Publications by authors named "Hannu Kiviranta"

103 Publications

Prenatal exposures to mixtures of endocrine disrupting chemicals and children's weight trajectory up to age 5.5 in the SELMA study.

Sci Rep 2021 May 26;11(1):11036. Epub 2021 May 26.

Department of Health Sciences, Karlstad University, Universitetsgatan 2, 651 88, Karlstad, Sweden.

Exposure to endocrine disrupting chemicals (EDCs) may impact early growth, although information is limited on exposure to combination of multiple EDCs. We aimed to evaluate the effect of prenatal exposure to EDC mixtures on birthweight z-scores and childhood weight trajectories. Twenty-six proven and suspected EDCs, were analyzed in prenatal urine and blood samples from 1118 mothers participating in the Swedish Environmental Longitudinal Mother and child Asthma and allergy (SELMA) study. Two growth parameters were estimated from each child's weight trajectory from birth to 5.5 years of age: infant growth spurt rate and age at infant peak growth velocity (PGV). Weighted quantile sum (WQS) regression was used to estimate the mixture effect and identify chemicals of concern. A one-unit increase in the EDC mixture WQS index, was associated with decreased birthweight z-scores of 0.11 (95% CI - 0.16, - 0.06), slower infant growth spurt rate of 0.01 (95% CI - 0.03, - 0.01, on the log scale), and delayed age at infant PGV of 0.15 months (95% CI 0.07, 0.24) after adjusting for potential confounders. Stratified analysis by sex, showed that delayed age at infant PGV was mostly observed in girls with 0.51 months (95% CI 0.26, 0.76). Identified chemicals of concern included perfluorinated alkyl substances (PFAS), Triclosan, phthalates, non-phthalate plasticizers, bisphenols, polycyclic aromatic hydrocarbons, pesticides and PCBs. Prenatal exposure to EDC mixtures was associated with lower birthweight and altered infant weight gain trajectories.
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http://dx.doi.org/10.1038/s41598-021-89846-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155069PMC
May 2021

Persistent organic pollutants and the size of ovarian reserve in reproductive-aged women.

Environ Int 2021 May 1;155:106589. Epub 2021 May 1.

Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet and Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden. Electronic address:

Industrial chemicals such as persistent organic pollutants (POPs) have been associated with reduced fertility in women, including longer time-to-pregnancy (TTP), higher odds for infertility, and earlier reproductive senescence. Fertility is highly dependent on the ovarian reserve, which is composed of a prenatally determined stock of non-growing follicles. The quantity and quality of the follicles decline with age, thereby eventually leading to menopause. In the clinical setting, assessing ovarian reserve directly through the histological analysis of follicular density in ovaries is not practical. Therefore, surrogate markers of ovarian reserve, such as serum anti-Müllerian hormone (AMH) are typically used. Here, we studied associations between chemical exposure and ovarian reserve in a cohort of pregnant women undergoing elective caesarean section (n = 145) in Stockholm, Sweden. Full data (histological, clinical, serum) were available for 50 women. We estimated the size of the reserve both directly by determining the density of follicles in ovarian cortical tissue samples, and indirectly by measuring AMH in associated serum samples. Concentrations of 9 organochlorine pesticides (OCPs), 10 polychlorinated biphenyls (PCBs), 3 polybrominated diphenylethers (PBDEs) and 9 perfluoroalkyl substances (PFAS) were determined in serum, and clinical data were retrieved from electronic medical records. Healthy follicle densities (median 0, range 0-193 follicles/mm) and AMH levels (median 2.33 ng/mL, range 0.1-14.8 ng/mL) varied substantially. AMH correlated with the density of growing follicles. Twenty-three chemicals detected in more than half of the samples were included in the analyses. None of the chemicals, alone or as a mixture, correlated with AMH, growing or atretic follicles. However, HCB, transnonachlor, PCBs 74 and 99 were associated with decreased non-growing follicle densities. HCB and transnonachlor were also negatively associated with healthy follicle density. Further, mixture of lipophilic POPs (PBDE 99, p,p'-DDE, and PCB 187) was associated with lower non-growing follicle densities. In addition, exposure to HCB, p,p'-DDE, and mixture of OCPs were significantly associated with higher odds of infertility. The results suggest that exposure to chemicals may reduce the size of ovarian reserve in humans, and strongly encourage to study mechanisms behind POP-associated infertility in women in more detail.
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http://dx.doi.org/10.1016/j.envint.2021.106589DOI Listing
May 2021

Persistent organic pollutants in pregnant women potentially affect child development and thyroid hormone status.

Pediatr Res 2021 Apr 6. Epub 2021 Apr 6.

Department of Women and Child Health, Hospital for Children and Adolescents and Center for Pediatric Research (CPL), Leipzig University, Leipzig, Germany.

Background: Potentially harmful effects of persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane (DDT) on prenatal development and the endocrine system have been controversially discussed.

Methods: Working with a German cohort of 324 pregnant women, we assessed POP levels and used robust linear regression models to determine potential associations between maternal POP concentrations and pre- and postnatal development in the children, as well as the thyroid hormone status of the mother and child.

Results: Maternal p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) and most measured PCBs positively correlated with postnatal weight gain. We detected no correlation between newborn birth weight and head circumference, respectively, and maternal PCB and p,p'-DDE serum levels, while body length at birth was negatively associated with the maternal serum concentration of PCB 183. Maternal p,p'-DDE and nearly all PCB serum levels showed a negative correlation with maternal free triiodothyronine (FT3). p,p'-DDE and PCB 74 and 118 were negatively associated with maternal thyroid-stimulating hormone levels. In addition, we identified significant associations between maternal POP levels and thyroid hormone parameters of the child.

Conclusions: These results indicate that POP exposure likely affects different aspects of pre- and postnatal development and impacts the thyroid hormone status of both mother and child.

Impact: Pregnant women in a German cohort display a substantial accumulation of POPs. Body mass index and age influence maternal serum POP levels. Maternal POP levels show correlations with the child's length at birth and weight gain, and FT3 levels in the mother and child. Our data provide additional evidence for the potentially harmful influence of POPs. Our data indicate that POPs influence pre- and postnatal development.
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http://dx.doi.org/10.1038/s41390-021-01488-5DOI Listing
April 2021

Exposure to persistent organic pollutants and the risk of type 2 diabetes: a case-cohort study.

Diabetes Metab 2021 Jan 27;47(5):101234. Epub 2021 Jan 27.

EPI-PHARE Scientific Interest Group in Epidemiology of Health Products, French National Agency for the Safety of Medicines and Health Products and the French National Health Insurance, Saint-Denis, Ile-de-France, France; IRSA, La Riche, France.

Aims: To explore exposure to 22 persistent organic pollutants (POPs) and incident type 2 diabetes in a population-based, prospective cohort.

Methods: This case-cohort study on 753 participants without type 2 diabetes at baseline, was followed-up over nine years, as part of the French D.E.S.I.R. cohort. We measured 22 POPs in fasting serum at baseline. The associations between baseline POP concentrations, pre-adjusted for lipids, BMI, age and sex, with incident type 2 diabetes, were assessed using Prentice-weighted Cox regression models (time scale: age), adjusted for traditional confounding factors. POPs were also modelled summed in functional groups: polychlorinated biphenyls (∑PCB) and organochlorines (∑OC) and also individually, after log-transformation, in adjusted Cox models.

