1) Demonstrate understanding of the meaning of key terms such as teratology, developmental toxicology, embryolethality, teratogenicity.
- Teratology- I had to Google this one, because it wasn't in the lecture slides, but apparently it's the study of abnormalities of physical development.
- Developmental toxicology- The study of substances that are toxic to the conceptus (i.e. the embryo and placenta) during prenatal development.
- Embryolethality- The death of the embryo.
- Teratogenicity- The ability of a substance to produce structural alterations in the conceptus, but not embryolethality.
2) Show awareness of factors that govern the susceptibility of the unborn to chemicals.
One of the major factors that governs the susceptibility of the unborn is age. In the embryonic period (roughly the first 8 weeks), the embryo is still developing organs (organogenesis), so exposure at this stage can disrupt the development of the organs. Hence, a lot of teratogens are at their most toxic during the embryonic stage. During the foetal period, organ development and growth are occurring. Toxicity at this stage can stunt growth, which is still pretty nasty, but not quite as nasty as not developing the organs in the first place.
A second factor is the ability of the drug to cross the placenta. This, in turn, is influenced by several other factors. One of these is molecular weight. Similar to absorption the GI tract, the lower the molecular weight, the more likely it is that the drugs are able to cross the placenta. Another factor is the size of the embryo. As the embryo grows, so too does the placenta and the number of vessels supplying it. As the number of vessels grows, blood flow to the embryo increases, and thus the amount of drug that gets to the embryo likewise increases.
A third point of interest is that the unborn have a very limited ability to metabolise drugs. CYP450 only begins appearing at around 6-7 weeks, and doesn't reach adult levels until around one year after birth. The placenta also contains some CYP450 enzymes, but they generally only have a minor role unless the mother has been exposed to CYP-inducing agents. Conjugative metabolism also occurs very little in the foetus, and there are also low levels of antioxidant enzymes so that foetuses are prone to oxidative stress.
3) Understand the main toxic outcomes accompanying in utero exposure to major human teratogens such as phenytoin, ethanol, and thalidomide.
4) Demonstrate knowledge of mechanism of action of 3 major human teratogens.
Phenytoin is a drug used to treat epilepsy, but it also has a risk of causing "foetal hydantoin syndrome" in foetuses. This syndrome is characterised by malformations, such as cleft lip, a low birth weight and mental defects. However, epilepsy could also have adverse effects on the foetus, so the poor woman is caught between a rock and a hard place. Bummer.
Phenytoin is thought to have its teratogenic effects via bioactivation into reactive epoxides. It undergoes two main bioactivation pathways. In the first pathway, CYP450 converts it into a reactive epoxide, which can damage proteins and DNA if it is not first detoxified by epoxide hydrolase to form a nontoxic diol metabolite. In the second pathway, foetal peroxidases convert phenytoin into phenytoin hydroperoxide, which can form reactive oxygen radicals. This second pathway can be blocked by antioxidants.
Ethanol is probably the teratogen of greatest concern nowadays as it's so readily available. It can cause Foetal Alcohol Syndrome (FAS) which is characterised by the FAS "triad" of symptoms: growth retardation, craniofacial abnormalities and a low IQ. It is not always easy to diagnose because there are other teratogens that have similar symptoms; however, it can be tested in the meconium (the first few stools passed by the baby after birth). These "meconium markers" include ethyl glucuronide, ethyl sulfate and fatty acid ethyl esters, which are metabolites of ethanol.
Aside from FAS, ethanol exposure can have somewhat milder effects in the form of ARND, or Alcohol-Related Neurodevelopmental Disorders. ARND doesn't have visible structural effects like FAS, though it does have CNS impairments. It is important to note that even mild alcohol use during pregnancy can affect the CNS. This might be particularly problematic in the early stages, when the woman might not even know that she's pregnant.
Once again, ethanol has several routes through which it can exert its teratogenic effects. In one route, ethanol is oxidised by alcohol dehydrogenase to form acetaldehyde, which is a protein and DNA adduct (protein/DNA adducts are mentioned in my previous post). In a second route, it can be oxidised by CYP2E1 to form hydroxyethyl radicals, which then form oxygen radicals, which then start destroying lipid membranes and may have roles in forming reactive aldehydes.
The third main teratogen that I'm going to cover is thalidomide, which is infamous for having caused birth defects all over the developed world and was a major impetus for the development of modern toxicology. It was originally developed to treat nausea and insomnia in pregnancy, and was well tolerated in mothers. However, babies who had been exposed to this in the first trimester of pregnancy were found to be prone to birth defects, most notably phocomelia (reduction or absence of limbs).
Unfortunately, I can't tell you how thalidomide exerts its teratogenic effects, because the scientific community doesn't know for sure either. It doesn't help that thalidomide has around 12 metabolites either. Here are some possible reasons:
- It blocks angiogenesis in rabbits, so maybe it blocks vascularisation in growing limb buds
- It inhibits integrin beta 1 and beta 2 which mediate attachment to the ECM, so maybe cell migration is inhibited
- Pro-apoptotic effects?
- Disruption of various metabolic processes?
- Binds to CRBN (cereblon), which is an E3 ubiquitin ligase. CRBN may have roles in limb development, as CRBN-deficient zebrafish have been found to have fin abnormalities.
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