Folate deficiency enhances arsenic effects on expression of genes involved in epidermal differentiation in transgenic K6/ODC mouse skin.
Chronic arsenic exposure in humans is associated with cancers of the skin, lung, bladder and other tissues. There is evidence that folate deficiency may increase susceptibility to arsenic effects, including skin lesions. K6/ODC mice develop skin tumors when exposed to 10ppm sodium arsenite for 5 months. In the current study, K6/ODC mice maintained on either a folate deficient or folate sufficient diet were exposed to 0, 1, or 10ppm sodium arsenite in the drinking water for 30 days. Total RNA was isolated from skin samples and gene expression analyzed using Affymetrix Mouse 430 2.0 GeneChips. Data from 24 samples, with 4 mice in each of the 6 treatment groups, were RMA normalized and analyzed by two-way ANOVA using GeneSpring. Top gene ontology (GO) categories for genes responding significantly to both arsenic treatment and folate deficiency include nucleotide metabolism and cell organization and biogenesis. For many of these genes, folate deficiency magnifies the response to arsenic treatment. In particular, expression of markers of epidermal differentiation, e.g., loricrin, small proline rich proteins and involucrin, was significantly reduced by arsenic in the folate sufficient animals, and reduced further or at a lower arsenic dose in the folate deficient animals. In addition, expression of a number of epidermal cell growth/proliferation genes and cellular movement genes was altered. These results indicate that arsenic disrupts the normal balance of cell proliferation and differentiation, and that folate deficiency exacerbates these effects, consistent with the view that folate deficiency is a nutritional susceptibility factor for arsenic-induced skin tumorigenesis.
Nelson
Gail M
GM
US Environmental Protection Agency, Research Triangle Park, NC 27711, United States.
Ahlborn
Gene J
GJ
Delker
Don A
DA
Kitchin
Kirk T
KT
O'Brien
Thomas G
TG
Chen
Yan
Y
Kohan
Michael J
MJ
Roop
Barbara C
BC
Ward
William O
WO
Allen
James W
JW
D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D001665:Binding Sites; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000097:blood; D005494:Folic Acid Deficiency / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006710:Homocysteine / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism; D017670:Sodium Compounds / Q000633:toxicity*; D014157:Transcription Factors / Q000378:metabolism
D018053:Arsenites; D002274:Carcinogens, Environmental; D017670:Sodium Compounds; D014157:Transcription Factors; D006710:Homocysteine; C017947:sodium arsenite; D005492:Folic Acid