Early menarche and other endocrine disrupting effects of per- and polyfluoroalkyl substances (PFAS) in adolescents from Northern Norway. The Fit Futures study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) comprise a large group of chemicals that are ubiquitous in the environment and include recognized persistent organic pollutants. The aim of this cross-sectional study was to investigate possible endocrine disrupting effects of different PFAS in adolescents. METHODS: Serum concentrations of PFAS, thyroid, parathyroid and steroid hormones were measured in 921 adolescents aged 15-19 years in the Fit Futures study, Northern Norway. The questionnaire included data on self-reported age at menarche and puberty development score (PDS). Multiple linear and logistic regression analyses and principle component analyses (PCA) were used to assess associations of PFAS with hormones concentrations and puberty indices. RESULTS: In girls, total PFAS (∑PFAS), perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), perfluorodecanoate (PFDA) were positively associated with dehydroepiandrosterone sulfate (DHEAS) and negatively associated with 11-deoxycorticosterone (11-DOC)/DHEAS ratio. In boys, the associations with 11-DOC/DHEAS ratio were positive for ∑PFAS, perfluoroheptanoate (PFHpA), perfluoroheptane sulfonate (PFHpS), PFOA, and PFOS. Perfluoroundecanoate (PFUnDA) was negatively associated with free thyroxine (fT4) and free triiodothyronine (fT3) in boys. PFNA and PFDA were also negatively associated with fT3 in boys. Serum parathyroid hormone concentration (PTH) was negatively associated with ∑PFAS and perfluorohexane sulfonate (PFHxS) in girls, and with PFOS in boys. PFDA and PFUnDA were positively associated with early menarche, while ∑PFAS and PFOA were positively associated with PDS in boys. No associations of PFAS with serum testosterone, follicle-stimulating hormone, or luteinizing hormone were found in either sex. In girls, PFOA was positively associated with free testosterone index (FTI). In boys, PFOA was positively associated with androstendione and 17-OH-progesterone, while PFHpA was positively associated with estradiol. CONCLUSIONS: Serum concentrations of several PFAS were associated with parathyroid and steroid hormones in both sexes, and with thyroid hormones in boys, as well as with early menarche in girls and higher PDS in boys.

Structure and Conformation of Individual Molecules upon Adsorption of a Mixture of Benzoporphyrins on Ag(111), Cu(111), and Cu(110) Surfaces.

The front cover artwork is provided by the groups of Prof. Dr. Hans-Peter Steinrück and Prof. Dr. Norbert Jux at the Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg. The image shows a mixture of six 2H-tetrakis-(3, 5-di-tert-butyl-phenyl)(x)benzoporphyrins (2H-diTTBP(x)BPs, x = 0, 1, 2-cis, 2-trans, 3, or 4) molecules forming a porous square structure on Ag(111) as observed in scanning tunneling microscopy (STM) at room temperature. Read the full text of the Research Article at 10.1002/cphc.202300355.

Structure and Conformation of Individual Molecules upon Adsorption of a Mixture of Benzoporphyrins on Ag(111), Cu(111), and Cu(110) Surfaces.

We investigated the adsorption behavior of a mixture of six 2H-tetrakis-(3, 5-di-tert-butylphenyl)(x)benzoporphyrins (2H-diTTBP(x)BPs, x=0, 1, 2-cis, 2-trans, 3, and 4) on Ag(111), Cu(111) and Cu(110) at room temperature by scanning tunneling microscopy (STM) under ultra-high vacuum conditions. On Ag(111), we observe an ordered two-dimensional square phase, which is stable up to 400 K. On Cu(111), the same square phase coexists with a stripe phase, which disappears at 400 K. In contrast, on Cu(110), 2H-diTTBP(x)BPs adsorb as immobile isolated molecules or dispersed short chains along the [1 1 ‾ ${\bar{1}}$ 0] substrate direction, which remain intact up to 450 K. The stabilization of the 2D supramolecular structures on Ag(111) and Cu(111), and of the 1D short chains on Cu(110) is attributed to van der Waals interactions between the tert-butyl and phenyl groups of neighboring molecules. From high-resolution STM, we can assign all six 2H-diTTBP(x)BPs within the ordered structures. Moreover, we deduce a crown shape quadratic conformation on Ag(111) and Cu(111), an additional saddle-shape on Cu(111), and an inverted structure and a quadratic appearance on Cu(110). The different conformations are attributed to the different degree of interaction of the iminic nitrogen atoms of the isoindole and pyrrole groups with the substrate atoms.

