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1.  Motor development following in utero exposure to organochlorines: a follow-up study of children aged 5–9 years in Greenland, Ukraine and Poland 
BMC Public Health  2015;15:146.
Prior studies on the association between prenatal exposure to polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE) and child motor development have found contradicting results. Using data collected in the INUENDO cohort in Kharkiv (Ukraine), Warsaw (Poland) and Greenland (N = 1,103) between the years 2002 and 2012, we examined relations of prenatal exposure to 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p′-DDE) and 2,2′,4,4′,5,5′-hexachlorobiphenyl (CB-153) on motor development and developmental milestones; crawling, standing-up and walking.
CB-153 and p,p′-DDE were measured in maternal blood in second or third trimester of pregnancy. Motor development was measured in terms of the parentally assessed screening tool Developmental Coordination Disorder Questionnaire 2007 and developmental milestones were assessed via retrospective parental reports of child age at the first time of crawling, standing-up and walking.
We saw no associations between tertiles of CB-153 and p,p′-DDE or log-transformed exposures and retrospective reports of the developmental milestones crawling, standing-up and walking in infancy or the motor skills measured as developmental coordination disorder at young school age.
In utero exposure to CB-153 and p,p′-DDE was not associated with parentally retrospectively assessed developmental milestones in infancy or parentally assessed motor skills at young school age. The use of a more sensitive outcome measure may be warranted if subtle effects should be identified.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-015-1465-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4332728
Child motor development; Developmental milestones; Dichlorodiphenyldichloroethylene (DDE); Organochlorines; Polychlorinated biphenyls (PCBs); Prenatal exposure
2.  Pregnancy serum concentrations of perfluorinated alkyl substances and offspring behaviour and motor development at age 5–9 years – a prospective study 
Environmental Health  2015;14:2.
In animal studies, perfluorinated alkyl substances affect growth and neuro-behavioural outcomes. Human epidemiological studies are sparse. The aim was to investigate the association between pregnancy serum concentrations of perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) and offspring behaviour and motor development at 5–9 years of age.
Maternal sera from the INUENDO cohort (2002–2004) comprising 1,106 mother-child pairs from Greenland, Kharkiv (Ukraine) and Warsaw (Poland) were analysed for PFOS and PFOA, using liquid-chromatography-tandem-mass-spectrometry. Exposures were grouped into country specific as well as pooled tertiles as well as being used as continuous variables for statistical analyses. Child motor development and behaviour at follow-up (2010–2012) were measured by the Developmental Coordination Disorder Questionnaire 2007 (DCDQ) and Strength and Difficulties Questionnaire (SDQ), respectively. Exposure-outcome associations were analysed by multiple logistic and linear regression analyses.
In the pooled analysis, odds ratio (OR) (95% confidence interval (CI)) for hyperactivity was 3.1 (1.3, 7.2) comparing children prenatally exposed to the highest PFOA tertile with those exposed to the lowest PFOA tertile. Comparing children in the highest PFOS tertile with those in the lowest PFOS tertile showed elevated but statistically non-significant OR of hyperactivity (OR (95% CI) 1.7 (0.9, 3.2)). In Greenland, elevated PFOS was associated with higher SDQ-total scores indicating more behavioural problems (β (95% CI) =1.0 (0.1, 2.0)) and elevated PFOA was associated with higher hyperactivity sub-scale scores indicating more hyperactive behaviour (β (95% CI) = 0.5 (0.1, 0.9)). Prenatal PFOS and PFOA exposures were not associated with motor difficulties.
Prenatal exposure to PFOS and PFOA may have a small to moderate effect on children’s neuro-behavioural development, specifically in terms of hyperactive behaviour. The associations were strongest in Greenland where exposure contrast is largest.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-069X-14-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4298045  PMID: 25567242
Behaviour; Child; Child development; Cohort study; Motor development; Perfluorooctanoate (PFOA); Perfluorooctane sulfonate (PFOS); Prenatal exposure, Delayed effects
3.  Prenatal Phthalate Exposures and Anogenital Distance in Swedish Boys 
Environmental Health Perspectives  2014;123(1):101-107.
Background: Phthalates are used as plasticizers in soft polyvinyl chloride (PVC) and in a large number of consumer products. Because of reported health risks, diisononyl phthalate (DiNP) has been introduced as a replacement for di(2-ethylhexyl) phthalate (DEHP) in soft PVC. This raises concerns because animal data suggest that DiNP may have antiandrogenic properties similar to those of DEHP. The anogenital distance (AGD)—the distance from the anus to the genitals—has been used to assess reproductive toxicity.
Objective: The objective of this study was to examine the associations between prenatal phthalate exposure and AGD in Swedish infants.
Methods: AGD was measured in 196 boys at 21 months of age, and first-trimester urine was analyzed for 10 phthalate metabolites of DEP (diethyl phthalate), DBP (dibutyl phthalate), DEHP, BBzP (benzylbutyl phthalate), as well as DiNP and creatinine. Data on covariates were collected by questionnaires.
Results: The most significant associations were found between the shorter of two AGD measures (anoscrotal distance; AGDas) and DiNP metabolites and strongest for oh-MMeOP [mono-(4-methyl-7-hydroxyloctyl) phthalate] and oxo-MMeOP [mono-(2-ethyl-5-oxohexyl) phthalate]. However, the AGDas reduction was small (4%) in relation to more than an interquartile range increase in DiNP exposure.
Conclusions: These findings call into question the safety of substituting DiNP for DEHP in soft PVC, particularly because a shorter male AGD has been shown to relate to male genital birth defects in children and impaired reproductive function in adult males and the fact that human levels of DiNP are increasing globally.
