[Show abstract][Hide abstract] ABSTRACT: The influence of sex, age, pubertal development and oral contraceptives on dehydroepiandrosterone (DHEA), DHEA sulphate (DHEAS), 17α-hydroxyprogesterone (17-OHP), Δ4-androstenedione (Adione), testosterone (T), calculated free testosterone (fT), free androgen index (FAI) and selected ratios in 1798 serum samples from healthy children, adolescents and young adults was evaluated. Samples were analysed by Turboflow-LC-MS/MS. Sex hormone-binding globulin was analysed by immunoassay. All steroid metabolite concentrations were positively associated with age and pubertal development in both sexes and generally higher in males than in females except for Adione. The pubertal rise in T in males was more pronounced compared to females, reflecting contribution from the testes. Ratios between steroid metabolites varied and depended on sex and age. All ratios were lower during infancy compared to later in life. Use of oral contraceptives significantly lowered serum concentrations of all steroid metabolites, fT, FAI, the 17-OHP/Adione, the Adione/T and the DHEA/Adione ratios, but not the DHEA/DHEAS ratio. We provide reference ranges for DHEA, DHEAS, 17-OHP, Adione, T, fT, FAI and selected ratios in relation to sex, age and pubertal development. Use of oral contraceptives strongly influences adrenal steroidogenesis and should be considered when diagnosing and monitoring treatment of patients with disorders of sex development.
[Show abstract][Hide abstract] ABSTRACT: Although common reproductive problems, such as male infertility and testicular cancer, present in adult life, strong evidence exists that these reproductive disorders might have a fetal origin. The evidence is derived not only from large epidemiological studies that show birth-cohort effects with regard to testicular cancer, levels of testosterone and semen quality, but also from histopathological observations. Many infertile men have histological signs of testicular dysgenesis, including Sertoli-cell-only tubules, immature undifferentiated Sertoli cells, microliths and Leydig cell nodules. The most severe gonadal symptoms occur in patients with disorders of sexual development (DSDs) who have genetic mutations, in whom even sex reversal of individuals with a 46,XY DSD can occur. However, patients with severe DSDs might represent only a small proportion of DSD cases, with milder forms of testicular dysgenesis potentially induced by exposure to environmental and lifestyle factors. Interestingly, maternal smoking during pregnancy has a stronger effect on spermatogenesis than a man's own smoking. Other lifestyle factors such as alcohol consumption and obesity might also have a role. However, increasing indirect evidence exists that exposure to ubiquitous endocrine disrupting chemicals, present at measurable concentrations in individuals, might affect development of human fetal testis. If confirmed, health policies to prevent male reproductive problems should not only target adult men, but also pregnant women and their children.
[Show abstract][Hide abstract] ABSTRACT: Background
Humans are exposed to tributyltin (TBT), previously used as an antifouling paint in ships, mainly through fish consumption. As TBT is a known obesogen, we studied the association of placenta TBT and other organotin compounds (OTCs) with ponderal index (PI) and growth during the first 18 months of life in boys.
In a prospective Finnish study, 110 placenta samples were collected from mothers of boys born in 1997-1999 with (n = 55) and without (n = 55) cryptorchidism. To account for the original study design, linear regression, weighted for sampling fractions of boys with (121/55) and without (5677/55) cryptorchidism from the total cohort, was used to study the association between placenta OTCs and children's weight, length, growth rates and PI up to 18 months of age.
Placenta TBT concentrations were above the limit of quantification (LOQ) in 99% of the samples. However, monobutyltin (MBT), dibutyltin (DBT) and triphenyltin (TPhT) concentrations were below LOQ in 90%, 35% and 57% of samples, respectively. Placenta TBT was positively associated (p = 0.024) with weight gain during the first three months of life, but no other significant associations were observed for weight or length gain. Also, no significant associations between placenta OTC concentrations and child length, weight or PI at any time point were found.