Impaired gross motor development in infants with higher PFAS concentrations.

Industrial produced perfluoroalkyl substances (PFAS) are environmentally persistent and found in humans around the globe. PFAS is transferred from mother to child during pregnancy and lactation and PFAS concentrations are high in infants. PFAS exposure in early life has been linked to a range of negative health effects. In the present study we have investigated PFAS concentrations in mothers (pregnancy week 18, 28 and 36 and six weeks, four and six months postpartum, n = 114) and in infants at six months age (n = 94), and studied the effects of PFAS status on infant gross motor development by Alberta Infant Motor Scale (AIMS) at age six months. PFAS concentrations declined in the mothers during pregnancy and postpartum period, and the highest concentrations were seen in infants aged six months. Parity was a strong negative predictor and fish intake a strong positive predictor of maternal PFAS status, while maternal concentrations of PFAS in pregnancy week 18 and months of exclusive breastfeeding determined the PFAS concentrations in infants at six months. Infants who scored below the median on gross motor development had higher PFAS concentrations than infants with a better gross motor development. Ninety percent of the women reported having fish for dinner at least once a week, with fatty fish as the most popular choice (72%). A higher maternal fish intake in pregnancy week 18 was associated with a poorer gross motor development in the infants at six months. Infant gross motor development is a marker of later cognitive outcome and our findings indicate that higher PFAS concentrations in young infants and maternal fatty fish intake may impair neurodevelopment.

Exposure to perfluoroalkyl substances (PFAS) and dyslipidemia, hypertension and obesity in adolescents. The Fit Futures study.

BACKGROUND: Prevalence of obesity, hypertension and dyslipidemia has been increasing in children and adolescents worldwide. Exposure to environmental pollutants may contribute to this development. Our aim was to study associations between perfluoroalkyl substances (PFAS) and dyslipidemia, hypertension and obesity in a population-based sample of adolescents. METHODS: Serum PFAS concentrations were measured in 940 adolescents, mean age 16.4 (SD 1.3) years, from the cross-sectional Fit Futures study by the UHPLC-MS/MS method. The following endpoints were used: hypertension (systolic blood pressure over 130 mmHg and/or diastolic blood pressure over 80 mmHg); obesity (body mass index over 2 z-score, WHO charts for adolescents); dyslipidemia (total cholesterol ≥ 5.17 mmol/L, and/or LDL-cholesterol ≥ 3.36 mmol/l, and/or apolipoprotein B ≥ 1.10 g/L). RESULTS: Perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), perfluorodecanoate (PFDA) and perfluoroundecanoate (PFUnDA) serum concentrations were positively associated with apolipoprotein B, total- and LDL cholesterol. The highest vs. lowest quartiles of total PFAS (∑PFAS), PFNA and PFDA concentrations were positively associated with the risk of dyslipidemia: OR 2.24 (95% CI 1.10-4.54), OR 2.30 (95% CI 1.16-4.57) and 2.36 (95% CI 1.08-5.16), respectively. The highest vs. lowest quartiles of ∑PFAS, perfluorohexane sulfonate (PFHxS), PFOS, perfluorooctanoate (PFOA) concentrations were positively associated with the risk of hypertension: OR 1.91 (95% CI 1.12-3.26), OR 2.06 (95% CI 1.16-3.65), 1.86 (95% CI 1.08-3.19) and 2.08 (95% CI 1.17-3.69) respectively. PFHxS and perfluoroheptane sulfonate (PFHpS) concentrations were positively associated with obesity. CONCLUSIONS: This cross-sectional study showed a possible link between several PFAS and dyslipidemia, hypertension and obesity in Norwegian adolescents.

Serum perfluoroalkyl substances (PFAS) and risk of asthma and various allergies in adolescents. The Tromsø study Fit Futures in Northern Norway.