Citation: Bornehag CG, Carlstedt F, Jönsson BA, Lindh CH, Jensen TK, Bodin A, Jonsson C, Janson S, Swan SH. 2015. Prenatal phthalate exposures and anogenital distance in Swedish boys. Environ Health Perspect 123:101–107;
PMCID: PMC4286276  PMID: 25353625
4.  Exposure determinants of phthalates, parabens, bisphenol A and triclosan in Swedish mothers and their children 
Environment International  2014;73:323-333.
Chemicals such as phthalates, parabens, bisphenol A (BPA) and triclosan (TCS), used in a wide variety of consumer products, are suspected endocrine disrupters although their level of toxicity is thought to be low. Combined exposure may occur through ingestion, inhalation and dermal exposure, and their toxic as well as combined effects are poorly understood.
The objective of the study was to estimate the exposure to these chemicals in Swedish mothers and their children (6–11 years old) and investigate potential predictors of the exposure. Urine samples from 98 mother–child couples living in either a rural or an urban area were analyzed for the concentrations of four metabolites of di-(2-ethylhexyl) phthalate (DEHP), three metabolites of di-iso-nonyl phthalate (DiNP), mono-ethyl phthalate (MEP), mono-benzyl phthalate (MBzP) and mono-n-butyl phthalate (MnBP), methylparaben (MetP), ethylparaben (EthP), propylparaben (ProP), butylparaben, benzylparaben, BPA, and TCS. Information on sociodemographics, food consumption habits and use of personal care products, obtained via a questionnaire, was used to investigate the associations between the urinary levels of chemicals and potential exposure factors.
There were fairly good correlations of biomarker levels between the mothers and their children. The children had generally higher levels of phthalates (geometric mean ΣDEHP 65.5 μg/L; ΣDiNP 37.8 μg/L; MBzP 19.9 μg/L; MnBP 76.9 μg/L) than the mothers (ΣDEHP 38.4 μg/L; ΣDiNP 33.8 μg/L; MBzP 12.8 μg/L; MnBP 63.0 μg/L). Conversely, the mother's levels of parabens (MetP 37.8 μg/L; ProP 13.9 μg/L) and MEP (43.4 μg/L) were higher than the children's levels of parabens (MetP 6.8 μg/L; ProP 2.1 μg/L) and MEP (28.8 μg/L). The urinary levels of low molecular weight phthalates were higher among mothers and children in the rural area (MBzP p = < 0.001; MnBP p = 0.001–0.002), which is probably due to higher presence of PVC in floorings and wall coverings in this area, whereas the levels of parabens were higher among the children in the urban area (MetP p = 0.003; ProP p = 0.004) than in the rural area. The levels of high molecular weight phthalates were associated with consumption of certain foods (i.e. chocolate and ice cream) whereas the levels of parabens were associated with use of cosmetics and personal care products.
•We quantified the levels of phthalates, BPA, parabens and triclosan in urine.•The levels were significantly correlated to certain foods and hygiene products.•Mothers had higher levels of parabens and a phthalate used in hygiene products.•Children had generally higher levels of phthalates present in food.
PMCID: PMC4207945  PMID: 25216151
BenP, benzylparaben; BPA, bisphenol A; BBzP, butylbenzyl phthalate; ButP, butylparaben; DEHP, di-(2-ethylhexyl) phthalate; DEP, diethyl phthalate; DiNP, di-iso-nonyl phthalate; DnBP, di-n-butyl phthalate; EthP, ethylparaben; MetP, methylparaben; 5-cx-MEPP, mono(2-ethyl-5-carboxy-pentyl) phthalate; 5-OH-MEHP, mono(2-ethyl-5-hydroxy-hexyl) phthalate; 5-oxo-MEHP, mono(2-ethyl-5-oxo-hexyl) phthalate; cx-MiNP, mono-(carboxy-isooctyl) phthalate; OH-MiNP, mono-(hydroxyl-isononyl) phthalate; oxo-MiNP, mono-(oxo-isononyl) phthalate; MBzP, mono-benzyl phthalate; MEP, mono-ethyl phthalate; MEHP, mono(2-ethylhexyl) phthalate; MnBP, mono-n-butyl phthalate; ProP, propylparaben; TCS, triclosan; Biomonitoring; Children; Urine; Exposure sources; Biomarker; Consumer products
5.  Fetal Exposure to Perfluorinated Compounds and Attention Deficit Hyperactivity Disorder in Childhood 
PLoS ONE  2014;9(4):e95891.
The association between exposure to perfluorinated compounds (PFCs) and attention deficit hyperactivity disorder (ADHD) diagnosis has been sparsely investigated in humans and the findings are inconsistent.
A matched case-control study was conducted to investigate the association between fetal exposure to PFCs and ADHD diagnosis in childhood.
The study base comprised children born in Malmö, Sweden, between 1978 and 2000 that were followed up until 2005. Children with ADHD (n = 206) were identified at the Department of Child and Adolescent Psychiatry. Controls (n = 206) were selected from the study base and were matched for year of birth and maternal country of birth. PFC concentrations were measured in umbilical cord serum samples. The differences of the PFC concentrations between cases and controls were investigated using Wilcoxon's paired test. Possible threshold effects (above the upper quartile for perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) and above limit of detection [LOD] for perfluorononanoic acid (PFNA)) were evaluated by conditional logistic regression.
The median umbilical cord serum concentrations of PFOS were 6.92 ng/ml in the cases and 6.77 ng/ml in the controls. The corresponding concentrations of PFOA were 1.80 and 1.83 ng/ml. No associations between PFCs and ADHD were observed. Odds ratios adjusted for smoking status, parity, and gestational age were 0.81 (95% confidence interval [CI] 0.50 to 1.32) for PFOS, 1.07 (95% CI 0.67 to 1.7) for PFOA, and 1.1 (95% CI 0.75 to 1.7) for PFNA.
