Concentrations of cadmium and lead in blood (BCd and BPb, respectively) are traditionally used as biomarkers of environmental exposure. We estimated the influence of genetic factors on these markers in a cohort of 61 monozygotic and 103 dizygotic twin pairs (mean age = 68 years, range = 49-86). BCd and BPb were determined by graphite furnace atomic absorption spectrophotometry. Variations in both BCd and BPb were influenced by not only environmental but also genetic factors. Interestingly, the genetic influence was considerably greater for nonsmoking women (h
The amount of the toxic metals cadmium and lead in the human environment has increased considerably during the last century because of anthropogenic activities (
The assessment of human exposure to Cd and Pb has traditionally been based on biomarkers, in particular concentrations in blood and urine. For both metals, concentrations in blood (BCd and BPb, respectively) are believed to reflect mainly ongoing exposure (
Using data from a sample of elderly twin pairs, we were interested in three research questions. First, what is the relative importance of genetic and environmental effects for BCd and BPb? Second, are there sex differences in the importance of these effects? Third, to what extent are the same genetic and environmental influences of importance for BCd and BPb?
Study group. The study group consisted of twins participating in The Swedish Adoption/Twin Study of Aging (SATSA) (
Metal analyses. We determined concentrations of BCd and BPb by graphite furnace atomic absorption spectrophotometry with Zeeman background correction (
Statistical analyses. Genetic analyses were based on quantitative genetic theory, which defines a phenotype as the sum of the effects of both genotype and environment (
The environmental component of variance for a particular trait can be decomposed into two subcomponents--one shared by family members and the other not. Shared environmental influences (c
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Estimates of genetic and environmental effects based on intraclass correlation have relatively large standard errors resulting in low power and do not use all available information simultaneously. Model-fitting approaches are more powerful and permit the analysis of several groups of twins simultaneously as tests of the relative fit of various models, and are now standard practice in twin research (
To achieve normal distribution of data BCd and BPb were log-transformed. We used residuals, adjusted for age and sex, from linear regression analyses in the calculation of intraclass correlation and model fitting. Analyses were first applied to the entire sample and then only to nonsmoking twin pairs, using new residuals for only nonsmoking twins. Because of the strong influence of smoking on the BCd concentrations (
Blood concentrations of Cd and Pb. The overall geometric mean BCd was 0.41 mug Cd/L (range = 0.05-6.8 mug Cd/L). Because smokers had highly elevated BCd, data for nonsmokers are given separately (Table 1). For nonsmokers, BCd was significantly higher for women than for men. Concentrations increased slightly across age. The geometric mean concentration of Pb in blood was 28 mug Pb/L (range = 5.6-150 mug/L). BPb was not influenced by smoking, and was slightly higher for men than for women (Table 1). Mean levels of BPb decreased slightly with age until approximately 70 years of age, after which they increased again. More importantly, total variance increased with age for BPb but was stabile across age groups for BCd. There were no differences in means or variances for the two zygosity groups, thus fulfilling one of the assumptions of the twin method.
Twin analyses: BCd. Intraclass correlations of BCd by sex and by age for the entire study group as well as for nonsmoking twins are given in Table 2. In general, MZ twins had higher correlations than DZ twins, indicating a genetic influence on BCd. Among nonsmokers, the pattern of correlations for women suggested a genetic effect whereas the considerably lower correlations for men suggested that environmental factors are of much greater importance than genetic effects.
Results from model-fitting analyses of BCd (Figure 1) mostly confirm the findings based on the comparison of intraclass correlations. When the entire sample was evaluated (regardless of smoking status), approximately 60% of the variation in BCd was due to genetic effects. Among nonsmoking twins, genetic effects were considerably more important for women than for men (65 and 13%, respectively). Analyses of nonsmoking twin pairs younger and older than 65 years of age showed no major cohort differences.
Twin analyses: BPb. The correlation for MZ twins was greater than that for DZ twin pairs among the women, suggesting the importance of genetic effects (Table 2). In contrast, the MZ and DZ correlations for men did not differ, indicating the importance of shared familial environment. The intraclass correlations for twin pairs (pooled across sex and smoking status) suggested a substantial cohort effect, with substantial genetic influences in the younger cohort and shared environmental influences in the older cohort. The sample size did not allow separate analyses by age group and sex simultaneously.
Model-fitting analyses indicated that approximately 44% of the variance in BPb in women was due to genetic factors, compared to only 3% in men (Figure 2). Shared environmental factors were significant for men bur not for women (37 and 3%, respectively). There was essentially no genetic influence at older ages. This in large part reflected a decrease in genetic effects among the older women, as there was essentially no genetic variance for the men at any age.
