Geno toxicity, carcinogenicity and teratogenicity

B. harm III year

1. Genotoxicity, Carcinogenicity & Teratogenicity Dr. K. Manohar Babu VJ’s College of Pharmacy

2. Genotoxicities Cytogenetic markers Examples for Genotoxicity agents Carcinogenicity Chimeric Animals Knock out Animals Examples for Carcinogenicity agents Teratogenicity Invitro techniques Examples for Teratogenicity agents Contents

3. Genotoxicity

4. Genotoxicity is ability of any agent to damage genetic material. Toxic effect of any Physical , Chemical and Biological agent on genetic material(DNA/ RNA) Genotoxicity results in mutations which may results in tumor or cancer

5. Causes

6. Genotoxic Anti-Cancer Agents

7. Applications of Genotoxicities Assessment of genotoxicity in occupational exposed individual. Testing of new pharmaceutical product for its safety. Testing of various products used by humans like Cosmetics, Food products.

8. Carcinogenicity

9. Carcinogenicity  is the ability of a chemical to induce tumors , increase their incidence of tumor occurrence when it is inhaled, ingested, dermally applied or injected.  Carcinogenicity studies are generally required for pharmaceuticals that are expected to be used continuously for at least six months or intermittently for the treatment of chronic or recurrent conditions.

10. Characters and properties of Carcinogenicity Abnormal, uncontrolled cell division Damage to genes controlling cell growth Cancer cells lose normal functions Divide rapidly Invade surrounding cells Metastasis: abnormal cells traveling to different sites and starting new tumors Tumor: abnormal enlargement Angiogenesis: Forming new blood vessels in tumor region

11. The objectives of carcinogenicity studies are to identify a tumorigenic potential in animals and to assess the relevant risk in humans.

12. Study Duration Carcinogenicity evaluations in genetically engineered animals generally involve an exposure period of 6 months, versus exposure periods of 18–24 months for carcinogenicity evaluations in standard-bred mice. The primary determinant of the duration of carcinogenicity evaluations in transgenic or knockout mice . The standard protocol for carcinogenicity bioassays in rasH2 transgenic and hemizygous p53 knockout mice involves 26 weeks of agent exposure, followed by complete histopathologic evaluation of tissues.

13. Chimeric Rat   is a single organism composed of cells with more than one distinct  genotype . 

14. Gene Knockout  : A  gene knockout  ( KO ) is a genetic technique in which one of an organism’s gene is made inoperative Knockout organisms  are used to study gene function, usually by investigating the effect of gene loss.

15. Teratogenicity

16. • Capacity of a drug to cause foetal abnormalities when administered to the pregnant mother • Teratogenicity testing came into being since the thalidomide tragedy of 1961 • High demand for a rapid, reliable and cost- effective method for detection of teratogenic toxicity 

17. Drugs can affect the foetus at 3 stages Fertilization and implantation- conception to 17 days (unnoticed failure of pregnancy) Organogenesis- 18-55 days of gestation (most vulnerable period) Growth and development- 56 days onward (developmental and functional abnormalities can occur)

18. In vitro techniques   Whole embryo culture test Rodent embryo culture (rat or mouse) • Culturing of whole embryos at early stage of organogenesis • Exposing of these to a potential teratogen • Endpoints generally used – Mortality – Malformation – Growth inhibition Whole embryo culture test Zebrafish embryo • Cover the whole period of organogenesis • Easy to maintain in large stocks due to their high fecundity • Develop rapidly ex utero, with most organs becoming functional between 3 and 5 days- post-fertilization ( dpf ) • Transparency of larval zebrafish • Reasonably tolerant to concentration of dimethylsulphoxide (DMSO) generally used as a solvent at drug screening • High concordance with mammalian data

19. Thank you