3. mutagen,carcino and teratogen

Bule Hora University
College of Health and Medical Sciences
Department Of Pharmacy
TOXICOLOGY
For 4th year Medical Laboratoy
Students
4/5/2022
Mutagens, Carcinogens and Teratogens 1
By:Aliyi G.(B.Pharm)

. Introduction to mutagenesis
. mutagens
3. Mutagenesis
2
4/5/2022
Mutagens, Carcinogens and Teratogens

Introduction to mutagenesis
3
Mutagenesis :-
 Genesis means to synthesize something.
 is a process by which the genetic information of
an organism is changed,
 resulting in a mutation.
 It may occur
 spontaneously in nature, or
 as a result of exposure to mutagens.
 It can also be achieved experimentally using
laboratory procedures.
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Introduction to mutagenesis cont’d,…
4
Mutagenesis as a laboratory technique
 Mutagenesis in the laboratory is an important
technique where by DNA mutations are
deliberately
engineered to produce
 mutant genes,
 proteins or
 strains of organisms.
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cont’d,…
5
 Types of Mutagenesis
I. Random mutagenesis
II. Site-directed mutagenesis
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cont’d,…
6
I. Random mutagenesis
 When an organism is exposed to a physical or
chemical mutagen,
 mutations are induced randomly in all genes of the
organism.
 Hence, this process of generating mutations is
known as random mutagenesis.
 The desired mutant is selected from the
mutagenised
population.
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cont’d,…
7
II. Site-directed mutagenesis
 Site-directed mutagenesis, also called site-
specific
mutagenesis or oligonucleotide-directed
mutagenesis,
 is a molecular biology technique
 in which a mutation is created at a defined site in a
DNA molecule.
 Oligonucleotide-directed mutagenesis
 is used to test the role of particular residues in the
structure, catalytic activity, and ligand-binding
capacity of a protein. 4/5/2022

Mutagen:
8
Definition
 “Mutagen is a physical, chemical or biological agent that
causes mutation by
 altering the genetic material which possibly results in the disease
condition.”
 Mutagens are the agents that damage genetic material, usually
DNA and
 results in genetic abnormalities.
Or
 Anything that causes mutations is known as mutagens.
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Definition Cont’d,…
9
 In genetics, mutagen induced changes are
known as mutation.
 However, not all mutations emerge due to
mutagens, some mutations arise spontaneously
by
 error in replication, hydrolysis or recombination
errors.
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Definition Cont’d,…
10
 The mutations are categorized under two broader categories;
 gene mutations and
 chromosomal mutations.
 Insertion, deletion, duplication, translocation, inversion are
some of the common types of gene mutations that occur
spontaneously in nature while
 trisomy, monosomy and numerical chromosomal
abnormalities are some of the chromosomal mutations.
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Types of mutagens
11
 Physical
 Radiation
 Heat
 Chemical
 Base analogs
 Alkylating agents
 intercalating agents
 Metal ions
 biological
 Viruses
 bacteria
 transposons
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12
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Physical agents
13
Radiation:
 Radiations are the first mutagenic agent reported in
1920.
 UV rays, X-rays, alpha rays, neutrons, and other ionizing
and non-ionizing radiations are mutagenic.
 Usually, radiation directly damages the DNA or
nucleotide structure.
 The radiation causes
 cross-linking of DNA or protein,
 chromosomal break,
 strand break or chromosomes loss,
 also, at the molecular level it prompts deletion of
bases or DNA strand breakages.
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Physical agents cont’d,…
14
Graphical illustration of the effect of UV- radiation on DNA
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Physical agents cont’d,…
15
Heat:
Heat is another mutagen that provokes
mutations in our DNA.
when we heat the DNA, over a certain degree
(>95°C),
 the DNA becomes denatured.
 Also, extreme heat also damages DNA and
breaks the phosphodiester bonds too.
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Chemical mutagens
16
 Chemicals are actually dangerous for the
entire world.
 The first mutagenic effect of the nitrogen
mustard was reported by charlotte Auerbach in
1942.
 the nitrogen mustard is a poisonous gas used
during the world war 1 and 2.
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Chemical mutagens cont’d,…
17
Base analogs:
 The base analogs are chemicals similar to the
 bases of DNA- purine and pyrimidines or
 structurally resemble the DNA bases.
 Bromouracil and aminopurine are two common base analogs
incorporated into DNA- instead of normal bases,
 during the process of replication.
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18
 The 5-bromouracil are artificially synthesized molecules- a
base analog utilized in the genetic research
 which is incorporated in DNA in place of the thymine.
 Instead of the methyl group of the thymine,
 the bromouracil contains Br group- highly resemble to the thymine.
 It pairs with the adenine as like the thymine and
 produces the mutation.
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19
The pairing of adenine and 5-bromouracil.
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20
Alkylating agents:
 Ethylnitrosourea, mustard gas and vinyl chloride
 are common alkylating agents that add alkyl group to
the DNA and
 damages it.
 The agents induce base-pairing errors by
 increasing ionization and
 produces gaps in the DNA strand.
 The alkylated purine bases are removed by the
phenomenon called depurination,
 although depurination is not mutagenic and
 can be repaired by the DNA repair pathway.
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21
Intercalating agents:
 Ethidium bromide (EtBr) used during the agarose gel
electrophoresis is one of the intercalating agents.
 Other intercalating agents like proflavine, acridine
orange,... operated by the same mechanism alike the
EtBr.
 The molecules intercalate between the bases of DNA
and disrupt its structure.
 If it is incorporated during the replication,
 it can cause frameshift mutation.
 It may also block transcription.
 The intercalating agents either
 cause deletion or insertion and 4/5/2022

