Ingrid Nordenson

Is the genotoxic effect of arsenic mediated by oxygen free radicals

Previous investigations have shown that trivalent arsenic is inducing chromosomal aberrations and sister chromatid exchanges (SCEs). In a search for the genotoxic mechanism we have studied the effects of the oxygen-radical-scavenging enzymes superoxide dismutase (SOD) and catalase (CAT) on arsenic-induced SCEs in cultured human lymphocytes. The results indicate that SOD and possibly also CAT have a protective effect against arsenic-induced DNA damage. Arsenic, which is emitted in environmental pollutions e.g. from smelters and coal-fired power plants, appears to be underestimated as environmental mutagen and potential synergist to ionizing radiation.

Cancer predictive value of cytogenetic markers used in occupational health surveillance programs: a report from an ongoing study by the European Study Group on Cytogenetic Biomarkers and Health

The cytogenetic endpoints in peripheral blood lymphocytes: chromosomal aberrations (CA), sister chromatid exchange (SCE) and micronuclei (MN) are established biomarkers of exposure for mutagens or carcinogens in the work environment. However, it is not clear whether these biomarkers also may serve as biomarkers for genotoxic effects which will result in an enhanced cancer risk. In order to assess this problem, Nordic and Italian cohorts were established, and preliminary results from these two studies indicated a predictive value of CA frequency for cancer risk, whereas no such associations were observed for SCE or MN. A collaborative study between the Nordic and Italian research groups, will enable a more thorough evaluation of the cancer predictivity of the cytogenetic endpoints. We here report on the establishment of a joint data base comprising 5271 subjects, examined 1965-1988 for at least one cytogenetic biomarker. Totally, 3540 subjects had been examined for CA, 2702 for SCE and 1496 for MN. These cohorts have been followed-up with respect to subsequent cancer mortality or cancer incidence, and the expected values have been calculated from rates derived from the general populations in each country. Stratified cohort analyses will be performed with respect to the levels of the cytogenetic biomarkers. The importance of potential effect modifiers such as gender, age at test, and time since test, will be evaluated using Poisson regression models. The remaining two potential effect modifiers, occupational exposures and smoking, will be assessed in a case-referent study within the study base.

Fragile site X chromosomes and X-linked mental retardation in severely retarded boys in a northern Swedish county. A prevalence study

In an unselected series of 96 severely mentally retarded boys (IQ < 50) born 1959–70 in a northern Swedish county, six had a fragile site on the distal end of the X chromosome (FraXq 28). The prevalence of the fragile X syndrome in severely retarded boys was 6 %. Next to trisomy 21, this fragile X syndrome appears to be the most common single cause of severe mental retardation in boys.

A Nordic data base on somatic chromosome damage in humans

Analyses of cytogenetic damage--chromosome aberrations (CA), micronuclei (MN), and sister-chromatid exchange (SCE)--are used to assess genotoxic exposure, on the supposition that higher levels of chromosome damage in peripheral lymphocytes reflect increased cancer risk. We attempt to test this hypothesis prospectively, by relating levels of cytogenetic damage to subsequent cancer morbidity in a cohort comprising 3190 subjects. All these subjects have been analyzed previously (1970-1988) for CA, MN, and/or SCE in studies of occupational and environmental exposure. The present paper describes the data base and assesses how the potential confounders smoking habits, sex, and age influence CA, MN, and SCE levels. Ten Nordic laboratories contributed data. In the present analyses, these data were treated separately to avoid the effects of interlaboratory differences. Point estimates from multiple regression analyses indicate that smoking may increase CA frequencies by up to 10-20% and SCE means by 5-8%, but that it has no effect on MN frequencies. Women had higher CA, MN, and SCE levels than men, but the sex effect was generally smaller than the effect of smoking. Age was positively associated with cytogenetic damage. Compared to the sex effect, the effect of a 10-year age increase was similar on CA, but less, 1-3%, on SCE. The amount of variation explained by the potential confounders taken together was generally low, often less than 20%. Thus, other still unknown factors must be the major sources of CA, MN, and SCE variability.

Clastogenic effects in human lymphocytes of power frequency electric fields: In vivo and in vitro studies

SummaryIn vivo and in vitro studies of the clastogenic effects of power frequency electric fields and transient electric currents have been performed. For the in vivo investigation peripheral lymphocytes from twenty switchyard workers were screened for chromosome anomalies. The rates of chromatid and chromosome breaks were found to be significantly increased compared to the rates in 17 controls.Exposure of human peripheral lymphocytes, in vitro, to a 50-Hz current with 1 mA/cm2 current density did not induce any chromosome damage. Exposure to ten 3 µs-long spark discharge pulses with a peak field strength in the samples of 3.5 kV/cm, however, resulted in chromosome breaks at a frequency similar to that induced in lymphocytes in vitro by ionizing radiation at 0.75 Gy.The biological significance of chromosomal damage induced in somatic cells is discussed.