We observed a trend towards higher weight gain from birth to 3 months of age with increasing placenta TBT concentration. These results should be interpreted with caution because obesogenic effects in animal experiments were seen after in-utero TBT exposures to doses that were orders of magnitude higher. Also the number of study subjects included in this study was limited.
Environmental Health 06/2014; 13(45). · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Some phthalates have shown anti-androgenic effects in rat offspring. Premature infants may be exposed to high amounts of specific phthalates during hospitalization and thus are potentially at risk.
Environmental Health Perspectives 05/2014; · 7.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Few human studies have examined bisphenol A (BPA) exposure in relation to semen quality and reproductive hormones in men, and results are divergent.Objectives: We examined associations between urinary BPA concentration and reproductive hormones, as well as semen quality, in young men from the general population.Methods: Our study population consisted of 308 young men from the general population. Urinary BPA concentration was measured by isotope dilution TurboFlow-liquid chromatography-tandem mass spectrometry. We used multiple linear regression analysis to estimate associations between BPA concentration and reproductive hormones and semen quality, adjusting for confounding factors.Results: We found that 98% of the men had detectable urinary levels of BPA. Median (5th-95th percentiles) BPA concentration was 3.25 ng/mL (0.59-14.89 ng/mL). Men with BPA concentrations above the lowest quartile had higher concentrations of serum testosterone, luteinizing hormone (LH), estradiol, and free testosterone compared with the lowest quartile (ptrend ≤ 0.02). Men in the highest quartile of BPA excretion had on average 18% higher total testosterone (95% CI: 8, 28%), 22% higher LH (95% CI: 6, 39%), and 13% higher estradiol (95% CI: 4, 24%) compared with lowest quartile. Men in the highest quartile of BPA also had significantly lower percentage progressive motile spermatozoa compared with men in the lowest quartile (-6.7 percentage points, 95% CI: -11.76, -1.63). BPA was not associated with other semen parameters. Adjusting for dietary patterns did not influence the results.Conclusions: The pattern of associations between BPA and reproductive hormones could indicate an antiandrogenic or antiestrogenic effect, or both, of BPA on the hypothalamic-pituitary-gonadal hormone feedback system, possibly through a competitive inhibition at the receptor level. However, additional research is needed to confirm our findings and to further test the suggested potential mechanisms.Citation: Lassen TH, Frederiksen H, Jensen TK, Petersen JH, Joensen UN, Main KM, Skakkebaek NE, Juul A, Jørgensen N, Andersson AM. 2014. Urinary bisphenol A levels in young men: association with reproductive hormones and semen quality. Environ Health Perspect 122:478-484; http://dx.doi.org/10.1289/ehp.1307309.
Environmental Health Perspectives 05/2014; 122(5):478-484. · 7.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background/Objectives:Total body fat percentage (%BF) evaluated by dual energy X-ray absorptiometry (DXA) scans (DXA %BF) is widely recognized as a precise measure of fatness. We aimed to establish national reference curves for DXA %BF, %BF calculated from skinfolds (SF %BF) and waist circumference (WC) in healthy children, and to compare agreement between the different methods.Subjects/Methods:Based on 11 481 physical examinations (anthropometry) and 1200 DXA scans from a longitudinal cohort of Danish children (n=2647), we established reference curves (LMS-method) for SF %BF, WC (birth to 14 years) and DXA %BF (8-14 years). Age- and sex-specific Z-scores for body mass index (BMI), WC and SF %BF were compared. Sensitivity and specificity were calculated for agreement of WC, SF %BF and BMI with DXA %BF to identify obese children (>+1 s.d.).Results:%BF differed with age, sex, pubertal stage and social class. SF %BF correlated strongly with DXA %BF (r=0.86). BMI and WC also correlated positively with DXA %BF (Z-scores; r= 0.78 and 0.69). Sensitivity and specificity were 79.5 and 93.8 for SF %BF, 75.9 and 90.3 for BMI and 59.2 and 95.4 for WC.Conclusions:SF %BF showed the highest correlation and best agreement with DXA %BF in identifying children with excess fat (+1 s.d.).European Journal of Clinical Nutrition advance online publication, 29 January 2014; doi:10.1038/ejcn.2013.282.
