindings
      • 0: 1de240ff62ed87f901631d02d048016d
      Hints
      • Use SELECT * only if you need all columns from table
      Backtrace
      • vendor/yajra/laravel-oci8/src/Oci8/Query/OracleBuilder.php:159
      • modules/BinViews/Models/File.php:63
      • modules/BinViews/Models/Library.php:65
      • modules/BinViews/Models/Library.php:64
      • view::binviews::layouts.manuscript:54
    • OracleBuilder.php#159CEBSBIN2.15msselect "BIN_FILE".*, "BIN_LIBRARY_FILES"."LIBRARY_ID" as "LARAVEL_THROUGH_KEY" from "BIN_FILE" inner join "BIN_LIBRARY_FILES" on "BIN_LIBRARY_FILES"."FILE_ID" = "BIN_FILE"."FILE_ID" where "BIN_LIBRARY_FILES"."LIBRARY_ID" = 9267 and "IS_DELETED" != 'T'
      Bindings
      • 0: 9267
      • 1: T
      Hints
      • The != operator is not standard. Use the <> operator to test for inequality instead.
      Backtrace
      • vendor/yajra/laravel-oci8/src/Oci8/Query/OracleBuilder.php:159
      • view::binviews::layouts.manuscript:52
      • vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:75
    • OracleBuilder.php#159CEBSBIN5.9msselect * from "BIN_REVIEW" where "BIN_REVIEW"."FILE_ID" = '1de240ff62ed87f901636abfb98503a9' and "BIN_REVIEW"."FILE_ID" is not null
      Bindings
      • 0: 1de240ff62ed87f901636abfb98503a9
      Hints
      • Use SELECT * only if you need all columns from table
      Backtrace
      • vendor/yajra/laravel-oci8/src/Oci8/Query/OracleBuilder.php:159
      • modules/BinViews/Models/File.php:63
      • modules/BinViews/Models/Library.php:65
      • modules/BinViews/Models/Library.php:64
      • view::binviews::layouts.manuscript:54
    • OracleBuilder.php#159CEBSBIN2.04msselect * from "BIN" where "BIN_ID" = 4194
      Bindings
      • 0: 4194
      Hints
      • Use SELECT * only if you need all columns from table
      Backtrace
      • vendor/yajra/laravel-oci8/src/Oci8/Query/OracleBuilder.php:159
      • modules/BinViews/Services/BreadcrumbService.php:32
      • modules/BinViews/Routes/breadcrumbs.php:55
      • vendor/diglactic/laravel-breadcrumbs/src/Generator.php:64
      • vendor/diglactic/laravel-breadcrumbs/src/Generator.php:42
    Modules\BinViews\Models\Library
    9Library.php#?
    Modules\BinViews\Models\LibraryGroup
    9LibraryGroup.php#?
    Modules\BinViews\Models\File
    8File.php#?
    Modules\BinViews\Models\Review
    8Review.php#?
    Modules\BinViews\Models\PublicationManuscript
    3PublicationManuscript.php#?
    Modules\BinViews\Models\Characteristic
    1Characteristic.php#?
      web
      null
        _token
        PG2exi2p3tcDfDToJtUDdKBDo210x0E8miWem5Sx
        ClearShow all
        Date ↕MethodURLData
        #12025-04-06 20:09:25GET/cebs/paper/41941783138