Results: There were 200 incident diabetes cases over nine years. Pre-adjusted POP concentrations were not related to diabetes risk for any of the 22 POPs examined. The fully-adjusted hazard ratios (HRs) per interquartile range of the pre-adjusted POPs, ranged from 0.87 (95% CI: 0.64,1.19) to 1.22 (0.93,1.59,). For dichlorodiphenyldichloroethylene (p, p'-DDE) and dichlorodiphenyltrichloroethane (p, p'-DDT), the HRs were 1.09 (0.83,1.43) and 0.89 (0.70,1.13), respectively. The HRs for PeCB, HCB, β-HCH, γ-HCH, oxychlordane, trans-nonachlor were 0.98 (0.85,1.13), 1.06 (0.84,1.33), 1.22 (0.93,1.59), 1.13 (0.89,1.42), 1.00 (0.76,1.31), 0.86 (0.66,1.13), respectively. HRs for ∑PCB, ∑OC and for individual log-transformed POPs did not differ significantly from one.

Conclusion: We did not observe any relations between exposure to POPs and diabetes in this population-based cohort. These results do not support causal inferences reported in previous studies linking serum POP concentrations and diabetes risk.
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http://dx.doi.org/10.1016/j.diabet.2021.101234DOI Listing
January 2021

Plasma metabolites associated with exposure to perfluoroalkyl substances and risk of type 2 diabetes - A nested case-control study.

Environ Int 2021 01 25;146:106180. Epub 2020 Oct 25.

Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.

Perfluoroalkyl substances (PFAS) are widespread persistent environmental pollutants. There is evidence that PFAS induce metabolic perturbations in humans, but underlying mechanisms are still unknown. In this exploratory study, we investigated PFAS-related plasma metabolites for their associations with type 2 diabetes (T2D) to gain potential mechanistic insight in these perturbations. We used untargeted LC-MS metabolomics to find metabolites related to PFAS exposures in a case-control study on T2D (n = 187 matched pairs) nested within the Västerbotten Intervention Programme cohort. Following principal component analysis (PCA), six PFAS measured in plasma appeared in two groups: 1) perfluorononanoic acid, perfluorodecanoic acid and perfluoroundecanoic acid and 2) perfluorohexane sulfonic acid, perfluorooctane sulfonic acid and perfluorooctanoic acid. Using a random forest algorithm, we discovered metabolite features associated with individual PFAS and PFAS exposure groups which were subsequently investigated for associations with risk of T2D. PFAS levels correlated with 171 metabolite features (0.16 ≤ |r| ≤ 0.37, false discovery rate (FDR) adjusted p < 0.05). Out of these, 35 associated with T2D (p < 0.05), with 7 remaining after multiple testing adjustment (FDR < 0.05). PCA of the 35 PFAS- and T2D-related metabolite features revealed two patterns, dominated by glycerophospholipids and diacylglycerols, with opposite T2D associations. The glycerophospholipids correlated positively with PFAS and associated inversely with risk for T2D (Odds Ratio (OR) per 1 standard deviation (1-SD) increase in metabolite PCA pattern score = 0.2; 95% Confidence Interval (CI) = 0.1-0.4). The diacylglycerols also correlated positively with PFAS, but they associated with increased risk for T2D (OR per 1-SD = 1.9; 95% CI = 1.3-2.7). These results suggest that PFAS associate with two groups of lipid species with opposite relations to T2D risk.
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http://dx.doi.org/10.1016/j.envint.2020.106180DOI Listing
January 2021

Non-occupational exposure to phthalates in Finland.

Toxicol Lett 2020 Oct 29;332:107-117. Epub 2020 Jun 29.

Finnish Institute of Occupational Health, PO Box 40, FI-00032 Työterveyslaitos, Finland.

The aim of this study was to assess phthalate exposure of non-occupationally exposed working aged population in Finland. Studied phthalates included diethyl phthalate (DEP), di-n-butyl phthalate (DnBP), diisobutyl phthalate (DiBP), benzyl butyl phthalate (BzBP), dicyclohexyl phthalate (DCHP), di(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DiNP), diisodecyl phthalate (DiDP), di(2-propylheptyl) phthalate (DPHP), and di-n-octyl phthalate (DnOP). Sample collection campaign took place in 2015. Metabolites of DEP, DnBP and DiBP were detected in all the first morning void urine samples of the non-occupationally exposed volunteers (n = 60; 42 women and 18 men; aged 25-63). Metabolite of BBP and secondary metabolites of DEHP and DiNP were detected in >90% of the samples. MCHP (1.7%), MEHP (18.3%), cx-MiNP (8.3%) and MnOP (1.7%) were less frequently detected. MiNP and OH-MPHP were not detected in any of the urine samples. The observed levels were mostly comparable to the levels published in the adult population in Europe and the US. One notable difference was the observed higher exposure of the Finnish study population to DnBP in comparison to the German, Austrian, Norwegian and US populations. The levels of individual phthalates did not often correlate very well with each other. In most cases, higher exposure to phthalates was seen in females in comparison to males, which is in accordance with other studies. The urinary levels were compared to the biomonitoring equivalents (BEs), which were calculated on the basis of published DNELs (derived no-effect levels). The P95 levels of individual phthalates remained below the respective BEs, the highest risk characterization ratio (RCR) being 0.88 for DnBP and the second highest 0.34 for DiBP. For other phthalates, the RCRs were below 0.2. Using the P95 levels, combined exposure to DnBP, DiBP, DEHP and BBP resulted in risk characterization ratio exceeding 1. This suggests a need to limit the exposure to these phthalates.
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http://dx.doi.org/10.1016/j.toxlet.2020.06.021DOI Listing
October 2020

Persistent organic pollutants, pre-pregnancy use of combined oral contraceptives, age, and time-to-pregnancy in the SELMA cohort.

Environ Health 2020 06 15;19(1):67. Epub 2020 Jun 15.

Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, USA.

Background: We are exposed to several chemicals such as persistent organic pollutants (POPs) in our everyday lives. Prior evidence has suggested that POPs may have adverse effects on reproductive function by disrupting hormone synthesis and metabolism. While there is age-related decline of fertility, the use of hormonal combined oral contraceptives (COCs) and its association to return of fertility remains controversial. The goal of this study is to investigate the association between exposure to POPs, both individually and as a mixture, and fecundability measured as time-to-pregnancy (TTP) according to pre-pregnancy use of COCs and age.

Methods: Using the SELMA (Swedish Environmental Longitudinal Mother and Child, Allergy and Asthma) study, we have identified 818 pregnant women aged 18-43 years (mean 29 years) with data on how long they tried to get pregnant and what was their most recently used contraceptive method. These data were collected at enrollment to the study (median week 10 of pregnancy). Concentrations of 22 POPs and cotinine were analyzed in the blood samples collected at the same time as the questions on TTP and pre-pregnancy use of contraceptive. Analyses were done on the association between POPs exposure and TTP measured as continuous (months) and binary (infertile for those with TTP > 12 months). To study the chemicals individually, Cox regression and logistic regression were used to estimate fecundability ratios (FRs) and odds ratios (ORs), respectively. Weighted quantile sum (WQS) regression was used to investigate the chemicals as a mixture where chemicals of concern were identified above the 7.6% threshold of equal weights. To perform the subgroup analysis, we stratified the sample according to use of COCs as the most recent pre-pregnancy contraception method and age (< 29 years, and ≥ 29 years). The models were adjusted for parity, regularity of menses, maternal body mass index (BMI) and smoking status, and stratified as described above.

Results: Prior to stratification, none of the POPs were associated with fecundability while increased exposure to HCB, PCB 74 and 118 had higher odds of infertility. Upon stratification, POP exposure was significantly associated with longer TTP in women aged ≥29 years who did not use COC. Specifically, PCBs 156, 180, 183, and 187 were associated with reduced fecundability while PCBs 99, 153, 156, 180, 183, and 187 had higher odds of infertility. As a mixture, we identified the chemicals of concern for a longer TTP include PCBs 118, 156, 183, and 187. Moreover, chemicals of concern identified with increased odds of infertility were PCB 74, 156, 183, 187, and transnonachlor.