22
The graphical illustration of the effect of an intercalating
agent on DNA.
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23
Metal ions:
 Metal ions also dangerous to our DNA as it acts
in varieties of different ways.
 Nickel, chromium, cobalt, cadmium, arsenic,
chromium and iron are some of the common metal
ions cause mutations.
 The metal ions work by
 producing ROS (reactive oxygen species),
 hindering the DNA repair pathway,
 cause DNA hypermethylation or
 may directly damages the DNA.
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Biological agents
24
Virus:
 HIV is causative agent of AIDS.
 Viruses are common mutagens that are well
known to us and creates lethal health issues.
 Viruses insert their DNA into our genome and
 disrupt the normal function of DNA or genes.
 Once it inserts DNA, the DNA is replicated,
transcribed and translate viral protein instead of
our own protein.
 Mature viral particle forms in a cell.
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Biological agents cont’d,…
25
Bacteria:
 Some bacteria are also dangerous for our DNA-
 cause inflammation.
 It provokes DNA damage and
 DNA breakage.
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Biological agents cont’d,…
26
Transposons:
 Less known biological mutagens are transposons.
 The transposons are non-coding DNA sequences,
 jumps from one place to another place in a genome
and
 influence the function of genes.
 Unlike the viral DNA, the transposons are our
own DNA believed to be originated from the
retroviruses.
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Effect of mutagens
27
 The mutagens are genotoxic- harmful to our
DNA in many ways,
 some directly affect the DNA
 some indirectly.
 therefore, the exact effect of each mutagen is
still unknown to us.
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Effect of mutagens cont’d,…
28
 At the chromosomal level, the mutagens can
alter the structure or number of chromosomes.
 As deletion, duplication, insertion, translocation,
monosomy and nondisjunction are some of the
chromosomal abnormalities produced by
mutagens.
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29
 At the molecular level, the mutagens create
different gene mutations results in
 loss of function,
 altered function or
 non-functional protein.
 It also alters the codon, deletes bases, alters
bases, breaks hydrogen bonds or
phosphodiester bonds and
 changes gene expression.
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30
 Some mutagens dysregulate cell proliferation
and cell death process and
 thus cause cancer, those are called carcinogens.
 Biological mutagens slower down the DNA
repair or DNA synthesis process.
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31
 Some of the common types of mutagens
based on their effect are enlisted here:
Teratogens:
 are the class of the mutagens
 which causes congenital malformations.
 X-rays, valproate and toxoplasma are common
physicals, chemical and biological teratogens,
respectively.
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32
Carcinogens:
 are the class of mutagens
 induces tumor formation and
 thus cause cancer.
 A wide variety of agents are categorized as
carcinogens.
 X-rays/ UV-rays, Aflatoxins and retroviruses are
common physicals, chemical and biological
carcinogens, respectively.
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33
Clastogens:
 are the class of mutagens responsible for
chromosomal
 breakage,
 deletion,
 duplication and
 rearrangements.
 UV-rays, Bleomycins and HIV viruses are common
types of physical, chemical, and biological
clastogens, respectively.
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34
non-specific mutagens:
 other unclassified mutagens are responsible
for DNA damage and
 non-functioning of the DNA repair pathway.
 X-rays/heat, innumerable and toxoplasma are
several non-specific mutagens.
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35
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Mutagens are useful
36
 Now, this is something interesting, scientists are
using various physical, chemical or biological
mutagens for various purposes.
 For example, an EtBr is used as an intercalating
dye during agarose gel electrophoresis
 It emits fluorescent and the DNA bands can be visualized
on a gel.
 The heat method is used during the polymerase
chain reaction for denaturation of DNA.
 This facilitates single-stranded DNA for various
applications.
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Mutagens are useful…
37
 The UV-rays are utilized for decontamination or
sterilization processes in genetics as well as
microbiology.
 The UV-light destroys all the bacteria or viruses
present in a culture room.
 Carcinogens and teratogens are used in cancer
research.
 Transposons are used as a vehicle for transferring
a gene of interest at a particular location in a
genome.
 Thus it is used in gene therapy experiments.
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 Cancer
 Carcinogenesis
 Carcinogen
CARCINOGENESIS
38
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Cancer
39
 A group of disease characterized by
 uncontrolled multiplication and
 spread of abnormal forms of the body's own cells.
 A multi-causal, multistage group of diseases the
mechanisms of which are still only partially known.
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Cancer cont’d,…
 Can originate almost anywhere in the body.
 Carcinomas
 The most common types of cancer
 Arise from the cells that cover external & internal body
surfaces.
 Lung, breast, and colon
 are the most frequent cancers of this type in the United
States.
 Sarcomas
 Arising from cells found in the supporting tissues of the body
 Bone, cartilage, fat, connective tissue, and muscle.
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40

