Pavel Langer

High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail

Aims/hypothesisA heavily polluted area of Eastern Slovakia was targeted by the PCBRISK cross-sectional survey to search for possible links between environmental pollution and both prediabetes and diabetes.MethodsAssociations of serum levels of five persistent organic pollutants (POPs), namely polychlorinated biphenyls (PCBs), 2,2′-bis(4-chlorophenyl)-1,1-dichloroethylene (p,p′-DDE), 2,2′-bis(4-chlorophenyl)-1,1,1-trichloro-ethane (p,p′-DDT), hexachlorobenzene (HCB) and β-hexachlorocyclohexane (β-HCH), with prediabetes and diabetes were investigated in 2,047 adults. Diabetes and prediabetes were diagnosed by fasting plasma glucose in all participants and by OGTT in 1,220 compliant participants.ResultsOur population was stratified in terms of individual POPs quintiles and associations between environmental pollution, prediabetes and diabetes were investigated. Prevalence of prediabetes and diabetes increased in a dose-dependent manner, with individuals in upper quintiles of individual POPs showing striking increases in prevalence of prediabetes as shown by OR and 95% CI for PCBs (2.74; 1.92–3.90), DDE (1.86; 1.17–2.95), DDT (2.48; 1.77–3.48), HCB (1.86; 1.7–2.95) and β-HCH (1.97; 1.28–3.04). Interestingly, unlike PCBs, DDT and DDE, increased levels of HCB and β-HCH seemed not to be associated with increased prevalence of diabetes. Nevertheless, individuals in the 5th quintile of the variable expressing the cumulative effect of all five POPs (sum of orders) had a more than tripled prevalence of prediabetes and more than six times higher prevalence of diabetes when compared with the 1st referent quintile.Conclusions/interpretationIncreasing serum concentrations of individual POPs considerably increased prevalence of prediabetes and diabetes in a dose-dependent manner. Interaction of industrial and agricultural pollutants in increasing prevalence of prediabetes or diabetes is likely.

The impacts of organochlorines and other persistent pollutants on thyroid and metabolic health

High prevalence of thyroid and metabolic disorders has been repeatedly observed in the population living in the area of eastern Slovakia highly polluted by a mixture of PCBs, DDE and HCB since about 50 years ago. Among thyroid disorders, increase of thyroid volume as measured by ultrasound volumetry may be suggested as one of notable findings which appeared possibly related to increased OCs levels and to autoimmunity signs (e.g. positive thyroperoxidase antibodies in blood and/or hypoechogenicity image obtained by ultrasound), while some participation of individual susceptibility and also of immunogenic effect of OCs and iodine in this iodine replete country cannot be excluded. Another notable finding has been the increase of blood FT4 and TT3 positively related to high PCBs level. Such increased FT4 level has been found associated with TSH level in hyperthyroid range in about 2% of examined population from polluted area. High prevalence of thyroid autoimmune disorders strongly supported the assumption on impaired immune system and thus also on presumably increased prevalence of other autoimmune disorders in highly exposed population. In addition, markedly increased prevalence of prediabetes and diabetes significantly related to major OCs (PCBs, DDE and HCB) levels and accompanied by increasing level of cholesterol and triglycerides has been observed. The observations also suggested a role of prenatal exposure to OCs in the development of several adverse health signs (e.g. increased prevalence of thyroid antibodies, impaired fasting glucose level, increased thyroid volume, decreased thymus volume, decreased neurobehavioral performance, increased hearing and dental disorders) in young generation born to highly exposed mothers in polluted area.