Conclusion: Serum concentrations of selected POPs, both as individual chemicals and as a mixture, were significantly associated with lower fecundability and increased odds of infertility in women aged 29 years and above not using COC as their most recent pre-pregnancy contraceptive. Our findings suggest that pre-pregnancy use of oral contraceptive and age may modify the link between POPs and fecundability. The differences of specific chemicals in the individual analysis and as a mixture support the need to study combination effects of chemicals when evaluating reproductive outcomes.
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http://dx.doi.org/10.1186/s12940-020-00608-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294652PMC
June 2020

Estimated PCDD/F TEQ and total TEQ concentrations in the serum of 7-10 year old Finnish children.

Chemosphere 2020 Oct 22;257:127137. Epub 2020 May 22.

Finnish Institute for Health and Welfare, Environmental Health Unit, P.O. Box 95, FI-70701, Kuopio, Finland.

Polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) and polychlorinated biphenyls (PCBs) are persistent organic pollutants that have detrimental health effects. As people are exposed to them mainly through the diet, EU has set maximum food dioxin and PCBs levels. EFSA CONTAM Panel made new risk assessment in 2018 that lowered the tolerable weekly intake (TWI) from 14 pg-TEQ/kg bw/week to 2 pg-TEQ/kg bw/week. Critical effect was decreased semen count at the age of 18-19 years if serum total TEQ at the age of 9 years exceeded the No Observed Adverse Effect Level (NOAEL) of 7 pg/g lipid. However, it is largely unknown to what extent NOAEL is exceed in European boys currently. We thus measured PCBs from small volume of serum in 184 Finnish children 7-10 years of age. To estimate the TEQ levels of children from measured PCB levels, we used our existing human milk PCDD/F and PCB concentrations to create a hierarchical Bayesian regression model that was used to estimate TEQs from measured PCBs. For quality control (QC), three pooled blood samples from 18 to 20 year old males were measured for PCDD/Fs and PCBs, and estimated for TEQs. In QC samples measured and estimated TEQs agreed within 84%-106%. In our estimate for 7-10 year old children, PCDD/F TEQ exceeded NOAEL only in 0.5% and total TEQ in 2.7% of subjects. Risk management following the decreased TWI proposed by the CONTAM Panel should be carefully considered if total TEQ in children is already largely below the NOAEL.
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http://dx.doi.org/10.1016/j.chemosphere.2020.127137DOI Listing
October 2020

Occupational Exposure of Plastics Workers to Diisononyl Phthalate (DiNP) and Di(2-propylheptyl) Phthalate (DPHP) in Finland.

Int J Environ Res Public Health 2020 03 19;17(6). Epub 2020 Mar 19.

Finnish Institute of Occupational Health, PO Box 40, FI-00032 Työterveyslaitos, Finland.

The aim of this study was to assess occupational exposure to diisononyl phthalate (DiNP) and di(2-propylheptyl) phthalate (DPHP] in Finland. Four companies took part in the research project: A cable factory, a plastic producing company, a producer of coated textiles, and a tarpaulin producer. The cable factory used DPHP (and occasionally also diisodecyl phthalate, DiDP), the plastic producing company used both DPHP and DiNP, and the latter two companies used DiNP in their production. Exposure was assessed by measuring phthalate metabolites in urine samples (biomonitoring) and by performing air measurements. Low-level occupational exposure to DiNP was observed in the company that produced coated textiles-out of eight workers, one extruder operator was exposed to DiNP at levels exceeding the non-occupationally exposed population background levels. Some workers in the cable factory and the plastics producing company were occupationally exposed to DPHP. Air levels of phthalates were generally low, mostly below the limit of quantification. All phthalate metabolite concentrations were, however, well below the calculated biomonitoring equivalents, which suggests that the health risks related to the exposure are low.
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http://dx.doi.org/10.3390/ijerph17062035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7143504PMC
March 2020

Effect of fatty fish or nut consumption on concentrations of persistent organic pollutants in overweight or obese men and women: A randomized controlled clinical trial.

Nutr Metab Cardiovasc Dis 2020 03 21;30(3):448-458. Epub 2019 Nov 21.

Section for Preventive Cardiology, Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway.

Background And Aims: While excess energy intake and physical inactivity constitute the obvious causes of body fat accumulation, persistent organic pollutants (POPs) are novel factors that have been linked to cardiometabolic disorders. Major sources of POPs are animal fats including fatty fish. Given the putative protective effects of fish on cardiovascular disease, we explored whether high consumption of fatty fish increased serum concentrations of POPs.

Methods And Results: Men and women aged 35-70 years with body mass index between 25 and 38 kg/m and at least 1 cardiometabolic component were randomized to high intakes of fatty fish (mostly farmed salmon, ∼630 g/week; n = 45), high intakes of nuts (∼200 g/week; n = 42) or a control group following their usual diet but restricting fatty fish and nuts for 6 months (n = 44). Concentrations of 15 POPs (5 organochlorinated compounds, 2 dioxin-like polychlorinated biphenyls and 8 non-dioxin-like polychlorinated biphenyls) and cardiometabolic risk factors were measured at baseline and end of the study. Results showed that changes in concentrations of individual and classes of POPs did not differ between the dietary groups and controls (p > 0.05). Among cardiometabolic risk factors HDL-cholesterol increased in the fatty fish group compared to controls (+0.10 mmol/L, CI (0.05-0.20); p = 0.005) while no changes were observed in the group consuming nuts.

Conclusion: Fatty fish consumption for 6 months did not increase the serum concentrations of POPs in individuals with overweight or obesity and metabolic risk. While this finding appears reassuring regarding short-term intakes of farmed salmon, long term variations in POPs in adipose stores require further study.
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http://dx.doi.org/10.1016/j.numecd.2019.11.006DOI Listing
March 2020

Early prenatal exposure to suspected endocrine disruptor mixtures is associated with lower IQ at age seven.

Environ Int 2020 01 24;134:105185. Epub 2019 Oct 24.

Icahn School of Medicine at Mount Sinai, New York, NY, United States; Karlstad University, Karlstad, Sweden. Electronic address:

Background: Endocrine disrupting chemicals (EDCs) are xenobiotics with the ability to interfere with hormone action, even at low levels. Prior environmental epidemiology studies link numerous suspected EDCs, including phthalates and bisphenol A (BPA), to adverse neurodevelopmental outcomes. However, results for some chemicals were inconsistent and most assessed one chemical at a time.

Objectives: To evaluate the overall impact of prenatal exposure to an EDC mixture on neurodevelopment in school-aged children, and identify chemicals of concern while accounting for co-exposures.

Methods: Among 718 mother-child pairs from the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy study (SELMA) study, we used Weighted Quantile Sum (WQS) regression to assess the association between 26 EDCs measured in 1st trimester urine or blood, with Wechsler Intelligence Scale for Children (IV) Intelligence Quotient (IQ) scores at age 7 years. Models were adjusted for child sex, gestational age, mother's education, mother's IQ (RAVEN), weight, and smoking status. To evaluate generalizability, we conducted repeated holdout validation, a machine learning technique.

Results: Using repeated holdout validation, IQ scores were 1.9-points (CI = -3.6, -0.2) lower among boys for an inter-quartile-range (IQR) change in the WQS index. BPF made the largest contribution to the index with a weight of 14%. Other chemicals of concern and their weights included PBA (9%), TCP (9%), MEP (6%), MBzP (4%), PFOA (6%), PFOS (5%), PFHxS (4%), Triclosan (5%), and BPA (4%). While we did observe an inverse association between EDCs and IQ among all children when training and testing the WQS index estimate on the full dataset, these results were not robust to repeated holdout validation.