BACKGROUND: Exposure to environmental pollutants may contribute to the development of asthma and other allergies. The aim of this study was to investigate possible associations between asthma and other allergies with exposure to perfluoroalkyl substances (PFASs) in adolescents from the Arctic region of Norway. METHODS: The Tromsø study Fit Futures 1 (TFF1) and 3-year follow-up Fit Futures 2 study (TFF2) included 675 adolescents that completed a questionnaire about health conditions and underwent a clinical examination with blood tests and fractional nitric oxide (FeNO) measurement. Serum concentrations of 18 PFASs were measured by UHPLC-MS/MS method. RESULTS: Total PFASs (ΣPFAS) serum concentration over 4th quartile was positively associated with asthma in the TFF1 (OR 3.35 (95% CI 1.54-7.29), p = 0.002). Total perfluorooctane sulfonate (ΣPFOS), linear PFOS (linPFOS), linear perfluorohexane sulfonate (linPFHxS) concentrations over 4th quartiles were associated with 2 times higher odds of asthma in the TFF1. The positive associations between ΣPFAS, ΣPFOS, linPFOS and asthma remained statistically significant in the TFF2. ΣPFAS and linPFHxS concentrations over 3rd tertiles were associated with positive marker of eosinophilic airways inflammation FeNO> 25 ppb. Concentrations of ΣPFOS and linPFOS over 3rd quartiles were positively associated with self-reported nickel allergy (OR 2.25 (95% CI 1.17-4.35) p = 0.016 and OR 2.53 (95% CI 1.30-4.90) p = 0.006, respectively). Allergic rhinitis, self-reported pollen allergy, food allergy and atopic eczema were not associated with PFASs concentrations. CONCLUSIONS: This study of Norwegian adolescents showed a positive association between several PFASs and asthma, as well as between PFOS and nickel allergy.

C-reactive protein and risk of venous thromboembolism: results from a population-based case-crossover study.

Long-term, low-grade inflammation does not seem to be a risk factor for venous thromboembolism. The impact of acute inflammation, regardless of cause, on risk of venous thromboembolism is scarcely studied. We aimed to investigate the impact of acute inflammation, assessed by C-reactive protein, on short-term risk of venous thromboembolism. We conducted a case-crossover study of patients with venous thromboembolism (n=707) recruited from a general population. Information on triggers and C-reactive protein levels were retrieved from hospital records during the 90 days before the event (hazard period) and in four preceding 90-day control periods. Conditional logistic regression was used to obtain ß coefficients for change in natural log (ln) transformed C-reactive protein from control to hazard periods and to determine corresponding odds ratios for venous thromboembolism. Median C-reactive protein was 107 mg/L in the hazard period, and ranged from 7 mg/L to 16 mg/L in the control periods. The level of C-reactive protein was 58% (95% CI 39-77%) higher in the hazard period than in the control periods. A one-unit increase in ln-C-reactive protein was associated with increased risk of venous thromboembolism (OR 1.79, 95% CI 1.48-2.16). The risk estimates were only slightly attenuated after adjustment for immobilization and infection. In stratified analyses, ln-C-reactive protein was associated with increased risk of venous thromboembolism in cases with (OR 1.55, 95% CI 1.01-2.38) and without infection (OR 1.77, 95% CI 1.22-2.57). In conclusion, we found that acute inflammation, assessed by C-reactive protein, was a trigger for venous thromboembolism.

Should we eat more fish - or less? / Bør vi spise mer fisk ­ eller mindre?

All food contains environmental toxins. The EU has set a new threshold for the level of environmental toxins that can be considered safe in the body. In Norway, the average intake exceeds this threshold, and fatty fish is the main source. Nevertheless, the Norwegian authorities recommend that all age groups eat more fish.

High level of heavy metals in crab meat. / Høyt nivå av tungmetaller i krabbe.

Crab meat is a popular seafood, but it sometimes contains large amounts of environmental toxins. The content is so high in many places in Norway that consumption of brown crab meat should generally be discouraged.

An automated high-throughput SPE micro-elution method for perfluoroalkyl substances in human serum.

An automated high-throughput solid phase extraction (SPE) micro-elution method for 8 perfluorosulfonic acids, 11 perfluorocarboxylic acids and fluorooctane sulfonamide in human serum was developed. Importance was attached to the application of small volumes of reagents and solvents in addition to low sample volumes (50 µL) in order to save the highly valuable sample material for follow-up and other studies. Instrumental analysis was performed by ultra high pressure liquid chromatography coupled to triple quadrupole mass spectrometry (UHPLC-MS/MS). The recoveries of perfluoroalkyl substances (PFASs) were satisfactory and between 70 and 120% for most of the compounds at the three investigated spike concentrations. Perfluorobutane sulfonate (PFBS) was slightly underestimated at high concentrations (20 ng/mL; 67%), whereas perfluoropentanoate (PFPA), perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) were overestimated with 134, 131 and 133% respectively, at low spike concentrations (0.2 ng/mL). The precision of the method was below 20% coefficient of variation (CV%) for all target compounds with the only exception of PFOS (22%) at low spike concentrations. Method detection limits ranged from 0.006 to 0.34 ng/mL. High sensitivity, accuracy, repeatability and robustness have been demonstrated for an appropriate concentration range. The applicability for real samples was satisfactory demonstrated by analysis of 40 sera samples from the general population from Tromsø, Norway.

