Cosmetic Breast Augmentation with Autologous Ex Vivo-Expanded Adipose-Derived Mesenchymal Stem/Stromal Cell (Stemform®)-Enriched Fat Grafts: A Study of the First Twenty-Two Real-World Patients.

BACKGROUND: Fat grafting is commonly utilized in breast surgery, and since it was first described, clinicians and researchers have stridden towards improvement of graft retention. Current advancements include adding adipose-derived mesenchymal stem/stromal cells (MSC(AT)s), which have demonstrated promise for improved graft retention. OBJECTIVES: This study reports outcomes for the first twenty-two patients undergoing breast augmentation (Stemform BA) or artificial implant replacement (Stemform AIR) with MSC(AT)-enriched fat in a real-world setting. METHODS: Autologous MSC(AT)s were isolated and expanded ex vivo, then mixed with lipoaspirate and injected as enriched fat for Stemform BA and AIR. The breast volume was measured preoperatively and at 3 and 12 months postoperative using a 3D Infinity Dual-Lens Camera and LifeVizApp software. Additionally, independent plastic surgeons evaluated clinical images, and patient satisfaction was obtained at equal time points. RESULTS: Twenty-two patients were included. All completed 3 and 12 months clinical follow-up and 3 months volume measurements. Nineteen patients completed 12 months volume measurements. The median fat graft retention at 12 months was 95.7% (IQR = 82.44-103.12%) for Stemform BA patients and 113.0% (IQR = 94.8-131.2%) for Stemform AIR patients. The Stemform BA patients had a median breast enlargement of 172.0% (IQR = 156.7-241.0%). The implant replacement volume of Stemform AIR patients was 102% (IQR = 85.1-130.3%). The patient reported 92.8% and 100% would elect to repeat treatment if they had the opportunity for Stemform BA and Stemform AIR, respectively. CONCLUSION: Breast augmentation and breast implant replacement patients receiving ex vivo-expanded MSC(AT)-enriched fat grafts had high graft retention and patient satisfaction scores. The paper confirms the clinical efficacy of using ex vivo-expanded MSC(AT)s. Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

PVC flooring at home and uptake of phthalates in pregnant women.

Phthalates are used as plasticizers in polyvinyl chloride (PVC) materials and it is known that phthalates may migrate into the surrounding environment and then become a source for human uptake. The aim of the study was to investigate whether residential PVC flooring was related to the urinary levels of phthalate metabolites determined in pregnant women. The data were from the Swedish SELMA study where sampling was conducted during the time period 2007-2010. Spot urine samples from 1674 women at the end of the first trimester were analyzed for 14 metabolites from seven phthalates and one phthalate alternative. Data on flooring material in the kitchen and the parents' bedrooms as well as potential confounders were collected by postal questionnaires at the same time as the urine samples were taken. Multiple regression modeling by least square geometric mean and weighted quantile sum regression was applied to log-transformed and creatinine-adjusted phthalate metabolite concentrations adjusted for potential confounders from questionnaire data. This study has found significantly higher urinary levels of the BBzP metabolite (MBzP) in pregnant women living in homes with PVC flooring as compared to homes with other flooring materials.

Occupational exposure to asphalt mixture during road paving is related to increased mitochondria DNA copy number: a cross-sectional study.