Conclusion: Among boys, early prenatal exposure to EDCs was associated with lower intellectual functioning at age 7. We identified bisphenol F as the primary chemical of concern, suggesting that the BPA replacement compound may not be any safer for children. Future studies are needed to confirm the potential neurotoxicity of replacement analogues.
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http://dx.doi.org/10.1016/j.envint.2019.105185DOI Listing
January 2020

Joint Analysis of Metabolite Markers of Fish Intake and Persistent Organic Pollutants in Relation to Type 2 Diabetes Risk in Swedish Adults.

J Nutr 2019 08;149(8):1413-1423

Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.

Background: There is conflicting evidence regarding the association between fish intake and type 2 diabetes (T2D) incidence, possibly owing to measurement errors in self-reported intake and coexposure to persistent organic pollutants (POPs) present in fish.

Objective: The aim of this study was to identify plasma metabolites associated with fish intake and to assess their association with T2D risk, independently of POPs, in Swedish adults.

Methods: In a case-control study nested in the Swedish Västerbotten Intervention Programme, fasting plasma samples from 421 matched T2D case-control pairs of men and women aged 30-60 y at baseline and 10-y follow-up samples from a subset of 149 pairs were analyzed using untargeted metabolomics. Moreover, 16 plasma POPs were analyzed for the 149 pairs who had repeated samples available. Fish-related plasma metabolites were identified using multivariate modelling and partial correlation analysis. Reproducibility of metabolites and metabolite patterns, derived via principal component analysis (PCA), was assessed by intraclass correlation. A unique component of metabolites unrelated to POPs was dissected by integrating metabolites and POPs using 2-way orthogonal partial least squares regression. ORs of T2D were estimated using conditional logistic regression.

Results: We identified 31 metabolites associated with fish intake that had poor to good reproducibility. A PCA-derived metabolite pattern strongly correlated with fish intake (ρ = 0.37, P < 0.001) but showed no association with T2D risk. Integrating fish-related metabolites and POPs led to a unique metabolite component independent of POPs, which tended to be inversely associated with T2D risk (OR: 0.75; 95% CI: 0.54, 1.02, P = 0.07). This component mainly consisted of metabolites reflecting fatty fish intake.

Conclusions: Our results suggest that fatty fish intake may be beneficial for T2D prevention, after removing the counteractive effects of coexposure to POPs in Swedish adults. Integrating metabolite markers and POP exposures appears a promising approach to advance the understanding of associations between fish intake and T2D incidence.
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http://dx.doi.org/10.1093/jn/nxz068DOI Listing
August 2019

Chlorinated persistent organic pollutants and type 2 diabetes - A population-based study with pre- and post- diagnostic plasma samples.

Environ Res 2019 07 19;174:35-45. Epub 2019 Apr 19.

Department of Public Health and Clinical Medicine, Section of Sustainable Health, Umeå University, Umeå, Sweden.

Background: Persistent organic pollutants (POPs) have been associated with type 2 diabetes (T2D), but causality is uncertain.

Objective: Within longitudinal population-based data from northern Sweden, we assessed how POPs associated with T2D prospectively and cross-sectionally, and further investigated factors related to individual changes in POP concentrations.

Methods: For 129 case-controls pairs matched by age, sex and date of sampling, plasma concentrations of hexachlorobenzene (HCB), dichlorodiphenyl-dichloroethylene (p,p'-DDE), dioxin-like (DL) polychlorinated biphenyl congeners (PCB-118 and PCB-156), and non-dioxin like (NDL-PCB: PCB-74, -99, -138 -153, -170, -180, -183 and PCB-187) were analyzed twice (baseline and follow-up, 9-20 years apart). The cases received their T2D diagnose between baseline and follow-up. Prospective (using baseline data) and cross-sectional (using follow-up data) odds ratios (ORs) for T2D on lipid standardized POPs (HCB, p,p'-DDE, ∑DL-PCBs, ∑NDL-PCBs) were estimated using conditional logistic regression, adjusting for body mass index (BMI) and plasma lipids. The influence of BMI, weight-change, and plasma lipids on longitudinal changes in POP concentrations were evaluated among non-diabetic individuals (n = 306).

Results: POPs were associated with T2D in both the prospective and cross-sectional assessments. Of a standard deviation increase in POPs, prospective ORs ranged 1.42 (95% CI: 0.99, 2.06) for ∑NDL-PCBs to 1.55 (95% CI: 1.01, 2.38) for HCB (p < 0.05 only for HCB), and cross-sectional ORs ranged 1.62 (95% CI: 1.13; 2.32) for p,p'-DDE to 2.06 (95% CI: 1.29, 3.28) for ∑DL-PCBs (p < 0.05 for all POPs). In analyses of non-diabetic individuals, higher baseline BMI, decreased weight and decreased plasma lipid concentrations were associated with a slower decrease of POPs. Cases had, besides a higher BMI, reduced cholesterol and weight gain at follow-up compared to controls, which can explain the higher ORs in the cross-sectional assessments.

Discussion: The association between POPs and T2D was confirmed, but an indication that individuals body fat history might influence POP-T2D associations weakens the epidemiological support for a causal association. It also warrants studies based on other exposure metrics than biomonitoring. In addition, we note that a cross-sectional design overestimates the ORs if T2D cases have successfully intervened on weight and/or blood lipids, as changes in these factors cause changes in POPs.
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http://dx.doi.org/10.1016/j.envres.2019.04.017DOI Listing
July 2019

Genes associated with Parkinson's disease respond to increasing polychlorinated biphenyl levels in the blood of healthy females.

Environ Pollut 2019 Jul 8;250:107-117. Epub 2019 Apr 8.

Department of Toxicogenomics, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands, 6229, ER Maastricht, the Netherlands.

Polychlorinated biphenyls (PCBs) are a class of widespread environmental pollutants, commonly found in human blood, that have been suggested to be linked to the occurrence of sporadic Parkinson's disease (PD). It has been reported that some non-coplanar PCBs accumulate in the brains of female PD patients. To improve our understanding of the association between PCB exposure and PD risk we have applied whole transcriptome gene expression analysis in blood cells from 594 PCB-exposed subjects (369 female, 225 male). Interestingly, we observe that in females, blood levels of non-coplanar PCBs appear to be associated with expression levels of PD-specific genes. However, no such association was detected in males. Among the 131 PD-specific genes affected, 39 have been shown to display similar changes in expression levels in the substantia nigra of deceased PD patients. Especially among the down-regulated genes, transcripts of genes involved in neurotransmitter vesicle-related functions were predominant.
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http://dx.doi.org/10.1016/j.envpol.2019.04.005DOI Listing
July 2019

DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia.

Environ Int 2019 05 15;126:24-36. Epub 2019 Feb 15.

National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, 48 Vas. Constantinou Ave., Athens 11635, Greece. Electronic address:

Objectives: To characterize the impact of PCB exposure on DNA methylation in peripheral blood leucocytes and to evaluate the corresponding changes in relation to possible health effects, with a focus on B-cell lymphoma.

Methods: We conducted an epigenome-wide association study on 611 adults free of diagnosed disease, living in Italy and Sweden, in whom we also measured plasma concentrations of 6 PCB congeners, DDE and hexachlorobenzene.

