Teratogenecity

Modes of Evaluation

By,
Ms.Pranita S. Joshi
M.Tech FBT
 Teratogenecity

Terratogen: agent that causes structural defects or anomalies of prenatal

development ,that are present,but not necessarily detecable at birth

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 Absence of limbs

Anotia

Abnormal swelling in
fetuses
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 Embryology

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 Degree & Nature of cellular lesion depends
on :

• Stage of embryo or fetal development when chemical is

administered
• Dosage, Route of administration & exposure schedule
• Ability of chemical to pass placenta & penetrate embryonic
tissue
• Ability of maternal tissue(esp. liver)to detoxify or bioactivate
chemical
• Biologic & chemical half life of the material or its metabolite
• Ability of damaged cells to repair or recover from cytotoxic
lesions

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 Teratogenic mechanisms

• Mutation
• Chromosomal non disjunction & breaks
• Altered nucleic acid integrity or function
• Lack of precursors & substrates needed for
biosynthesis
• Absorption failures of essential materials
• Reduction in energy supplies
• Osmolar imbalance

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 Teratogens in animals
CLASS EXAMPLES
Dietary deficiencies Vit. A,D,E,ascorbic acid riboflavin,folate,
Trace elements(Zn,Mn,Mg,Co), Protein
Hormone deficiency Pituitary,thyroid,insulin
Vitamin antagonists Antifolic drugs,6-amino nicotinamide,3-
acylpyridine
Hormone antagonists Thiouracil derivatives
Vitamin excess Vit.A, nicotinic acid
Hormone excess Cortisone,vasopressine,thyroxine,androgen
s,estrogens,epinephrine
Crabs Galactose, bacterial LPS
Antibiotics Dactinomycine,penicillin,tetracyclin,
streptomycin
Heavy metals Methyl
mercury,EDTA,lead,thallium,strontium,
selenium
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 Contd…
CLASS EXAMPLES
Azo dyes Trypan blue, Evans blue,niagara sky,
Agents producing hypoxia C0, CO2
Drugs & chemicals Nicotine, quinine, ricin, saponin,
thiadiazole, boric acid, THALIDOMIDE,
caffeine,morphine etc.

Insecticides,herbicides,fungicides DDT
Solvents DMSO,chloroform,ethanol,CCl4,
glycol,formamides,sulfonates,PEG
Natural substances Rubatoxin B,aflatoxinB1,ochratoxin
A,ergotamine,jimson weed etc
Physical agents Radiation,hypo- & hyperthermia,hypoxia

Infections 10 viruses known, including Rubella,

Cytomegaloivirus,syphilis,gonorrhoea
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 Drug & Chemical toxicity in the Human Fetus
Alcohol Muscular hypotonia
Antibacterials
streptomycin 8th nerve damage
chloramphenicol Death (grey syndrome)
Anticoagulants
sodium warfarin Hemorrhage, death
Antidiabetics
Insulin(shock) Fetal loss
Tolbutamide Thromocytopeania
Hormones
Predisolone Acute fetal distress
ACDH Adrenocortical suppression
Sedatives Behavioural changes
Smoking Premature birth,prenatal death,small
babies
Anasthetics Newborn depression
Solvents Newborn depression

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 Modes of Teratogenecity evaluation
1. Spp. & strain of test animal
(multilevel approach)
Level 1. rodent
level 2. carnivore
level 3. ungulate
level 4. non human primate
Results are interpreted using
statistical methods :
1.Two way analysis of
variance
2. Regression analysis
3. Chi square test
4. Fischer’s exact test
Insignificance:
1.Large no. of animals
2.Cost of warehouses
2. Imaging techniques
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Tissue culture & avian eggs
(fetuses isolated by
hysterectomy)
Analyzed for:
1.Sex,
2.Body weight(gm),
3.Amniotic fluid(ml),
In vivo In vitro 4.weight of major viscera
(brain,heart,eyes,liver,
kidney,spleen,lungs)
Insignificance-
1.Authorities doesn’t agree
2.Embyos have no ways for
excretion
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 Imaging Techniques

