Further Development Of A Reconstructed Skin Micronucleus Assay
Published: March 25th, 2007
by Curren, Rodger D., Aardema, Marilyn, Hayden, Patrick J., Mun, Greg, Hu, Ting, Wilt, Nathan, Gibson, Dave SOURCE
Presented at the Society of Toxicology Annual Meeting, 2007
SUMMARY
We have previously reported initial investigations of a novel micronucleus assay which utilizes a 3-dimensional human skin model EpiDerm™ supplied by MatTek Corporation (Ashland, MA). The advantage of this in vitro system is that it might potentially replace second-tier animal studies (or possibly first-tier non-specific traditional in vitro assays) in the genotoxicity evaluation of many materials, especially cosmetics ingredients. If so, it could then satisfy the requirement for non-animal testing of cosmetics ingredients after 2009 imposed by the European Seventh Amendment to the Cosmetics Directive. An important advantage of this assay system is that materials can be applied topically to the surface of the in vitro human skin model in a fashion similar to probable human exposure. In addition to previously reported positive responses with mitomycin C, vinblastine sulfate, MNNG and methyl methane sulfonate, four non-genotoxins (as shown by lack of micronucleus induction activity in an in vivo rodent skin model) have now been shown to induce no response in the reconstituted skin model. The non-genotoxins (4-nitrophenol, 1,2 epoxydodecane, trichloroethylene, and 2-ethyl-1,3-hexanediol) were tested up to levels of approximately 50% survival. The model has been further characterized by measuring expression of xenobiotic metabolizing enzymes. Although many enzymes were constitutively expressed, 3-methylcholanthrene and â-naphthoflavone strongly increased expression of CYP1A1 and CYP1B1, and slightly enhanced expression of CYP2C19, CYP2D6, CYP3A4 and CYP3A5. Overall, the in vitro model showed an enzyme expression pattern very similar to normal human skin. It appears that this model may be very useful for detecting of micronuclei induction in a structurally complex tissue of human origin.
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