Results: We identified 650 CpG sites whose methylation correlates strongly (FDR < 0.01) with plasma concentrations of at least one PCB congener. Stronger effects were observed in males and in Sweden. This epigenetic exposure profile shows extensive and highly statistically significant overlaps with published profiles associated with the risk of future B-cell chronic lymphocytic leukemia (CLL) as well as with clinical CLL (38 and 28 CpG sites, respectively). For all these sites, the methylation changes were in the same direction for increasing exposure and for higher disease risk or clinical disease status, suggesting an etiological link between exposure and CLL. Mediation analysis reinforced the suggestion of a causal link between exposure, changes in DNA methylation and disease. Disease connectivity analysis identified multiple additional diseases associated with differentially methylated genes, including melanoma for which an etiological link with PCB exposure is established, as well as developmental and neurological diseases for which there is corresponding epidemiological evidence. Differentially methylated genes include many homeobox genes, suggesting that PCBs target stem cells. Furthermore, numerous polycomb protein target genes were hypermethylated with increasing exposure, an effect known to constitute an early marker of carcinogenesis.

Conclusions: This study provides mechanistic evidence in support of a link between exposure to PCBs and the etiology of CLL and underlines the utility of omic profiling in the evaluation of the potential toxicity of environmental chemicals.
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http://dx.doi.org/10.1016/j.envint.2019.01.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063446PMC
May 2019

Concentrations of brominated and phosphorous flame retardants in Finnish house dust and insights into children's exposure.

Chemosphere 2019 May 8;223:99-107. Epub 2019 Feb 8.

Norwegian Institute of Public Health, Department of Environmental Exposure and Epidemiology, P.O. Box 4404, Nydalen, 0403, Oslo, Norway.

Brominated and phosphorous flame retardants (BFRs, PFRs) are added to household and consumer products to reduce their flammability. Some FRs are persistent in the environment and may have adverse health effects. As exposure indoors contributes significantly to total exposure, we wanted to estimate the exposure of children (3 years of age) through dust ingestion, inhalation, and dermal absorption. We measured 17 BFRs and 10 PFRs in indoor dust, predicted their respective concentrations in the indoor air and assessed children's exposure. Among the BFRs, decabromodiphenyl ether (BDE-209) had highest median level in the dust (411 ng/g) followed by decabromodiphenyl ethane (DBDPE, 119 ng/g) and bis-ethylhexyl tetrabromophthalate (BEH-TEBP, 106 ng/g). Among the PFRs, trisbutoxyethyl phosphate (TBOEP) had the highest concentration (11100 ng/g) followed by tris(2-chloroisopropyl) phosphate (TCIPP, 1870 ng/g) and triphenyl phosphate (TPHP, 773 ng/g). FR concentration in air predicted from dust concentrations were within the interquartile range of experimental data for 10/13 of BFRs and 4/8 of PFRs compared. Dust ingestion was the major route of exposure (75-99%) for higher molecular weight BFRs, TBOEP and phenyl based PFRs (73-77%). Inhalation was important for volatile BFRs like pentabromobenzene (PBB 71%) and pentabromotoluene (PBT 52%) and dermal exposure for volatile chlorinated PFRs (TCEP 84%, TCIPP 77%). Margins of Exposure (MoE) were calculated as the ratio of total exposure to oral Reference Dose (RfD). MoEs were lowest for TCEP (220), TBOEP (240) and TCIPP (830), and > 1000 for all other FRs. These MoEs imply no risk for Finnish children by the studied FRs.
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http://dx.doi.org/10.1016/j.chemosphere.2019.02.027DOI Listing
May 2019

Identification of Sex-Specific Transcriptome Responses to Polychlorinated Biphenyls (PCBs).

Sci Rep 2019 01 24;9(1):746. Epub 2019 Jan 24.

Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands.

PCBs are classified as xenoestrogens and carcinogens and their health risks may be sex-specific. To identify potential sex-specific responses to PCB-exposure we established gene expression profiles in a population study subdivided into females and males. Gene expression profiles were determined in a study population consisting of 512 subjects from the EnviroGenomarkers project, 217 subjects who developed lymphoma and 295 controls were selected in later life. We ran linear mixed models in order to find associations between gene expression and exposure to PCBs, while correcting for confounders, in particular distribution of white blood cells (WBC), as well as random effects. The analysis was subdivided according to sex and development of lymphoma in later life. The changes in gene expression as a result of exposure to the six studied PCB congeners were sex- and WBC type specific. The relatively large number of genes that are significantly associated with PCB-exposure in the female subpopulation already indicates different biological response mechanisms to PCBs between the two sexes. The interaction analysis between different PCBs and WBCs provides only a small overlap between sexes. In males, cancer-related pathways and in females immune system-related pathways are identified in association with PCBs and WBCs. Future lymphoma cases and controls for both sexes show different responses to the interaction of PCBs with WBCs, suggesting a role of the immune system in PCB-related cancer development.
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http://dx.doi.org/10.1038/s41598-018-37449-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346099PMC
January 2019

Associations between repeated measure of plasma perfluoroalkyl substances and cardiometabolic risk factors.

Environ Int 2019 03 10;124:58-65. Epub 2019 Jan 10.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Background: Perfluoroalkyl substances (PFAS) are persistent synthetic chemicals that may affect components of metabolic risk through the peroxisome proliferator-activated receptor but epidemiological data remain scarce and inconsistent.

Objective: To estimate associations between repeated measurements of the main PFAS in plasma and total cholesterol, triglycerides and hypertension among the control subjects from a population-based nested case-control study on diabetes type 2 in middle-aged women and men.

Methods: Participants (n = 187) were free of diabetes at both baseline and follow-up visits to the Västerbotten Intervention Programme, 10 years apart: during 1990 to 2003 (baseline) and 2001 to 2013 (follow-up). Participants left blood samples, completed questionnaires on diet and lifestyle factors, and underwent medical examinations, including measurement of blood pressure. PFAS and lipids were later determined in stored plasma samples. Associations for the repeated measurements were assessed using generalized estimating equations.

Results: Six PFAS exceeded the limit of quantitation. Repeated measures of PFAS in plasma, cardiometabolic risk factors and confounders, showed an average decrease of triglycerides from -0.16 mmol/l (95% confidence interval [CI]: -0.33, 0.02 for PFOA) to -0.26 mmol/l (95% CI: -0.50, -0.08 for PFOS), when comparing the highest tertile of PFAS plasma levels with the lowest. Associations based on average PFAS measurements and follow-up triglycerides revealed similar inverse associations, although attenuated. The estimates for cholesterol and hypertension were inconsistent and with few exception non-significant.

Conclusions: This study found inverse associations between PFAS and triglycerides, but did not support any clear link with either cholesterol or hypertension.
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http://dx.doi.org/10.1016/j.envint.2019.01.007DOI Listing
March 2019

Perfluoroalkyl substances and risk of type II diabetes: A prospective nested case-control study.

Environ Int 2019 02 19;123:390-398. Epub 2018 Dec 19.

Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Background: Perfluoroalkyl substances (PFAS) have drawn much attention due to bioaccumulation potential and their current omnipresence in human blood. We assessed whether plasma PFAS, suspected to induce endocrine-disrupting effects, were prospectively associated with clinical type 2 diabetes (T2D) risk.

Methods: We established a nested case-control study within the Swedish prospective population-based Västerbotten Intervention Programme cohort. Several PFAS were measured in plasma from a subset of 124 case-control pairs at baseline (during 1990-2003) and at 10-year follow-up. T2D cases were matched (1:1) according to gender, age and sample date with participants without T2D (controls). Conditional logistic regressions were used to prospectively assess risk of T2D by baseline PFAS plasma concentrations. Associations between long-term PFAS plasma levels (mean of baseline and follow-up) and insulin resistance (HOMA2-IR) and beta-cell function (HOMA2-B%) at follow-up were prospectively explored among 178 and 181 controls, respectively, by multivariable linear regressions.