Cancer cont’d,…
 Lymphomas:
 Arise in the lymph nodes and tissues of the body’s
immune system.
 Leukemias:
 Cancers of the immature blood cells that grow in the
bone marrow
 Tend to accumulate in large numbers in the
bloodstream.
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41

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42 Mutagens, Carcinogens and Teratogens

Cancer cont’d,…
 Age is a primary risk factor;
 ~77 percent of all cancers being diagnosed in
people aged 55 and older.
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43

Cancer cont’d,…
 Causes
 All cancers are a result of multiple mutations.
 Internal
 Inherited mutations &
 Only 5–10%
 Environmental/acquired factors
 90–95% of mutations
 Tobacco , diet, radiation,
 Alcohol, & infectious organisms.
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44

Cancer cont’d,…
45
 Some viruses associated with human
cancers
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Carcinogenesis
 DNA repair genes.
 Code for proteins whose normal function is
 to correct errors that arise when cells duplicate their DNA
prior to cell division.
 Mutations in DNA repair genes can
 lead to a failure in repair,
 which in turn allows subsequent mutations to
accumulate.
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46

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Cancer:
 the result of malfunctions within the regulation of the
cell cycle,
 such that injured or mutated cells
 which are normally killed are allowed to progress
through the cell cycle, accumulating mutations.
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48

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Stages of carcinogenesis
50
 Carcinogenesis is a complex multistage process, usually
involving
 More than one genetic change as well as
 Epigenetic factors which do not by themselves produce
cancer but
 increase the likelihood that the genetic mutation(s) will
eventually result in cancer.
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Stages of carcinogenesis cont’d,…
51
Initiation
 Phenomenon of gene alteration, which may result from the
interaction of ultimate carcinogens with DNA in the target cell.
 Initiating event involves cellular genome – MUTATIONS.
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cont’d,…
52
 Results from DNA mutations
 Mutations may occur in oncogenes/proto-
oncogenes or
tumor suppressor genes.
 Initiated cells may remain ‘dormant’, and rarely
become
neoplastic cells without undergoing promotion and
progression.
 Irreversible
 Single treatment can induce mutation.
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cont’d,…
53
Promotion
 A phenomenon of gene activation in which the latent altered
phenotype of the initiated cell becomes expressed through
selection and clonal expansion.
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cont’d,…
54
 Results from clonal expansion of initiated cells

No direct DNA modification

Nongenotoxic; don’t induce cancer by themselves.