BACKGROUND: Asphalt workers are exposed to polyaromatic hydrocarbons (PAHs) from hot mix asphalt via both inhalation and dermal absorption. The use of crumb rubber modified (CRM) asphalt may result in higher exposure to PAHs and more adverse effects. Our aim is to assess occupational exposure to PAHs from conventional and CRM asphalt paving by measuring PAH metabolites in urine, and to investigate the effects on mitochondrial DNA copy number (mtDNAcn) and telomere length. METHODS: We recruited 116 workers paving conventional asphalt, 51 workers paving CRM asphalt and 100 controls in Sweden, all males. A repeated-measures analysis included 31 workers paving both types of asphalt. Urine and blood samples were collected pre-working on Monday morning and post-working on Thursday afternoon after 4 days working. PAH metabolites: 1-hydroxypyrene (1-OH-PYR) and 2-hydroxyphenanthrene (2-OH-PH) were measured in urine by LC-MS/MS. Relative mtDNAcn and telomere length were measured by quantitative PCR. RESULTS: Conventional and CRM asphalt workers showed higher 1-OH-PYR and 2-OH-PH than controls (p < 0.001 for all). Relative mtDNAcn were 0.21 units (p < 0.001) higher in conventional asphalt workers and 0.13 units (p = 0.010) higher in CRM asphalt workers compared to controls. Relative telomere length did not differ across occupational groups, but it was positively associated with increment of 2-OH-PH (ß = 0.075, p = 0.037) in asphalt workers. The repeated-measures analysis showed no difference in either increment of 1-OH-PYP, or changes in effect biomarkers (mtDNAcn or telomere length) between paving with conventional and CRM asphalt. Increment of 2-OH-PH was smaller after paving with CRM asphalt. CONCLUSIONS: Road asphalt paving in open areas resulted in PAHs exposure, as shown by elevation of PAH metabolites in urine. Asphalt workers may experience oxidative stress, evidenced by alternation in mtDNAcn; however the effects could not be fully explained by exposure to PAHs from the asphalt mixture.

Accuracy of Clinical Tests in Detecting Disk Herniation and Nerve Root Compression in Subjects With Lumbar Radicular Symptoms.

OBJECTIVES: To investigate the accuracy of 3 commonly used neurodynamic tests (slump test, straight-leg raise [SLR] test, femoral neurodynamic test) and 2 clinical assessments to determine radiculopathy (radiculopathy I, 1 neurologic sign; radiculopathy II, 2 neurologic signs corresponding to 1 specific nerve root) in detecting magnetic resonance imaging (MRI) findings (extrusion, subarticular nerve root compression, and foraminal nerve root compression). DESIGN: Validity study. SETTING: Secondary care. PARTICIPANTS: We included subjects (N=99; mean age, 58y; 54% women) referred for epidural steroid injection because of lumbar radicular symptoms who had positive clinical and MRI findings. Positive clinical findings included the slump test (n=67), SLR test (n=50), femoral neurodynamic test (n=7), radiculopathy I (n=70), and radiculopathy II (n=33). Positive MRI findings included extrusion (n=27), subarticular nerve compression (n=14), and foraminal nerve compression (n=25). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Accuracy of clinical tests in detecting MRI findings was evaluated using sensitivity, specificity, and receiver operating characteristics analysis with area under the curve (AUC). RESULTS: The slump test had the highest sensitivity in detecting extrusion (.78) and subarticular nerve compression (1.00), but the respective specificity was low (.36 and .38). Radiculopathy I was most sensitive in detecting foraminal nerve compression (.80) but with low specificity (.34). Only 1 assessment had a concurrent high sensitivity and specificity (ie, radiculopathy II) in detecting subarticular nerve compression (.71 and .73, respectively). The AUC for all tests in detecting extrusion, subarticular nerve compression, and foraminal nerve compression showed ranges of .48 to .60, .63 to .82, and .33 to .57, respectively. CONCLUSIONS: In general, the investigated neurodynamic tests or assessments for radiculopathy lacked diagnostic accuracy. The slump test was the most sensitive test, while radiculopathy II was the most specific test. Most interestingly, no relationship was found between any neurodynamic test and foraminal nerve compression (foraminal stenosis) as visualized on MRI.

Prenatal phthalate exposure was associated with croup in Swedish infants.

AIM: This study examined whether prenatal phthalate exposure was associated with lower or upper airway inflammation in infants. METHODS: From 2007 to 2010, we used liquid chromatography-tandem mass spectrometry, adjusted for creatinine, to analyse 14 phthalate metabolites and one phthalate replacement in the urine of 1062 Swedish mothers at a median of 10 weeks of pregnancy. This was used to determine any associations between prenatal phthalate exposure and croup, wheezing or otitis in their offspring until 12 months of age, using logistic regression, adjusted for potential confounders. RESULTS: There were significant associations between phthalate metabolites of butyl-benzyl phthalate (BBzP) and di-ethyl-hexyl phthalate (DEHP) concentrations in maternal prenatal urine and croup in 1062 infants during the first year of life, when adjusted for potential confounders. A dose-response relationship was found between prenatal phthalates exposure and maternal reported croup in the children, with a significant association in boys. There was no clear indication with regard to associations between prenatal phthalate exposure and wheezing or otitis media in the children during the first year of life. CONCLUSION: Our analysis suggests that exposure to BBzP and DEHP phthalates was associated with maternal reports of croup in infants up to 12 months of age.

