Toxic Responses, cont.

Teratogenesis, cont.

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)

• Agents are often specific, and sometimes embryo-lethal without teratogenesis.
• Genetic effects are common.
• Generally the first trimester after the initial period (the first three weeks for humans) are most sensitive to teratogenesis.
• Often agents affect specific processes/organ systems and thus show a strong dependence on timing (most effective when specific organ is developing).
• Early mutation events often have little or no effect. Evidently damaged eggs etc. simply do not develop or die very early (spontaneous abortion).
• Events occurring prior to fertilization seem to have no effect - Children of Hiroshima and Nagasaki survivors showed no increased incidence of birth defects, cancer, etc. even by over forty years of age (as long as their mothers were not exposed during pregnancy).

Manifestations of teratogenesis include:

• Death,
  • can result early or late with large dose exposures.
• Malformation,
  • tends to follow exposure during organogenesis.
• Growth retardation,
  • growth is retarded during foetal development.
• Functional disorders.

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:

• mutation
• chromosome aberrations
• mitotic interference
• substrate deficiency
• energy deficiency
• enzyme inhibition
• osmolality

Mutagenesis

Mutagenesis effects show up in offspring for multicellular organisms (as opposed to bacteria).

Mutation - define as a heritable change in cell genotype.

• Mutation types:
  • Base-pair transformation:
    • By chemical modification of a base, e.g. deamination of cytosine to uridine:
      or adenine to hypoxanthine.
    • Incorporation of base analogues, e.g. 5-Bromouridine for thymine gives A-BrU bp (OK) and G-BrU bp (mutation)
  • Base-pair deletion or addition.
    • Frame-shift mutation. Addition or deletion of a single base (or two bases) causes a complete misreading of the gene sequence.
  • Chromosome breakage and deletions.
    • Deletions or rearrangements of DNA segments
    • Unequal partition or non-disjunction (unequal division of chromosomes).
  • Metaphase poisoning - interference with mitosis/meiosis may result in polyploidy.

Tissue Lesions

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:

• Tubular fluid - plasma may reach 500:1 in some cases (98-99% of sodium and water are reabsorbed in tubular lumen).
• Cellular concentration can also be very high:
  • gentamycin and cephalorididine are both nephrotoxic, apparently due to concentration in cells of the proximal tubule.

Damage within organs depends on anatomy and physiology.

Examples:

• Liver
  • 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)
• Lungs
  • 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