European journal of clinical nutrition 01/2014; · 3.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adrenal disorders like Congenital Adrenal Hyperplasia result in abnormal adrenal size and morphology, but little is known about the clinical value of magnetic resonance imaging (MRI) in determining adrenal volume.
To evaluate the potential usefulness of MR methodology to estimate adrenal size in healthy children, and to evaluate determinants of adrenal volume such as age, gender, body size, pubic hair stage and serum level of adrenal androgens.
235 healthy children (116 girls) (age range 10.0-14.8 years) were examined by MRI. Clinical examinations (anthropometry and pubertal staging) were performed and five androgen metabolites measured in blood samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
It was possible to determine adrenal volume in 115/235 children using MRI. The adrenals were not measurable in 51% of children due to breathing and moving artefacts. The median volume of the right adrenal gland was 0.46 mL in girls and 0.46 mL in boys. The median volume of the left adrenal gland was 0.34 mL in girls and 0.40 mL in boys. Adrenal size was positively associated with body surface area (estimate B=0.34 mL/year, p=0.003), age (estimate B=0.05 mL/year, p=0.021) and pubic hair stage (estimate B=0.05 mL/stage, p=0.075). No associations between adrenal size and serum levels of adrenal androgens were observed.
It was possible to determine adrenal volume by MRI in only 50% of healthy children aged 10-15 years. Adrenal volume increased with age and Tanner stage of pubic hair. Future studies will unravel if adrenal MRI is useful when evaluating children with adrenal diseases. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: IntroductionInsulin-like factor 3 (INSL3) is a promising marker of Leydig cell function with potentially high clinical relevance. Limited data of INSL3 levels in relation to other reproductive hormones in healthy pubertal boys exist.AimTo evaluate longitudinal serum changes in INSL3 compared to luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, inhibin B, and anti-Müllerian hormone (AMH) during puberty in healthy boys.Methods
Ten boys were included from the longitudinal part of the COPENHAGEN Puberty Study. Pubertal evaluation, including testicular volume, was performed and blood samples drawn every 6 months for 5 years. Serum concentrations of testosterone were determined by a newly developed LC-MS/MS method, and serum concentrations of INSL3, AMH, inhibin B, FSH and LH, respectively, were determined by validated immunoassays.ResultsSerum INSL3 levels increased progressively with increasing age, pubertal onset and testicular volume. In six of ten boys, LH increased prior to the first observed increase in INSL3. In the remaining four boys, the increase in LH and INSL3 was observed at the same examination. The increases in serum concentrations of LH, testosterone and INSL3 were not parallel or in ordered succession and varied inter-individuallyConclusion
We demonstrated that INSL3 concentrations were tightly associated with pubertal onset and increasing testicular volume. However, the pubertal increases in LH, INSL3, and testosterone concentrations were not entirely parallel, suggesting that INSL3 and testosterone may be regulated differently. Thus, we speculate that INSL3 provides additional information on Leydig cell differentiation and function during puberty compared with traditional markers of testicular function.
