9 – Teratology 1 Flashcards
What is teratology?
- Study of the causes, mechanisms and manifestations of developmental deviations of either structural or functional nature
What are the % of causes of malformations? (3)
- 25% genetic or chromosomal factors
- 10% known genetic factors
- 65% unknown
Causes of abnormal development: 4 broad categories
- Genetic
- Infectious
- Nutritional
- Toxic (smallest % of abnormal development problems)
- (Physical)
What are some principles of teratology?
- Susceptibility depends on environment and genetics
- Susceptibility varies with developmental stage
- Act in specific ways on developing cells to initiate sequences of abnormal developmental events
- There are various final manifestations of abnormal development
- Access of agents to developing tissues depends on physical nature of the agent
What does the susceptibility to teratogenesis depend on?
- Genotype of conceptus and manner in which it interacts with adverse environmental factors
o Gene=intrinsic
o Environment=extrinsic (anything outside the embryo, including the mother!) - *interaction between environment and genetics
o Usually a mixture between the two
Cortisone in mice: example with susceptibility
- Cleft palates
- *does not do that in rats
- **genetic component example
Thalidomide: example with susceptibility
- Teratogenic in people but not most other species
Why are there such differences in species?
- Absorption
- Excretion
- Metabolism and biotransformation
- Placental differences
Teratogens
- Agents that interfere with abnormal or normal development
- **DESTORY CELLS
**What does susceptibility to teratogenesis vary with?
- Developmental stage at time of exposure to an adverse influence
o 1. Pre-differentiation
o 2. Early differentiation
o 3. Advanced organogenesis
1st trimester
- most important=organ development *high susceptibility
- 2nd: maturation
- 3rd: growth (neurologic, immune problems, behavioural): growth retardation
Implantation
- Usually a week
- Not particularly susceptible
Right after implantation (organogenesis)
- Fetus in active stage of growth
- ***PRIME SUSCEPTIBLIITY
o High metabolic activity - Some organ cells develop
o If agent comes in and destroys all cells=no organ - Day 30: Declines in susceptibility
Appearance of SER in liver
- Major specie differences!
- *development is usually later in pregnancy
o More susceptible as it is closer to when they are born - If have=metabolize the teratogen=REDUCES IT
o Unless it requires bioactivation=will increase it!
Teratogenic agents act in specific ways (mechanisms): ‘following steps’
- Mechanism
- Pathogenesis
- Common pathway (usually 1st trimester, but not always)
- *results in a defect
a. May vary depending on time period
b. May have a variety of teratogens that could cause it
Example of some mechanisms that teratogenic agents act
-mutation
-chromosomal abnormality
-mitotic interference
-altered DNA
-lack of precursors of substrates
-reduced/altered energy sources
-enzyme inhibition
-osmolar imbalances
-altered membranes
Mutation
o strong acids, X-rays, alkylating agents
Chromosomal abnormality(=NOT hereditary, can occur during mitosis or meiosis)
o X-rays, chemicals, viruses
Mitotic interferance
o Drugs, X-rays
- Lack of precursors or substrates
o Needs lots of nutrients, may affect protein synthesis (anti-biotics!), transcription, incorporation of base pairs
o *Vitamin deficiencies (Vit A and E), minerals (zinc, Mg): protein synthesis (get Vit A and E from colostrum!)
o Failure of absorption: Cu, Zn, sulfates (Gut or placental level)
If mom is okay then likely a placental problem (not the feed)=placental transport is a big factor!
Reduced/altered energy sources
o Cyanide=ETC
o Fluorine=Kreb’s cycle
Enzyme inhibition
o Especially those in DNA or protein synthesis and repair
o *Many enzymes contain Zn, so if animals have a Zn problem that may be the cause
Osmolar imbalances
o If edema develops between ectoderm or mesoderm=can’t interact problem
If a nutrient growth factor=abnormal development
o Not common in vet med
Altered membranes
o **Too much Vit A=will cause defects (animals AND people) (also deficiency)
Very potent
What are some causes of abnormal embryogenesis?
- **Excessive cell death (cytotoxic)
a. If destroy enough cells=loss of cell type and fetus will abort and die - Failure of cell interaction
a. Need to interact to develop a new cell type - Mechanical disruption (ex. osmolar changes)
- Reduced biosynthesis (ex. mineral and vitamin deficiencies)
- Impaired morphogenic movement
a. Common with the palate and the urogenital tract (cell-cell, time, nutrient interactions) (ex. kidneys failing to migrate) - Altered differentiation schedules
What are the different sites of teratogenesis?
- Fetus: direct
- Fetal-placental unit
- Mother: altered homeostasis
- Father: sperm (ex. lead and nitrogen (mustard) products)
What might the final manifestations of abnormal development be?
- *Death: if enough cells destroyed (1st or any stage if high enough)
- Malformation: morphological defects=quite small and minor period (1st trimester)
o If destroy to few cells=might be able to repair - *intrauterine growth retardation=common (in last trimester or throughout)
- Postnatal functional deficiency
What does the access of the adverse agent to the fetus depend on?
- physical nature of agent
What are the factors affecting fetal dose?
- Maternal dose
- Maternal absorption rate
- Maternal metabolism
- Plasma half life (little relationship to teratogenic potential)
- Protein binding
- Placental transfer
- Molecular weight (those below 600g)
- Charge (neutral=cross placenta)
Protein binding
- If drug is highly protein bound=likely can’t get across the placenta
- But some will sequester in fetus
- **double edged sword
Dose in the mother vs. fetus
- *can not extrapolate the dose to the fetus
- Ex. mercury=goes to fetus no problem=may be extremely abnormal (human problem)
Dose effect
- No effect zone=functional zone
o Debatably (may not even have one) - **Teratogenic zone=NARROW
o Needs to happen at right time and place - Embryo lethal zone
- Maternal lethal zone
Plasma half life
- *do not consider it in interpreting data
- Very little relationship to teratogenic potential
- FALSE: that all teratogens with a short half-life are not and those with long are
Weight and charge
- Those under 600g=more teratogenic
- Neutral ones=more teratogenic
Dose and developmental age
- If give right at susceptible period=need a smaller dose
- If give in 3rd semester=not as much of an effect
Types of drug interaction
- Interference (ex. with the metabolism and makes it highly teratogenic)
- Nill effect
- Additive effect
- Potentiation (synergism)
Teratology testing considerations
- Route administration
- Dose of drug
a. If damage liver or liver=more teratogenic - Duration of treatment
- Animal species (off label use might get you in trouble)
- Number of animals
What are some environmental considerations?
- Diet
- Housing
- Climate
- Handling
- Infections