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 Congenital cardiac anomalis
Cardiac Anomali
Ventricle Hypoplasia
Valvular abnormality
Septal defects
- Ventricular SD - Atrial SD
Great vessel defects
Other perinatal conditions
causing CHF
Fetal arrhythmias
Premature contractions
Tachyarrhythmia
Bradycardia
(atreioventricular blocks)
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Consequences Imaging Technique
Proximal aorta is stenotic & aortic 2D Echocardiography
arch perfused by ductus artreriorus
- pulmonic stenosis 4D ECG & doppler
- aortic stenosis
Associates Down’s syndrome 3D color Doppler
Pulmonary atresia& right side 3D color Doppler
neperotropy don’t develop in fetus
leading to Down’s syndrome
Cardiac tumors,dextrocardia Sonography/
ultrasound
Irregularity of cardiac rhythm Ultrasound/Sonography
Premature atrial & ventricle M-mode ECG
contractions
Congestive heart failures M-mode ECG
Associated with fetal demise, Doppler/M-mode
maternal autoimmune disease,
structural cardiac defects
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 Color Doppler imaging
• Principle:
change in frequency of
sonic energy reflected from
moving targets(RBCs) to
gauge direction & velocity
of cells.
This gives audible &
visuals which are traced
• Available in 2D &3D
formats
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Immense importance in
diagnosis of:
1. Structural & rhythm
abnormalities
2. Valvular stenosis
3. Insufficient cinesis
4. Congestive Heart failure
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 Ultrasound imaging
• Principle:
works by transmitting a sound Structures seen & measured are:
wave by transducer or 1. Aortic arch/ascending
transducer array & listening aorta/valve
to the reflected signals over 2. Superior vena cava
widely scanned area. Signal 3. Right atrium
processing construct an image 4. Tricuspid valve
to profile the scanned area
5. Aortic & pulmonary valves
• 5-7 mHz transducer
6. Comparative sizes of vessels
• Optimal time 18-20 wks
(< 28 weeks)

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 Other imaging techniques
Technique Application

Computer Tomography (CT) •Ovarian cancer

•GTD-gestational trophoblastic disease
(not well established) •Uterine Leiomyomas
•Cervical cancer
•Endometrial cancer

Magnetic Resonance Imaging •Congenital anomalies of uterus

(MRI) •Asherman’s syndrome
•Pelvic inflammatory disease
•Ovarian masses
(cost & safety issues)

Color Flow Imaging (CFI) •Blighted ovum-early missed abortion

•Placental evaluation
•IUGR- Intrauterine growth retardation
•Blood vessels, their anatomical location,
direction & velocity of flow
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 MRI showing the cortical
development of fetal brain

MRI of fetus showing lever lesion at 24

weeks. Arrow showing lesion & *
showing lever
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 Possible future methodologies

Postnatal • For physiological & behavioral studies

• Inefficiencies of using rats
evaluation • CNS maturation is on still going

•Max. similarity of results with humans

Additional spp. Of •Cost efficiency
test animals •Ease of study

Improved Improvements are needed in-

monitoring of •Monitoring
•Reporting & analyzing
human populations •Follow up action

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 Recommendations
• Screening chemicals already in the environment for
Terratogenic effect by monitoring the chemicals for:
1. Increasing quantity
2. Interactions

• Women suspecting of being pregnant must avoid

taking non prescribed drugs, exposure to chemicals &
radiations

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 Significance of teratology studies

• If diagnosis is made early, termination of pregnancy

can be achieved.
• However, with recent advances, major anomalies like
hypoplastic left heart are treatable & patient may
choose to continue pregnancy

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 Concluding Remarks

• If a chemical is found to be Teratogenic, should it’s

use ever continue? under what circumstance? at
what concentration? These answers largely depend
on the method available for testing & in turn will
influence the methodologies to be sought.
• Much more fundamental knowledge is still required
to become more rational in the field of teratology.

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 REFERENCES
• Casarett & Doull’s Toxicology;The basic science of
poisons 2nd ed.,Macmillan publishing Co.Inc;
Teratogens, Raymond D. Haribson
• Survey & evaluation of techniques used in testing
chemical substance for Terratogenic effects,PB273
195,Tracor Jitco
• Environment & birth defects, 1973, J.G.Wilson

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THANK
YOU

“Every
Child Is
Special”
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