No direct mutation

Cell signaling and gene expression are altered,

leading to increased cell mitogensis and/or reduced apoptosis.

Leads to the formation of preneoplastic cells

Long duration and reversible, especially at earlier stage

Tumor promoters (not mutagenic) do not directly interact with
DNA ---altered expression of genes
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cont’d,…
55
Progression
 The last irreversible stage of multistage carcinogenesis,
 which usually develops from the cells in the stage of promotion.
 Characterised by
 irreversibility,
 genetic instability,
 faster growth,
 invasion,
 metastization, and
 changes in the biochemical, metabolical and morphological
characteristics of cells – malignant phenotypes
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cont’d,…
56
 Results from additional genomic structural alterations
 Leads to the formation of benign or malignant neoplasms
 Chemicals that impact on the progression stage are usually
genotoxic agents.
 Agents that only cause the transition of a cell from the stage
of promotion to that of progression are termed progressor
agents.
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57
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Carcinogen
58
Defn.
 is Substance that can cause cancer by inhalation,
ingestion or skin.
 Carcinogens either produce:
 New neoplastic growth in a tissue or organ or
 Increase the incidence and/or multiplicity of background
spontaneous neoplastic formation in the target tissue.
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Carcinogen cont’d,…
59
 Carcinogens can be
 chemicals,
 physical agents (such as Uv light and gamma radiation),
and
 biological agents (such as viruses).
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60
 Carcinogen - can be divided into two major categories:
 Based on whether or not they are mutagenic in in-vitro
mutagenicity assay.
A. DNA-damaging agents (genotoxic)
 Mutagenic in in-vitro assays
 Considered to produce permanent alterations in the
genetic material of the host in vivo
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61
B. Epigenetic agents (nongenotoxic)
 Not mutagenic in in-vitro assays
 Don’t alter the primary sequence of DNA but are
considered to alter the expression or repression of
certain genes and/or to produce perturbations in signal
transduction pathways that influence cellular events
related to proliferation, differentiation, or apoptosis.
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62
Table: characteristics of Genotoxic and Nongenotoxic
Carcinogens
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A.DNA-damaging agents (genotoxic)
63
Direct acting carcinogens
 are intrinsically reactive compounds
 do not require metabolic activation
 Examples include
 N-methyl-N-nitrosourea and N-methyl-N-nitro-N-
nitrosoguanidine;
 the alkyl alkanesulfonates such as methyl methanesulfonate;
 the lactones such as beta propiolactone and the nitrogen
and sulfur mustards.
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DNA-damaging agents (genotoxic)
cont’d,…
64
Indirect-acting carcinogens
 require metabolic activation by cellular enzymes
 to form the ultimate carcinogenic species.
o Examples include
o dimethylnitrosamine,
o benzo[a]pyrene,
o 7,12-dimethylbenz[a]anthracene,
o aflatoxin B1and
o 2-acetylaminofluorene
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DNA-damaging agents (genotoxic)
cont’d,…
65
Radiation and oxidative DNA damage
 can occur directly or indirectly.
Inorganic agents
such as
 arsenic,
 chromium and
 nickel
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66
Table: Examples of Genotoxic Carcinogens
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B. Epigenetic Agents
67
 Many epigenetic agents favor the proliferation of cells with an
altered genotype and
 allow the clonal expansion of these altered or “initiated” cells.
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Epigenetic Agents cont’d,…
68
Epigenetic agents can be divided into four major categories
Hormones
 such as conjugated estrogens and diethylstilbestrol
Immunosuppressive xenobiotics
 such as azathioprine and cyclosporin A
Solid state agents,
 which include plastic implants and asbestos
Tumor promoters
 rodent models, which include 12-O-tetradecanoylphorbol-
13-acetate, TCDD and phenobarbital
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69
Table: Some Nongenotoxic Chemical
Carcinogens
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Chemical Carcinogens
70
 Classification of Chemical Carcinogens in Relation to Their
Action on One or More Stages of Carcinogenesis.
Initiating agent (incomplete carcinogen):
 a chemical capable only of initiating cells.
 Polycyclic hydrocarbons
 e.g. Benzo(a)pyrene) and nitrosamines,
 biological agents
 such as viruses, and
 physical agents
 such as X-rays and UV light.
