Developmental Toxicology 1

Question 1

What are the major three target organs

Answer 1

-Liver
-Kidney
-Respiratory system

Question 2

What is Developmental toxicology

Answer 2

adverse effects of xenobiotics that occur between conception to puberty (recall diethylstilbestrol)

Question 3

What is Teratogenesis

Answer 3

adverse effects of xenobiotics that occur between conception and birth (recall thalidomide)

Question 4

What are the three causes of developmental toxicity (broad)

Answer 4

1. Known genetic factors (~25%)
2. Known environmental factors (~10-15%)
3. Unknown multifactorial causes (~60%)

Question 5

Describe the known genetic factors of toxicity

Answer 5

-Most common are chromosomal abnormalities and single -gene defects

Question 6

Describe the known environmental factors

Answer 6

-Infections (bacteria, viruses; ~3%)
-Maternal factors (.g., disease, nutrition ~4%)
-Environmental toxicants and drugs (xenobiotics), referred to as teratogens (5%)
-Ionizing radiation and other physical factors (~1-2%)

Question 7

Describe the unknown multifactorial causes

Answer 7

-Genetic-environmental interactions
-Epigenetics: especially important during gametogenesis (formation of egg and sperm) in parents, and subsequently in early development between zygote and blastocyst stage (referred to as “imprinting”)
Transgenerational effects - effects occur F3 generation

Question 8

What is wilson’s first general principle of teratology

Answer 8

1. Susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which this interacts with adverse environmental factors

Question 9

What is wilson’s second general principle of teratology

Answer 9

2. Susceptibility to teratogenesis varies with the development stage at the time of exposure to an adverse influence

Question 10

What is wilson’s third general principle of teratology

Answer 10

3. Teratogenic agents act in specific ways (mechanisms) on developing cells and tissues to initiate sequences of abnormal developmental events (pathogenesis)
   adverse outcome pathway

Question 10

What is wilson’s fourth general principle of teratology

Answer 10

4. The access of adverse influences to developing tissues depends on the nature of the influence (agent)
   ADME

Question 11

What is wilson’s fifth general principle of teratology

Answer 11

5. The four manifestations of deviant development are death, malformation, growth retardation, and functional deficit

Question 12

What is wilson’s sixth general principle of teratology

Answer 12

6. Manifestations of deviant development increase in frequency and degree as dosage increases, from the no effect to the totally lethal level
   dose defines the poison

Question 13

Principles I & II: Susceptibility

Answer 13

• Genotype of embryo/fetus (intrinsic factors) and environment (extrinsic factors, which include maternal factors and external environmental factors) are the major considerations
• Sensitivity varies throughout gestation

Question 14

2. Organogenesis (day 21-56 in humans; 1st trimester)

Answer 14

• Highly sensitive developmental stage due to significant cell division, differentiation, migration, and “remodeling” during organ and tissue development
• There are key developmental events that coincide with peaks of sensitivity
• Recall thalidomide: amelia (missing limbs) and phocomelia (shortened limbs) due to exposure during this specific period of development (20-36 days after fertilization in humans)

Question 14

General Developmental stages: 1 Early Development (fertilization to implantation)

Answer 14

• Usually lower sensitivity to teratogen exposure at this stage
• Gastrulation: formation of ectoderm, mesoderm and endoderm (cell differentiation), and then migration of these cellular “germ layers”
• Teratogens can cause malformations of eye, brain and face during this period

Question 15

3. Fetal Period

Answer 15

• Pre-differentiation and organogenesis are referred to as the embryonic period; structural/morphological effects of teratogens are most prevalent
• Involves histogenesis and functional maturation of organs and tissues; thus teratogenic effects are more functional in nature (e.g. CNS, behaviour, immune system, reproductive system)
• Significant growth occurs during fetal period and reduced growth (birth weight) is a common effect of teratogens