Toxicology PHTXt 834

Spring 2023

Reproductive and Developmental Toxicology

Part 2

Tutorial 9

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 Tutorial Outline
Factors determining the capacity of an agent to produce birth defects

Mechanism and pathogenesis of developmental toxicity

Relationship between maternal and developmental toxicity

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I) Factors determining the capacity of an agent to produce
birth defects:
1. Susceptibility to teratogenesis depends upon: Genotype of the
conceptus & maternal genome
2. Developmental stage / time of exposure
3. Dose & duration of exposure to a teratogen
4. Specific ways in which a teratogen acts on the developing
cells.
5. Manifestations of abnormal development are: Death,
malformation, growth retardation & functional disorders

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 1) Effect of time of exposure on teratogenicity:

Zygote
Blastocyst

Gastrulation Organogenesis
(After implantation Fetogenesis
Preimplantation involves formation of
(Formation of neural tube
& Internal organs )
ectoderm, mesoderm,
and endoderm layers)

Toxicity can lead to

Toxicity can lead to: structural malformations
for ex: Toxicity can lead to
 No / slight effect Toxicity can lead to Cleft palate by: effects on growth &
on growth teratogenesis  TCDD functional maturation
Or  High levels of
 Death glucocorticoids 5
1) Which of the following is true regarding the effect of
time of exposure in teratogenicity?

a) Chemicals affecting the DNA synthesis have their most toxic effect in the
preimplantation stage.

b) Organogenesis starts from the 3rd week of gestation till the 8th week and is
considered of the lowest susceptibility to malformations.

c) Fetogenesis starts after the end of organogenesis and exposure at this stage can
lead to functional abnormalities such as decrease in fertility.

d) A & B

e) A & C 6
2) Illustrate using an example how the time of exposure
affects the teratogenicity?
Rubella virus
(German measles)

First weeks of gestation Weeks 8 to 12

Defects of the visual and

Hearing impairment
cardiovascular system

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2) Effect of dose or exposure level on
teratogenicity

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3) Answer the following questions:
a) Explain the effect of dose in the teratogenic response occurring in each DRC.
b) Give an example of drug for each DRC.
c) Indicate which DRC represents the drugs of most concern in teratology.

% Response

% Response
% Response

Dose Dose Dose

a) Drugs can cause death at a) Drugs can cause death and a) Drugs doesn't cause
higher doses than those required malformation at almost the malformation but causes death
to produce malformation. same dose. or retardation.
b)For ex: Thalidomide b)For ex: Actinomycin D b)For ex: Chloramphenicol

c) This DRC represents the

drugs of most concern
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II) Mechanism and pathogenesis of
developmental toxicity

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 4) Match the following drugs with its teratogenic effect
in Column A & Mechanism of teratogenicity in Column B
Column A Column B
A. Cardiac & neurological defects E. Limited amount of detoxification
Thalidomide B &H
B. Phocomelia & antioxidant enzymes in fetus
Diethylstilbestrol D & G C. Craniofacial abnormalities & F. Interaction with hox genes

mental retardation G. Causes failure of tissues from

Isotretinoin A & F
D. Structural & functional Mullerian duct to either transform
Ethanol C&E
into normal tissues ( in females) or
abnormalities of the reproductive
degenerate (in males)
tract
H. Oxidative stress and anti-
angiogenesis 11
5) Which of the following statements is false about
developmental toxicity?

a) Malformation occurs when the toxic effect overwhelms the repair mechanism.

b) Thalidomide can lead to blindness & deafness.

c) The co-administration of cocaine & norepinephrine can lead to hypoxia in fetus and
premature labor.

d) One of the reasons for ethanol toxicity in fetus is that the placenta allows free entry
of ethanol and toxic metabolites like acetaldehyde into the fetal compartment.

e) None of the above.

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6) Diethylstilbestrol is a ………………………..that can lead to
reproductive tract abnormalities in offspring if its exposure
was during weeks………………….of gestation

a) Narcotic drug / 3 to 8

b) Non-steroidal estrogen / 6 to 12

c) Vitamin A derivative / 6 to 10

d) Synthetic drug / 8 to 12

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III) Relationship between maternal and
developmental toxicity

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Relationship between maternal and developmental
toxicity
• Genetics
• Diseases
• Nutrition
• Stress
• Placenta

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Relationship between maternal and developmental
toxicity
1. Genetics:
The genetic makeup of the pregnant female has been well documented
as a determinant of developmental outcome

2. Disease:
May be causes of several types of defects in the fetus.
 Chronic hypertension
 uncontrolled maternal diabetes mellitus
 certain infections (e.g., cytomegalovirus and Toxoplasma gondii)
 Hyperthermia  neural defects in the fetus. 16
Relationship between maternal and developmental
toxicity
3. Nutrition
 Dietary insufficiencies
 protein-calorie malnutrition
 Deficiencies of vitamins, trace elements, and/or enzyme cofactors
 Folate  reduces the incidence of neural tube defects.
4. Stress
Low birth weight and congenital malformations.
5. Placental toxicity
In pregnancy Plasma volume increases albumin decreases  PPB
decreases  fewer binding sites of toxicant  free toxicant increases
 greater tendency to enter tissue
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7) Mrs. Y is a pregnant female that is always under high stress because of
her overload at work. She always eats junk food and doesn’t care about
taking her folic acid supplement that was prescribed to her for pregnancy.
What malformations do you expect to happen to the fetus in this case?

a) Low birth weight & cleft palate.

b) Neural tube defect & congenital malformations.

c) Congenital malformations & cleft palate.

d) Low birth weight & neural tube defect.

e) A&B

f) B&C

g) B&D
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h) A&C
8) Give an example showing the effect of the genetic make up of the
pregnant female on the development of the toxicity in her fetus.
The incidence of cleft lip and/or palate was found to occur more frequently in whites than in
blacks.

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9) All of the following are diseases that if present in
pregnant female can cause defects in fetus except:
a) Uncontrolled diabetes

b) Hypertension

c) Hyperthermia

d) Migraine

e) Cytomegalovirus infection

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10) All of the following is true regarding the guide lines for
animal testing for developmental toxicity except:

a) Laboratory animal testing and surveillance of the human population are necessary
to provide adequate public health protection.

b) Animal test data is collected for drugs whose exposure is voluntary and usually to
high dosages.

c) The general goal of these guidelines is to identify the therapeutic index of the
exposed drug.

d) None of the above.

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11) Match the following drugs with its category in Column
A & risk in taking them in pregnancy in Column B
Column A Column B
F. Low concern for risk in pregnancy
Folic acid D&G A. Category B
G. No risk in pregnancy
Accutane B & H B. Category X H. Risk in pregnancy outweighs the
benefit
Ventolin C & J C. Category C
I. Positive evidence of human fetal risk
A&F D. Category A J. Animal studies show adverse effect
Glucophage
and no well-controlled studies in
Phenytoin E&I E. Category D humans
Good Luck 
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