[Show abstract][Hide abstract] ABSTRACT: Several non-persistent industrial chemicals have shown endocrine disrupting effects in animal studies and are suspected to be involved in human reproductive disorders. Among the non-persistent chemicals which have been discussed intensively during the past years are phthalates, bisphenol A, triclosan and parabens because of their anti-androgenic and/or estrogenic effects.Phthalates are plastizers used in numerous of industrial products. Bisphenol-A is the main component of polycarbonate plastics and epoxy resins. Parabens and triclosan are anti-microbial preservatives and other phenols such as benzophenone-3 act as UV-screener, while chloro-phenols and phenyl phenols are used as pesticides and fungicides in agriculture.In spite of the widespread use of industrial chemicals, knowledge about exposure sources and human biomonitoring studies among different segments of the population are very limited. In Denmark we have no survey programs for non-persistent environmental chemicals as it is known in some countries like USA (NHANES) and Germany (GerES). However, we have analyzed the excretion of seven parabens, nine phenols and metabolites of eight different phthalates in urine samples collected during the past 6 years from four Danish cohorts. Here we present biomonitoring data in more than 3600 Danish children, adolescents, young men and pregnant women from the general population. Our study shows that nearly all Danes were exposed to the six most common phthalates, to bisphenol A, triclosan and benzophenon-3 and to at least two of the parabens. The exposure to other non-persistent chemicals was also widespread. Our data indicates decreasing excretion of two common phthalates (DnBP and DEHP) over time.
[Show abstract][Hide abstract] ABSTRACT: Age at pubertal onset varies substantially in healthy girls. Although genetic factors are responsible for more than half of the phenotypic variation, only a small part has been attributed to specific genetic polymorphisms identified so far. Follicle-stimulating hormone (FSH) stimulates ovarian follicle maturation and estradiol synthesis which is responsible for breast development. We assessed the effect of three polymorphisms influencing FSH action on age at breast deveopment in a population-based cohort of 964 healthy girls. Girls homozygous for FSHR -29AA (reduced FSH receptor expression) entered puberty 7.4 (2.5-12.4) months later than carriers of the common variants FSHR -29GG+GA, p = 0.003. To our knowledge, this is the strongest genetic effect on age at pubertal onset in girls published to date.
[Show abstract][Hide abstract] ABSTRACT: Experimental studies have shown that dioxin-like chemicals may interfere with aspects of the endocrine system including growth. However, human background population studies are, however, scarce. We aimed to investigate whether early exposure of healthy infants to dioxin-like chemicals was associated with changes in early childhood growth and serum IGF1. In 418 maternal breast milk samples of Danish children (born 1997-2001) from a longitudinal cohort, we measured polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and polychlorinated biphenyls (pg or ng/g lipid) and calculated total toxic equivalent (total TEQ). SDS and SDS changes over time (ΔSDS) were calculated for height, weight, BMI, and skinfold fat percentage at 0, 3, 18, and 36 months of age. Serum IGF1 was measured at 3 months. We adjusted for confounders using multivariate regression analysis. Estimates (in parentheses) correspond to a fivefold increase in total TEQ. TEQ levels in breast milk increased significantly with maternal age and fish consumption and decreased with maternal birth year, parity, and smoking. Total TEQ was associated with lower fat percentage (-0.45 s.d., CI: -0.89; -0.04), non-significantly with lower weight and length at 0 months, accelerated early height growth (increased ΔSDS) (ΔSDS 0-18 months: +0.77 s.d., CI: 0.34; 1.19) and early weight increase (ΔSDS 0-18: +0.52 s.d., CI: 0.03; 1.00), and increased IGF1 serum levels at 3 months (+13.9 ng/ml, CI: 2.3; 25.5). Environmental exposure to dioxin-like chemicals was associated with being skinny at birth and with higher infant levels of circulating IGF1 as well as accelerated early childhood growth (rapid catch-up growth).
