Jónrit Halling

Impact of dietary exposure to food contaminants on the risk of Parkinson's disease

This study aimed to investigate the association of Parkinsons disease (PD) with dietary exposure to polychlorinated biphenyls (PCBs) and methylmercury (MeHg) in a community with increased exposure levels. A total of 79 clinically verified idiopathic PD cases and 154 controls matched by sex and age were examined in this case-control study in the Faroe Islands. Blood and hair samples were collected and a questionnaire recorded lifetime information on residence, dietary habits, smoking history, and occupational exposure to solvents, pesticides, and metals. Both unconditional and conditional logistic regression analyses were used to estimate the odds ratio (OR) and 95% confidence interval (CI) in regard to relevant exposure variables. Increased ORs for dietary intakes of whale meat and blubber during adult life were statistically significant. The ORs for occupational exposure to solvents, pesticides and metals also suggested an increased risk for PD. Current serum concentrations of summation operator PCB and related contaminants suggested slightly increased ORs, although only beta-hexachlorocyclohexane (beta-HCH) was statistically significant. Increased intake of whale meat and blubber in adult life was significantly associated with PD, thus suggesting a positive association between previous exposure to marine food contaminants and development of PD.

Linkage disequilibrium between the CYP2C19*17 allele and wildtype CYP2C8 and CYP2C9 alleles: identification of CYP2C haplotypes in healthy Nordic populations

PurposeTo determine the distribution of clinically important CYP2C genotypes and allele frequencies in healthy Nordic populations with special focus on linkage disequilibrium.MethodsA total of 896 healthy subjects from three Nordic populations (Danish, Faroese, and Norwegian) were genotyped for five frequent and clinically important CYP2C allelic variants: the defective CYP2C8*3, CYP2C9*2, CYP2C9*3, and CYP2C19*2 alleles, and the CYP2C19*17 allele that causes rapid drug metabolism. Linkage disequilibrium was evaluated and CYP2C haplotypes were inferred in the entire population.ResultsTen CYP2C haplotypes were inferred, the most frequent of which (49%) was the CYP2C wildtype haplotype carrying CYP2C8*1, CYP2C9*1, and CYP2C19*1. The second most frequent haplotype (19%) is composed of CYP2C19*17, CYP2C8*1, and CYP2C9*1. This predicted haplotype accounts for 99.7% of the CYP2C19*17 alleles found in the 896 subjects.ConclusionCYP2C19*17 is a frequent genetic variant in Nordic populations that exists in strong linkage disequilibrium with wildtype CYP2C8*1 and CYP2C9*1 alleles, which effectively makes it a determinant for a haplotype exhibiting an efficient CYP2C substrate metabolism.

Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population

ObjectiveThe purpose of the study was to study the distribution of poor and extensive metabolizers of CYP2C19 and CYP2D6 and to genotype for CYP2C8 and CYP2C9 among 312 randomly selected Faroese.Methods and resultsThe participants were phenotyped for CYP2D6 with the use of sparteine. The distribution of the sparteine metabolic ratio (sparteine/didehydrosparteines) was bimodal, and 14.5% (n=44; 95% CI: 10.7–18.9%) of the subjects were phenotyped as poor metabolizers. The frequency of poor metabolizers was higher (P=0.0002; χ2 test) among the Faroese than in other European populations (7.4%). Genotype analyses for the CYP2D6*3, *4, *6 and *9 alleles were performed using real-time polymerase chain reaction (PCR) (TaqMan, Foster City, CA, USA), and we found 14.6% (n = 45) (95% CI: 10.8–19.0%) with deficient CYP2D6 genes (*3/*4, *4/*4, *4/*6, *6/*6) in the Faroese population. The subjects were phenotyped for CYP2C19 with the use of mephenytoin and 10 subjects, i.e., 3.2% (95% CI: 1.6–5.9%) were phenotyped as poor metabolizers. Genotype analysis for the CYP2C19*2 and *3 alleles was performed by means of PCR analysis, and 2.9% (n=9) (95% CI: 1.3–5.4%) of the Faroese were found to have a deficient CYP2C19 gene all explained by the CYP2C19*2/*2 genotype. The allele frequencies of the CYP2C9*2 and CYP2C9*3 alleles were 8.8% (95% CI: 6.7–11.4%) and 5.3% (95% CI: 3.7–7.4%), respectively, while the CYP2C8*3 allele frequency was 6.9% (95% CI: 5.0–9.2%). Real-time PCR (TaqMan) was used for both CYP2C9 and CYP2C8 genotype analyses.ConclusionThe frequency of CYP2D6 poor metabolizers is twofold higher among the Faroese population than other Caucasians, while the frequencies of Faroese subjects with decreased CYP2C19, CYP2C8 and CYP2C9 enzyme activity are the same as seen in other Caucasian populations. A possible consequence might be a higher incidence of side effects among Faroese patients taking pharmaceuticals that are CYP2D6 substrates.

