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A sentinel phenotype is a clinical disorder or syndrome that (1) occurs sporadically as a consequence of a single, highly penetrant mutant gene, (2) is a dominant or X-linked trait of considerable frequency and low fitness, and (3) is uniformly expressed and accurately diagnosable with minimal effort at or near birth. Although 1828 autosomal dominant traits are known in human beings, 36 can be considered as candidate sentinel phenotypes, along with 5 X-linked disorders. Based on surveys of malformations in infants and children, 16 additional traits are proposed beyond previous lists. In Hungary, the 24 syndromes or defects with reliable manifestations in newborn infants occur with a frequency of 2.5-3.3 per 10 000 live births. As markers of human mutations, sentinel phenotypes have the advantage of representing germinal mutations that result in significant health problems. There are severe disadvantages that have, to date, prevented the launching of a field demonstration of the value of these phenotypes in mutation epidemiology. Agreement on a list of phenotypes has been delayed by continued recognition of two or more distinct genetic diseases within what was once thought to be a single disorder. For the same reason, most of the candidate sentinel phenotypes have not been assigned unique codes in the International Classification of Diseases. Each of the disorders is so rare and has features that overlap with so many other syndromes that highly trained clinical dysmorphologist and pediatric ophthalmologists would have to be engaged in any study. The sentinel phenotype approach, like other strategies in mutation epidemiology, would encounter problems with linkage among files of data, privacy, and access to sufficiently large populations. In contrast with the approach using multiple protein variants (as in the study of blood from offspring of survivors of the atomic bombs in Hiroshima and Nagasaki), the sentinel phenotype approach would likely be much less expensive and would encounter far fewer false attributions of paternity, but also would require a much larger study population. The best option for the present, in our opinion, is to broaden and sustain critical discussion of the approach. Perhaps the goal should be to plan a field demonstration by involving appropriate clinicians, epidemiologists, and public health officials. A pilot effort underway in Hungary may well give insight to applying the approach in a significantly larger population.
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We do not know how many mutations are being produced in human populations by exposure to environmental mutagens. If these mutagens caused a persistent rise in mutation rates, then ultimately there would be a proportional increase in the frequency of a variety of genetic diseases, including those that are difficult to treat and that require life-long care of affected individuals. In contrast, modern medical practices are relaxing selection pressure selectively with respect to disease, leading to a gradual increase in the frequency of certain genetic and partly genetic diseases that can be effectively treated. The pattern of this increase would differ from condition to condition, depending upon the mode of inheritance and the extent to which selection is relaxed; except for some special cases, the anticipated increase would generally be slow. Additional economic burdens on future society and families imposed by relaxed selection would mainly involve expenditures for relatively inexpensive treatments, and not those for expensive life-long care. Moreover, individuals treated successfully can be expected to contribute productively to society. With education and counseling for those who survive serious dominant and X-linked disorders, and with the development of accurate, inexpensive prenatal diagnosis, the presumed dysgenic effects of relaxed selection could be balanced.
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Experimental research designed to determine the effects of variations in diet on the carcinogenic and mutagenic processes is difficult to conduct and even more difficult to interpret in terms of the likely response that such variations will have on the expression of human cancer and mutation. Although some of these difficulties may be due to a failure to persuade adequate numbers of highly trained nutritionists to enter into this type of research, a more germaine reason may be that the high level of complexity of both diet and the disease processes is such as to confound present efforts at interpretation. It is suggested that a stepwise analysis of the effects of dietary factors on each critical stage in carcinogenesis or mutagenesis may ultimately lead to results that are more easily interpreted in terms of human response. To this end it is proposed that studies of DNA-carcinogen or DNA-mutagen adduct formation, or other DNA damage, DNA replication and relevant DNA repair at the target site may be a useful guide to the effect of nutritional changes on mutation and/or cancer initiation. DNA replication at various stages of carcinogenesis, modification of hormonal levels, modification of immune response, or other factors as influenced by diet may provide markers for cancer development. The integration of this data to give an overall perception of the effects of nutrition is briefly discussed.
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The problems that arise in the interpretation of experimental data on chemical carcinogenesis are addressed. In particular, the difficulties in demonstrating negative results are shown to present problems in delineating carcinogens from noncarcinogens. The use of the virtually safe dose estimated under the assumption of low dose linearity is shown to lead to potentially anomalous results if used indiscriminately in bioassays in which no statistically significant increase in tumor occurrence is induced. It is suggested that there is a need to establish an operational definition of negativity in carcinogenesis, with the realization that this definition may be revised in light of new information. The establishment of negativity in aligning data from positive and negative experiments and in considering possible thresholds is also discussed.