Results: After adjusting for gender, age, sample year, diet and body mass index, the odds ratio of T2D for the sum of PFAS (Σ z-score PFAS) was 0.52 (95% confidence interval, CI: 0.20, 1.36), comparing third with first tertile; and 0.92 (95% CI: 0.84, 1.00) per one standard deviation increment of sum of log-transformed PFAS. Among the controls, the adjusted β of HOMA2-IR and HOMA-B% for the sum of PFAS were -0.26 (95% CI: -0.52, -0.01) and -9.61 (95% CI: -22.60, 3.39) respectively comparing third with first tertile.

Conclusions: This prospective nested case-control study yielded overall inverse associations between individual PFAS and risk of T2D, although mostly non-significant. Among participants without T2D, long-term PFAS exposure was prospectively associated with lower insulin resistance.
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http://dx.doi.org/10.1016/j.envint.2018.12.026DOI Listing
February 2019

Methodological issues in a prospective study on plasma concentrations of persistent organic pollutants and pancreatic cancer risk within the EPIC cohort.

Environ Res 2019 02 23;169:417-433. Epub 2018 Nov 23.

Department of Community Medicine, UiT-The Arctic University of Norway, Tromsø, Norway.

Background: The use of biomarkers of environmental exposure to explore new risk factors for pancreatic cancer presents clinical, logistic, and methodological challenges that are also relevant in research on other complex diseases.

Objectives: First, to summarize the main design features of a prospective case-control study -nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort- on plasma concentrations of persistent organic pollutants (POPs) and pancreatic cancer risk. And second, to assess the main methodological challenges posed by associations among characteristics and habits of study participants, fasting status, time from blood draw to cancer diagnosis, disease progression bias, basis of cancer diagnosis, and plasma concentrations of lipids and POPs. Results from etiologic analyses on POPs and pancreatic cancer risk, and other analyses, will be reported in future articles.

Methods: Study subjects were 1533 participants (513 cases and 1020 controls matched by study centre, sex, age at blood collection, date and time of blood collection, and fasting status) enrolled between 1992 and 2000. Plasma concentrations of 22 POPs were measured by gas chromatography - triple quadrupole mass spectrometry (GC-MS/MS). To estimate the magnitude of the associations we calculated multivariate-adjusted odds ratios by unconditional logistic regression, and adjusted geometric means by General Linear Regression Models.

Results: There were differences among countries in subjects' characteristics (as age, gender, smoking, lipid and POP concentrations), and in study characteristics (as time from blood collection to index date, year of last follow-up, length of follow-up, basis of cancer diagnosis, and fasting status). Adjusting for centre and time of blood collection, no factors were significantly associated with fasting status. Plasma concentrations of lipids were related to age, body mass index, fasting, country, and smoking. We detected and quantified 16 of the 22 POPs in more than 90% of individuals. All 22 POPs were detected in some participants, and the smallest number of POPs detected in one person was 15 (median, 19) with few differences by country. The highest concentrations were found for p,p'-DDE, PCBs 153 and 180 (median concentration: 3371, 1023, and 810 pg/mL, respectively). We assessed the possible occurrence of disease progression bias (DPB) in eight situations defined by lipid and POP measurements, on one hand, and by four factors: interval from blood draw to index date, tumour subsite, tumour stage, and grade of differentiation, on the other. In seven of the eight situations results supported the absence of DPB.

Conclusions: The coexistence of differences across study centres in some design features and participant characteristics is of relevance to other multicentre studies. Relationships among subjects' characteristics and among such characteristics and design features may play important roles in the forthcoming analyses on the association between plasma concentrations of POPs and pancreatic cancer risk.
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http://dx.doi.org/10.1016/j.envres.2018.11.027DOI Listing
February 2019

No evidence of the role of early chemical exposure in the development of β-cell autoimmunity.

Environ Sci Pollut Res Int 2019 Jan 13;26(2):1370-1378. Epub 2018 Nov 13.

Scientific Laboratory, Clinicum, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland.

Exposure to environmental chemicals can modulate the developing immune system, but its role in the pathogenesis of type 1 diabetes is largely unexplored. Our objective was to study the levels of circulating concentrations of environmental pollutants during the first years of life and their associations with the later risk of diabetes-predictive autoantibodies. From two birth-cohort studies including newborn infants with HLA-conferred susceptibility to type 1 diabetes (FINDIA and DIABIMMUNE), we identified case children with at least one biochemical diabetes-associated autoantibody (n = 30-40) and from one to four autoantibody-negative controls per each case child matched for age, gender, diabetes-related HLA-risk, delivery hospital, and, in FINDIA, also dietary intervention group. Plasma levels of 13 persistent organic pollutants and 14 per- and polyfluorinated substances were analyzed in cord blood and plasma samples taken at the age of 12 and 48 months. Both breastfeeding and the geographical living environment showed association with circulating concentrations of some of the chemicals. Breastfeeding-adjusted conditional logistic regression model showed association between decreased plasma HBC concentration at 12-month-old children and the appearance of diabetes-associated autoantibodies (HR, 0.989; 95% Cl, 0.978-1.000; P = 0.048). No association was found between the plasma chemical levels and the development of clinical type 1 diabetes. Our results do not support the view that exposure to the studied environmental chemicals during fetal life or early childhood is a significant risk factor for later development of β-cell autoimmunity and type 1 diabetes.
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http://dx.doi.org/10.1007/s11356-018-3659-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331740PMC
January 2019

Longitudinal trends of per- and polyfluoroalkyl substances in children's serum.

Environ Int 2018 12 8;121(Pt 1):591-599. Epub 2018 Oct 8.

Department of Health Security, National Institute for Health and Welfare (THL), FI-70150 Kuopio, Finland.

Studies suggest negative health impacts from early life exposure to per- and polyfluoroalkyl substances (PFASs). However, information on longitudinal exposure to PFASs during childhood is scarce for background-exposed individuals. This study sought to fill this gap by investigating children's longitudinal exposure trends through measurement of PFAS serum concentrations and calculation of body burdens (μg, total in body). Blood of 54 Finnish children was sampled 2005-2015 and analyzed for 20 PFASs at 1, 6 and 10.5 years of age. The body burden was calculated by multiplying the serum concentration by the volume of distribution and the bodyweight for each individual. Associations between serum concentrations or body burdens and parameters, such as sex, breastfeeding duration, body mass index as well as indoor dust and air PFAS concentrations, were evaluated. Serum concentrations of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorohexane sulfonic acid (PFHxS) decreased significantly (p < 0.001) with age. In contrast to serum concentrations, body burdens stayed unchanged or even increased significantly (p < 0.05), except for PFOA in female children. Breastfeeding duration was positively correlated (p < 0.001) with serum concentrations of PFHxS, PFOS, PFOA and PFNA at 1 year of age. Some associations were found at 10.5 years with sex and indoor PFAS concentrations. Observations of longitudinal decreasing trends of serum concentrations can be misleading for understanding exposure levels from external media during childhood, as the serum concentration is influenced by parallel temporal changes and growth dilution. Body burdens account for growth dilution and thus better reflect differences in early-life to adolescence exposure than serum concentrations.
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http://dx.doi.org/10.1016/j.envint.2018.09.006DOI Listing
December 2018

Incorporating regulatory guideline values in analysis of epidemiology data.

Environ Int 2018 11 28;120:535-543. Epub 2018 Aug 28.

Dept of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Dept of Health Sciences, Karlstad University, Karlstad, Sweden.