CYP2D6 polymorphism in relation to tramadol metabolism: a study of faroese patients.

Several studies have demonstrated the impact of CYP2D6 polymorphism on the pharmacokinetics of tramadol. However, the relationship between the O-demethylation of tramadol and O-desmethyltramadol (M1) and CYP2D6 activity has not previously been investigated with tramadol in multimedicated outpatients under steady-state conditions. Hence, the aim of this study was to determine if the well documented pharmacokinetics of tramadol regarding CYP2D6 could be verified in a study including 88 multimedicated Faroese patients, treated with tramadol at steady-state conditions. Further, the study aimed to investigate whether the previously observed frequency of CYP2D6 poor metabolizers (PMs) in the Faroese, which was shown to be double that of other Europeans, was evident in a patient group medicated with a CYP2D6 substrate. The patients were CYP2D6-phenotyped by the intake of sparteine, followed by urine collection over 12 hours. Sparteine and its metabolites were assayed by gas chromatography. Genotype analyses for the CYP2D6*3, *4, *6, and *9 alleles were performed by polymerase chain reaction and Taqman technology. Plasma and urinary concentrations of (+/−)-tramadol and (+/−)-M1 were determined by high-performance liquid chromatography. With use of CYP2D6 phenotyping, 10 patients (11.5% [95% confidence interval (CI), 5.7-20.1%]) were classified as CYP2D6 PMs, and 8 (9.3% [95% CI, 4.1-17.3%]) of these were genotyped as CYP2D6 PMs. The PM frequency was not statistically significantly higher than that in other European populations (7%-10%). The concentrations of (+)-M1 when corrected for dose (nM/mg) and the (+)-M1/(+)-tramadol ratio were approximately 14-fold higher in the extensive metabolizers (EMs) than in the PMs. In conclusion, the impact of the CYP2D6 polymorphism on the pharmacokinetics of tramadol was clearly demonstrated in a group of multimedicated patients treated with tramadol under steady-state conditions. Further, the frequency of PMs was not higher than that in other European populations, as previously shown in different Faroese groups, possibly because of discontinued tramadol treatment in Faroese patients who were PMs.

The role of vitamin D levels and vitamin D receptor polymorphism on Parkinson's disease in the Faroe Islands

The role of vitamin D in Parkinsons disease (PD) has been proposed and both low serum 25-hydroxyvitamin D levels (25(OH)D) and vitamin D receptor polymorphisms (VDR) have been linked to PD. The aim of this study is to investigate the associations among 25(OH)D and three VDR polymorphisms and PD in the Faroese population where the prevalence of PD is high. We conducted a case-control study where 121 cases were studied for 25(OH)D levels and VDR polymorphisms against 235 randomly selected controls, matched by gender and age. No significant difference was observed in 25(OH)D levels between PD cases and controls (P=0.49), although cases had slightly lower values than controls. As well, no differences were found in genotype frequencies between cases and controls in the VDR polymorphisms studied (ApaI, BsmI, TaqI) (P=0.70, P=0.56 and P=0.54, respectively). However, we found that VDR ApaI/AC genotype was significantly associated with 25(OH)D levels (P=0.01). Although our results indicate no association between PD and vitamin D polymorphisms and/or 25(OH)D levels, the study cannot exclude a weak association. However, the known doubling in PD prevalence in the Faroe Islands cannot be explained by the polymorphisms examined in the VDR gene or the 25(OH)D levels and has to be explored further.

