Archives of toxicology. Supplement. = Archiv fur Toxikologie. Supplement最新文献

The purpose of the study was to obtain a comprehensive picture of the expression of cytochrome P450s (CYP) in the human lung, broncho-alveolar macrophages (BAM), and peripheral blood lymphocytes. The methods used were reverse transcriptase-polymerase chain reaction (RT-PCR) with gene-specific primers and immunohistochemistry with specific anti-peptide antibodies. In RT-PCR, CYPs 1A1, 2B6/7, 2E1, 2F1, 3A5 and 4B1 were detected in cDNA prepared from whole lung tissue. BAMs expressed CYPs 1B1, 2B6/7, 2C, 2E1, 2F1, 3A5 and 4B1. These tissues lacked CYPs 1A2, 2A6, 2D6, and 3A7. In peripheral blood lymphocytes, only CYP1B1 and CYP2E1 mRNAs were consistently detected. In immunohistochemistry with anti-CYP3A antibodies, epithelial staining of CYP3A5 was observed in 100% of individuals, while only about 20% exhibited CYP3A4 staining. CYP3A5 protein was localized in the bronchial wall, bronchial glands, bronchiolar epithelium, alveolar epithelium, vascular endothelium and alveolar macrophages. The results indicate that several different xenobiotic-metabolizing CYPs are present in the human lung, possibly contributing to in situ activation of pulmonary procarcinogens.

Stress refers to a physiological and emotional state of man and higher animals in which the autonomic regulation is overstrained and temporarily disturbed under the impact of conflicting stimuli. Stress activates, invigorates, acts life-sustaining, and initiates and drives adaptive changes towards improved fitness. While the positive action is commonly underestimated, much attention is given to the discomfort and the strain of efforts required during coping. The label of stress as being bad and the core of suffering has been applied with particular empathy to laboratory animals, for they are kept in captivity and are exposed to experimental procedures. The husbandry conditions to which the animals are adapted are commonly standardized. This applies to procedures for subacute and chronic toxicity testing. Acute toxicity tests are the classical example of stress research in which the demands on the organism exceed the limits of its regulative capacity. Stressors are: the test compound, the procedure proper and preceding treatment of the animal. The experimental stress contributes to model the real situation. The weighting between the stressors may modify the outcome of the test.

Current understanding of the genetic and metabolic basis of relations between heterozygosity and animal performance under non-polluted conditions is relevent to interpreting apparently inconsistent findings concerning the relative advantage of allozyme polymorphism during contaminant exposure. Many interrelated factors which may influence and even compromise those relations include species (lifestyle, reproductive behaviour etc), lifestage, environmental influences and a variety of background genetic effects (limited parentage, null alleles, aneuploidy, genomic imprinting etc). Nevertheless, there is some promise that single-locus responses may be diagnostic for specific pollutants. In addition, limited evidence to date supports the a priori expectation that reduced energy requirements for maintenance metabolism may facilitate longer survival of multiple-locus heterozygotes during exposure to contaminants with toxic effects that result either in the reduced acquisition or availability of metabolizable energy, and/or a reduction in the efficiency with which metabolizable energy is used to fuel metabolic processes. More work is required to fully establish this trend in response to specific contaminant types, to assess any direct consequences of underlying differences in protein metabolism, and to resolve the interactive effects of contaminant mixtures. But the functional value of genetic variation within populations is confirmed. Reduced genetic diversity may not only compromise the capacity of an impacted population for genetic adaptation in the face of further environmental challenge, but may also result in increased energy requirements, lower production efficiency and reduced reproductive output. These metabolic consequences of reduced genetic polymorphism would further lower that population's potential for survival under lethal conditions of contaminant exposure, and also affect the genetic makeup of populations through differential reproduction under conditions of sublethal stress.

Though a developing body of data indicates polymorphism at GST genes influences cancer susceptibility, it is unclear why a genotype is associated with one cancer but not another. We believe the GST exert a critical role in normal cell house-keeping activities. GSTM1, GSTM3 and GSTT1 influence tumorigenesis because these enzymes utilise the products of UV-induced oxidative stress. Further support for the importance of these genes in the protection of skin from UV comes from studies in systemic lupus erythematosus (Ollier et al, 1996). Thus, GSTM1 null is associated with increased anti-Ro (but not anti-La) antibodies, a phenotype associated with photosensitivity. At present there is no basis for predicting which cancers will be influenced by GST polymorphisms though other studies do indicate that the GSTs are critical in the metabolism of environmental carcinogens. For example, GSTT1 null confers an increased risk of astrocytoma (Hand et al, 1996). While brain tumours are not clearly associated with environmental pollutants, N-methyl-N-nitrosourea, processed meats and occupation have been implicated. Why GSTT1 but not GSTM1 or GSTM3 influences the risk of astrocytoma is unclear. GSTM3 appears a good susceptibility candidate, as some astrocytes demonstrate strong expression (Hand et al, 1996). Susceptibility to squamous cell cancer of the larynx, a pathology associated with chronic consumption of tobacco and alcohol, is also influenced by allelism at GSTM3 (Jahnke et al, 1996). The roles of CYP2D6 and CYP1A1 are even more unclear, though the finding that systemic agents such as arsenic predispose to multiple BCC, suggests that CYP2D6-mediated hepatic detoxification of photosensitizing agents may be important. Importantly, the extent of altered risk conferred by genotypes is generally 2-3 fold and it is necessary to identify which other genes interact with the GST so that haplotypes associated with 10-20 fold increases in risk can be defined.

The development of the preimplantation embryo seems morphologically very simple, and embryologists previously assumed that an embryo that developed to the blastocyst stage was fully capable of normal development after transfer to the uterus of a recipient female. This complacency was disturbed by reports that exposure of early embryos to mutagens such as methylnitrosourea led to fetal abnormalities, decreased birth rates, and decreased life-span. Even more disturbing are recent reports that culture of early embryos in supposedly benign conditions can adversely affect their subsequent development. Techniques have been developed for the production of cattle and sheep embryos by in-vitro fertilization and by cloning. Such embryos must be cultured for several days before they can be transferred, and, in some cases, this has been related to abortion, very high birthweight, physical abnormalities and peri-natal mortality of the calves and lambs. This syndrome may result from an unbalanced development of the trophoblast relative to the inner-cell mass, possibly related to the presence of serum, glucose, or ammonium in the culture medium. An analogous phenomenon has been observed in human in-vitro fertilization where babies from single pregnancies have below-normal birth-weight. There is also evidence to suggest that the in-vitro environment of the gametes before fertilization can affect subsequent embryonal and fetal development. Exposure of mouse oocytes to vitrification solutions has been shown to lead to fetal malformations, and treatment of bull sperm with glutathione improves early embryo development. The common thread in these diverse observations is that development can be affected by events that occur long before any defect is apparent. Consequently, the production of a morphologically normal embryo is no guarantee that fetal development and post-natal life will be normal. This is of immediate concern in human reproductive medicine due to the increasing use of sperm injection for fertilization, and the emergence of in-vitro oocyte maturation. Further development and application of reproductive techniques would benefit from a toxicological evaluation of risk factors and exposure limits.