Fundamental to regulatory guidelines is to identify chemicals that are implicated with adverse human health effects and inform public health risk assessors about "acceptable ranges" of such environmental exposures (e.g., from consumer products and pesticides). The process is made more difficult when accounting for complex human exposures to multiple environmental chemicals. Herein we propose a new class of nonlinear statistical models for human data that incorporate and evaluate regulatory guideline values into analyses of health effects of exposure to chemical mixtures using so-called 'desirability functions' (DFs). The DFs are incorporated into nonlinear regression models to allow for the simultaneous estimation of points of departure for risk assessment of combinations of individual substances that are parts of chemical mixtures detected in humans. These are, in contrast to published so-called biomonitoring equivalent (BE) values and human biomonitoring (HBM) values that link regulatory guideline values from in vivo studies of single chemicals to internal concentrations monitored in humans. We illustrate the strategy through the analysis of prenatal concentrations of mixtures of 11 chemicals with suspected endocrine disrupting properties and two health effects: birth weight and language delay at 2.5 years. The strategy allows for the creation of a Mixture Desirability Function i.e., MDF, which is a uni-dimensional construct of the set of single chemical DFs; thus, it focuses the resulting inference to a single dimension for a more powerful one degree-of-freedom test of significance. Based on the application of this new method we conclude that the guideline values need to be lower than those for single chemicals when the chemicals are observed in combination to achieve a similar level of protection as was aimed for the individual chemicals. The proposed modeling may thus suggest data-driven uncertainty factors for single chemical risk assessment that takes environmental mixtures into account.
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http://dx.doi.org/10.1016/j.envint.2018.08.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261378PMC
November 2018

Association of Maternal Insecticide Levels With Autism in Offspring From a National Birth Cohort.

Am J Psychiatry 2018 11 16;175(11):1094-1101. Epub 2018 Aug 16.

From the Department of Psychiatry, Columbia University Medical Center, and New York State Psychiatric Institute, New York; the Department of Epidemiology, Columbia University Mailman School of Public Health, New York; the Department of Health Security, National Institute for Health and Welfare, Kuopio, Finland; the Department of Child Psychiatry, University of Turku, Turku, Finland; the Department of Biostatistics, Columbia University Mailman School of Public Health, New York; the University of Oulu, Faculty of Medicine, Oulu, Finland; the Biobank Borealis of Northern Finland, Oulu University Hospital, Oulu, Finland; and the Department of Child Psychiatry, Turku University Hospital, Turku, Finland.

Objective: Autism is a complex neurodevelopmental disorder with a largely unknown etiology. To date, few studies have investigated prenatal exposure to toxins and risk of autism by using maternal biomarkers of exposure. Persistent organic pollutants are lipophilic halogenated organic compounds and include the insecticide dichlorodiphenyltrichloroethane (DDT), as well as its metabolite p,p'-dichlorodiphenyl dichloroethylene (p,p'-DDE), and polychlorinated biphenyls (PCBs). The objective of this study was to test whether elevated maternal levels of persistent organic pollutants are associated with autism among offspring.

Method: The investigation was derived from the Finnish Prenatal Study of Autism, a national birth cohort study based on a nested case-control design. Cases of autism among children born between 1987 and 2005 were ascertained by national registry linkages. In cases of childhood autism and matched control subjects (778 matched case-control pairs), maternal serum specimens from early pregnancy were assayed for levels of p,p'-DDE and total levels of PCBs.

Results: The odds of autism among offspring were significantly increased with maternal p,p'-DDE levels that were in the highest 75th percentile, with adjustment for maternal age, parity, and history of psychiatric disorders (odds ratio=1.32, 95% CI=1.02, 1.71). The odds of autism with intellectual disability were increased by greater than twofold with maternal p,p'-DDE levels above this threshold (odds ratio=2.21, 95% CI=1.32, 3.69). There was no association between total levels of maternal PCBs and autism.

Conclusions: These findings provide the first biomarker-based evidence that maternal exposure to insecticides is associated with autism among offspring. Although further research is necessary to replicate this finding, this study has implications for the prevention of autism and may provide a better understanding of its pathogenesis.
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http://dx.doi.org/10.1176/appi.ajp.2018.17101129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377859PMC
November 2018

Association of In Utero Persistent Organic Pollutant Exposure With Placental Thyroid Hormones.

Endocrinology 2018 10;159(10):3473-3481

Helmholtz Zentrum München-German Research Center for Environmental Health, Molecular EXposomics, Neuherberg, Germany.

In utero exposure to persistent organic pollutants (POPs) can result in thyroid function disorder, leading to concerns about their impact on fetal and neonatal development. The associations between placental levels of various POPs and thyroid hormones (THs) were investigated. In a prospective Danish study initially established for assessing congenital cryptorchidism, 58 placenta samples were collected from mothers of boys born with (n = 28) and without (n = 30) cryptorchidism. The concentrations of polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs), organotin chemicals (OTCs), organochlorine pesticides (OCPs), T4, T3, and rT3 were measured. The associations between placental THs and various POPs were analyzed using multiple linear regression. Five PBDEs, 35 PCBs, 14 PCDD/Fs, 3 OTCs, 25 OCPs, T4, T3, and rT3 were measured. No correlation between THs and the odds of cryptorchidism was found. Several POPs were significantly associated with THs: (1) T4 was inversely associated with BDEs 99, 100, ΣPBDE, and 2378-TeCDD, and positively associated with 1234678-HpCDF; (2) T3 was positively associated with 2378-TeCDF and 12378-PeCDF; and (3) rT3 was positively associated with PCB 81, 12378-PeCDF, and 234678-HxCDF, and inversely associated with tributyltin, ΣOTC, and methoxychlor. These results revealed that POP exposures were associated with TH levels in placenta, which may be a possible mechanism for the impacts of POP exposures on children's growth and development. This study provides new insight into the complexity of thyroid-disrupting properties of POPs. More research is needed to elucidate the biological consequences of POP exposures.
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http://dx.doi.org/10.1210/en.2018-00542DOI Listing
October 2018

Perfluoroalkyl acids and their precursors in floor dust of children's bedrooms - Implications for indoor exposure.

Environ Int 2018 10 24;119:493-502. Epub 2018 Jul 24.

Department of Environmental Science and Analytical Chemistry (ACES), Stockholm University, SE-10691 Stockholm, Sweden.

We analysed floor dust samples from 65 children's bedrooms in Finland collected in 2014/2015 for 62 different per- and polyfluoroalkyl substances (PFASs) with a simple and highly efficient method. Validation results from the analysis of standard reference material (SRM) 2585 were in good agreement with literature data, while 24 PFASs were quantified for the first time. In the dust samples from children's bedrooms, five perfluoroalkyl carboxylic acids (PFCAs) and perfluorooctane sulfonic acid (PFOS) were detected in more than half of the samples with the highest median concentration of 5.26 ng/g for perfluorooctanoic acid (PFOA). However, the dust samples were dominated by polyfluoroalkyl phosphoric acid esters (PAPs) and fluorotelomer alcohols (FTOHs) (highest medians: 53.9 ng/g for 6:2 diPAP and 45.7 ng/g for 8:2 FTOH). Several significant and strong correlations (up to ρ = 0.95) were found among different PFASs in dust as well as between PFASs in dust and air samples (previously published) from the same rooms. The logarithm of dust to air concentrations (log K) plotted against the logarithm of the octanol-air partition coefficient (log K) resulted in a significant linear regression line with R > 0.88. Higher dust levels of PFOS were detected in rooms with plastic flooring material in comparison to wood (p < 0.05). Total estimated daily intakes via dust (EDI) and air (EDI) of perfluoroalkyl acids (PFAA), including biotransformation of precursors to PFAAs, were calculated for 10.5-year-old children. The total EDI for PFOA and PFOS were estimated to be 0.007 ng/kg bw/day and 0.006 ng/kg bw/day, respectively, in an intermediate exposure scenario. The sum of the total EDIs for all PFAAs was slightly higher for dust than air (0.027 and 0.019 ng/kg bw/day). Precursor biotransformation was generally important for total PFOS intake, while for the PFCAs, FTOH biotransformation was estimated to be important for air, but not for dust exposure.
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http://dx.doi.org/10.1016/j.envint.2018.06.009DOI Listing
October 2018

Persistent Organochlorine Pollutants in Plasma, Blood Pressure, and Hypertension in a Longitudinal Study.