[Show abstract][Hide abstract] ABSTRACT: Many phthalates, parabens and phenols are suspected to have endocrine disrupting properties in humans. They are found in consumer products, including food wrapping, cosmetics and building materials. The foetus is vulnerable and exposure to these chemicals is of particular concern for pregnant women. We therefore studied current exposure to several commonly used phthalates, parabens and phenols in 200 healthy, pregnant Danish women. A total of 200 spot urine samples were collected between weeks 8-30 of pregnancy and analysed for 10 phenols, 7 parabens and 16 phthalate metabolites by LC-MS/MS. The 33 analytes represent 26 non-persistent compounds. The majority of analytes were present in urine from most women. Thus, in 174 of the 200 women, metabolites of more than 13 (>50%) of 26 compounds were detected simultaneously. The number of compounds detected per woman (either as the parent compound or its metabolite (s)) ranged from 7 to 21 with a median of 16. The majority of compounds correlated positively with each other within and between chemical groups suggesting joint exposure sources. Estimated daily intakes (DI) of phthalates and bisphenol A (BPA) were below their individual tolerable daily intake (TDI) and with Hazard Quotients (HQ) below 1. In conclusion, we found detectable levels of phthalate metabolites, parabens and phenols in almost all pregnant women, suggesting combined multiple exposures. Although the individual estimated DI of phthalates and BPA was below TDI, our results still raise concern. As current toxicological risk assessments in humans do not take into account simultaneous exposure, the true cumulative risk for the foetus may be underestimated.
[Show abstract][Hide abstract] ABSTRACT: Geographical differences in occurrence of diseases in male reproductive organs including malformation in reproductive tract have been reported between Denmark and Finland. The reason for these differences is unknown, but differences in exposure to chemicals with endocrine disrupting abilities have been suggested. Among these chemicals are perfluoro¬alkylated substances (PFASs) a group of water and grease repellent chemicals used in outdoor clothes, cookware, food packaging and textiles. We therefore investigated differences in PFASs exposure levels between Denmark and Finland and associated PFASs levels in cord blood with congenital cryptorchidism. Boys from a joint ongoing prospective birth cohort study were included. We analyzed PFASs levels in cord blood serum samples from 29 Danish boys with congenital cryptorchidism; 30 healthy Danish matched controls recruited from 1997-2001, 30 Finnish cases and 78 Finnish healthy matched controls recruited from 1997-1999. Additionally, 48 Finnish cases recruited from 2000-2002 were included. PFOA and PFOS were detected in all 215 Danish and Finnish cord blood samples with significantly higher levels in Danish (medians; PFOA 2.6 ng/mL, PFOS 9.1 ng/mL) compared to Finnish (medians; PFOA: 2.1 ng/mL, PFOS 5.2 ng/mL) samples. We found no associations between cord blood PFOA and PFOS levels and congenital cryptorchidism after adjustment for confounders. Our data indicate that women in Denmark and Finland are generally exposed to PFOA and PFOS but with country differences in exposure levels. We found no statistical significant association between PFOA and PFOS levels in cord blood and congenital cryptorchidism, however, our study was small and larger studies are warranted.
[Show abstract][Hide abstract] ABSTRACT: To construct new Danish growth charts for 0 to 20-year-olds and compare them with Danish references from 1982 and with World Health Organization (WHO) standards for children aged 0 to five years from 2006, by applying similar inclusion and exclusion criteria.
Anthropometric data from three contemporary Danish population-based studies were combined. References for height were based on healthy Caucasian children born at term. A total of 12,671 height measurements (8,055 in boys and 4,616 in girls) were included. Reference charts were developed using the Generalized Additive Models for Location, Scale and Shape.
From pre-pubertal ages, a secular increase in height was observed for both genders. The differences were most pronounced in puberty and final heights were increased by 1.4cm in boys and 2.9cm in girls. Reference curves for height were superimposable with standard curves based on the selective WHO criteria. In boys, an upward shift in body mass index (BMI) above median levels was found. Danish children were longer/taller and heavier and they had larger head circumferences than those reported in the recent multiethnic WHO standards.