High Prevalence of Anti-Glutamic Acid Decarboxylase (Anti-GAD) Antibodies in Employees at a Polychlorinated Biphenyl Production Factory

Abstract An increased prevalence of thyroid antibodies was seen in employees of a factory that formerly produced polychlorinated biphenyls (PCBs). In this study, the authors expand the evaluation of possible long-term PCB effects by comparing the prevalence of glutamic acid decarboxylase (anti-GAD) antibodies with the development of diabetes mellitus. The sera of 240 factory employees and 704 control subjects were analyzed. Anti-GAD antibody values exceeded 1.20 U/ml in all employees (40.4%), was 4 times higher (p < .001) than in all controls (10.5%), and were 5 times higher in employees aged 51-60 yr (53.2%) than in age-matched controls (10.5%) (p < .001). Although the prevalence of diabetes could not be determined from this retrospective study, this is the first report of a possible relationship between xenobiotics and the prevalence of anti-GAD antibodies, and it supports the concept of an immunomodulatory effect of PCBs. However, such antibodies may be present decades before the development of clinical diabetes, and not all anti-GAD antibody-positive individuals become diabetic. Presently, it is unknown whether there is an increased prevalence of diabetes among the former factory employees.

Increased thyroid volume, prevalence of thyroid antibodies and impaired fasting glucose in young adults from organochlorine cocktail polluted area: Outcome of transgenerational transmission?

In 137 females (F) and 94 males (M) aged 21-35 years from organochlorines (OCs) polluted area (POLL) increased thyroid volume (ThV), prevalence of antibodies to thyroperoxidase (TPOab), thyrotropin receptor (TRab) and of impaired fasting glucose (IFG) was found compared to 116 F and 107 M from background pollution area (BCGR). In F and M from POLL also strikingly increased level of PCBs, DDE and HCB was found. Such findings were compared to the generation of their parents aged 41-55 years consisting of 320F/213M from POLL and 406F/231M from BCGR. However, in spite of strikingly lower level of those OCs in young adults from POLL, they showed about the same prevalence of adverse health signs as the old generation. From such reason 44 young F and 40 young M with lowest PCBs level from POLL were selected to obtain nearly the same PCB level as found in all young F and M from BCGR. In such PCB adjusted groups the prevalence of TPOab, TRab, IFG and increased ThV was still significantly higher than that in all young subjects from BCGR. At the same time, also the level of DDE and HCB in such PCBs adjusted groups was considerably lower. It was concluded that such adverse effects in young adults from POLL possibly did not result from their actual OCs levels, but very likely from their exposure to high OCs levels of their mothers during their prenatal and perinatal life. Thus, the data may be compatible with present views on transgenerational transmission of endocrine disruptors action.

Regulation of gene expression for lipogenic enzymes in the liver and adipose tissue of hereditary hypertriglyceridemic, insulin-resistant rats: effect of dietary sucrose and marine fish oil

Hypertriglyceridemia is closely linked to insulin resistance. Increased dietary intake of n-3 polyunsaturated fatty acids reverses both hypertriglyceridemia and insulin resistance. To evaluate molecular mechanisms responsible for the hypotriglyceridemic effects of n-3 polyunsaturated fatty acids, the expression of genes for lipogenic enzymes in liver and white and brown adipose tissue was estimated in hereditary hypertriglyceridemic rats which underwent an euglycemic hyperinsulinemic clamp. Before the clamp, animals were fed a basal or a high (63%) sucrose diet with or without fish oil for two weeks. Results were compared to data obtained from control animals subjected to the identical protocol. In hereditary hypertriglyceridemic rats, gene expression for malic enzyme was increased in liver and in brown adipose tissue but not in white adipose tissue. The high sucrose diet raised malic enzyme mRNA levels in liver of both hereditary hypertriglyceridemic and control rats, and this effect was more pronounced in brown adipose tissue. Supplementing the high sucrose diet with fish oil led to a suppression of malic enzyme gene expression in liver and brown adipose tissue of control rats. However, this inhibitory effect was not as pronounced in the hereditary hypertriglyceridemic rats. Raised levels of fatty acid synthase mRNA in liver and brown adipose tissue of control rats fed high sucrose diet were suppressed by consumption of diet high in n-3 fatty acids. On the other hand, in hereditary hypertriglyceridemic rats fed high sucrose diet, fish oil supplementation failed to suppress increased levels of fatty acid synthase mRNA in liver and in brown adipose tissue. It appears that hereditary hypertriglyceridemic rats have elevated levels of mRNA for lipogenic enzymes in liver and brown adipose tissue and dietary control leading to an alteration of hypertriglyceridemia influences gene expression of lipogenic enzymes only under special dietary circumstances.