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Chemical Carcinogens cont’d,…
71
Promoting agent:
 a chemical capable of causing the expansion of initiated cell
clones e.g.
 tetradecanoyl phorbol acetate,
 phenobarbital,
 2,3,7,8-tetracholorodibenzo-p-dioxin ,
 cholic acid,
 androgens and estrogens,
 natural and synthetic are effective promoting agents.
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72
Progressor agent:
 a chemical capable of converting an initiated cell or a cell in
the stage of promotion to a potentially malignant cell
 e.g.
 hydrogen peroxide,
 arsenic salts,
 hydroxyurea, and
 organic peroxides, e.g. benzoyl peroxide, benzene .
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73
Complete carcinogen:
 a chemical possessing the capability of inducing cancer
from normal cells,
usually possessing properties of initiating,
promoting, and progressor agents
e.g.
 aflatoxin,
 tobacco smoking,
 soluble nickel salts, can be genotoxic carcinogen.
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75
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Teratogenesis
Teratogen
TERATOGEN
76
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Introduction
77
 Teratology (Greek word teratos=“ monster ” Gensis-
”producing”)
 is a specialized area of embryology.
 It is the study of the etiology of abnormal development
(the study of birth defects).
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Introduction cont’d,…
78
 A teratogen
 is defined as any agent that results in structural or functional
abnormalities (malformation ) in the fetus or in the child after
birth,
 as a consequence of maternal exposure during pregnancy.
 Birth defects are known to occur in 3- 5% of all newborns.
 They can do direct damage to the fetus, causing abnormal
development.
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79
 Teratogens are substances that may produce
physical or functional defects in the human
embryo or fetus after the pregnant woman is
exposed to the substance.
 Alcohol and cocaine are examples of such
substances.
 Exposure to the teratogen affects the fetus or
embryo in a variety of ways, such as the
 duration of exposure,
 the amount of teratogenic substance, and
 the stage of development the embryo or fetus is in
during the exposure.
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80
 They affect the embryo or fetus in a number of
ways, causing
 physical malformations,
 problems in the behavioral or emotional
development of the child, and
 decreased intellectual quotient (IQ) in the child.
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81
 The agents responsible for the disruptions are called
teratogens.
 Mutagens and carcinogens also are the causes of abnormal
development but their mode of action differ.
 Teratogens are agents that affect the embryo at dose levels.
 They are harmless to adult organisms and
 do not permanently damage the genetic material.
 On the other hand,
 mutagens are agents that alter the genes, whereas
 carcinogens are agents that lead to excessive growth and loss of
differentiation, generally in adult tissue.
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Causes of teratogenesis
82
 Abnormalities caused by genetic events, e.g.
 mutation in genes,
 structural changes in chromosomes etc. are called
malformations.
 Abnormalities caused by environmental agents
are
called disruptions. May be either
 biological (e.g. viruses and parasites) or
 Non biological such as physical factors (e.g.
temperature,
radiation) and
 chemical factors (e.g. drug, chemicals
and nutritional imbalances). 4/5/2022

Causes of teratogenesis
83
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Causes of teratogenesis cont’d,…
84
Characteristics of environmental induced
teratogenesis
Stage sensitivity
 Susceptibility to teratogen varies from stage of gestation
 From fertilization to early post – implantation (pre-embryonic period)
o Days 0-17 post conception
o Prior to implantation and organ differentiation
o Not usually associated with teratogenesis
o Effect of teratogen is all (embryonic lethality) or none effect.
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85
 Embryonic period
o Days 18-60 post conception
o Implantation to time of organogenesis
o Period of major organ development
o Greater risk of malformation; morphological
defects .
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86
 The fetal period: Fetal → neonatal stage
o > 8 weeks post conception until term
o Fetal growth
o CNS and some organs continue to develop
o e.g. eyes, ears, teeth, external genitalia
o Abnormalities also occurs e.g. ethanol
o Functional disorders,
o growth retardation,
o carcinogenesis.
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87
Figure: Sensitivity to teratogenic exposure at different stages of
embryonic and fetal development