We recommend national implementation of these contemporary 2014 Danish references for anthropometric measurements. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: We hypothesised that antenatal exposure to ubiquitous phthalates may lead to an earlier menarche and a lower prevalence of polycystic ovarian syndrome (PCOS) and polycystic ovarian morphology (PCO) in adolescence. The Western Australian Pregnancy Cohort (Raine) Study recruited 3000 women at 18 weeks of gestation in 1989-91, 1377 had antenatal serum stored without thawing at -80°C. An unselected subset was evaluated in the early follicular phase for PCO and PCOS by ultrasound and serum evaluation in adolescence. Serum was analysed for Anti-Mullerian Hormone (AMH), inhibin B, sex-hormone binding globulin (SHBG), testosterone, androstenedione and DHEAS. 400 µL of the frozen maternal serum underwent isotope diluted liquid chromatography - tandem mass spectrometry (LC-MS/MS), with preceding enzymatic deconjugation followed by solid phase extraction to determine phthalate exposure. 244 girls attended assessment and most common phthalate metabolites were detectable in the majority of the 123 samples available. Several phthalates were negatively associated with maternal SHBG, associations with maternal androgens were less consistent. The sum of the metabolites of di-(2-ethylhexyl) phthalate (DEHP) were associated with a non-significant tendency towards an earlier age at menarche (p=0.069). Uterine volume was positively associated with mono-(carboxy-iso-octyl) phthalate (MCiOP) (p=0.018). Exposure to monoethyl phthalate (MEP) and the sum of all phthalate metabolites (Σall phth.m) was protective against PCOS in adolescence (p=0.001, p=0.005, respectively). There were negative associations of MEP with PCO (p=0.022), and MEP with serum AMH (p=0.031). Consequently our data suggests that antenatal exposure to environmental phthalates may be associated with oestrogenic and/or anti-androgenic reproductive effects in adolescent girls.
[Show abstract][Hide abstract] ABSTRACT: Human exposure to modern non-persistent chemicals is difficult to ascertain in epidemiological studies as exposure patterns and excretion rates may show temporal and diurnal variations. The aim of this study was to assess the temporal variability in repeated measurements of urinary excretion of bisphenol A (BPA) and seven other phenols. All analytes were determined using TurboFlow-LC-MS/MS. Two spot, three first morning and three 24-h urine samples were collected from 33 young Danish men over a three months period. Temporal variability was estimated by means of intraclass correlation coefficients (ICCs). More than 70% of the urine samples had detectable levels of BPA, triclosan (TCS), benzophenone-3 (BP-3) and sum of 2,4-dichlorophenol and 2,5-dichlorophenol (ΣDCP). We found low to moderate ICCs for BPA (0.10-0.42) and ΣDCP (0.39-0.72), whereas the ICCs for BP-3 (0.69-0.80) and TCS (0.55-0.90) were higher. The ICCs were highest for the two spot urine samples, which were collected approximately 4 days apart, compared with the 24-h urine samples and the first morning urine samples, which were collected approximately 40 days apart. A consequence of the considerable variability in urinary excretion of BPA may be misclassification of individual BPA exposure level in epidemiological studies, which may lead to attenuation of the association between BPA and outcomes. Our data do not support that collection of 24-h samples will improve individual exposure assessment for any of the analysed phenols.
Environmental Research 08/2013; · 3.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate whether genetic polymorphisms in the FSH pathway (FSHB-211 G→T and FSHR 2039 A→G) affect serum levels of FSH, antimüllerian hormone (AMH), and age at pubertal onset. FSH secretion and FSH signal transduction are enhanced in carriers of FSHB GG and FSHR AA, respectively. Furthermore, the combined genotype FSHB GG+FSHR AA is the most favorable for male gonadal function, but the effect of this genotype has never been evaluated in peripubertal females. AMH is a marker of ovarian function and is negatively correlated with FSH in prepubertal girls.
Secondary analyses of a prospective cohort study.
We examined 78 healthy girls twice yearly for 6 years; the median age at baseline was 9.3 years.
Hormone levels were measured by immunoassays, and DNA was isolated from blood and genotyped by restriction fragment length polymorphism of polymerase chain reaction-amplified regions.