The current study revealed no support for an association between fetal exposure to PFOS, PFOA, or PFNA and ADHD.
PMCID: PMC3997434  PMID: 24760015
6.  Human biological monitoring of suspected endocrine-disrupting compounds 
Asian Journal of Andrology  2013;16(1):5-16.
Endocrine-disrupting compounds are exogenous agents that interfere with the natural hormones of the body. Human biological monitoring is a powerful method for monitoring exposure to endocrine disrupting compounds. In this review, we describe human biological monitoring systems for different groups of endocrine disrupting compounds, polychlorinated biphenyls, brominated flame retardants, phthalates, alkylphenols, pesticides, metals, perfluronated compounds, parabens, ultraviolet filters, and organic solvents. The aspects discussed are origin to exposure, metabolism, matrices to analyse, analytical determination methods, determinants, and time trends.
PMCID: PMC3901881  PMID: 24369128
biomarkers of exposure; biomonitoring; blood; environmental contaminants; fetal; hormonal effects; mass spectrometry; quantitative analytical analysis; serum; urine
7.  Effects of diesel exposure on lung function and inflammation biomarkers from airway and peripheral blood of healthy volunteers in a chamber study 
Exposure to diesel exhaust causes inflammatory responses. Previous controlled exposure studies at a concentration of 300 μg/m3 of diesel exhaust particles mainly lasted for 1 h. We prolonged the exposure period and investigated how quickly diesel exhaust can induce respiratory and systemic effects.
Eighteen healthy volunteers were exposed twice to diluted diesel exhaust (PM1 ~300 μg/m3) and twice to filtered air (PM1 ~2 μg/m3) for 3 h, seated, in a chamber with a double-blind set-up. Immediately before and after exposure, we performed a medical examination, spirometry, rhinometry, nasal lavage and blood sampling. Nasal lavage and blood samples were collected again 20 h post-exposure. Symptom scores and peak expiratory flow (PEF) were assessed before exposure, and at 15, 75, and 135 min of exposure.
Self-rated throat irritation was higher during diesel exhaust than filtered air exposure. Clinical signs of irritation in the upper airways were also significantly more common after diesel exhaust exposure (odds ratio=3.2, p<0.01). PEF increased during filtered air, but decreased during diesel exhaust exposure, with a statistically significant difference at 75 min (+4 L/min vs. -10 L/min, p=0.005). Monocyte and total leukocyte counts in peripheral blood were higher after exposure to diesel exhaust than filtered air 20 h post-exposure, and a trend (p=0.07) towards increased serum IL-6 concentrations was also observed 20 h post-exposure.
Diesel exhaust induced acute adverse effects such as symptoms and signs of irritation, decreased PEF, inflammatory markers in healthy volunteers. The effects were first seen at 75 min of exposure.
PMCID: PMC4029460  PMID: 24321138
Diesel exhaust; Chamber experiment; Lung function; Biomarkers; Respiratory inflammation
8.  Monoacylglycerols Activate TRPV1 – A Link between Phospholipase C and TRPV1 
PLoS ONE  2013;8(12):e81618.
Phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate generates diacylglycerol, inositol 1,4,5-trisphosphate and protons, all of which can regulate TRPV1 activity via different mechanisms. Here we explored the possibility that the diacylglycerol metabolites 2-arachidonoylglycerol and 1-arachidonoylglycerol, and not metabolites of these monoacylglycerols, activate TRPV1 and contribute to this signaling cascade. 2-Arachidonoylglycerol and 1-arachidonoylglycerol activated native TRPV1 on vascular sensory nerve fibers and heterologously expressed TRPV1 in whole cells and inside-out membrane patches. The monoacylglycerol lipase inhibitors methylarachidonoyl-fluorophosphonate and JZL184 prevented the metabolism of deuterium-labeled 2-arachidonoylglycerol and deuterium-labeled 1-arachidonoylglycerol in arterial homogenates, and enhanced TRPV1-mediated vasodilator responses to both monoacylglycerols. In mesenteric arteries from TRPV1 knock-out mice, vasodilator responses to 2-arachidonoylglycerol were minor. Bradykinin and adenosine triphosphate, ligands of phospholipase C-coupled membrane receptors, increased the content of 2-arachidonoylglycerol in dorsal root ganglia. In HEK293 cells expressing the phospholipase C-coupled histamine H1 receptor, exposure to histamine stimulated the formation of 2-AG, and this effect was augmented in the presence of JZL184. These effects were prevented by the diacylglycerol lipase inhibitor tetrahydrolipstatin. Histamine induced large whole cell currents in HEK293 cells co-expressing TRPV1 and the histamine H1 receptor, and the TRPV1 antagonist capsazepine abolished these currents. JZL184 increased the histamine-induced currents and tetrahydrolipstatin prevented this effect. The calcineurin inhibitor ciclosporin and the endogenous “entourage” compound palmitoylethanolamide potentiated the vasodilator response to 2-arachidonoylglycerol, disclosing TRPV1 activation of this monoacylglycerol at nanomolar concentrations. Furthermore, intracerebroventricular injection of JZL184 produced TRPV1-dependent antinociception in the mouse formalin test. Our results show that intact 2-arachidonoylglycerol and 1-arachidonoylglycerol are endogenous TRPV1 activators, contributing to phospholipase C-dependent TRPV1 channel activation and TRPV1-mediated antinociceptive signaling in the brain.
PMCID: PMC3847081  PMID: 24312564
9.  Dural lesions in decompression for lumbar spinal stenosis: incidence, risk factors and effect on outcome 
European Spine Journal  2011;21(5):825-828.
Decompression for lumbar spinal stenosis is one of the most frequent operations on the spine today. The most common complication seems to be a peroperative dural lesion. There are few prospective studies on this complication regarding incidence and effect on long-term outcome; this is the background for the current study.
