Genotoxicology

Its about gene and DNA damage on nanomaterials

1. Genotoxicity ARAVINTH MSc-Nanoscience and Technology Alagappa University Karaikudi

2. INTR OD U C T ION Mutation is a broad term covering a whole range of changes to the informational molecule, DNA (made up of the four nucleotides: the purines, adenine and guanine, and the pyrimidines, thymine and cytosine) packaged into chromosomes, of an organism from gene changes to modifications of the number and structure of chromosomes Point mutations are changes to the sequence of nucleotides and may involve the substitution of individual bases

3. Genotoxicity Genotoxicity describes the property of chemical agents that damages the genetic information within a cell causing mutations, which may lead to cancer The alteration can have direct or indirect effects on the DNA: the induction of mutations and direct DNA damage leading to mutations

4. T he study of chemical, physical or biological agents that can change the sequence or structure of DNA What is Genetic Toxicology 4 DNA damage can be: at nucleotide level in DNA, or at the chromosomal level induced by direct mechanisms (chemical or metabolite interacts with DNA) induced by indirect mechanisms (chemical or metabolite affects other cellular macromolecules, e.g. mitotic spindle fibers )

5. Why We Evaluate Genotoxicity 7 7 Germ Cells spermatocytes, oocytes Somatic Cells Heritable Damage (genetic damage to offspring) Infertility Cancer Other Diseases DNA damage is associated with many human diseases

6. ME CHANISM The genotoxic substances induce damage to the genetic material in the cells through interactions with the DNA sequence and structure For example, the transition metal chromium interacts with DNA in its high-valent oxidation state so to incur DNA lesions leading to carcinogenesis The metastable oxidation state Cr(V) is achieved through reductive activation

7. Another example of a genotoxic substance causing DNA damage are pyrrolizidine alkaloids (PAs) These substances are found mainly in plant species and are poisonous to animals, including humans; about half of them have been identified as genotoxic and many as tumorigenic

8. Hazard identification/Lead prioritization Companies want products to be safe and to be seen as safe for intended uses Predict whether a chemical is a carcinogen Predict whether a chemical could cause heritable germ cell damage Early testing “screening” allows Companies/Regulators to prioritize chemicals to spend further resources on (e.g. EPA ToxCast™) Mechanistic information Determine mechanism of action for carcinogens (genotoxic vs. non-genotoxic) Basic science: study of DNA damage/repair Objectives of Genetic Toxicology Testing 8

9. What are the Genetic Toxicology Tool s 10 Hundreds of assays developed to measure DNA damage Assays grouped by endpoint measured Types of DNA damage endpoints include: Mutations Changes in chromosome structure or number DNA damage DNA repair Biomarkers of DNA damage Endpoints can be measured in: bacteria, yeast, fungi, plants, invertebrates, mammalian cells in culture, animals and humans