Carriers of FSHB GG+FSHR AA had higher FSH before pubertal onset (median 2.2 vs. 1.5 IU/L) and lower AMH (13.8 vs. 19.4 pmol/L) compared with carriers of other genotypes. In crude analysis, girls with FSHB GG+FSHR AA entered puberty earlier, 9.7 vs. 10.6 years. However, the difference was no longer statistically significant after including interval-, right-, and left-censored data in a probit analysis.
The combined effect of FSHB GG+FSHR AA may potentiate the FSH pathway, which increases serum levels of FSH and reduces AMH. Common variations in genes regulating follicle growth may affect AMH levels independently of the number of resting primordial follicles.
Fertility and sterility 07/2013; · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: STUDY QUESTION: Is the placental burden of organotin compounds (OTCs) associated with congenital cryptorchidism in infant offspring from Finland and Denmark? SUMMARY ANSWER: Increasing concentrations of OTCs had a negative association with cryptorchidism in Finland, whereas a positive association was found in Denmark. WHAT IS KNOWN ALREADY: The rapid increase in the prevalence of cryptorchidism suggests that environmental factors, such as endocrine disruptors, may be involved. OTCs are endocrine disruptors at very low concentrations due to activation of the retinoid X receptor (RXR). STUDY DESIGN, SIZE, DURATION: Between the years 1997 and 2001, placentas from mothers of cryptorchid boys and from healthy controls were collected from Denmark (39 cases, 129 controls) and Finland (56 cases, 56 controls). In Denmark 33 and 6 boys, and in Finland 22 and 34 boys had mild or severe cryptorchidism, respectively. The association between concentrations of four OTCs [monobutyltin (MBT), dibutyltin (DBT), tributyltin (TBT) and triphenyltin (TPhT)] and case-control status was estimated. PARTICIPANTS/MATERIALS, SETTING, METHODS: In both countries, placenta samples were selected from larger cohorts. In Finland placenta samples were collected from boys with cryptorchidism at birth and matched controls (nested case-control design). Matching criteria were parity, maternal smoking (yes/no), diabetes (yes/no), gestational age (±7 days) and date of birth (±14 days). Numbers of controls per case was 1. In Denmark, all available placentas from cryptorchid boys were chosen and control placentas were selected randomly from the total Danish cohort (case-cohort design). The average number of controls per case was 3.3. OTCs in placenta samples were analysed with liquid extraction, ethylation and gas chromatography-mass spectrometry determination and coded by country-specific tertiles. MAIN RESULTS AND THE ROLE OF CHANCE: Generally, the concentrations of OTCs were very low. For most analytes, a large proportion of samples (29-96% depending on the country and case-control status) had OTC concentrations below the limit of quantification (LOQ). As an exception, the concentration of TBT was >LOQ in 99% of Finnish placentas. The mean concentrations of DBT and TBT were 1.5 and 7 times higher in Finland than in Denmark, respectively. For DBT in Danish placentas, the odds ratio (OR) for cryptorchidism in the second tertile (0.10-0.14 ng/g) when compared with the first tertile (<0.10 ng/g, <LOQ) was 3.13 (95% CI 1.19-8.26) and the OR for the third tertile (≥0.15 ng/g) when compared with the first tertile was 4.01 (95% CI 1.42-11.33). For TBT in Finnish placentas, the OR for cryptorchidism in the second tertile (0.10-0.39 ng/g) when compared with the first tertile (<0.1 ng/g) was 0.61 (95% CI 0.18-2.01) and the OR for the third tertile (≥0.40 ng/g) when compared with the first tertile was 0.13 (95% CI 0.03-0.54). LIMITATIONS, REASONS FOR CAUTION: The main limitation of the study was the relatively small number of mother-boy pairs that limits the extrapolation of the study results to the general population. Also misclassification of exposure is a reason for caution for two reasons: because the concentrations of most OTCs were below or only barely above the LOQ in a large proportion of samples and because it is not known how well OTCs measured from placenta represent exposure at the time window that is relevant for cryptorchidism occurrence. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to measure the concentrations of OTCs from human placenta samples, and to associate these concentrations to cryptorchidism. As opposite results were obtained with regard to OTC concentration in placenta and cryptorchidism status in Finland and Denmark, and no mechanism is known at the moment by which OTCs could affect testicular descent, these results cannot be generalized to other populations. However, some animal tests described in the literature show opposite effects of OTCs on fat deposition at different ranges of exposure. It is also clearly shown in the literature that TBT has an impact on sexual development of gastropods through RXR. As TBT is known to activate human RXR, further laboratory studies should be designed to explore the potential impact of TBT on male sexual development. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the European Commission (QLK4-CT-1999-01422, QLK4-CT-2001-00269, QLK4-2002-0063, FP7/2008-2012: DEER 212844), The Danish Medical Research Council (9700833, 9700909), Danish Agency for Science (Technology and Innovation 09-067180), the Svend Andersen's Foundation, Velux Foundation and Novo Nordisk Foundation, the Turku University Central Hospital, Sigrid Jusélius Foundation and the Academy of Finland.There are no competing financial, personal or professional interests.
