+++
WHAT IS GENETIC TOXICOLOGY?
++
Genetic toxicology is the study of the actions of chemical and physical agents on DNA. It encompasses genotoxicity, mutagenesis, and epigenetic alterations. Mutagenicity refers to induction of alterations in the DNA sequence that can be transmitted to daughter cells during cell division. Genotoxicity is a broader term that includes formation of DNA adducts, DNA strand breaks, sister chromatid exchanges, and unscheduled DNA synthesis. Epigenetic modifications are transmissible during cell division, but do not involve changes in the DNA sequence. Epigenetic alterations include changes in DNA methylation, histone modifications, and micro RNA expression. Potential health impacts of genotoxicity include cancer, genetic disorders, developmental toxicity, and epigenetically mediated transgenerational effects.
++
Early genetic toxicology studies focused on mutagenesis by environmental chemicals and radiation. Mutagenesis induced by x-rays was first discovered in the 1920s, and chemical mutagenesis by mustard gas was discovered in the 1940s, both in Drosophila. The first demonstration of mutagenesis in a mammal, by x-rays in mice, was published in 1951. Discovery of the structure of DNA in 1953 led to research into how chemicals and physical agents interact with DNA and development of in vivo and in vitro assays to identify mutagenic agents. The National Toxicology Program (NTP) was established in response to a Congressional recommendation to “launch a program of testing mutagenicity of all compounds produced in commercial quantities” in the National Institute of Environmental Health Sciences (NIEHS), one of the National Institutes of Health (NIH).
++
The field of (quantitative) structure-activity relationship (SAR and QSAR) modeling began in the early 1960s and grew as the database of molecular structures, reactivity, and toxicity, as well as computational methods grew in the subsequent decades. In the 1970s and 1980s, numerous relatively rapid in vitro and in vivo genotoxicity and mutagenicity tests were developed. Perhaps the most well-known of these is the so-called Ames test for mutagenicity utilizing the bacterium Salmonella typhimurium. In the 1980s and 1990s, much basic research focused on identifying molecular pathways involved in mediating toxicity. With the advent of transgenic mouse models, studies of global or tissue-specific and/or inducible deletion or overexpression of genes became possible in vivo. Epidemiologic research focused on the roles of specific genes in modulating toxicity, so-called gene-environment interactions. A large focus was on analyzing the impact of specific common genetic polymorphisms in xenobiotic metabolizing enzymes on susceptibility to diseases caused by occupational or environmental exposures.
++
Since the first draft sequence of the human genome in 2000 and the completion of the human genome sequence in 2003, there has been rapid development of so-called ‘omics technologies that allow for global analyses of biological molecules within samples. Application of these technologies to toxicology holds promise for more efficient identification of genotoxic chemicals and deciphering of mechanisms of genotoxicity.
+++
TYPES OF GENOTOXICITY AND CELLULAR DNA DAMAGE RESPONSES