Molecular effects of 1-naphthyl-methylcarbamate and solar radiation exposures on human melanocytes.
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.
Department of Clinical Chemistry and Toxicology, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil, 05508-000. Electronic address: biferrucio@usp.br.
Bianca
B
Ferrucio
Department of Clinical Chemistry and Toxicology, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil, 05508-000. Electronic address: manoela.santos@usp.br.
Manoela
M
Tiago
NIEHS Molecular Genomics Core Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA, 27709. Electronic address: fannin@niehs.nih.gov.
Richard D
RD
Fannin
NIEHS Molecular Genomics Core Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA, 27709. Electronic address: liuliw@niehs.nih.gov.
Liwen
L
Liu
NIEHS Molecular Genomics Core Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA, 27709. Electronic address: gerrish@niehs.nih.gov.
Kevin
K
Gerrish
Department of Clinical Chemistry and Toxicology, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil, 05508-000. Electronic address: silvya@usp.br.
Silvya Stuchi
SS
Maria-Engler
NIEHS Molecular Genomics Core Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA, 27709. Electronic address: paules@niehs.nih.gov.
Richard S
RS
Paules
Department of Clinical Chemistry and Toxicology, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil, 05508-000. Electronic address: smbarros@usp.br.
Silvia Berlanga de Moraes
SBM
Barros
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D012721:Carbaryl / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004249:DNA Damage; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000187:drug effects* / Q000528:radiation effects*; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D013472:Sunlight; D014466:Ultraviolet Rays / Q000009:adverse effects*
D012721:Carbaryl
1-naphthyl-methylcarbamate; Carbaryl; Melanocytes; Melanomagenesis; Microarray; Solar radiation