Materials and methods
Swespine, the Swedish Spine Register documents the majority (>80%) of lumbar spine operations in Sweden today. Within the framework of this register, totally 3,699 operations for spinal stenosis during a 5-year period were studied regarding complications and 1-year postoperative outcome. Mean patient age was 66 (37–92) years and 44% were males. Fourteen percent were smokers and 19% had undergone previous lumbar spine surgery.
The overall incidence of a peroperative dural lesion was 7.4%, 8.5% of patients undergoing decompressive surgery only and 5.5% of patients undergoing decompressive surgery + fusion (p < 0.001). A logistic regression analysis demonstrated that (high) age (p < 0.0004), previous surgery (p < 0.036) and smoking (p < 0.049) were significantly predictive factors for dural lesions. An odds ratio estimate demonstrated an age-related risk increase with 2.7% per year. The risk for dural lesions also increased with number of levels decompressed. The 1-year outcome was identical in the two groups with and without a dural lesion.
A dural lesion was seen in 7.4% of decompressive operations for spinal stenosis. High age, previous surgery and smoking were risk factors for sustaining a lesion, which, however, did not affect the 1-year outcome negatively.
PMCID: PMC3337897  PMID: 22146791
Spinal stenosis; Complication; Surgery; Outcome
10.  Swespine: the Swedish spine register 
European Spine Journal  2013;22(4):953-974.
Swespine, the Swedish National Spine Register, has existed for 20 years and is in general use within the country since over 10 years regarding degenerative lumbar spine disorders. Today there are protocols for registering all disorders of the entire spinal column.
Materials and methods
Patient-based pre- and postoperative questionnaires, completed before surgery and at 1, 2, 5 and 10 years postoperatively. Among patient-based data are VAS pain, ODI, SF-36 and EQ-5D. Postoperatively evaluation of leg and back pain as compared to preoperatively ("global assessment"), overall satisfaction with outcome and working conditions are registered in addition to the same parameters as preoperatively evaluation. A yearly report is produced including an analytic part of a certain topic, in this issue disc prosthesis surgery.
More than 75,000 surgically treated patients are registered to date with an increasing number yearly. The present report includes 7,285 patients; 1-, 2- and 5-year follow-up data of previously operated patients are also included for lumbar disorders as well as for disc prosthesis surgery.
For the degenerative lumbar spine disorders (disc herniation, spinal stenosis, spondylolisthesis and DDD) significant improvements are seen in all aspects as exemplified by pronounced improvement regarding EQ-5D and ODI. Results seem to be stable over time. Spinal stenosis is the most common indication for spine surgery. Disc prosthesis surgery yields results on a par with fusion surgery in disc degenerative pain. The utility of spine surgery is well documented by the results.
Results of spine surgery as documented on a national basis can be utilized for quality assurance and quality improvement as well as for research purposes, documenting changes over time and bench marking when introducing new surgical techniques. A basis for international comparisons is also laid.
PMCID: PMC3631024  PMID: 23575657
Spine surgery; Outcome; Register; Disc herniation; Spondylolisthesis; Spinal stenosis
11.  Environmental mercury exposure, semen quality and reproductive hormones in Greenlandic Inuit and European men: a cross-sectional study 
Asian Journal of Andrology  2012;15(1):97-104.
Several animal studies indicate that mercury is a male reproductive toxicant, but human studies are few and contradictory. We examined semen characteristics and serum levels of reproductive hormones in relation to environmental exposure to mercury. Blood and semen samples were collected from 529 male partners of pregnant women living in Greenland, Poland and Ukraine between May 2002 and February 2004. The median concentration of the total content of mercury in whole blood was 9.2 ng ml−1 in Greenland (0.2–385.8 ng ml−1), 1.0 ng ml−1 in Poland (0.2–6.4 ng ml−1) and 1.0 ng ml−1 in Ukraine (0.2–4.9 ng ml−1). We found a significantly positive association between the blood levels of mercury and serum concentration of inhibin B in men from Greenland (β=0.074, 95% confidence interval (CI)=0.021 to 0.126) and in an analysis including men from all three regions (β=0.067, 95% CI=0.024 to 0.110). The association may be due to beneficial effects of polyunsaturated fatty acids (PUFAs), which are contained in seafood and fish. No significant association (P>0.05) was found between blood concentrations of mercury and any of the other measured semen characteristics (semen volume, total sperm count, sperm concentration, morphology and motility) and reproductive hormones (free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone and LH×testosterone) in any region. In conclusion, the findings do not provide evidence that environmental mercury exposure in Greenlandic and European men with median whole blood concentration up to 10 ng ml−1 has adverse effects on biomarkers of male reproductive health.
PMCID: PMC3739114  PMID: 23223027
blood mercury concentration; environmental mercury exposure; male fertility; reproduction; reproductive hormones; semen characteristics; semen quality
12.  Prognostic factors in lumbar spinal stenosis surgery 
Acta Orthopaedica  2012;83(5):536-542.
Background and purpose
A considerable number of patients who undergo surgery for spinal stenosis have residual symptoms and inferior function and health-related quality of life after surgery. There have been few studies on factors that may predict outcome. We tried to find predictors of outcome in surgery for spinal stenosis using patient- and imaging-related factors.
Patients and methods
109 patients in the Swedish Spine Register with central spinal stenosis that were operated on by decompression without fusion were prospectively followed up 1 year after surgery. Clinical outcome scores included the EQ-5D, the Oswestry disability index, self-estimated walking distance, and leg and back pain levels (VAS). Central dural sac area, number of levels with stenosis, and spondylolisthesis were included in the MRI analysis. Multivariable analyses were performed to search for correlation between patient-related and imaging factors and clinical outcome at 1-year follow-up.
