Lecture 11 Teratogenesis PDF

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Very detailed lectures notes with extra reading on the lectures done by Dr Stephanie Kermorgant. Very helpful to clarify points in the lecture, with material cross-checked and taken from the recommended textbook...

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Cell Biology and D

Lecture 11

3/11/17

Teratogenesis Teratogenesis can be summarised as environmental assaults on human developments. The real definition outlies the process by which congenital malformations are produced in an embryo or a foetus.  

Embryonic cells communicate with their environment during normal development An example of this is environmental sex determination whereby in most turtles and in all crocodilians the sex is determined after fertilisation by the incubation

Exogenous agents that cause birth defects are called teratogens which produce their effects during certain critical periods of development, particularly between weeks 3 and 8 which is when most organs are forming in the foetus.  Prior to week 3, exposure to these teratogens does not usually produce congenital anomalies because a teratogen encountered at this time either damages most or all of the cells of an embryo resulting in its death or it kills only a few cells allowing the embryo to recover

Environmental signals can disrupt normal development  

2 to 5% of human infants are born with anatomical abnormality (e.g missing limbs, digits, extra digits, and lack of heart valves) Birth defects can be caused by mutation and also the environment

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Lecture 11

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The medical term for birth defects is called congenital anomalies Malformations – caused by inherited or spontaneous genetic defects (mutations, abnormal number of chromosomes translocation (movement of one thing to another place)) Disruptions – caused by exogenous agents (chemicals, viruses, radiation and excessive heat Some congenital anomalies can be the result of either malformation or disruption   

Chondrodysplasia punctate – abnormal bone mineralisation, underdevelopment of nasal cartilage, short fingers Malformation – mutation in CDPX2 (gene product is an enzyme necessary for cartilage growth) Disruption – Warfarin (anticoagulant) inhibits the function of the enzyme

Some agents in the environment can cause genetic damage 

Mutagens: e.g. X rays, ultraviolet radiations, free radicals, viruses

The foetus is not completely protected from the environment  

Norman Gregg in 1941, an Australian ophthalmologist was the first to connect birth defects with environmental agents If a woman contracted German measles (rubella) during first trimester of pregnancy, there was a 1:6 chance of birth defects (eye cataracts, heart malformations, deafness).

Wilson’s principles of teratology (James Wilson 1956) 1. Susceptibility to the teratogenic effect of an agent depends on the genotype of the embryo, the genotype of the mother

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2. There are critical periods of development when embryos are susceptible to being disrupted by teratogenic agents (organogenesis) 3. Teratogenic agents act in specific ways on genes, cells and tissues to disrupt normal sequences 4. Several conditions affect the ability of a teratogen to disrupt normal development (e.g. route and degree of maternal exposure, rate of transfer through the placenta) 5. There are 4 manifestations of disrupted development: death, malformation, growth retardation and functional defects 6. Manifestations of abnormal development increase in frequency and degree as the dosage of the teratogen increases (exceptions such as endocrine disruptors)

Thalidomide upregulates BMP signalling and downregulates WNT signalling 

In areas of specific combination of Hox proteins RA is expressed

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BMP2 is required for anterior-posterior patterning in limb formation

Wnt signalling causes the expression of fibroblast growth factors (FGFs) in surface ectoderm

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Mercury is selectively absorbed by regions of the developing cerebral cortex

More and more untested chemical compounds enter the environment  Over 50,000 artificial chemicals are currently used in the USA  200 to 500 new compounds are manufactured each year  Most industrial chemicals have not screened for teratogenic effects  Reasons: expensive, different metabolism between humans and test animals Alcohol – the most devastating teratogen in terms of frequency and costs 

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Babies born with foetal alcohol syndrome (FAS) are characterised by their small head size, indistinct philtrum (the pair of ridges that runs between the nose and mouth above the centre of the upper lip), narrow vermillion border on the upper lip and low nose bridge FAS babies have very small brains and often show poor development because of deficiencies of neuronal and glial migration The average IQ is 68, showing that they are mentally retarded A single drink during susceptible time in pregnancy can lead to foetal alcohol effect which is different from FAS. There is no distinct facial appearance change but lower functional and intellectual abilities

The effect of alcohol on foetus varies due to difference in alcohol dehydrogenase  

Some alleles of the alcohol-metabolising enzymes appear to be better than others at detoxifying ethanol 30 to 40% of the children born to alcoholic mothers will be affected by FAS

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Mouse model explains the effect of alcohol on the face and nervous system When mice are exposed to alcohol at the time of gastrulation, ethanol induces defects of the face and brain that are comparable to those in humans with FAS  The mouse model of FAS can be used to study the ways by which ethanol causes its effects on the embryo

Neural crest cell migration and differentiation is affected in FAS

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Neural crest cells form various cell types     

Cartilage/bone Schwann cells and other glia Neurones Melanocytes Paracrine factors regulate formation of various cell types

In addition, apoptosis in pharyngeal arches correlates with loss of Sonic Hedgehog expression

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Cranial neural crest cells migrate to pharyngeal arches In mice, ethanol downregulates shh. Shh is required for the formation of the facial skeleton

The facial skeleton is affected in FAS

Ethanol-induced apoptosis can delete millions of neurons

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Failure of neural tube closure

Ethanol blocks the function of cell adhesion molecule L1  Possible reason for mental retardation  Mutations in human L1 cause syndrome similar to FAS

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Retinoic acid   

Involved in normal development but can disrupt development if present in the wrong amounts or at wrong times 13-cis retinoic acid (Accutane) used to treat severe cystic acne If used during pregnancy – syndrome in infant (absent ears, small jaw, abnormal CNS)

Developmental disruption due to retinoic acid changing Hox gene expression   

Retinoic acid acts through Hox genes which control anterior-posterior patterning in early developmental stages Cranial neural crest cells are transformed into more posterior neural crest cells No formation of facial cartilage

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Valproic acid    

Used for treatment of epilepsy, bipolar disorder and migraine among others The drug blocks the absorption of folate (Vitamin B9) by the embryo. Folate is critical for neural tube closure Animal experiments – Valproic acid decreases the level of Pax1 transcription in chick somites. Malformation of vertebrae and ribs Might cause autism (similar neurological alterations in exposed rats as in humans with autism

Pathogens can act as teratogens  Rubella virus produces a protein that stops mitosis by blocking kinases necessary for cell cycle progression  Many organs affected  First 5 weeks of pregnancy are most critical as this is the time of the formation of the heart, eyes and ears

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Lecture 11

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Protists and bacteria are rarely teratogenic but some can damage the foetus  

Toxoplasma gondii (cats, rabbits) cause foetal brain and eye defects in human embryos Treponema pallidum (Syphilis bacterium) can either kill embryos or produce deafness and facial damage

Heat can act as a teratogen  

Hypothermia dangerous to foetus Maternal temperature higher than 38.9oC during the first six weeks of pregnancy can affect neural tube closure

Veratrum californicum produces alkaloids that block the function of Sonic Hedgehog (Shh) signalling which is required for cell proliferation in the midline of the face

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