Female exposure to phthalates and time to pregnancy: a first pregnancy planner study.

STUDY QUESTION: Is female exposure to phthalate metabolites associated with reduced fecundity, as estimated by prolonged time to pregnancy (TTP)? SUMMARY ANSWER: Female exposure to monoethyl phthalate (MEP) but not monobutyl phthalate (MBP), monobenzyl phthalate (MBzP) and monoethylhexyl phthalate (MEHP) was associated with a longer TTP. WHAT IS KNOWN ALREADY: Male exposure to phthalates is potentially associated with adverse effects on human fecundity in epidemiological studies, but little is known about the potential effects on female reproduction. STUDY DESIGN SIZE AND DURATION: A cohort study with prospective data based on 229 women from a Danish cohort of 430 first pregnancy planning couples enrolled in 1992-1994. In 2009, urinary analyses of phthalate metabolites were performed on stored urine samples from this cohort. PARTICIPANTS/MATERIALS, SETTING AND METHODS: We analyzed MEP, MBP, MBzP and MEHP in female morning spot urine samples collected daily during the first 10 days of menstrual cycles after discontinuation of contraception. The exposure assessment was based on the mean of two measurements from each woman collected in a period of 6 menstrual cycles. We used Cox regression with discrete time to estimate fecundability ratios (FRs) and 95% CI in relation to the average urine metabolite concentration exposure level, controlled for age and BMI, and the time-varying variables smoking and alcohol. MAIN RESULT AND ROLE OF CHANCE: Urinary concentration of MEP was associated with a decreased fecundity (adjusted FR 0.79; 95% CI: 0.63; 0.99) corresponding to a 21% decreased probability of conception for each natural log (ln) unit increase in MEP. No significant association with TTP was found for MBP, MBzP and MEHP. LIMITATIONS REASONS FOR CAUTION: Subfertile women were overrepresented in the study population due to exclusion of 77 high fertile women who became pregnant in the first cycle when urine collection began. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that female exposure to MEP may have an adverse effect on female fecundity, but these findings need to be replicated in a larger and newer cohort study with sufficient exposure contrast if the use of diethyl phthalate (DEP) and thereby MEP in the future potentially should be regulated in cosmetics and industrial consumer products. STUDY FUNDING/COMPETING INTERESTS: The original data collected were founded by Aarhus University Research Foundation, the Danish Medical Research Council and the Danish Medical Health Insurance Foundation. There are no conflicts of interest to be declared. TRIAL REGISTRATION NUMBER: N/A.

Diverging temporal trends of human exposure to bisphenols and plastizisers, such as phthalates, caused by substitution of legacy EDCs?

Phthalates and phenolic substances were investigated in urine samples from first-time mothers in Uppsala, Sweden, collected between 2009 and 2014. These substances have a comparably fast metabolism and urinary metabolites are predominantly analysed. The main aim was to investigate if measures to decrease production and use of certain phthalates and bisphenol A (BPA) have resulted in decreased human exposure, and to determine if exposures to replacement chemicals have increased. Temporal trends were evaluated for metabolites (n=13) of seven phthalates, a phthalate replacer, four different bisphenols, triclosan, one organophosphate-based flame retardant, and for two pesticides. The results showed downward trends of several phthalates which are in the process of being regulated and phased out. Concomitantly, an increasing trend was seen for a metabolite of the phthalate replacer Di-iso-nonylcyclohexane 1,2-dicarboxylate (DiNCH). Bisphenol A (BPA) showed a downward trend, whereas bisphenol F, identified as one of the substitutes for BPA, showed an increasing trend. The decreasing trend of triclosan is likely due to declining use within the EU. Temporal trend studies of urine samples make it possible to investigate human exposure to rapidly metabolised substances and study how measures taken to regulate and replace problematic chemicals affect human exposure.