Several factors predicted outcome statistically significantly. Duration of leg pain exceeding 2 years predicted inferior outcome in terms of leg and back pain, function, and HRLQoL. Regular and intermittent preoperative users of analgesics had higher levels of back pain at follow-up than those not using analgesics. Low preoperative function predicted low function and dissatisfaction at follow-up. Low preoperative EQ-5D scores predicted a high degree of leg and back pain. Narrow dural sac area predicted more gains in terms of back pain at follow-up and lower absolute leg pain.
Multiple factors predict outcome in spinal stenosis surgery, most importantly duration of symptoms and preoperative function. Some of these are modifiable and can be targeted. Our findings can be used in the preoperative patient information and aid the surgeon and the patient in a shared decision making process.
PMCID: PMC3488183  PMID: 23083437
13.  A Nested Case-Control Study of Intrauterine Exposure to Persistent Organochlorine Pollutants and the Risk of Hypospadias 
PLoS ONE  2012;7(9):e44767.
Environmental exposures to endocrine disrupting chemicals have been suggested as a risk factor for male genital abnormalities such as hypospadias. The aim of this case-control study was to investigate the association between fetal exposure to persistent organochlorine pollutants (POP) and the risk for hypospadias.
Methodology/Principal Findings
The Southern Sweden Maternity Cohort (SSMC) contains serum samples collected in early pregnancy among women in Southern Sweden. Linkages with the Medical Birth Register, the Malformation Register and the In-patient Register resulted in 390 SSMC mothers who had given birth to a boy with hypospadias in year 1986–2002 (mean 1995). For 237 of these (cases) sufficient amounts of serum for the chemical analyses were available. For each case, a control boy from the SSMC was randomly selected, matched for maternal age, birth year, parity and maternal smoking. PCB-153, p,p’-DDE and hexachlorbenzene (HCB) were used as biomarkers for POP exposure. The exposures were categorized into quartiles based on the distributions among the controls. There were no statistically significant trends between the a priori categorisation of the exposure variables and the risk for hypospadias. However, when the upper HCB quartile (>26 ng/ml) was compared to the other quartiles an odds ratio of 1.65 (95% CI 1.02 to 2.69) was obtained. p,p′-DDE levels above median (>1.0 ng/ml) compared to levels below 0.1 ng/ml gave an OR of 1.69 (95% CI 0.97 to 2.93).
The present study suggests that fetal exposure to HCB and p,p’-DDE may be a risk factor for hypospadias.
PMCID: PMC3459969  PMID: 23028613
14.  Phthalates and Perfluorooctanesulfonic Acid in Human Amniotic Fluid: Temporal Trends and Timing of Amniocentesis in Pregnancy 
Environmental Health Perspectives  2012;120(6):897-903.
Background: Measures of prenatal environmental exposures are important, and amniotic fluid levels may directly reflect fetal exposures during hypothesized windows of vulnerability.
Objectives: We aimed to detect various phthalate metabolites and perfluorooctanesulfonic acid (PFOS) in human amniotic fluid, to study temporal exposure trends, and to estimate potential associations with gestational week of amniocentesis and maternal age and parity at amniocentesis.
Methods: We studied 300 randomly selected second-trimester amniotic fluid samples from a Danish pregnancy-screening biobank covering 1980 through 1996. We used only samples from male offspring pregnancies. We assayed the environmental pollutants by liquid chromatography/triple quadrupole mass spectrometry and analyzed data using generalized linear regression models.
Results: We detected the di(2-ethylhexyl) phthalate (DEHP) metabolite mono(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP) at a median concentration of 0.27 ng/mL [interquartile range (IQR): 0.20–0.37 ng/mL], the diisononyl phthalate (DiNP) metabolite mono(4-methyl-7-carboxyheptyl) phthalate (7cx-MMeHP) at 0.07 ng/mL (IQR: 0.05–0.11 ng/mL), and PFOS at 1.1 ng/mL (IQR: 0.66–1.60 ng/mL). An increase of 1 calendar year was associated with 3.5% lower [95% confidence interval (CI): –4.8%, –2.1%] 5cx-MEPP levels and with 7.1% higher (95% CI: 5.3%, 9.0%) 7cx-MMeHP levels. For each later gestational week of amniocentesis, 5cx-MEPP was 9.9% higher (95% CI: 4.8%, 15.2%), 7cx-MMeHP was 8.6% higher (95: CI: 2.7%, 14.9%), and PFOS was 9.4% higher (95: CI: 3.3%, 15.9%). We observed no associations with maternal age or parity.
Conclusions: Measured metabolite levels appeared to parallel decreasing DEHP exposure and increasing DiNP exposure during the study period. The environmental pollutant levels were positively associated with later gestational age at amniocentesis during pregnancy weeks 12–22.
PMCID: PMC3385442  PMID: 22398305
amniocentesis; amniotic fluid; biobank; biomonitoring; perfluorinated compounds; phthalates; pregnancy; temporal trend
15.  Association between Pregnancy Loss and Urinary Phthalate Levels around the Time of Conception 
Environmental Health Perspectives  2011;120(3):458-463.
Background: Animal studies indicate that some phthalate metabolites may harm female reproductive function.
Objectives: We assessed the associations between exposure to phthalate metabolites and pregnancy loss.
Methods: Using a previously established cohort of couples planning their first pregnancy, we analyzed four primary and two oxidized secondary phthalate metabolites in urine samples collected on day 10 after the first day of the last menstrual period before conception occurred (n = 128) and during the previous cycle (if any, n = 111). Subclinical embryonal loss was identified by repeated measurement of urinary human chorionic gonadotropin, and information on clinical spontaneous abortions was obtained by telephone interview with the mother.
