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1

Teratology

The study of congenital defects

2

Annual # of birth defects in live births in US

7% (~200,000)

3

Number of infant deaths, stillbirths, and spontaneous abortions believed to be due to defects in prenatal development.

>500,000

4

Percentage of defects due to spontaneous genetic errors

20-30%

5

Percentage of defects relatable to the use of certain drugs

6%

6

Percentage of defects of which the cause remains unknown

60%

7

How many drugs does the average woman take during her pregnancy?

10 (most without supervision of physician)

8

How many women are exposed to potential chemical teratogens in their jobs annually in the US?

125,000

9

What % of abnormalities can be detected at birth?

<50%

10

What % of early embryos are estimated to die unrecognized?

30%

11

What % of recognized pregnancies abort spontaneously?

15%

12

In some cases a birth defect may be detected but a causal link to a specific agent may not be made, why?

because that defect is only expressed under conditions of a genetic predisposition or of certain physiological or pathological states or environmental stresses

13

What is a major problem with most human teratological studies?

They are confined to the perinatal period and do not adequately evaluate the maturation process.

14

If children are monitored for about 5 years after birth the total number of defects discovered...

increases 6 times (and some anomalies such as cardiac defects or behavioural problems may not be detected until even later)

15

Diethylstilbestrol (DES)

Girls exposed to this do not develop vaginal adenocarcinomas until puberty.

16

Give an example of a drug that has different teratogenicity in humans vs other species.

Thalidomide - essentially nonteratogenic in rodents but potent teratogen in humans
(Teratogenicity of thalidomide dose 0.5-1 mg/kg in humans = 5 g/kg in rodents)

17

List 17 proven or suspected human teratogens.

1. Aminopterin
2. Androgens
3. Busulfan
4. Chlorambucil
5. Colchicine
6. Cyclophosphamide
7. Diethylstilbestrol
8. Isotretinoin (Accutane)
9. Mercaptopurine
10. Methylmercury
11. Methotrexate
12. Phenytoin
13. Procarbazine
14. Progestins
15. Radioiodine
16. Thalidomide
17. Valproic acid

18

List 7 teratogenic anticancer drugs

1. Aminopterin
2. Busulfan
3. Chlorambucil
4. Cyclophosphamide
5. Mercaptopurine
6. Methotrexate
7. Procarbazine

19

Describe the critical period

The natures and frequencies of birth defects produced by any given teratogen depend on the developmental stage at the time of exposure.

20

When is a human most sensitive to chemical damage?

As an embryo or fetus

21

Why is the embryo/fetus so sensitive to chemical damage?

An extremely high rate of cellular proliferation and differentiation over a brief period of time

22

Give an example of the high rate of cellular proliferation and differentiation in a short amount of time.

the DNA content of a mouse fetus increases 1 million fold in the 1st half of gestation

23

Describe the developmental process and teratologic consequences for fertilization to blastocyst implantation.

Developmental process - Cellular division
Teratologic consequence - prenatal death

24

Describe the developmental process and teratologic consequence for embryonic period.

Developmental process - cellular differentiation and organogenesis
Teratologic consequence - major morphologic abnormalities

25

Describe the developmental process and teratologic consequence for the fetal period.

Developmental process - histologic differentiation and functional development
Teratologic consequence - functional defects and minor morphologic abnormalities

26

How can cleft palate be induced in mice?

Introduction of teratogens between gestational days 8-13

27

Describe the 5 steps to the closure of the palate.

1. Initial proliferation of cells
2. Synthesis of intercellular substances
3. Elevation of the two palatal shelves from the vertical to the horizontal position
4. Midline contact and fusion
5. Formation of the bony plate

28

List 4 teratogens that affect cleft palate and their critical periods.

1. 6-aminonicotinamide - days 8-13
2. Dexamethasone - day 13
3. 2,3,5-trichlorophenoxyacetic acid - day 12
4. TCDD - days 10-12