Acute respiratory effects and biomarkers of inflammation due to welding-derived nanoparticle aggregates.

PURPOSE: Welders are exposed to airborne particles from the welding environment and often develop symptoms work-related from the airways. A large fraction of the particles from welding are in the nano-size range. In this study we investigate if the welders' airways are affected by exposure to particles derived from gas metal arc welding in mild steel in levels corresponding to a normal welding day. METHOD: In an exposure chamber, 11 welders with and 10 welders without work-related symptoms from the lower airways and 11 non-welders without symptoms, were exposed to welding fumes (1 mg/m3) and to filtered air, respectively, in a double-blind manner. Symptoms from eyes and upper and lower airways and lung function were registered. Blood and nasal lavage (NL) were sampled before, immediately after and the morning after exposure for analysis of markers of oxidative stress. Exhaled breath condensate (EBC) for analysis of leukotriene B4 (LT-B4) was sampled before, during and immediately after exposure. RESULTS: No adverse effects of welding exposure were found regarding symptoms and lung function. However, EBC LT-B4 decreased significantly in all participants after welding exposure compared to filtered air. NL IL-6 increased immediately after exposure in the two non-symptomatic groups and blood neutrophils tended to increase in the symptomatic welder group. The morning after, neutrophils and serum IL-8 had decreased in all three groups after welding exposure. Remarkably, the symptomatic welder group had a tenfold higher level of EBC LT-B4 compared to the two groups without symptoms. CONCLUSION: Despite no clinical adverse effects at welding, changes in inflammatory markers may indicate subclinical effects even at exposure below the present Swedish threshold limit (8 h TWA respirable dust).

Determinants of patient satisfaction after surgery for central spinal stenosis without concomitant spondylolisthesis: a register study of 5100 patients.

PURPOSE: Satisfaction with the outcome of treatment is a widely used outcome measure but information about the determinants of patient satisfaction after surgery for central spinal stenosis (CSS) are lacking. The aim of the study was to analyze determinants of patient satisfaction 1 year after surgery for CSS without degenerative spondylolisthesis (DS). METHODS: This prospective register study included 5100 patients operated for CSS without DS. 88 % received decompression only (D) and 12 % had decompression and fusion (DF). The patient reported outcome measures were the EuroQol-5D, the Short-Form 36, the visual analogue scale for leg and back pain, the Oswestry disability index and the self-estimated walking distance. Logistic regression reporting odds ratios (OR) for being satisfied was utilized. RESULTS: There were significant baseline differences between satisfied and dissatisfied patients in all patient reported outcome measures except leg pain. Factors decreasing the likelihood for satisfaction included previous spine surgery OR: 0.4 (95 % CI: 0.3-0.5), smoking OR: 0.6 (95 % CI: 0.4-0.8), unemployment OR: 0.6 (95 % CI: 0.4-0.9), back pain exceeding 1 year OR: 0.6 (95 % CI: 0.4-0.9), back pain predominance OR: 0.7 (95 % CI: 0.5-0.8). Fusion surgery did not predict satisfaction OR: 1.3 (95 % CI: 0.9-1.9). Preoperative self-estimated walking distance >1000 m predicted satisfaction, OR: 2.4 (95 %: 1.6-3.6). CONCLUSIONS: Numerous factors have predictive value for satisfaction of outcome after surgery for CSS without DS. The results from this study can constitute background data in the shared decision making process when discussing surgery with patients suffering from CSS.

Aggregation of Calcium Silicate Hydrate Nanoplatelets.

We study the aggregation of calcium silicate hydrate nanoplatelets on a surface by means of Monte Carlo and molecular dynamics simulations at thermodynamic equilibrium. Calcium silicate hydrate (C-S-H) is the main component formed in cement and is responsible for the strength of the material. The hydrate is formed in early cement paste and grows to form platelets on the nanoscale, which aggregate either on dissolving cement particles or on auxiliary particles. The general result is that the experimentally observed variations in these dynamic processes generically called growth can be rationalized from interaction free energies, that is, from pure thermodynamic arguments. We further show that the surface charge density of the particles determines the aggregate structures formed by C-S-H and thus their growth modes.