Results: Pregnancy loss (n = 48) was increased among women with urinary concentration of monoethylhexyl phthalate (MEHP) in the upper tertile in the conception sample compared with women in the lowest tertile [adjusted odds ratio (OR) = 2.9; 95% confidence interval (CI): 1.1, 7.6]. The corresponding OR for subclinical embryonal loss (n = 32) was 40.7 (95% CI: 4.5, 369.5).
Conclusions: The phthalate metabolite MEHP was associated with higher occurrence of pregnancy loss. Because this is the first human study to show this association and the sample size is small, the findings need to be corroborated in independent studies.
PMCID: PMC3295336  PMID: 22113848
abortion; MEHP; phthalates; pregnancy loss
16.  Searching for early breast cancer biomarkers by serum protein profiling of pre-diagnostic serum; a nested case-control study 
BMC Cancer  2011;11:381.
Serum protein profiles have been investigated frequently to discover early biomarkers for breast cancer. So far, these studies used biological samples collected at or after diagnosis. This may limit these studies' value in the search for cancer biomarkers because of the often advanced tumor stage, and consequently risk of reverse causality. We present for the first time pre-diagnostic serum protein profiles in relation to breast cancer, using the Prospect-EPIC (European Prospective Investigation into Cancer and nutrition) cohort.
In a nested case-control design we compared 68 women diagnosed with breast cancer within three years after enrollment, with 68 matched controls for differences in serum protein profiles. All samples were analyzed with SELDI-TOF MS (surface enhanced laser desorption/ionization time-of-flight mass spectrometry). In a subset of 20 case-control pairs, the serum proteome was identified and relatively quantified using isobaric Tags for Relative and Absolute Quantification (iTRAQ) and online two-dimensional nano-liquid chromatography coupled with tandem MS (2D-nanoLC-MS/MS).
Two SELDI-TOF MS peaks with m/z 3323 and 8939, which probably represent doubly charged apolipoprotein C-I and C3a des-arginine anaphylatoxin (C3adesArg), were higher in pre-diagnostic breast cancer serum (p = 0.02 and p = 0.06, respectively). With 2D-nanoLC-MS/MS, afamin, apolipoprotein E and isoform 1 of inter-alpha trypsin inhibitor heavy chain H4 (ITIH4) were found to be higher in pre-diagnostic breast cancer (p < 0.05), while alpha-2-macroglobulin and ceruloplasmin were lower (p < 0.05). C3adesArg and ITIH4 have previously been related to the presence of symptomatic and/or mammographically detectable breast cancer.
We show that serum protein profiles are already altered up to three years before breast cancer detection.
PMCID: PMC3189190  PMID: 21871081
Biomarkers; Breast cancer; Early diagnosis; 2D-nanoLC-MS/MS; Prospective; Proteomics; SELDI-TOF MS
17.  Correlation between disability and MRI findings in lumbar spinal stenosis 
Acta Orthopaedica  2011;82(2):204-210.
Background and purpose
MRI is the modality of choice when diagnosing spinal stenosis but it also shows that stenosis is prevalent in asymptomatic subjects over 60. The relationship between preoperative health-related quality of life, functional status, leg and back pain, and the objectively measured dural sac area in single and multilevel stenosis is unknown. We assessed this relationship in a prospective study.
Patients and methods
The cohort included 109 consecutive patients with central spinal stenosis operated on with decompressive laminectomy or laminotomy. Preoperatively, all patients completed the questionnaires for EQ-5D, SF-36, Oswestry disability index (ODI), estimated walking distance and leg and back pain (VAS). The cross-sectional area of the dural sac was measured at relevant disc levels in mm2, and spondylolisthesis was measured in mm. For comparison, the area of the most narrow level, the number of levels with dural sac area < 70 mm2, and spondylolisthesis were studied.
Before surgery, patients with central spinal stenosis had low HRLQoL and functional status, and high pain levels. Patients with multilevel stenosis had better general health (p = 0.04) and less leg and back pain despite having smaller dural sac area than patients with single-level stenosis. There was a poor correlation between walking distance, ODI, the SF-36, EQ-5D, and leg and back pain levels on the one hand and dural sac area on the other. Women more often had multilevel spinal stenosis (p = 0.05) and spondylolisthesis (p < 0.001). Spondylolisthetic patients more often had small dural sac area (p = 0.04) and multilevel stenosis (p = 0.06).
Our findings indicate that HRQoL, function, and pain measured preoperatively correlate with morphological changes on MRI to a limited extent.
PMCID: PMC3235292  PMID: 21434811
18.  Dural lesions in lumbar disc herniation surgery: incidence, risk factors, and outcome 
European Spine Journal  2009;19(3):439-442.
In lumbar disc herniation surgery, dural lesions seem to be the most common complication today. Studies on incidence of and outcome after a dural lesion are mainly based on retrospective studies. In a prospective study within the framework of the Swedish Spine Register, 4,173 patients operated on for lumbar disc herniation were evaluated using pre- and 1-year postoperative protocols and complication registration. Mean patient age was 41 (18–81) years and 53% of the patients were male. 93% of the operations were performed on the two lowermost lumbar levels. The incidence of dural lesions in the material was 2.7%. In patients with previous disc surgery, the incidence was doubled, 5%, a significant increase (P = 0.02). Patients with dural lesions preoperatively had more back pain and inferior scores in general health and role emotional domains of the SF-36. These factors, however, were because they had been operated on previously, not related to the dural lesion as such. The relative improvement after surgery was similar whether a dural lesion had occurred or not. It is concluded that a dural lesion is a technical complication which must be solved at the time of surgery but which does not bear any negative implications on the long-term outcome for the patient.
PMCID: PMC2899750  PMID: 20013002
Lumbar disc herniation; Complication; Surgery; Outcome
19.  TRPV1 in Brain Is Involved in Acetaminophen-Induced Antinociception 
PLoS ONE  2010;5(9):e12748.