Serum osteoprotegerin and future risk of cancer and cancer-related mortality in the general population: the Tromsø study.

The purpose was to investigate the association between serum osteoprotegerin (OPG) and risk of incident cancer and cancer mortality in a general population. OPG was measured in serum collected from 6,279 subjects without prior cancer recruited from a general population. Incident cancer and cancer-related mortality were registered from inclusion in 1994-95 until end of follow-up December 31, 2008. Cox regression models were used to estimate crude and adjusted (for age, sex and other confounders) hazard ratios and 95% confidence intervals (HR 95% CI). There were 948 incident cancers and 387 deaths in the cohort during 71,902 person-years of follow up (median 13.5 years). Subjects with serum OPG in the upper tertile had 79% higher risk of incident gastrointestinal cancer than those in the lowest tertile (HR 1.79, 95% CI 1.19-2.67). In women <60 years, serum OPG (per SD 0.81 ng/ml) was associated with reduced risk of incident cancer (all cancers merged; 0.73; 0.57-0.94) and breast cancer (0.51; 0.31-0.83) after adjustment. Subjects in the upper tertile of OPG had higher risk of cancer-related mortality (1.63; 1.16-2.28), particularly mortality from cancer in the gastrointestinal system (2.28; 1.21-4.28) compared to those in the lowest OPG tertile. No significant association was detected between OPG and risk of death from cancer in the respiratory system or death from prostatic cancer. Our findings from a large population based cohort study suggest that serum OPG was associated with increased risk of incident gastrointestinal cancer, inversely associated with breast cancer, and predicts cancer-related mortality.

Cystatin C is associated with risk of venous thromboembolism in subjects with normal kidney function--the Tromsø study.

BACKGROUND: Previous studies have shown an association between impaired kidney function, assessed by cystatin C-based estimated glomerular filtration rate, and venous thromboembolism. The aim of this study was to investigate whether serum cystatin C was associated with a risk of venous thromboembolism among subjects with normal kidney function in a prospective population-based study. DESIGN AND METHODS: Cystatin C was measured in serum from 3251 men and women with normal kidney function, aged 25-84 years, who participated in the Tromsø study in 1994-1995. Normal kidney function was defined as a creatinine-based estimated glomerular filtration rate greater than 90 mL/min/1.73 m(2) and absence of microalbuminuria. Incident venous thromboembolism was registered from the date of inclusion through to the end of follow-up, September 1, 2007. Cox-regression models were used to calculate hazard ratios with 95% confidence intervals for venous thromboembolism. RESULTS: There were 83 incident venous thromboembolic events, of which 53 (63.9 %) were provoked, during a median of 12.3 years of follow-up. A one standard deviation (0.11 mg/L) increase in serum cystatin C levels was associated with a 43% (hazard ratio 1.43; 95% confidence interval 1.17-1.72) increased risk of total venous thromboembolism. Subjects with cystatin C levels in the top quartile (≥ 0.87 mg/L) had a 2.5-fold (hazard ratio 2.51; 95% confidence interval 1.27-4.96) increased risk of venous thromboembolism compared to those with levels in the bottom quartile (≤ 0.72 mg/L) in adjusted analysis. The risk estimates were even higher for provoked venous thromboembolism (hazard ratio 3.11; 95% confidence interval 1.23-7.86). CONCLUSIONS: Serum cystatin C levels were associated with the risk of venous thromboembolism in subjects with normal kidney function. Our findings suggest that elevated serum cystatin C levels may promote venous thrombosis beyond reflecting impaired kidney function.

A wax ester and astaxanthin-rich extract from the marine copepod Calanus finmarchicus attenuates atherogenesis in female apolipoprotein E-deficient mice.