Cotinine Validation of Self-Reported Smoking During Pregnancy in the Swedish Medical Birth Register.

INTRODUCTION: Self-reported data on smoking during pregnancy from the Medical Birth Register of Sweden (MBR) are widely used. However, underreporting of such behavior may occur, leading to biases. It is of importance to validate the smoking data in the MBR. The main objective was to investigate the agreement between self-reported smoking data from the MBR and cotinine levels in maternal serum among women from the general population in the region of Skåne, Sweden. We also estimated the transfer of cotinine from mother to fetus. METHODS: From a cohort used previously to investigate the relationship between intrauterine environmental exposures and offspring neuropsychiatric outcomes, there were 204 control children retrieved from the MBR with data on maternal smoking in early pregnancy registered. Data on maternal and umbilical cord cotinine at delivery were available for these children from a regional biobank. RESULTS: There was a high agreement between cotinine levels and MBR smoking data (κ = 0.82) and a high correlation between cotinine levels in maternal and umbilical cord serum (r s = 0.90, P < .001). Of the self-reported nonsmokers, 95% (95% confidence interval: 89% to 97%) were classified as nonsmokers after cotinine measurements. CONCLUSION: In these data, we found that the agreement between mothers' self-reported smoking habits during pregnancy and their levels of serum cotinine was high, as was the transfer of cotinine from mother to fetus. This indicates that birth register data on pregnancy smoking in Sweden could be considered a valid measure.

Gender differences in the surgical treatment of lumbar disc herniation in elderly.

PURPOSE: Outcome after lumbar disc herniation (LDH) surgery in middle-aged patient is usually reported to fulfill the criteria for successful outcome. It is also known that women in these years have an inferior outcome compared to men. This study evaluates whether the same gender differences exist in elderly. METHOD: In the national Swedish register for spine surgery (SweSpine) we identified 1668 patients ≥65 years. 1250 of these patients had both pre- and 1-year postoperative data registered, 53 % males with mean age 70.6 ± 5.0 (mean ± SD) and 47 % females with mean age 71.3 ± 5.2. All were surgically treated due to LDH between 2000 and 2012. RESULTS: Before surgery both men and women had severe impairment, compared to normative data, in all patient-reported outcome measures (PROMs), with women having inferior status to men. Improvement by surgery was similar in both genders but neither of them reached normative values in quality of life as compared to normative age-matched individuals. As a consequence of this women 1 year after surgery had more back and leg pain, higher consumption of analgesics, greater impairment in walking distance and inferior scoring in virtually all registered PROMs compared to men (all p < 0.005). In spite of this women were as satisfied with the surgical outcome as the men. CONCLUSION: Elderly women with LDH surgery report inferior outcome compared to males, mainly as a result of being referred to surgery with an inferior status but are despite this as satisfied with outcome as the men.

Gender differences in patients scheduled for lumbar disc herniation surgery: a National Register Study including 15,631 operations.

PURPOSE: Previous studies have shown gender differences in preoperative status and outcome of spine surgery. This study explores whether gender differences in preoperative demographics exist in patients scheduled for lumbar disc herniation (LDH) surgery. METHODS: This study includes the preoperative data of the 15,631 patients operated for LDH between years 2000 and 2010, registered in the national Swedish spine register (SweSpine). We analysed preoperative gender differences in age, smoking habits, walking distance, consumption of analgesics, back and leg pain (Visual Analogue Scale; VAS), quality of life (EuroQol; EQ 5D and Short Form-36 Questionnaire; SF-36) and disability (Oswestry Disability Index; ODI). RESULTS: 44 % of the patients were women (mean age 45 ± 13) and 56 % men (mean age 44 ± 13). More women than men were smokers (26 versus 21 %, p < 0.001). Women also reported inferior walking ability (less than 100 metre walking ability 37 vs 30 %; p < 0.001), consumed more analgesics (92 versus 84 %; p < 0.001), reported higher level of pain (mean difference VAS leg 6 (95 % CI 5-7)), had inferior health-related quality of life (mean difference EQ 5D 0.07 (95 % CI 0.05-0.08)) and had higher disability (mean difference ODI 6 (95 % CI 5-6)). CONCLUSIONS: Women scheduled for LDH surgery report inferior clinical status than men scheduled for the same operation. We have in the literature found no evidence-based data that support such a difference, and the reason for the discrepancy is unclear.

