|Lecture Notes:: 1 April||
Teratogenesis is highly complex, but one should expect that it should be easy to disturb such a complex and highly coordinated process as development, and that the timing of the disturbance should be important. (Timbrell 4th, Figures 6.22, p 239 and 6.23, p 240)
Manifestations of teratogenesis include:
Dose-Response: Clearly seems to be a "no effect" level for most if not all teratogens for the first three manifestations; little evidence for concentration on functional disorders. There is a clear need to hit a minimal number of cells to manifest an effect, and the number of cells effected shows a clear dose/response effect.
Mechanisms of teratogenesis include:
Mutagenesis effects show up in offspring for multicellular organisms (as opposed to bacteria).
Mutation - define as a heritable change in cell genotype.
Tissue sensitivities vary as do exposures.
Concentrations of toxins will generally be highest at point of exposure. Thus skin, GI tract and lungs often suffer disproportionate damage.
Similarly, liver will receive high concentrations due to being the portal of entry from the GI tract.
Kidney experiences high concentrations due to concentrating mechanisms:
Damage within organs depends on anatomy and physiology.
- Different cell types, variations in enzyme concentrations, thus P450 concentrations increase towards the central veins, toxins created created by P450 are particularly damaging in this area. (overhead Figure 6.4, classic liver lobule; Figure 6.5, hepatic acinus)
- Irritation: Ammonia, Chlorine - bronchoconstrictors.
- Lining/cell damage: can lead to increased permeability and necrosis with fluid buildup.
- for volatiles of low solubility damage may reach to alveoli.
- for high water solubility substances damage will occur higher up, in trachea or branchi.
- Fibrosis (e.g. silicosis, asbestosis)
- damage occurs via a sequence of events:
- particle uptake
- lysosome puncture
- cell digestion
- process is repeated giving aggregation of lymphoid tissue and stimulation of collagen formation leading to fibrotic lesions.
- Ischaemic cell injury (overhead Figure 6.7) - Not discussed Spring 2010
Last modified 1 April 2010
© RA Paselk 2001