The aim of this study was to investigate the effect of dietary supplementation with an oil extracted from the zooplankton copepod Calanus finmarchicus [calanus oil (CO)] on atherosclerosis in apoE-deficient (apoE(-/-)) mice. Thirty 6-wk-old female apoE(-/-) mice (n = 10/group) were fed: 1) a Western-type, high-fat diet (HFD); 2) HFD supplemented with 1% (wt:wt) CO; or 3) HFD supplemented with 0.88% (wt:wt) corn oil + 0.12% (wt:wt) EPA+DHA ethyl esters (EPA+DHA) for 13 wk. Dietary CO supplementation lowered total aorta atherogenesis by 36.5% compared to the HFD (P < 0.01), whereas the reduction in the lesion prone aortic arch was 34.8% (P < 0.01). The degree of aortic atherogenesis was intermediate in mice fed EPA+DHA compared to those fed HFD and CO. The effect on atherogenesis was paralleled by reduced expression of hepatic genes for the proinflammatory cytokines, Ccl2, Icam1, Il1b, and Nfkb1, in mice fed CO compared to those fed HFD. For mice fed EPA+DHA, gene expression did not differ compared to those fed CO or HFD. Plasma concentrations of total cholesterol, TG, and cytokines did not differ between the groups at the end of the study. However, mice fed CO gained more weight compared to those fed HFD but not compared to those fed EPA+DHA. In conclusion, dietary CO supplementation attenuated atherosclerotic lesion formation in female apoE(-/-) mice and may be an effective and safe dietary intervention to reduce the development of atherosclerosis. However, further studies are warranted to elucidate the underlying physiological and molecular mechanisms.

Cystatin C as risk factor for cardiovascular events and all-cause mortality in the general population. The Tromsø Study.

BACKGROUND: Glomerular filtration rate<60 mL/min/1.73 m2 is associated with increased cardiovascular risk. Cystatin C is believed to be a better tool than creatinine for detection of mild renal dysfunction (>60 mL/min/1.73 m2) and possibly a more sensitive marker for cardiovascular risk and all-cause mortality. We examined the association of cystatin C with cardiovascular morbidity and all-cause mortality in a prospective population-based study. METHODS: Cystatin C was measured in 2852 men and 3153 women in the Tromsø Study 1994/95. Gender-specific associations during 12 years of follow-up for all-cause mortality and 9.5 years for myocardial infarction (MI) and ischaemic stroke were assessed (Cox proportional hazard ratios, HRs). RESULTS: During follow-up, 591 MIs, 293 ischaemic strokes and 1262 deaths occurred. In women, HR for all-cause mortality was increased in the upper cystatin C quartile (≥0.93 mg/L) compared with the lowest quartile (≤0.73 mg/L); 1.38, 95% confidence interval 1.04-1.84. A significant interaction with gender was observed. One SD (0.17 mg/L) increase in cystatin C was associated with 9% higher risk of death in women, also when persons with a cancer history were excluded. Crude HRs for MI and ischaemic stroke were increased in both genders, but the associations did not persist after multivariable adjustments. No independent associations with end points were observed in non-gender-specific analyses. CONCLUSIONS: Cystatin C was not independently associated with fatal and non-fatal MI or ischaemic stroke in the general population. However, cystatin C was a risk factor for all-cause mortality in women.

[Middle-aged female presenting with headache, blurred vision and skin rash]. / Ei kvinne i 50-åra med hovudverk, uklart syn og utslett.

BACKGROUND: Autoimmune hyperlipidemia (AIH) is a rare cause of secondary hyperlipidemia. A few cases of AIH have been reported in multiple myeloma. MATERIAL AND METHODS: A female in her fifties was referred to the outpatient clinic presenting with headache, blurred vision and skin rash. Physical examination with subsequent laboratory and histological examinations revealed severe hyperlipidemia secondary to secretory multiple myeloma with monoclonal IgG kappa protein and erythrocytosis secondary to a erythropoietin secreting adenoma in the liver. RESULTS AND INTERPRETATION: Treatment for multiple myeloma (induction treatment and autologous hematological stem cell transplantation) gained partial remission and was associated with normalization of serum lipids. There was no need for further medical treatment of the hyperlipidemia. Three years after the initial treatment, serum concentrations of triglycerides and total cholesterol increased in parallel with monoclonal IgG kappa protein. Total cholesterol and triglycerides decreased and remained within the reference ranges after retreatment with a second autologous stem cell transplantation. Surgical removal of the hepatic adenoma caused normalisation of the erythropoietin concentration and resolution of the erythrocytosis. The present case reports two rare complications (AIH and erythrocytosis) to multiple myeloma and hepatic adenoma, with regression of complaints and normalisation of laboratory tests after adequate treatment of underlying diseases.