Lumbar disc herniation surgery in children: outcome and gender differences.

INTRODUCTION: Lumbar disc herniation (LDH) in children is rare. Few studies have evaluated the outcome of surgery and none in a prospective study design. PURPOSE: To evaluate preoperative disability and postoperative outcome in children operated on for LDH. METHODS: Through a 10-year period, 74 children aged <18 years were included in SweSpine register for LDH with pre- and perioperative data registered, 48 with 1-year follow-up data. Demographics and outcome measurements were described according to the SweSpine protocol. RESULTS: All patients reported preoperatively severe impairment in terms of pain, quality of life and function, girls to a higher extent. Significant postoperative improvement was seen in all patients, leaving no patients dissatisfied with outcome. The PROMS were 1 year after surgery within normal ranges, but remained slightly lower for girls. CONCLUSION: Operative treatment of LDH in growing individuals leads to very good outcome with high degree of patient satisfaction.

The outcome of lumbar disc herniation surgery is worse in old adults than in young adults.

Background and purpose - The outcome of surgical treatment of lumbar disc herniation (LDH) has been thoroughly evaluated in middle-aged patients, but less so in elderly patients. Patients and methods - With validated patient-reported outcome measures (PROMs) and using SweSpine (the national Swedish Spine Surgery Register), we analyzed the preoperative clinical status of LDH patients and the 1-year postoperative outcome of LDH surgery performed over the period 2000-2012. We included 1,250 elderly patients (≥ 65 years of age) and 12,840 young and middle-aged patients (aged 20-64). Results - Generally speaking, elderly patients were referred for LDH surgery with worse PROM scores than young and middle-aged patients, they improved less by surgery, they experienced more complications, they had inferior 1-year postoperative PROM scores, and they were less satisfied with the outcome (with all differences being statistically significant). Interpretation - Elderly patients appear to have a worse postoperative outcome after LDH surgery than young and middle-aged patients, they are referred to surgery with inferior clinical status, and they improve less after the surgery.

Charge regulation in biomolecular solution.

Proteins and other biomolecules contain acidic and basic titratable groups that give rise to intricate charge distributions and control electrostatic interactions. 'Charge regulation' concerns how the proton equilibria of these sites are perturbed when approached by alien molecular matter such as other proteins, surfaces and membranes, DNA, polyelectrolytes etc. Importantly, this perturbation generates a charge response that leads to attractive intermolecular interactions that can be conveniently described by a single molecular property ­ the charge capacitance. The capacitance quantifies molecular charge fluctuations, i.e. it is the variance of the mean charge and is an intrinsic property on par with the net charge and the dipole moment. It directly enters the free energy expression for intermolecular interactions and can be obtained experimentally from the derivative of the titration curve or theoretically from simulations. In this review, we focus on the capacitance concept as a predictive parameter for charge regulation and demonstrate how it can be used to estimate the interaction of a protein with other proteins, polyelectrolytes, membranes as well as with ligands.

Targeted proteomic analyses of nasal lavage fluid in persulfate-challenged hairdressers with bleaching powder-associated rhinitis.