Types Teratogens
88
 Teratogens are classified into four types:
1. physical agents,
2. metabolic conditions,
3. infection and
4. drugs and chemicals
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A list of some teratogenic agents causing birth defects
89
Natural Teratogens
Some poisonous plants like Skunk cabbage
veratrum, Ionizing radiations
Pharmaceutical Teratogens
Thalidoamide ,Tetracycline, Streptomycin ,Valproic
acid, Warfarin, Diethylstilbestrol, Retionic acid,
Pencillin
Industrial Teratogens
Lead, Methyl, mercury, Cadmium,
Arsenic
Microbial Teratogens
Treponema pallidum (syphilis), Herpes simplex,
Rubella (German measles),Cytomeagalo virus (CMV)
Metabolic conditions in the
mother
Diabetes, Auto immune disease (including Rh
incompatibility), Phenylketonuria, Dietary
deficiencies, malnutrition 4/5/2022

Microbial teratogens cont’d,…
90
 This class of teratogens includes infectious microorganisms.
 These microbes affect 1-5% of all live births and
 are among the leading causes of neonatal morbidity and
mortality.
 General symptoms include
 premature birth,
 growth retardation,
 neurological abnormalities,
 damage of the eye, liver, heart and ear along with bone lesions.
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91
Rubella
 Abnormal babies are born to women suffering from
Rubella (German measles) during the first five weeks
of pregnancy.
 The abnormalities include,
 microphthalmia,
 cataracts,
 glaucoma,
 cardiac malformations,
 hearing loss and
 mental retardation. 4/5/2022

 The mode of action of the pathogen
 can be direct viral effects or damage to immune
response.
 In 1969, Rubella vaccine was introduced.
 Since then the cases of congenital Rubella
syndrome have decreased significantly .
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92

93
Cytomegalovirus (CMV) & Herpes
simplex
 Cytomegalovirus infection early in gestation is fatal
while infection of later embryos might lead to
 blindness ,
 deafness,
 cerebral palsy and
 mental retardation.
4/5/2022

 CMV damage including
 hepatitis,
 gestational prematurity,
 anemia.
 Mode of action of CMV is similar to that of rubella
virus,
 i.e. cell lysis and immune response.
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94

95
Toxoplasma
 Toxoplasma goondii is a protozoan parasite carried
by rabbits and cats.
 It can cross the placenta causing
 hydrocephaly,
 microphthalmia,
 brain lesions and
 multiple organ damage.
4/5/2022

 Fetal infection occurs approximately one in four
thousand pregnancies.
 The fetal damage caused by the teratogen is
maxmium if the mother is infected in third trimester
resulting in 60% of the infected new born.
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96

97
Syphilis
 Treponema pallidum is the cause of syphilis.
 Several hundred children are born each year with syphilis.
 Early infection most often results in spontaneous abortion.
 New born which survive are anemic
 having spleen and liver malformations.
 Infection during late pregnancy results in
 deafness,
 dental and bony abnormalities,
 cardiovascular defects and
 skin lesions.
4/5/2022

Teratogenic Drugs
98
 Analgesic
 Anticonvulsant
 Anticoagulant  Antidepressant
 Ant thyroid
 Vitamin A
•Metal toxic
•Sedative/ hypnotics
•Aminoglycosides
IN the first trimester pregnant
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Analgesic (Aspirin)
99
 Gastroschisis
 Decrease prostaglandin => decrease uterine
contraction => delayed onset of labor &
prolonged period of pregnancy.
 During delivery => severe bleeding because
aspirin decrease platelet aggregation.
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Anticonvulsant
100
 Women with epilepsy 5-10% risk of anomalies.
 Range of anomalies varies with drugs.
 Risk increases with numbers and dose of drugs.
 Including :
 Carbamazepine,
 phenytoin,
 valproic acid.
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Anticonvulsant
101
 Fetal hydantoin
syndrome :
 cranio facial malformation:
-Cleft lip and palate
-Broad nasal bridge
-Abnormal ears
 congenital heart disease
 limb malformation
 mental and growth
retardation
4/5/2022