Associations between Cd and Pb. There was a moderate association (r = 0.30, n = 210) between BCd and BPb in nonsmoking individuals. Thus, the next logical step was to evaluate whether this association can be attributed to the same genetic factors for BCd and BPb, or to environmental influences of importance for blood concentrations of both metals. We evaluated this association by computing cross-twin cross-trait correlations for nonsmoking twin pairs, i.e., the correlation of BPb in one twin with BCd in the cotwin. Because there were no differences in the cross-correlations for MZ and DZ pairs, only environmental influences could have contributed to the association. Thus, the association between BCd and BPb could be attributed entirely to environmental factors of mutual importance for levels of the two metals.
To our knowledge, this is the first empirical demonstration that individual differences in concentrations of BCd and BPb in part reflect genetic variation. Interestingly, genetic effects were of greater importance for women than men. In men the variation in blood metal concentrations could be attributed almost entirely to environmental factors. Elucidation of the genetic mechanisms that influence blood metal concentrations in women would enable identification of risk groups that are particularly sensitive to toxic metal exposure.
Genes can act and interact in a variety of ways before their effects on the phenotype (BCd or BPb) are observable. Specific genetic factors influencing BCd and BPb have not yet been investigated, but may include genes regulating absorption, distribution, metabolism, and excretion. Heritability estimates were greater for the pooled sample of men than for nonsmokers only. This suggests that some of the genetic influences for BCd reflect genetic influences for smoking status. The pronounced genetic influence on BCd in nonsmoking women is particularly interesting because women in general have higher concentrations of Cd in blood and in the kidneys, the main target organ for Cd toxicity (
BCd levels increase across age in men bur not in women (
Genetic effects for BPb variation were also greater for women than for men. Pb is neurotoxic and very low concentrations may affect the central nervous system, especially during prenatal development (
Variation in male BPb was mainly influenced by environmental factors. Part of the variation may reflect individual differences in dietary habits. Studies on the concentrations of Pb in diet, collected in duplicate during 7 consecutive days by 15 women (105 diets total), showed a total range of 5-80 lag Pb (
There was a moderate association between BCd and BPb levels among nonsmokers that was entirely attributable to environmental influences. The lack of a genetic mediator for this covariation is notable and is in striking contrast to findings for components of the metabolic syndrome (
Although this is the first known report of genetic influences on blood metal concentrations in a large number of individuals, the number of pairs for the analyses was small by twin study standards. The classical twin study has much greater power to identify significant genetic rather than shared environmental effects (
Interindividual variation in BCd and BPb concentrations is not entirely attributable to environmental exposure. Genetic influences on blood concentrations of Cd and Pb were most pronounced in nonsmoking women. Thus blood metal concentrations are influenced by different factors in men and women and are not the direct indicators of exposure as previously believed. This new knowledge will improve the evaluation of exposure and internal dose--important parts in the risk assessment process. It is important to study the effect in a younger population and to characterize the genetic influences on metal concentrations to identify risk groups in the population.
Address correspondence to M. Vahter, Institute of Environmental Medicine, Karolinska Institutet, Box 210, S-171 77 Stockholm, Sweden. Telephone: 46 8 728 7540. Fax 46 8 337039. E-mail: marie.vahter@imm.ki.se
We thank M. Baecklund for help with preliminary analyses.
The Swedish Adoption Twin Study of Aging was supported by the National Institute on Aging (granis AG-04563 and AG- 10175), the MacArthur Foundation Research Network on Successful Aging, and the Swedish Council for Social Research. In addition, the Swedish Environmental Protection Agency provided support for this study.
Received 28 December 1999; accepted 30 March 2000.
Table 1. BCd and BPb in blood by sex and zygosity.
a Geometric mean.
Table 2. Intraclass correlations of BCd and BPb concentrations in MZ and DZ twin pairs by sex and age group.
Data for BCd and BPb are given for ali pairs. BCd data for nonsmokers are given separately.
a The number of twin pairs is given by sex in Table 1. In those younger than 65 years of age there were 18 and 39 MZ and DZ twin pairs, respectively. There were 11 MZ and 18 DZ nonsmoking pairs. In those older than 65 years of age there were 43 and 64 MZ and DZ twin pairs, respectively. There were 32 MZ and 44 DZ nonsmoking pairs.
GRAPH: Figure 1. Sources of variation of concentration of cadmium in blood. Abbreviations: c
GRAPH: Figure 2. Sources of variation of concentration of lead in blood. Abbreviations: c
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By Lars Bjorkman[1,2]; Marie Vahter[1] and Nancy L. Pedersen[1,3]
1Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 2Department of Basic Oral Science, Karolinska Institutet, Stockholm, Sweden; 3Department of Medical Epidemiology, Karolinska Institutet, Stockholm and Department of Psychology, University of Southern California, Los Angeles, California, USA