Prenatal toxicology

Question 1

describe teratogenicity

Answer 1

the science of studying abnormal development of embryos

Question 2

describe human teratogen

Answer 2

A human teratogen is an agent that alters the structure or growth of the developing embryo or fetus,
leading to birth defects

Question 3

describe the types of human teratogen

Answer 3

• drugs
• infectious agents
• environmental chemicals
• physical agents
• maternal factors
• mechanical factors

Question 4

describe the relationship between timing of exposure and drug-induced teratogenicity

Answer 4

• first two weeks - death of embryo or embryo
  survives without birth defects (one or nothing)
• weeks 3 to 8 - organogenesis; most sensitive to teratogen exposure
• week 9 to birth - functional disturbance e.g. cognitive deficiency

Question 5

Placenta transporters

Answer 5

Fetal capillary endothelium and syncytiotrophoblast
- efflux transporters on the apical membrane (e.g.,
MDR1) protects fetus by exporting drugs

Partial protection

Question 6

Placental metabolism

Answer 6

CYPs
* expressed in placenta - play a minor role in drug metabolism
* however induced following maternal exposure to enzymatic inducers, e.g.,
smoking, alcohol

Question 7

describe the role of placenta in limiting prenatal exposure to xenobiotics

Answer 7

Placenta acts a partial barrier to limit prenatal exposure to xenobiotics
drugs cross the placenta via passive diffusion or drug transporters

Question 8

describe thalidomide teratogenicity

Answer 8

• between day 21 and day 36 post conception, a single dose exposure was sufficient to cause defects
• caused limb malformations (phocomelia (shortened limbs) and amelia (no limbs)), eye and ear damage, internal organ damage

Question 9

theories of thalidomide teratogenicity

Answer 9

• antiangiogenesis (inhibit new blood vessel formation)
• reactive oxygen species formation and cell death
• cereblon as a thalidomide-binding protein

Question 10

describe the associated molecular mechanism of thalidomide teratogenicity

Answer 10

Cereblon
coded by the CRBN gene in human
forms an E3 ubiquitin ligase complex with DDB1, Cullin 4 and Roc1
- involved in the breakdown of substrate proteins
- a drug binding-deficient cereblon (YW/AA) rescued the fish from thalidomide-induced fin malformations
- affects SALL4 binding

Question 11

describe the clinical
use of thalidomide derivatives

Answer 11

immunomodulatory drugs (IMiDs)
* treat multiple myeloma
thalidomide, lenalidomide, pomalidomide

Question 12

describe fetal alcohol spectrum disorder

Answer 12

Prenatal alcohol exposure is the leading cause of preventable birth defects
- wide sensitive window - brain development spans the major part of gestation

Question 13

fetal alcohol spectrum disorder most severe form

Answer 13

Fetal alcohol syndrome
- facial defects
- prenatal/postnatal growth retardation
- neurodevelopmental impairment

Question 14

describe biomarkers for confirmation of maternal alcohol consumption during pregnancy

Answer 14

FAEE synthase - detected in neonatal meconium
[precursor to faeces] and hair

phospholipase D - detected in maternal blood

SULT (ethyl sulfate) -
detected in maternal urine
UGT (ethyl sulfate) -

Question 15

Mechanisms of alcohol teratogenicity - oxidative

Answer 15

CYP2E1 –> reactive oxygen species (ROS) –> lipid peroxidation –> reactive aldehydes –> PROTEIN AND DNA ADDUCTS

CYP2E1 –> hydroxyethyl radicals –> PROTEIN AND DNA ADDUCTS

ADH/CYP2E1–> acetaldehyde –> PROTEIN AND DNA ADDUCTS

Results: cell damage and death

Question 16

Mechanisms of alcohol teratogenicity

Answer 16

produces protein and dna adducts that result in cell damage and death and therefore birth defects

Question 17

Mechanisms of alcohol teratogenicity - non- oxidative

Answer 17

FAEE synthase –> FAEE –> causes damage and cell death

phospholipase D –> phosphatidylethanol –> disrupt cell signaling –> birth defects