Anticoagulant
102
Warfarin and coumadin
 Fetal warfarin syndrome:
-Nasal hypoplasia (bones
appears small)
-Bone stippling
-Mental retardation
 Respiratory distress syndrome
 Fetal and maternal hemorrhage
4/5/2022

Vitamin A (Retinoic Acid)
103
 Carnie-facial dismorphism
 Cleft palate (facial malformation)
 Thymic aplasia (missing of organ)
 Neural tube defect ( birth defect of brain)
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Other Teratogenic drug
104
 Thalidomide
 Diethylstilbestrol
 Tetracycline
 Chloramphenicol
 Aminoglycosides
 Sulfamethoxazole And
Trimethoprim
4/5/2022

Teratogenic drug cont’d,…
105
Thalidomide
 A sedative-hypnotic drug used in Europe from 1957
to 1961.
 It was marketed for
 morning sickness,
 nausea and
 Insomnia.
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106
 Women who had taken the drug from gestation days 35 to 50 gave
birth
◦ To offspring suffering from a spectrum of different
malformations, mainly
◦ amelia (absence of limbs) or
◦ phocomelia (severe shortening of limbs).
◦ Other malformations included:
◦ absence of the auricles with deafness,
◦ defects of the muscles of the eye and face, and
◦ malformations of the heart, bowel, uterus, and gallbladder.
 The compound was withdrawn from the market in 1961 after about
10,000 cases had occurred.
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107
Diethylstilbestrol
 A synthetic non-steroidal estrogen widely used from the
1940s to the 1970s in the US
 to prevent threatened miscarriage by stimulating
synthesis of estrogen and progesterone in the placenta.
 In 1970’s female offspring to have vaginal adenocarcinoma
at age 15 – 22yrs.
 22-58% females developed uterine, cervical or tubal changes
=> infertility, miscarriage etc…
 Male offspring => undescended or small testes etc…
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108
Tetracycline
 Protein synthesis inhibitor
 Inhibit the binding of aminoacyl-tRNA to the
mRNA ribosomes complex
 by binding to the 30S ribosomal subunit in mRNA
translation complex .
 SIDE EFFECTS
 dental discoloration in children
 maternal hepatotoxicity (drug that cause injury to
liver) with large parenteral doses.
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109
Chloramphenicol
 Bacteriostatic drug that stop bacterial growth by inhibiting
protein synthesis
• Prevent protein chain elongation by inhibiting peptidyl
transferase activity of bacterial chromosome
• Intravenous chloramphenicol use has been associated with
Gray Baby syndrome.
 This occur in newborn infants
 because their liver enzymes not yet fully developed.
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110
Adverse effects
 Hypotension
 Cyanosis
 The condition can be prevented by using the drug
at recommended doses & monitoring blood levels.
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111
Aminoglycosides
EG: GENTAMICIN, STREPTOMYCIN
• Have several potential antibiotic mechanisms
• Disrupt the integrity of the bacterial cell
membrane.
Adverse effects:
 Nephrotoxicity…usually reversible and mild.
 Ototoxicity… irreversible, manifests itself mainly
as vestibular dysfunction.
 Loss of hearing can also occur.
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112
Sulfamethoxazole,Trimethoprim
 Sulfonamide is a bacteriostatic antibiotic
 Structural analogs and competitive antagonist
of PABA.
 Inhibit normal bacterial utilisation of PABA for the synthesis
of folic acid
• Used as a bacteriostatic antibiotic in treatment
of urinary tract infections.
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113
 Adverse Effects
Most common
 Fever, skin rashes, dermatitis, photosensitivity,
urticaria, NVD
 Stevens-Johnson syndrome
 Serious and potentially fatal type of skin and mucous
membrane eruption associated with sulfonamide use.
 Relatively uncommon
 <1% of treatment courses
4/5/2022

115
4/5/2022

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