This document discusses genetic toxicology and genotoxicity. It defines genotoxicity as the property of chemicals that damage genetic material in cells, potentially causing mutations and cancer. Two examples are given of genotoxic substances - chromium, which interacts with DNA to cause lesions, and pyrrolizidine alkaloids found in some plants, which are toxic and genotoxic. Genetic toxicology testing is used to identify hazards, prioritize chemicals for further study, determine mechanisms of carcinogenesis, and includes a variety of assays measuring endpoints like mutations, chromosome damage, and DNA repair in different organisms.

1. ARAVINTH
MSc-Nanoscience and Technology
Alagappa University
Karaikudi

2. INTRODUCTION
 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. THESTUDYOFCHEMICAL,PHYSICALORBIOLOGICALAGENTS THATCAN
CHANGETHESEQUENCEORSTRUCTUREOFDNA
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. MECHANISM
 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 TOOLS
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