Hypertension 2018 06 30;71(6):1258-1268. Epub 2018 Apr 30.

Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine (A.T., J.S., I.A.B.).

Persistent organochlorine pollutants (POPs) have shown to be involved in the atherosclerotic process and to cause endothelial cell dysfunction. To assess longitudinally whether plasma concentrations of different POPs were associated with blood pressure and risk of hypertension in middle-aged women and men. Study subjects were 850 participants in the VIP (Västerbotten Intervention Programme) with 2 blood samples and blood pressure measurements, 10 years apart, during 1990 to 2003 (baseline) and during 2000 to 2013 (follow-up). Dioxin-like and nondioxin-like polychlorinated biphenyls (DL-PCBs, NDL-PCBs) and p,p'-dichlorodiphenyldichloroethylene (DDE) were measured. Associations were assessed using generalized estimating equations. At baseline sampling 49% and at follow-up 64% had hypertension. DL-PCBs and DDE, but not NDL-PCBs or hexachlorobenzene, were associated with hypertension. Only the association for DL-PCBs remained statistically significant after lipid-standardization and adjustment for body mass index and total serum lipids. The multivariable-adjusted odds ratio of hypertension based on repeated measurements were 1.52 (95% confidence interval, 1.08-2.13) for DL-PCBs (third versus first tertile of lipid-standardized POPs). In stratified adjusted analyses, odds ratio for those born after 1950 increased to 3.99 (95% confidence interval, 2.15-7.43), whereas no association was observed among those born earlier. Based on repeated measurements, the accumulated exposure to DL-PCBs and DDE, although less clear for the latter, may disrupt the normal blood pressure levels and increase the odds of hypertension. Moreover, individuals experiencing early-life POP exposure may be at elevated risk of vascular POP effects.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.10691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959216PMC
June 2018

Pre-diagnostic blood immune markers, incidence and progression of B-cell lymphoma and multiple myeloma: Univariate and functionally informed multivariate analyses.

Int J Cancer 2018 09 26;143(6):1335-1347. Epub 2018 Apr 26.

Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.

Recent prospective studies have shown that dysregulation of the immune system may precede the development of B-cell lymphomas (BCL) in immunocompetent individuals. However, to date, the studies were restricted to a few immune markers, which were considered separately. Using a nested case-control study within two European prospective cohorts, we measured plasma levels of 28 immune markers in samples collected a median of 6 years before diagnosis (range 2.01-15.97) in 268 incident cases of BCL (including multiple myeloma [MM]) and matched controls. Linear mixed models and partial least square analyses were used to analyze the association between levels of immune marker and the incidence of BCL and its main histological subtypes and to investigate potential biomarkers predictive of the time to diagnosis. Linear mixed model analyses identified associations linking lower levels of fibroblast growth factor-2 (FGF-2 p = 7.2 × 10 ) and transforming growth factor alpha (TGF-α, p = 6.5 × 10 ) and BCL incidence. Analyses stratified by histological subtypes identified inverse associations for MM subtype including FGF-2 (p = 7.8 × 10 ), TGF-α (p = 4.08 × 10 ), fractalkine (p = 1.12 × 10 ), monocyte chemotactic protein-3 (p = 1.36 × 10 ), macrophage inflammatory protein 1-alpha (p = 4.6 × 10 ) and vascular endothelial growth factor (p = 4.23 × 10 ). Our results also provided marginal support for already reported associations between chemokines and diffuse large BCL (DLBCL) and cytokines and chronic lymphocytic leukemia (CLL). Case-only analyses showed that Granulocyte-macrophage colony stimulating factor levels were consistently higher closer to diagnosis, which provides further evidence of its role in tumor progression. In conclusion, our study suggests a role of growth-factors in the incidence of MM and of chemokine and cytokine regulation in DLBCL and CLL.
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http://dx.doi.org/10.1002/ijc.31536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100111PMC
September 2018

Novel volumetric adsorptive microsampling technique for determination of perfluorinated compounds in blood.

Anal Biochem 2018 03 31;545:49-53. Epub 2018 Jan 31.

National Institute for Health and Welfare, Environmental Health Unit, Neulaniementie 4, FI-70210, Kuopio, Finland.

Microsampling is an attractive option for significantly reducing the volume of blood taken for chemical analysis allowing for blood samples taken as a 'finger-prick' with a lancet. A novel, volumetric adsorptive microsampling (VAMS™) device, which reproducibly collects a small volume of 10 μL whole blood in a hematocrit-independent manner, is evaluated in a human biomonitoring setting, and has been utilized for analysis of several perfluoroalkyl acids (PFAA). The results show that the VAMS technique is applicable for PFAA analysis, method has good linearity, repeatability, accuracy and is sufficiently sensitive for samples from general populations. The stability of PFAAs with VAMS devices is shown to be acceptable, which supports the sampling and transportation strategy of several study designs. Furthermore, as well as allowing for a quick and efficient extraction and analysis flow path, the VAMS microsampler is an easy to use device in a real-world sample collection scenario.
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http://dx.doi.org/10.1016/j.ab.2018.01.015DOI Listing
March 2018

Determination of thyroid hormones in placenta using isotope-dilution liquid chromatography quadrupole time-of-flight mass spectrometry.

J Chromatogr A 2018 Jan 24;1534:85-92. Epub 2017 Dec 24.

Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Molecular EXposomics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.

The transplacental passage of thyroid hormones (THs) is of great significance since the maternal THs are vitally important in ensuring the normal fetal development. In this paper, we determined the concentrations of seven THs, viz. L-thyroxine (T), 3,3',5-triiodo-l-thyronine (T), 3,3',5'-triiodo-l-thyronine (rT), 3,3'-diiodo-l-thyronine (T), 3,5-diiodo-l-thyronine (rT), 3-iodo-l-thyronine (T) and 3-iodothyronamine (TAM), in placenta using isotope dilution liquid chromatography quadrupole time-of-flight mass spectrometry. We optimized the method using isotopically labeled quantification standards (C-T, C-T, C-rT and C-T) and recovery standard (C-T) in combination with solid-liquid extraction, liquid-liquid extraction and solid phase extraction. The linearity was obtained in the range of 0.5-150 pg uL with R values >0.99. The method detection limits (MDLs) ranged from 0.01 ng g to 0.2 ng g, while the method quantification limits (MQLs) were between 0.04 ng g and 0.7 ng g. The spike-recoveries for THs (except for T and TAM) were in the range of 81.0%-112%, with a coefficient of variation (CV) of 0.5-6.2%. The intra-day CVs and inter-day CVs were 0.5%-10.3% and 1.19%-8.88%, respectively. Concentrations of the THs were 22.9-35.0 ng g T, 0.32-0.46 ng g T, 2.86-3.69 ng g rT, 0.16-0.26 ng g T, and < MDL for other THs in five human placentas, and 2.05-3.51 ng g T, 0.37-0.62 ng g T, 0.96-1.3 ng g rT, 0.07-0.13 ng g T and < MDL for other THs in five mouse placentas. The presence of T was tracked in placenta for the first time. This method with improved selectivity and sensitivity allows comprehensive evaluation of TH homeostasis in research of metabolism and effects of environmental contaminant exposures.
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http://dx.doi.org/10.1016/j.chroma.2017.12.048DOI Listing
January 2018