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Recent in vitro studies have shown that some chemical UV filters mimic the effect of progesterone in the activation of the CatSper Ca2+ channel in human spermatozoa. However, so far, the extent of exposure of human spermatozoa to chemical UV filters via the presence of these chemicals in seminal fluid has been unknown. Here, we present levels of UV filters measured in human seminal fluid and comparisons to levels measured in concurrently collected urine and serum samples. In total nine UV filters were analysed by TurboFlow-LC–MS/MS in paired urine, serum, and seminal fluid samples from 300 young Danish men from the general population; each man collected one of each sample type within 1 h. The samples were collected during February–December 2013 and only six of the men reported having used sunscreen during the 48 h preceding the sample collection. Four of the examined UV filters could be detected in seminal fluid samples at levels above LOD in more than 10% of the samples. Benzophenone (BP), benzophenone-1 (BP-1), and benzophenone-3 (BP-3) were most frequently detected in, respectively, 18%, 19%, and 27% of the seminal fluid samples albeit at levels one to two orders of magnitude lower than the levels observed in urine. 4-methyl-benzophenone (4-MBP) was detectable in 11% of the seminal fluid samples while in <5% of the urine samples. Overall 45% of the men had at least one of the UV filters present in their seminal fluid at detectable levels. For BP-1 and BP-3 individual levels in urine and seminal fluid were significantly correlated, while this was not evident for BP nor 4-MBP. In conclusion, chemical UV filters are present in men’s seminal fluid; some of which can activate the human sperm-specific CatSper Ca2+ channel and thereby potentially interfere with the fertilisation process.

Background Bisphenol A (BPA) is a non-persistent chemical with endocrine disrupting abilities used in a variety of consumer products. Fetal exposure to BPA is of concern due to the elevated sensitivity, which particularly relates to the developing brain. Several epidemiological studies have investigated the association between prenatal BPA exposure and neurodevelopment, but the results have been inconclusive. Objective To assess the association between in utero exposure to BPA and Attention Deficit/Hyperactivity Disorder (ADHD-) symptoms and symptoms of Autism Spectrum Disorder (ASD) in 2 and 5-year old Danish children. Method In the prospective Odense Child Cohort, BPA was measured in urine samples collected in gestational week 28 and adjusted for osmolality. ADHD and ASD symptoms were assessed with the use of the ADHD scale and ASD scale, respectively, derived from the Child Behaviour Checklist preschool version (CBCL/1½-5) at ages 2 and 5 years. Negative binomial and multiple logistic regression analyses were performed to investigate the association between maternal BPA exposure (continuous ln-transformed or divided into tertiles) and the relative differences in ADHD and ASD problem scores and the odds (OR) of an ADHD and autism score above the 75th percentile adjusting for maternal educational level, maternal age, pre-pregnancy BMI, parity and child age at evaluation in 658 mother-child pairs at 2 years of age for ASD-score, and 427 mother-child pairs at 5 years of age for ADHD and ASD-score. Results BPA was detected in 85.3% of maternal urine samples even though the exposure level was low (median 1.2 ng/mL). No associations between maternal BPA exposure and ASD at age 2 years or ADHD at age 5 years were found. Trends of elevated Odds Ratios (ORs) were seen among 5 year old children within the 3rd tertile of BPA exposure with an ASD-score above the 75th percentile (OR = 1.80, 95% CI 0.97,3.32), being stronger for girls (OR = 3.17, 95% CI 1.85,9.28). A dose-response relationship was observed between BPA exposure and ASD-score at 5 years of age (p-trend 0.06) in both boys and girls, but only significant in girls (p-trend 0.03). Conclusion Our findings suggest that prenatal BPA exposure even in low concentrations may increase the risk of ASD symptoms which may predict later social abilities. It is therefore important to follow-up these children at older ages, measure their own BPA exposure, and determine if the observed associations persist.

Parabens are used as anti-microbial preservatives in a range of consumer products, especially in cosmetics. In vitro and animal studies have shown weak estrogenic and other endocrine disrupting effects of parabens, including reduced testosterone levels in exposed male rats. The knowledge of paraben exposure, distribution and excretion in humans is limited. In this study we determined the concentration of five parabens; methyl-, ethyl-, n -propyl-, n -butyl- and benzylparaben in urine, serum and seminal plasma samples from 60 healthy Danish men. To conduct the study a sensitive and specific method using LC–MS/MS for simultaneous determination of the five parabens was developed for all three different matrices. Highest concentrations of the parabens were found in urine, wherein methyl-, ethyl-, n -propyl- and n -butyl parabens were measurable in 98%, 80%, 98% and 83% of the men, respectively. Benzyl paraben was only measurable in urine from 7% of the men. Methyl- and n -propyl parabens were also measurable in the majority of serum and seminal plasma samples, whereas the other parabens could only be detected in some of the samples. In all the three matrices significant correlations between the parabens were seen. Furthermore, urinary paraben concentrations correlate to the paraben concentrations in both serum and seminal plasma.