Fragile X syndrome in mildly mentally retarded children in a northern swedish county. A prevalence study

In an extensive etiological study of an unselected series of mildly mentally retarded children (MMR) (IQ 50–70) born 1959–1970 in a northern Swedish county, 5 of 110 boys (4.5%) and none of 61 girls had a fragile site on the distal end of the X‐chromosome (Fra Xq 28). Consequently fragile X was seen in 2.9% of the total series of 171 children. In a combined series of severe and mild mental retardation, the incidence of the fragile X syndrome was calculated to be 1:3000 in the county of Vasterbotten. Next to trisomy 21 the fragile X syndrome was the most common single identified cause of MMR in boys. A cytogenetic investigation using special cultural conditions and banding techniques should be performed in cases of mental retardation of unclear etiology and in possible female carriers.

Homozygosity for the transthyretin-met30-gene in two Swedish sibs with familial amyloidotic polyneuropathy

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited disorder. Recent biochemical studies have revealed that amyloid protein in FAP of Japanese, Swedish and Portuguese origin mainly consists of a variant transthyretin (TTR) (formerly called prealbumin) with one amino acid substitution of methionine for valine at position 30. In a 56‐year‐old man with typical polyneuropathy, gastrointestinal problems and vitreous amyloid, we diagnosed homozygosity for the TTR‐met30‐gene using RFLP analysis. In a family study, a sister presented the same homozygous RFLP pattern; however, in a careful clinical investigation we were not able to demonstrate any of the typical symptoms of FAP, nor could we demonstrate amyloid deposits in a biopsy skin specimen. This is the first report of homozygosity for the TTR‐met30‐gene, and it shows that the mutation of the protein involved in amyloid formation may be necessary but is clearly not sufficient for the clinical symptoms.

Interaction between Some Common Genotoxic Agents

The clastogenic effects of arsenic, lead and sulphur dioxide and the protective effect of selenium were studied in short-term lymphocyte cultures. The three agents selected are the major toxic substances in emissions from copper smelters. Cells from non-smoking, healthy individuals were exposed to individual agents and combinations of the four agents (sodium arsenite, lead acetate, sodium sulphite and sodium selenite) and the cells were analysed for chromosome aberrations and sister chromatide exchanges. Selenium showed an antagonistic (protective) effect against the other agents. No synergistic effects were found, and the interactions between arsenic, lead and sulphur dioxide were mainly antagonistic. These rather unexpected findings indicate that mixed exposure from copper smelters, and other mixed exposures where arsenic, lead and sulphur dioxide are involved, may cause less genetic damage than expected and that an adequate dietary supplement of selenium may reduce the genotoxic effects of these agents.

Chromosomal effects in lymphocytes of 400 kV-substation workers

SummaryIn a previous study we found an increased rate of chromosomal aberations in substation workers. To follow up this finding we in this study present data from 38 employees of electric power companies; 19 of the subjects worked with the repair and maintenance of circuit breakers and disconnectors in 400 kV-substations. The other 19 served as controls and were only exposed to normal environmental electromagnetic fields. Coded blood samples were sent to a laboratory for determination of the rate of chromosomal aberrations (CA), sister chromatid exchanges (SCE), and cells with micronuclei (MN). Compared to the control group the exposed men displayed a statistically significant increase in CA and cells with MN. No increase was found in the frequency of SCE. Since “in vitro” studies of lymphocytes exposed to transient electric currents (spark discharges) produced similar results the increase in chromosomal damage in substation workers may be associated with exposure to transient electric currents during work.

Chromosomal Aberrations and Cancer Risk

Chromosomal aberrations in lymphocytes were studied in patients with untreated cancers of the lung and skin (basal cell carcinoma) and in controls matched for sex, age, and smoking habits. Patients with skin cancer were found to have a significantly increased rate of chromosome type aberrations. Among the patients with lung cancer, there was a tendency towards an increased rate of aberrations which, however, did not reach statistical significance. The results suggest that an increased rate of chromosomal aberrations in cultured lymphocytes is an indicator of genetic damage which may increase the cancer risk.