Hairdressers have an increased risk for developing airway symptoms, for example, asthma and rhinitis. Persulfates, which are oxidizing agents in bleaching powder, are considered important causal agents for these symptoms. However, the underlying mechanisms are unclear. The aim was therefore to measure proteomic changes in nasal lavage fluid from persulfate-challenged subjects to identify proteins potentially involved in the pathogenesis of bleaching powder-associated rhinitis or candidate effect biomarkers for persulfate. Also, oxidized peptides were measured to evaluate their usefulness as biomarkers for persulfate exposure or effect, for example, oxidative stress. Samples from hairdressers with and without bleaching powder-associated rhinitis were analyzed with liquid chromatography tandem mass spectrometry using selected reaction monitoring to target 246 proteins and five oxidized peptides. Pathway analysis was applied to obtain a functional overview of the proteins. Several proteins involved in biologically meaningful pathways, functions, or disorders, for example, inflammatory responses, oxidative stress, epithelium integrity, and dermatological disorders, changed after the persulfate challenge. A list with nine proteins that appeared to be affected by the persulfate challenge and should be followed up was defined. An albumin peptide containing oxidized tryptophan increased 2 h and 5 h after the challenge but not after 20 min, which indicates that such peptides may be useful as oxidative stress biomarkers.

Amniotic fluid phthalate levels and male fetal gonad function.

BACKGROUND: Prenatal exposure to phthalates may pose a threat to human male reproduction. However, additional knowledge about the in vivo effect in humans is needed, and reported associations with genital abnormalities are inconclusive. We aimed to study prenatal di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) exposure in relation to cryptorchidism, hypospadias, and human fetal Leydig cell function. METHODS: We studied 270 cryptorchidism cases, 75 hypospadias cases, and 300 controls. Second-trimester amniotic fluid samples were available from a Danish pregnancy-screening biobank (n = 25,105) covering 1980-1996. We assayed metabolites of DEHP and DiNP (n = 645) and steroid hormones (n = 545) by mass spectrometry. We assayed insulin-like factor 3 by immunoassay (n = 475) and analyzed data using linear or logistic regression. RESULTS: Mono(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP, DEHP metabolite) was not consistently associated with cryptorchidism or hypospadias. However, we observed an 18% higher (95% confidence interval [CI] = 5%-33%) testosterone level, and a 41% lower (-56% to -21%) insulin-like factor 3 level in the highest 5cx-MEPP tertile compared with the lowest. Mono(4-methyl-7-carboxyheptyl) phthalate (7cx-MMeHP, DiNP metabolite) showed elevated odds ratio point estimates for having cryptorchidism (odds ratio = 1.28 [95% CI = 0.80 to 2.01]) and hypospadias (1.69 [0.78 to 3.67]), but was not consistently associated with the steroid hormones or insulin-like factor 3. CONCLUSIONS: Data on the DEHP metabolite indicate possible interference with human male fetal gonadal function. Considering the DiNP metabolite, we cannot exclude (nor statistically confirm) an association with hypospadias and, less strongly, with cryptorchidism.

Toluene diisocyanate: Induction of the autotaxin-lysophosphatidic acid axis and its association with airways symptoms.

Diisocyanates are industrial chemicals which have a wide range of applications in developed and developing countries. They are notorious lung toxicants and respiratory sensitizers. However, the mechanisms behind their adverse effects are not adequately characterized. Autotaxin (ATX) is an enzyme producing lysophosphatidic acid (LPA), and the ATX-LPA axis has been implicated in lung related inflammatory conditions and diseases, including allergic asthma, but not to toxicity of environmental low-molecular-weight chemicals. We investigated effects of toluene diisocyanate (TDI) on ATX induction in human lung epithelial cell models, and we correlated LPA-levels in plasma to biomarkers of TDI exposure in urine collected from workers exposed to <5ppb (parts per billion). Information on workers' symptoms was collected through interviews. One nanomolar TDI robustly induced ATX release within 10min in vitro. A P2X7- and P2X4-dependent microvesicle formation was implicated in a rapid ATX release and a subsequent protein synthesis. Co-localization between purinergic receptors and ATX was documented by immunofluorescence and confocal microscopy. The release was modulated by monocyte chemoattractant protein-1 (MCP-1) and by extracellular ATP. In workers, we found a dose-response relationship between TDI exposure biomarkers in urine and LPA levels in plasma. Among symptomatic workers reporting "sneezing", the LPA levels were higher than among non-symptomatic workers. This is the first report indicating induction of the ATX-LPA axis by an environmental low-molecular-weight chemical, and our data suggest a role for the ATX-LPA axis in TDI toxicity.