Background Cardiac rehabilitation (CR) has proven health benefits and, according to international guidelines, CR must be offered to all eligible patients. Studies have reported lower uptake of CR among migrants, and migrants are known to face several barriers in their access to healthcare, of which language is the most common. The aim of this study is to examine the provision of CR core components for migrants; and the role of language barriers in the provision of CR in Danish hospitals and municipalities. Methods This is a descriptive study based on repeated nationwide surveys conducted in 2013 and 2015 by the Danish Cardiac Rehabilitation Database. The surveys collected information on provision and organization of CR in hospitals ( n  = 35) and municipalities ( n  = 98) in Denmark. The survey in 2015 had additional items related to migrants, such as provision of interpreter services and multilingual information material. Results Not all CR core components were provided by hospitals to non-Danish speaking patients. There was no improvement from 2013 to 2015. Hospitals had full coverage (19/19) of interpreter services compared to 84% (26/31) of municipalities. Provision of multilingual information material was low in hospitals 32% (6/19) and in municipalities 3% (1/31). Conclusion This study found language-related barriers in migrants’ access to CR, in the form of inadequate provision of CR core components for non-Danish speaking patients at some Danish hospitals and suboptimal provision of interpreter services in municipalities. The findings call for increased attention to language barriers and further studies are needed to map the extent of the problem.

Phthalates comprise a large class of chemicals used in a variety of consumer products. Several have anti-androgenic properties, and in rodents prenatal exposure has been associated with reduced anogenital distance (AGD)-the distance from the anus to the genitals in male offspring. Few human studies have been conducted, but associations between the anti-androgenic phthalates and male AGD have been reported. We aimed to study the association between phthalate exposure in late pregnancy in Danish women pregnant in 2010-2012 and AGD in their male infants at 3 months of age (n = 273). In the Odense child cohort study, urinary concentrations of 12 phthalate metabolites of diethyl, di-n-butyl, diisobutyl, di(2-ethylhexyl), butylbenzyl, and diisononyl phthalate (DEP, DnBP, DiBP, DEHP, BBzP, and DiNP, respectively) were measured among 245 mothers of boys at approximately gestational week 28 (range, 20.4-30.4) and adjusted for osmolality. AGD, penile width, and weight were measured 3 months after the expected date of birth. Associations between prenatal phthalate and AGD and penile width were estimated using multivariable linear regression adjusting for age and weight-for-age standard deviation score. Phthalate levels were lower in this population than in a recent Swedish study in which phthalates were measured in the first trimester. No consistent associations were seen between any prenatal phthalate and AGD or penile width. Most associations were negative for exposures above the first quartile, and for ln-transformed exposures modeled as continuous variables, but there were no consistent dose-response patterns, and associations were not statistically significant (p > 0.05). We found no significant trends towards shorter AGD in boys with higher phthalates exposures in this low exposed Danish population. Jensen TK, Frederiksen H, Kyhl HB, Lassen TH, Swan SH, Bornehag CG, Skakkebaek NE, Main KM, Lind DV, Husby S, Andersson AM. 2016. Prenatal exposure to phthalates and anogenital distance in male infants from a low-exposed Danish cohort (2010-2012). Environ Health Perspect 124:1107-1113; http://dx.doi.org/10.1289/ehp.1509870.

Abstract Background The peptide hormone insulin-like factor 3 (INSL3) is a marker for Leydig cell function and the clinical use of serum INSL3 measurements has been suggested by several groups. Aim (1) To establish a reference range for liquid chromatography–tandem mass spectrometry (LC-MS/MS) of serum INSL3 in healthy boys and men; and (2) to compare the associations of serum INSL3 and testosterone (T) to pubertal stage, lifestyle factors, diurnal variation, body composition, and human chorionic gonadotropin (hCG) stimulation. Results In a reference range based on LC-MS/MS analysis of serum from 1073 boys and men, INSL3 increased from levels close to the detection limit (0.03 µg/L) in prepubertal boys to a maximum mean level of 1.3 µg/L (95% CI, 0.9-2.7) in young men (19-40 years of age) and decreased slightly in older men (0.1 µg/L per decade). Serum T, but not INSL3, was associated with body mass index or body fat percentage and with alcohol consumption. Smoking was positively associated with serum T, but negatively associated with INSL3. There were significant diurnal variations in both INSL3 and T in men (P < 0.001), but serum INSL3 varied substantially less, compared with serum T (± 11% vs ± 26%). Mean serum INSL3 increased after hCG stimulation, but less than T (+ 17% vs + 53%). In both healthy men and in patients suspected of testicular failure, baseline serum INSL3 was more closely associated to the hCG-induced increase in serum T than baseline T itself. Conclusion Measurement of serum INSL3 by LC-MS/MS has promise as a marker of testicular disorders.

