Molecular and cellular pathology: summary

Introduction. The aim of the molecular and cellular pathology group in the Bremerhaven Workshop was to test for evidence of biological changes which were indicative of exposure to toxic chemicals, as well as to their adverse effects. Much of the study focused on the liver of the flatfish dab Llmanda limanda. The liver was chosen as it is an integrator of many functions including detoxication/activation of toxic chemicals, digestion and storage, excretion and synthesis of the egg yolk protein vitellogenin. There is also a considerable body of literature on pollutant chemical impact on the cellular pathology of fish liver to aid interpretation. The approach was based on the detection of molecular and cellular changes resulting from chemical contamination. The identification of early onset changes, which may ultimately lead to overt disease is a key requirement in assessment of the effects of environmental pollution. Diseased fish are likely to be rapidly eliminated from the population, hence assessment based on such fish may prove difficult, and even if samples are available, higher level complications resulting from the primary lesion will be a confounding factor. In fact, it is only through the mechanistic linking of changes in molecular and cellular processes with the later pathological endpoints that it will be possible to establish causal relationships. An additional component of the investigation examined developmental abnormalities and chromosomal aberrations in embryos of dab sampled along the transect. An integrated perspective. The results of this investigation of dab in the North Sea show a considerable degree of internal consistency, as well as clearly following the trend of declining levels of chemical contaminants along the transect towards the central North Sea. A pattern emerges from the data showing lysosomal, cellular, tissue and embryonic damage of the type expected due to the toxic action of xenobiotics. The additional evidence of proliferation of the smooth endoplasmic reticulum in hepatocytes, together with an increase in the activity of the inducible detoxicatiodactivation enzyme EROD, further supports the premise that the fish have been exposed to inducerxenobiotics, which is consistent with the analytical chemical data (Cofino et al. 1992). Proliferation of smooth endoplasmic reticulum (SER) and induction of EROD also provide a reasonable mechanistic explanation for the enhanced generation of superoxide radicals, through futile cycling, at the most contaminated sites, while radical attack on lysosomes is probably a contributory factor to the clear evldence for lysosomal membrane injury and consequent dysfunction. The presence of phospholipidosis (accumulation of phospholipid membrane components in lysosomes) in severely damaged livers is also consistent with autophagy of chemically damaged proliferated endoplasmic reticulum and failure of the functionally impaired lysosomes to degrade the ingested membranes, which results in the characteristic pathological presentation of this lysosomal storage disease condition. The presence of foci of altered cells at the most contaminated sites needs to be interpreted carefully. Comparison with the data from other species lends support to the conclusion that the high prevalence of foci is indicative of exposure to xenobiotic pollutants. The relationship of foci to neoplastic change in dab cannot at the present state of our knowledge be determined and requires further experimental investigation. It is, perhaps, worth commenting that neoplastic change in itself is of little significance in ecological terms unless the incidence in the population is extremely high. The value of pursuing the 'neoplastic pathway' is that this type of disease is probably indicative of exposure to carcinogenic xenobiotics, although