Acetaminophen, the major active metabolite of acetanilide in man, has become one of the most popular over-the-counter analgesic and antipyretic agents, consumed by millions of people daily. However, its mechanism of action is still a matter of debate. We have previously shown that acetaminophen is further metabolized to N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z -eicosatetraenamide (AM404) by fatty acid amide hydrolase (FAAH) in the rat and mouse brain and that this metabolite is a potent activator of transient receptor potential vanilloid 1 (TRPV1) in vitro. Pharmacological activation of TRPV1 in the midbrain periaqueductal gray elicits antinociception in rats. It is therefore possible that activation of TRPV1 in the brain contributes to the analgesic effect of acetaminophen.
Methodology/Principal Findings
Here we show that the antinociceptive effect of acetaminophen at an oral dose lacking hypolocomotor activity is absent in FAAH and TRPV1 knockout mice in the formalin, tail immersion and von Frey tests. This dose of acetaminophen did not affect the global brain contents of prostaglandin E2 (PGE2) and endocannabinoids. Intracerebroventricular injection of AM404 produced a TRPV1-mediated antinociceptive effect in the mouse formalin test. Pharmacological inhibition of TRPV1 in the brain by intracerebroventricular capsazepine injection abolished the antinociceptive effect of oral acetaminophen in the same test.
This study shows that TRPV1 in brain is involved in the antinociceptive action of acetaminophen and provides a strategy for developing central nervous system active oral analgesics based on the coexpression of FAAH and TRPV1 in the brain.
PMCID: PMC2941447  PMID: 20862299
20.  Association of maternal serum concentrations of 2,2', 4,4'5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE) levels with birth weight, gestational age and preterm births in Inuit and European populations 
Environmental Health  2010;9:56.
Epidemiological studies on the association between maternal exposure to persistent organic pollutants (POPs) and fetal growth alteration report inconsistent findings which weights in favor of additional studies.
Blood samples were collected from interviewed pregnant women in Greenland (572), Kharkiv (611) and Warsaw (258) and were analyzed for CB-153 and p,p'-DDE by gas chromatography-mass spectrometry. Data on birth weight, gestational age and preterm birth were obtained for 1322 singleton live births. We examined the association between natural log-transformed serum POPs concentration and birth weight and gestational age using multiple linear regression and the association with prematurity using logistic regression controlling for potential confounding factors.
The median serum concentrations of CB-153 and p,p'-DDE were for Inuit mothers 105.6 and 298.9, for Kharkiv mothers 27.0 and 645.4 and for Warsaw mothers 10.7 and 365.2 ng/g lipids, respectively. Increase in CB-153 concentration by one unit on the log scale in Inuit mothers serum was associated with significant decrease in infant birth weight of -59 g and gestational age by -0.2 week. Decreases observed in the cohorts in Kharkiv (-10 g and -0.1 week) and in Warsaw (-49 g and -0.2 week) were not statistically significant. Increase in p,p'-DDE concentration by one unit on the log scale was associated with a statistically significant decrease in infant birth weight of -39.4 g and -104.3 g and shortening of gestational age of -0.2 week and -0.6 week in the Inuit and Warsaw cohorts, respectively. In the Kharkiv cohort decrease in birth weight (-30.5 g) was not significant, however a shortening of gestational age of -0.2 week per increase in p,p'-DDE concentration by one unit on the log scale was of the borderline significance. There was no significant association between CB-153 and p,p'-DDE concentrations and risk of preterm birth however, in all cohorts the odds ratio was above 1.
In utero exposure to POPs may reduce birth weight and gestational age of newborns however, new insights as to why results vary across studies were not apparent.
PMCID: PMC2944244  PMID: 20819217
21.  A Nested Case-Control Study of Intrauterine Exposure to Persistent Organochlorine Pollutants in Relation to Risk of Type 1 Diabetes 
PLoS ONE  2010;5(6):e11281.
The incidence of type 1 diabetes in Europe is increasing at a rate of about 3% per year and there is also an increasing incidence throughout the world. Type 1 diabetes is a complex disease caused by multiple genetic and environmental factors. Persistent organochlorine pollutants (POPs) have been suggested as a triggering factor for developing childhood type 1 diabetes. The aim of this case-control study was to assess possible impacts of in utero exposure to POPs on type 1 diabetes.
Methodology/ Principal Findings
The study was performed as a case-control study within a biobank in Malmö, a city located in the Southern part of Sweden. The study included 150 cases (children who had their diagnosis mostly before 18 years of age) and 150 controls, matched for gender and day of birth. 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB-153) and the major DDT metabolite 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p′-DDE) were used as a biomarkers for POP exposure. When comparing the quartile with the highest maternal serum concentrations of PCB-153 with the other quartiles, an odds ratio (OR) of 0.73 (95% confidence interval [CI] 0.42, 1.27) was obtained. Similar results was obtained for p,p′-DDE (OR 0.56, 95% CI 0.29, 1.08).
The hypothesis that in utero exposure to POPs will trigger the risk for developing type 1 diabetes was not supported by the results. The risk estimates did, although not statistically significant, go in the opposite direction. However, it is not reasonable to believe that exposure to POPs should protect against type 1 diabetes.
PMCID: PMC2890585  PMID: 20585661
22.  Fetal loss and maternal serum levels of 2,2',4,4',5,5'-hexachlorbiphenyl (CB-153) and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) exposure: a cohort study in Greenland and two European populations 
Environmental Health  2010;9:22.
In the present study, the aim is to examine the risk of fetal loss related to environmental 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) or 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) exposure.
We related LC/MS/MS measurements of CB-153 and p,p'-DDE in serum samples to interview-data on previous fetal loss in populations of pregnant women from Poland, Ukraine and Greenland.