Genetic predisposition to Parkinson's disease: CYP2D6 and HFE in the Faroe Islands.

Objective To investigate whether the genetic variants of CYP2D6 and HFE are more frequent in Parkinsons disease (PD) patients compared with controls in a population where the prevalence of these variants and PD are increased. Methods Blood samples were collected from 79 PD patients and 154 controls in the Faroe Islands. Genotyping for the ‘CYP2D6*3, *4, *6 and *9’ alleles and for the C282Y and H63D mutations were performed by real-time polymerase chain reaction before Taqman assessment. Results The frequency of CYP2D6 poor metabolizers among the patients was not higher compared with the frequency found in the control group (χ2 test, P=0.86). The odds ratio was 0.92 (95% confidence interval: 0.44–1.90). Neither was a difference in HFE genotype or allele frequencies found between the patients and the controls, and the C282Y and H63D mutation carrier frequencies did not reveal any difference (χ2 test, P=0.50 and 0.60, respectively). Conclusion This study does not support an association between PD and mutations of the CYP2D6 and HFE genes, although a weak association cannot be excluded. The high frequency of PD in the Faroes is most likely the result of interactions between multiple genetic and environmental factors, still to be identified.

Semen quality and reproductive hormones in Faroese men: a cross-sectional population-based study of 481 men

Objectives To determine semen quality and reproductive hormone levels in young Faroese men. Design Descriptive cross-sectional study of Faroese men compared with Danish men. Setting Faroese one-centre study. Participants 481 men born from 1981 to 1987 and investigated from 2007 to 2010. Outcome measures Sperm concentration, semen volume, total sperm count, sperm motility, sperm morphology and reproductive hormone levels. Results Sperm concentrations for the Faroese men were lower than for the Danish men (crude median 40 vs 48 mill/ml, p<0.0005). Semen volume was higher, and thus the total sperm counts did not differ (159 vs 151 mill, p=0.2). Motility and morphology did not differ between the Faroese and Danes. The inhibin B/follicle-stimulating hormone ratios for the Faroese men were lower than for the Danes (64 vs 76, p=0.001). Similarly, lower total testosterone/luteinising hormone (LH) ratio (4.6 vs 6.0, p<0.0005) and lower calculated free-testosterone/LH ratio (94 vs 134, p<0.0005) were detected for the Faroese men. Conclusions Semen quality among the Faroese men is at the same low level as reported for Danish men, and the reproductive hormone levels furthermore indicated a lower Leydig cell capacity for testosterone production. The influence of environmental exposure and genetic factors on semen quality has to be studied further.

Spermatogenic capacity in fertile men with elevated exposure to polychlorinated biphenyls

BACKGROUND Endocrine disrupting industrial chemicals, such as polychlorinated biphenyls (PCBs), are suspected to adversely affect male reproductive functions. OBJECTIVES The Faroe Islands community exhibits an unusually wide range of exposures to dietary contaminants, and in this setting we examined the possible association between PCB exposure and semen quality and reproductive hormones in fertile Faroese men. METHODS Participants in this cross-sectional study include 266 proven fertile men residing in the Faroe Islands. PCB levels and hormone profiles were measured in serum samples taken at the clinical examination that included semen quality parameters. RESULTS A significant positive association was seen between serum-PCB and the testosterone/estradiol ratio (p=0.04). In the unadjusted analyses, elevated PCB exposure was associated with increased serum concentrations of SHBG (p=0.01) and FSH (p=0.05). We found no association between the serum PCB concentration and the semen quality variables. CONCLUSION In this population of highly exposed fertile men, the current serum-PCB concentration was associated with higher androgen/estrogen ratio. Further studies are needed to establish the findings and further document PCB-associated hormonal effects, any time windows of increased susceptibility, and the role of PCB in sub-fecundity.