Alcoholics have a higher frequency of chromosomal aberrations and sister-chromatid exchanges (SCEs) in their peripheral lymphocytes. In human and mammalian cells in vitro, ethanol generally does not induce genetic damage, but it induces SCEs in the presence of an exogenous metabolic system. In human lymphocytes in vitro, ethanol induces SCEs in the presence of alcohol dehydrogenase. In animals in vivo, ethanol induces a variety of genetic effects, including SCEs, micronuclei, dominant lethal mutations and aneuploidy in mouse eggs. There is some indication that ethanol may lead to genetic damage in sperm. In bacteria, ethanol is at best marginally active. Ethanol leads to anomalous chromosome segregation in Aspergillus, to mutations in yeast, to chromosomal aberrations and SCEs in plant root tips and to disturbances of meiosis and micronuclei in tetrads in Zea and Tradescantia respectively. The first metabolite of ethanol, acetaldehyde is mutagenic in a variety of test systems. The mutagenic activity of acetaldehyde in bacteria is questionable, but there is no doubt of its mutagenic activity in a variety of eukaryotic test systems in vitro as well as in vivo.
Different pathways of alcohol metabolism, the alcohol dehydrogenase pathway, the microsomal ethanol-oxidizing system and the catalase pathway are discussed. Alcohol consumption leads to accelerated ethanol metabolism by different mechanisms including an increased microsomal function. Microsomal induction leads to interactions of ethanol with drugs, hepatotoxic agents, steroids, vitamins and to an increased activation of mutagens/carcinogens. A number of ethanol-related complications may be explained by the production of its first metabolite, acetaldehyde, such as alterations of mitochondria, increased lipid peroxidation and microtubular alterations with its adverse effects on various cellular activities, including disturbances of cell division. Nutritional factors in alcoholics such as malnutrition are discussed especially with respect to its possible relation to cancer.
The determination of acetaldehyde levels in blood and other tissues is a difficult task, and depends on the method used. Different methods and their pros and cons are discussed in detail. Quantitative results are shown for endogenous acetaldehyde levels and for acetaldehyde levels during alcohol intoxication. One article pertains to acetaldehyde bound to blood and tissue proteins.
Alcohol consumption is believed to involve genetic factors. In this paper genetically determined metabolic factors influencing the alcohol metabolism, such as different types of alcohol dehydrogenase and aldehyde dehydrogenase are discussed.
Different types of alcohol dehydrogenase and of aldehyde dehydrogenase lead to different blood acetaldehyde levels. With respect to acetaldehyde levels in human blood 3 types can be distinguished: (1) the normal range, (2) the acute aldehyde syndrome, and (3) the chronic aldehydism. Acetaldehyde is electrophilic and reacts with nucleophilic groups of various macromolecules including DNA. Acetyldehyde inhibits synthetic and metabolic pathways, it interferes with the polymerization of tubulin and stimulates collagen synthesis. By depletion of cellular glutathione levels, acetaldehyde leads to lipid peroxidation and to the formation of malonaldehyde. There are indications that acetaldehyde may play a role in positively reinforcing mood changes induced by alcohol in humans.
Alcohol consumption is associated with an increase in the incidence of cancers of several sites, including oesophagus, larynx and mouth. The mechanism of the induction of cancer by alcohol is not clear. Humans are exposed to a variety of carcinogenic N-nitroso compounds. Ethanol changes the pharmacokinetics of nitrosamines in rats particularly by decreasing the ability of the liver to metabolize them. A hypothesis is put forward that the influence of alcohol on human cancer is mediated by its effect on the metabolism and distribution of nitrosamines from the diet, from tobacco smoke and from endogenous synthesis.
The adverse effects of ethyl alcohol on the hypothalamic pituitary gonadal axes of men and women are discussed with particular attention being given to effects of alcohol upon reproduction. Data obtained from acute and chronic alcohol exposure studies are presented. The putative pathophysiologic mechanisms responsible for disturbed reproductive performances in alcohol abusing individuals are discussed where sufficient data are available.
Sentinel phenotypes are indicators of germinal dominant gene mutations. 23 sentinel abnormalities and 2 sentinel childhood tumours (bilateral retinoblastoma and Wilms' tumour), i.e., 25 sentinel anomalies of autosomal dominant origin were selected from the material of the Hungarian Congenital Malformation Registry, 1980-1984. Furthermore, cases of sentinel childhood tumours from the Hungarian Childhood Tumour Registry and some extra notifications of sentinel abnormalities were also included. Experts examined index patients and their parents in order to confirm or exclude nosological diagnosis, to separate sporadic and familial cases, to obtain environmental history and to give genetic counselling. The revised total observed prevalence of 25 sentinel anomalies was 3.80 per 10,000 livebirths. Only 12% of cases examined were familial. According to the statistical power calculation, 47,500 livebirths are needed to detect a doubling of mutation rate with probabilities of type I and II errors of 0.05 level. In Hungary the average number of yearly births was 135,548 in the study period.