Exposure to polychlorinated biphenyls and hearing impairment in children.

The objective of this cross-sectional epidemiological study was to assess if long-term exposure to polychlorinated biphenyls (PCBs) is associated with hearing impairment. Four hundred and thirty-three children aged 8-9 years residing in an area polluted by PCBs in Eastern Slovakia were examined otoscopically, tympanometrically and by pure tone audiometry. PCB levels in their serum were determined by gas chromatography. Transient otoacoustic emissions (TEOAE) were measured in a subgroup of 161 children. The mean of the sum of PCB concentrations in serum was 528.2ng/g serum lipids (median 321ng/g serum lipids). Serum PCB concentrations were associated with an increase of hearing threshold at low frequencies and a negative correlation between serum PCBs and the amplitude of TEOAE response was observed in the uppermost tertile of children grouped with regard to serum PCBs, not related to thyroid hormone levels. It was concluded that long-term environmental exposure to PCBs is associated with subclinical but diagnosable hearing deficits.

Relative effect potency estimates of dioxin-like activity for dioxins, furans, and dioxin-like PCBs in adults based on two thyroid outcomes.

Background: Toxic equivalency factors (TEFs) are an important component in the risk assessment of dioxin-like human exposures. At present, this concept is based mainly on in vivo animal experiments using oral dosage. Consequently, the current human TEFs derived from mammalian experiments are applicable only for exposure situations in which oral ingestion occurs. Nevertheless, these “intake” TEFs are commonly—but incorrectly—used by regulatory authorities to calculate “systemic” toxic equivalents (TEQs) based on human blood and tissue concentrations, which are used as biomarkers for either exposure or effect. Objectives: We sought to determine relative effect potencies (REPs) for systemic human concentrations of dioxin-like mixture components using thyroid volume or serum free thyroxine (FT4) concentration as the outcomes of interest. Methods: We used a benchmark concentration and a regression-based approach to compare the strength of association between each dioxin-like compound and the thyroid end points in 320 adults residing in an organochlorine-polluted area of eastern Slovakia. Results: REPs calculated from thyroid volume and FT4 were similar. The regression coefficient (β)-derived REP data from thyroid volume and FT4 level were correlated with the World Health Organization (WHO) TEF values (Spearman r = 0.69, p = 0.01 and r = 0.62, p = 0.03, respectively). The calculated REPs were mostly within the minimum and maximum values for in vivo REPs derived by other investigators. Conclusions: Our REPs calculated from thyroid end points realistically reflect human exposure scenarios because they are based on chronic, low-dose human exposures and on biomarkers reflecting body burden. Compared with previous results, our REPs suggest higher sensitivity to the effects of dioxin-like compounds.