Sperm Aneuploidy in Faroese Men with Lifetime Exposure to Dichlorodiphenyldichloroethylene (p,p´-DDE) and Polychlorinated Biphenyl (PCB) Pollutants.

Background: Although it is known that sperm aneuploidy contributes to early pregnancy losses and congenital abnormalities, the causes are unknown and environmental contaminants are suspected. Objectives: Our goal was to evaluate associations between lifetime exposure to organochlorines, specifically dichlorodiphenyldicholorethylene (p,p´-DDE) and polychlorinated biphenyls (PCBs), and sperm aneuploidy in men from the general population of the Faroe Islands, a population with a known history of organochlorine exposures. Methods: Serum and semen samples from men (n = 90) 22–44 years old who participated in Faroe Islands health studies were analyzed for p,p´-DDE and PCBs 118, 138, 153, and 180 and adjusted for total lipids. Cord blood and age-14 serum were available for a subgroup (n = 40) and were also analyzed for p,p´-DDE and PCBs. Sperm fluorescence in situ hybridization (FISH) for chromosomes X, Y, and 18 was used to determine rates of XX18, XY18, YY18, and total disomy. Multivariable adjusted Poisson models were used to estimate the relationship between organochlorine exposure and sperm disomy outcomes. Results: Adult p,p´-DDE and total PCB serum concentrations were both associated with significantly increased rates of XX18, XY18, and total disomy. Age-14 p,p´-DDE and PCB concentrations were both associated with significantly increased rates of XX, XY, and total disomy in adulthood. Associations between cord blood concentrations of p,p´-DDE and PCBs and sperm disomy in adulthood were not consistently significant. Conclusions: Organochlorine exposures measured at age 14 and in adulthood were associated with sperm disomy in this sample of high-exposure men, suggesting that the impacts of persistent pollutants on testicular maturation and function require further investigation. Citation: Perry MJ, Young HA, Grandjean P, Halling J, Petersen MS, Martenies SE, Karimi P, Weihe P. 2016. Sperm aneuploidy in Faroese men with lifetime exposure to dichlorodiphenyldichloroethylene (p,p´-DDE) and polychlorinated biphenyl (PCB) pollutants. Environ Health Perspect 124:951–956; http://dx.doi.org/10.1289/ehp.1509779

Health effects associated with measured levels of contaminants in the Arctic

The Human Health Assessment Group has over the past decade recommended that effect studies be conducted in the circumpolar area. Such studies examine the association between contaminant exposure in the Arctic populations and health effects. Because foetuses and young children are the most vulnerable, effect studies are often prospective child cohort studies. The emphasis in this article is on a description of the effects associated with contaminant exposure in the Arctic. The main topics addressed are neurobehavioural, immunological, reproductive, cardiovascular, endocrine and carcinogenic effect. For each topic, the association between exposure and effects is described, and some results are reported for similar studies outside the Arctic.The Human Health Assessment Group has over the past decade recommended that effect studies be conducted in the circumpolar area. Such studies examine the association between contaminant exposure in the Arctic populations and health effects. Because foetuses and young children are the most vulnerable, effect studies are often prospective child cohort studies. The emphasis in this article is on a description of the effects associated with contaminant exposure in the Arctic. The main topics addressed are neurobehavioural, immunological, reproductive, cardiovascular, endocrine and carcinogenic effect. For each topic, the association between exposure and effects is described, and some results are reported for similar studies outside the Arctic.