In total, 1710 women were interviewed, and 678 of these had at least one previous pregnancy. The risk of ever experiencing a fetal loss increased at higher levels of CB-153 and p,p'-DDE exposure, with an adjusted odds ratio (OR) of 2.4; confidence interval (CI) (1.1-5.5) for CB-153>200 ng/g lipid compared to 0-25 ng CB-153/g lipid and OR of 2.5 CI (0.9-6.6) for p,p'-DDE>1500 ng/g lipid compared to 0-250 ng DDE/g lipid. However, no clear dose response associations were observed. The results further suggest that high level of organochlorine serum concentrations may be related to repeated loss.
The risk of fetal loss may increase at higher levels of CB-153 and p,p'-DDE exposure, although lack of dose response and inconsistencies between countries did not allow for firm conclusions.
PMCID: PMC2877014  PMID: 20459724
23.  The Swedish Spine Register: development, design and utility 
European Spine Journal  2009;18(Suppl 3):294-304.
The Swedish Spine Register enables monitoring of surgical activities focusing on changes in trends over time, techniques utilized and outcome, when implemented in general clinical practice. Basic requirements for a prosperous register are unity within the profession, mainly patient-based documentation and a well functioning support system. This presentation focuses on the development and design of the register protocol, problems encountered and solutions found underway. Various examples on how the results can be presented and utilized are given as well as validation. Register data demonstrate significant gender differences in lumbar disc herniation surgery with females having more pain, lower quality of life and more pronounced disability preoperatively while improvement after surgery is similar between genders. Quality of life after surgery for degenerative disorders is significantly improved for disc herniation, stenosis, spondylolisthesis and disc degenerative disorders. Over the last 10 years, surgical treatment for spinal stenosis has increased gradually while disc herniation surgery decreases regarding yearly number of procedures. An added function to the register enables more complex prospective clinical studies to include register data together with data suitable for the individual study. A common core set of demographic, surgical and outcome parameters would enable comparisons of clinical studies within and between nations.
PMCID: PMC2899320  PMID: 19495812
Spine Register; Development; Degenerative lumbar spine; Core data set
24.  Fertility and Markers of Male Reproductive Function in Inuit and European Populations Spanning Large Contrasts in Blood Levels of Persistent Organochlorines 
Environmental Health Perspectives  2007;116(3):269-277.
We synthesized the main findings from an international epidemiologic study on the impact of biopersistent organic pollutants (POPs) on human reproductive function.
Data sources and extraction
We used a database with interview and biological data from 2,269 women and their spouses, and 18 published core papers.
Data synthesis
The study did not provide direct evidence of hormone-like activity of the polychlorinated biphenyl (PCB) congener CB-153 and the main dichlorodiphenyltrichloroethane (DDT) metabolite, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p′-DDE), as serum concentrations of these compounds were not consistently related to either endogenous or exogenous hormone activity in serum. Nevertheless several links bewteen POP exposure and biomarkers of male reproductive function were identified. First, an association between high CB-153 serum levels and low sperm counts was detected within a subgroup of men with short androgen receptor CAG repeat length. Second, a relationship between increased CB-153 serum concentrations and decreased sperm motility was seen in all four studied regions, and indications of reduced neutral α-glucosidase activity in seminal plasma point to a post-testicular effect. Third, damage of sperm chromatin integrity was considerably less frequent in Greenlandic Inuits compared with that in European groups, and only in the latter was impairment of sperm chromatin integrity related to POPs. Despite these effects, fertility in terms of time taken to conceive was not related to POPs except in Inuits. A likely explanation of the latter was not identified.
POPs may interfere with male reproductive function without major impact on fertility. The data do not provide direct evidence for endocrine disruption, hence other mechanisms should also be considered.
PMCID: PMC2265036  PMID: 18335090
Inuit; polymorphisms; reproductive health; semen quality; sex hormone receptors; time to pregnancy; xenobiotics
25.  Dietary exposure to methyl mercury and PCB and the associations with semen parameters among Swedish fishermen 
Environmental Health  2007;6:14.
Dietary POP exposure have shown negative effects on sperm motility and sperm chromatin integrity, as well as an increased proportion of Y-chromosome bearing sperms. However, it has been suggested that in epidemiological studies investigating persistent organochlorine pollutant (POP)-toxicity, other pollutants occurring simultaneously may carry an increased risk of effects, which may obscure a clear interpretation of the role of POP toxicity. One such pollutant is methyl mercury (MeHg), which has been found in fatty fish from the Baltic Sea and as a consequence men with a high consumption of such fish has been found to have twice the MeHg levels compared to men with a low fish consumption.
The aim of the present study was to assess if exposure to MeHg affects male reproductive function, assessed by measuring human sperm motility, sperm concentration, total sperm count, sperm chromatin integrity and the proportion of Y-chromosome bearing sperms. Secondly we also investigated a possible interaction between MeHg and 2, 2', 4, 4', 5, 5'-hexachlorobiphenyl (CB-153), a biomarker for POP exposure, with respect to sperm outcome measures.
Blood and semen samples were collected from 195 Swedish fishermen with a mean age of 47 (range 24–67 years). Blood levels of MeHg ranged from 0.11 to 16.59 μg/L (median 2.25 μg/L) and serum levels of CB-153 from 37 to 1460 ng/g lipid (median 190 ng/g lipid).
The analyses revealed no association between MeHg and any of the outcomes investigated. Although men with low MeHg and high CB-153 had slightly higher DNA Fragmentation Index and fraction of Y-chromosome bearing sperms than men with low levels of both compounds, the effects were not statistically significant. In conclusion, we did not find any associations between MeHg exposure and semen quality or quantity in the dose range observed neither was any synergistic effects between MeHg and CB-153 noted.
PMCID: PMC1871583  PMID: 17488503

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