Developmental Toxicology

57%

___ % of pregnancies detected by human chorionic gonadotropin (hCG) at 8-9 days after fertilization do not develop as clinically detectable pregnancies

spontaneous abortion

15-20% of recognizable pregnancies end in ________ — 90% in the first
trimester

>20 weeks

2% of pregnancies end in miscarriage, which is _____ weeks

2-3%

____% of newborns have a major malformation severe enough to require hospitalization

teratology

The study of malformation or serious deviations from normal type of organism

aka: Branch of science concerned with production, development, anatomy, and classification of malformed fetuses

teratogen

any agent that causes birth defect

Hippocrates and Aristotle

who stated “abnormal development originates in physical causes
(e.g., uterine trauma) and maternal stress”

Ambrois Paré, French surgeon (1649)

who stated “birth defects result from narrowness of uterus, faulty
posture of pregnant woman, or physical trauma”

Camille Dareste (1890s)

Who discovered that timing of an insult is more an important than the nature, when it comes to malformations

Bridges and Morgan

who is responsible for the drosophila experiments / studying genetics of development

Fred Hale (1935)

who studied nutrient deficiencies in pigs?

*environmental exposure leading to malformations

Rubella: eye, heart and ear defects

Gregg 1941

what was the first human malformation by environmental agent studied?

who studied this?

prescribed for anxiety, insomnia, morning sickness, and nausea

what was Thalidomide used for?

5,000-7,000 infants born with limb malformations in
Germany

• only 40% children survived

what was the consequence of Thalidomide use during pregnancy?

Changed scope of impact of how external factors influence developing organism (especially humans)

what was the main overall impact of the Thalidomide birth defects?

Thalidomide increased DNA oxidation, which deregulates the gene for limb development

what is the DNA oxidation mechanism of Thalidomide?

scientists mutated the cereblon (CRBM) protein which Thalidomide binds to

how was the effect of Thalidomide inhibited in zebrafish embryos?

specifically the 20-36 days after fertilization (in the1st trimester of
pregnancy) (before limbs are formed)

what is the susceptible period of exposure for Thalidomide?

Gametogenesis

Gametes fuse to form embryo

blastocyst

a hollow ball of cells (4-6 days)

 DDT
 Nicotine
 methyl methane sulfonate (used in cancer treatment)

what are 3 known chemicals that are toxic to blastocytes?

gastrulation (6-21 days)

formation of three primary germ layers: ectoderm, mesoderm, and endoderm

teratogens

Gastrulation stage is susceptible to . . .

Malformations in eye, brain, and face

what malformations may come from gastrulation toxicity?

Organogenesis

when are rudiments of most bodily structures established?

CNS or reproductive organs

what is affected in exposure during the fetal period (56 days - birth)

<1%

___% of birth defects are from chemical and environmental influences

65%

__% of birth defects are of unknown etiology

50-60

______ chemicals or conditions alter prenatal development in humans

increases estrogen and progesterone synthesis by the placenta

what does Diethylstilbestrol (DES) do?

young women ages 15-22 were observed with vaginal adenocarcinoma

• - Female offspring: vaginal and cervical
  carcinomas and uterine, cervix, and
  fallopian tube abnormalities
  - Male offspring: epididymal cysts,
  hypotrophic testes, decreased semen
  volume, and poor semen quality

what effect did babies whose mothers took Diethylstilbestrol (DES) have

Reduced psychomotor and intellectual development – fine structural
alterations in CNS

what is the most significant effect of fetal alcohol syndrome?

Malformed face, ears, limbs, heart, CNS, skeleton

+ potential link to schizophrenia

what is the effect of excessive retinoid (Accutane) use during pregnancy?

category X

Accutane carries a pregnancy _________ warning, meaning it is a known human teratogen

Spina bifida: backbone and spinal canal do not close before birth

what is the developmental defect of valproic acid?

dose of which high restorative growth potential, cellular homeostatic mechanisms, and maternal metabolic defenses are overcome

Threshold phenomenon

lack of threshold

exposure to chemical has potential to cause developmental toxicity (e.g., point mutation)

be absorbed in the mother’s body AND pass through the placenta

for a drug to affect an embryo, it must . . .

- Hepatic metabolism: decrease xenobiotic transformation
- Gastrointestinal tract: increases in gastric emptying time
- Excretory system: decreased intestinal motility
- Increases time of chemicals in upper GI tract

what are 3 significant changes in maternal physiology?

cardiac output increases by 50%

how is the cardiovascular system affected by pregnancy?

1. DNA, Molecular, and Epigenetic Alterations
2. Maternal influences
3. Endocrine disruption

what are the 3 mechanisms of developmental toxicity?