Background: In animals, some phthalates impair male reproductive development and function. Epidemiological studies have reported inconsistent evidence of associations between phthalates and markers of human testicular function. Objectives: We aimed to provide estimates of the effects of phthalate exposure on reproductive hormone levels and semen quality in healthy men. Methods: A total of 881 men gave urine, serum, and semen samples. Serum levels of testosterone, estradiol (E2), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and inhibin-B; semen quality; and urinary concentrations of 14 phthalate metabolites, including metabolites of di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP), were assessed. The proportions of DEHP and DiNP excreted as their respective primary metabolites [mono(2-ethylhexyl) phthalate (MEHP) and mono-isononyl phthalate (MiNP)] were calculated and expressed as percentages (%MEHP and %MiNP, respectively). Results: The free androgen index was 15% lower [95% confidence interval (CI): -23, -8%] for men in the highest %MiNP quartile compared to the lowest quartile (p < 0.001) after adjusting for confounders, and 9% lower (95% CI: -16, -1%) in the highest %MEHP quartile (p = 0.02). %MEHP and %MiNP were negatively associated with the ratio of testosterone/LH and testosterone/FSH. %MEHP was negatively associated with total testosterone, free testosterone, and ratio of testosterone/E2. %MiNP was positively associated with SHBG. There was little evidence of associations between urinary phthalate metabolites or sums of phthalates with reproductive hormones or semen quality Conclusion: Our data suggest that both testosterone production and pituitary—hypothalamic feedback may be compromised in individuals excreting a high proportion of primary metabolites of long-chained phthalates relative to the proportion of secondary metabolites.

Background Prenatal phthalate exposure has been suggested to alter immune responses and increase the risk of asthma, eczema and rhinitis. However, few studies have examined the effects in prospective cohorts and only one examined rhinitis. We therefore studied associations between maternal urinary concentrations of phthalate metabolites and asthma, eczema and rhinitis in offspring aged 5 years. Methods From 552 pregnant women in the Odense Child Cohort, we quantified urinary concentrations of 12 phthalate metabolites in third trimester. We assessed asthma, rhinitis and eczema in their offspring at age 5 years with a questionnaire based on the International Study of Asthma and Allergies in Childhood (ISAAC), and conducted logistic regression adjusting for relevant confounders. Results 7.4% of the children had asthma, 11.7% eczema and 9.2% rhinitis. Phthalate exposure was low compared to previous cohorts. No significant associations between prenatal phthalate exposure and asthma were found. Odds ratios (ORs) of child rhinitis with a doubling in ΣDiNP m and di-2-ethylhexyl phthalate metabolite (ΣDEHP m ) concentrations were, respectively, 1.15 (95% confidence interval (CI) 0.97,1.36) and 1.21 (CI 0.93,1.58). The OR of eczema when doubling ΣDiNP m was 1.24 (CI 1.00,1.55), whereas the OR of using medicine against eczema when doubling a di-ethyl phthalate (DEP) metabolite was 0.81 (CI 0.68,0.96). Conclusion The lack of association between maternal phthalate exposure and asthma in the offspring may be due to low exposure and difficulties in determining asthma in 5-year-olds. The higher odds of rhinitis may raise public concern but further research in larger cohorts of older children is warranted.

Background Bisphenol A (BPA) is widely used in the manufacturing of plastics. BPA can pass the placental barrier and influence fetal development. Due to its estrogenic and anti-androgenic properties, BPA may contribute sex-specific differences in developmental effects. We examined associations between maternal urinary concentrations of BPA and birth size. Methods In this cohort study of 832 mother-child pairs from the Odense Child Cohort, pregnant women provided spot urine samples at gestational week 28, which were analyzed for BPA by isotope diluted LC-MS/MS. Osmolality adjusted urinary BPA concentrations were categorized into quartiles. Mother-child characteristics were obtained from hospital records and questionnaires. Linear regression analyses examining the association between BPA concentrations and offspring birth size (weight, length, head, and abdominal circumference) were performed for the full cohort and stratified by offspring sex. Results BPA was detected above the limit of detection in 85% of the urine samples with a median concentration of 1.33 ng/ml. In the full cohort, birth weight decreased significantly across increasing quartiles of maternal urinary BPA concentration, with the exception of the third quartile, which showed no significant association. In sex-stratified analyses, statistically significant decreases in birth weight were observed among male offspring in the highest quartile of maternal urinary BPA concentrations (β: -115 g, 95% CI: − 225, -4, p  = 0.04) compared to male offspring of the lowest quartile and a possible dose-response association was suggested (p-trend = 0.06). No statistically significant associations were observed for birth weight amongst female offspring. Conclusions Our findings suggest a negative association between maternal urinary BPA exposure and birth weight, driven by a lower birth weight in male offspring. Further research is required to explore the underlying mechanisms of BPA’s possible sex-specific associations.