Human Mutagenicity Studies
Somatic mutations arise in vivo in humans and can be measured and analyzed with precision. At the fundamental level, these mutations provide probes for investigating basic mutagenic mechanisms while, at the practical level, they provide biomarkers for assessing environmental health hazards. An important aspect of somatic mutations is their role in human diseases such as cancer.
The primary interest of our laboratory is somatic mutations that arise in vivo in human T-lymphocytes. We have developed a method for quantitating these events in the “reporter gene” hypoxanthine-guanine phosphoribosyltransferase (hprt) and have used it in a variety of human studies. One kind of study measures mutation induction in vivo in individuals exposed to environmental mutagens and carcinogens as a biomarker for assessing environmental cancer risks.
Mutant T-cells arising in vivo in humans can be isolated and characterized in vitro. Therefore, our laboratory has a major commitment in determining molecular mutational spectra. This has proved fruitful both for establishing basic mutagenic mechanisms and as a means for assessing the specificity of environmental mutagens/carcinogens.
Other studies of in vivo T-cell hprt mutations have revealed an unanticipated level of complexity. For example, in vivo mutations in T-lymphocytes arise preferentially in dividing as opposed to quiescent cells. Since most T-cells in vivo are in an arrested Go stage of the cell cycle, we have exploited this observation to detect immunologically relevant T-cells in individuals with autoimmune diseases. Such cells are more likely to be dividing, and thus more likely to have undergone mutation, than are quiescent cells.
Other studies have examined the role of development in somatic mutation. Lymphocyte mutations in the fetus, as determined in placental blood samples, are markedly different at the molecular level from those found in adults, indicating a fundamentally different mutational mechanism. This mechanism involves the differentiation of T-cells that results in rearrangement of their T-cell receptor (TcR) genes during thymic ontogeny. Rearrangement involves V(D)J recombinase w hich also induces illegitimate deletions in other genes, and may be an important fetal mutagenic mechanism in prenatal carcinogenesis.
Our mutational studies in T-cells, therefore, include molecular analyses of TcR genes. Also, we are developing additional reporter genes. Our laboratory has a concentrated effort in identifying individual susceptibiity to environmental mutagens and carcinogens as part of our overall interest in genetic predisposition to cancer. A major effort over the past two years has been the identification of T-lymphocytes with “mutator phenotypes” that arise in vivo in normal individuals.
Ballinger SW, Judice SA, Nicklas JA, Albertini RJ, O’Neill, JP (2002) DNA Sequence Analysis of Interlocus Recombination Between the human T-Cell Receptor Gamma Variable (GV) and Beta Diversity-Joining (BD/BJ) Sequences on chromosome 7 (Inversion 7). Environ and Mol Mutagenesis 40(2):85-92
Kirman CR, Sweeney LM, Teta MJ, Sielken RL, Valdez-Flora C, Albertini RJ, Gargas ML (2004) Addressing nonlinearity in the exposure-response relationship for a genotoxic carcinogen: Cancer potency estimates for ethylene Oxide. (2004) Risk Analysis 24(5): 1165-1183.
McDiarmid MA, Engelhardt S, Oliver M, Gucer P, Wilson D, Kane R, Kabat M, Kaup B, Anderson L, Hoover D, Brown L, Handwerger B, Albertini RJ, Jacobson-Kram D, Thorne C, Squibb K. (2004) Health effects of depleted uranium on exposed Gulf War veterans: A ten-year follow-up. J Toxicol Environ Health 67(4), 277-296.
Albertini RJ. (2004) Mechanistic insights from biomarker studies: Somatic mutations and rodent/human comparisons following exposure to a potential carcinogen. IARC Scientific Publications 157:153-177
Albertini RJ, (2010) Judice SA, Recio L, Walker VE. Hprt mutant frequency and p53 gene status in mice chronically exposed by inhalation to benzene. Chem Biol Interact.184(1-2):77-85