Further indications for genetic heterogeneity of euthyroid familial goiter

Iodine deficiency is the most important etiological factor for euthyroid endemic goiter. However, family and twin pair studies also strongly indicate a genetic prediposition. In euthyroid goiters molecular defects in the thyroglobulin (TG), and Na+/I− symporter (NIS) gene have been identified. Numerous mutations in the Pendrin (PDS) gene have been found in families with PDS characterized by deafness and euthyroid goiter. Moreover, family studies indicated two major candidate loci MNG-1 on chromosome 14q31 and Xp22. However, all previous linkage studies investigated only one family. To clarify the general relevance of these previously identified two major candidate loci for the etiology of euthyroid goiter we investigated four families with a total number of 74 family members by linkage analysis with microsatellite markers. Moreover, we analyzed the thyroid candidate genes TG, thyroperoxidase (TPO), NIS, TSH receptor, and PDS. In a further family with 12 members in whom we have previously demonstrated linkage to the MNG-1 locus we investigated the Xp22 locus and the PDS gene in addition to our initial study. Linkage analysis results of our study are not significant enough to definitely exclude or confirm linkage to the investigated candidate genes and loci. Nevertheless, we obtained very weak indications for possible linkage to Xp22 in one family by a maximal multipoint LOD score of 1.15, and cosegregation of haplotypes among affected family members. Moreover, in another family linkage to PDS was indicated by a maximal multipoint LOD score of 1.87 as well as cosegregation of haplotypes. However, sequencing of the PDS gene did not reveal germline mutations. A significant total NPL score of 6.5 for PDS over all families most likely indicated linkage to a genomic region close to PDS. Furthermore, the likelihood of linkage to MNG-1 and Xp22 is reduced, because multipoint LOD scores were below 1 or negative. In all families there was no significant evidence for linkage for the thyroid candidate genes TG, TPO, NIS, or the TSH receptor. In conclusion, a general role of MNG-1 and Xp22 for the etiology of euthyroid goiter is unlikely but cannot clearly excluded. The multipoint parametric and nonparametric LOD scores further suggest genetic heterogeneity in the etiology of familial euthyroid goiter. To identify other susceptibility loci it is necessary to perform genome-wide linkage analysis studies with more families.

What We Learned from the Study of Exposed Population to PCBs and Pesticides

During previous fifteen years several field surveys were carried out in the large area subjected to environmental pollution by polychlorinated biphenyls and pesticides. The attention has been focused to the analyses of organochlorine (OCs) levels in environmental (superficial waters, air, soil, wildlife, foods) and human samples. Among adverse health ef- fects the attention has been focused to thyroid volume and thyroid autoimmune disorders, pituitary-thyroid interrelations, metabolic disorders and diabetes in adults and to cognitive, behavioral and psychoneuromotoric disorders, impairment of hearing apparatus and dental defects in schoolchildren. Original data were obtained showing possible transgenerational transmission of certain adverse health effects possibly by previous prenatal and perinatal exposure of young adults to high organochlorine levels of their mothers. In participants from heavily polluted area with high blood organochlorine levels a significantly higher prevalence of adverse health signs was found compared to those from the area with considerably lower pollution. However, considerable attention was also paid to the problem of individual susceptibility to adverse health effects.

Nuclear 3,5,3′-triiodothyronine receptors and malic enzyme activity in liver of rats fed fish oil or cocoa butter

The role of different fat supplements (fish oil and cocoa butter), applied intragastrically for 3 weeks, on specific binding of T3 by rat liver nuclear receptors was examined. Fish oil (rich in n-3 polyunsaturated fatty acids) supplementation resulted in a significant (P < 0.05) enhancement of the maximal binding capacity (MBC) for T3 with a diminution of the apparent association constant (Ka). No changes in nuclear receptor MBC or Ka were observed after cocoa butter administration. Moreover, the rate of fatty acid synthesis in the liver was evaluated by measuring malic enzyme (EC. 1.1.1.40.) activity in rat liver cytosol, which was found to be decreased in both the cocoa butter- (P < 0.002) and the fish oil- (P < 0.001) treated rats. Interestingly, in fish oil-supplemented animals, not even a higher MBC value for the T3 receptors in liver nuclei and specific binding of T3 to its receptor were able to restore the activity of malic enzyme in liver cytosol. The findings of the same level of thyroid hormones—thyroxine (T4) and triiodothyronine (T3)—in blood of all groups showed that there was apparently no effect of fat supplementation on the thyroid function. However, it may be hypothesized that the decrease of malic enzyme activity in both fat-treated groups may have resulted from a decreased T4 to T3 conversion in liver cells. The data suggest the following: (a) increased dietary fat intake is accompanied by lower lipogenesis in the liver in relation to the degree of fat unsaturation; (b) although polyunsaturated dietary fat increases T3 receptor binding to liver nuclei; (c) thus, an uncoupling between T3 binding and action on malic enzyme activity during raised fish oil intake cannot be ruled out.