[Show abstract][Hide abstract] ABSTRACT: Bisphenol A (BPA), triclosan (TCS), benzophenone-3 (BP-3), dichoro- and phenyl phenols are industrial chemicals present in numerous consumer products such as polycarbonate plastics, preservatives in personal care products, sun screens, pesticides and fungicides, respectively, and they are all suspected endocrine disrupters. In this study the urinary excretion of eight phenols in Danish children recruited from the general population were investigated. One 24h urine and two consecutive first morning samples were collected from each of 129 healthy Danish children and adolescents (6-21 years). The concentrations of urinary phenols were analyzed by a new on-line TurboFlow-liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Most of the analyzed phenols were detectable in more than 80% of the 24h urine samples and the median concentration of BPA, TCS, BP-3, 2,4-dichorophenol and 2,5-dichorophenol (analyzed as ∑DCP), 2-phenylphenol and 4-phenylphenol were 1.37, 1.45, 1.41, 0.65, 0.36 and 0.53ng/mL, respectively. The ranges of the excreted TCS and BP-3 were wide; from below limit of detection to maximum levels of 955ng/mL and 162ng/mL, respectively, while the other phenols were excreted in a more narrow range with maximum levels below 25ng/mL. Concentrations in first morning urine were in general higher than in 24h urine and comprised 30-47% of the absolute amount excreted during 24h. The youngest children aged 6-10 years had a significantly higher urinary BPA concentration (ng/mL) and also a relatively higher daily BPA excretion (ng/kg bw/24h) than the older children and adolescents. The opposite pattern was observed for TCS, BP-3 and ∑DCP for which urinary levels increased significantly with age. No gender difference or associations to pubertal development were observed. In conclusion, our study showed that Danish children were exposed to multiple phenols simultaneously. Small children were relatively more exposed to BPA than older children, while higher exposures to TCS, BP-3 and ∑DCP were seen among adolescents.
International journal of hygiene and environmental health 03/2013; · 2.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:Longer androgen receptor gene CAG trinucleotide repeats, AR (CAG)n, have been associated with reduced sensitivity of the androgen receptor (AR) in vitro as well as in humans. Furthermore, short AR (CAG)n have been associated with premature adrenarche.Objective:The aim of the study was to evaluate associations between the AR (CAG)n polymorphism and development of pubic hair, levels of androgens, and body fat content in healthy boys.Methods:A longitudinal study of 78 healthy boys (age 6.2-12.4 years at inclusion) from the COPENHAGEN Puberty Study was conducted with clinical examinations and blood samples drawn every 6 months. The AR (CAG)n length was established by direct DNA sequencing and reproductive hormones were measured in serum by standardized analyses.Results:Median AR (CAG)n length was 22 (range, 17-30). Before puberty (at 10 years of age), boys with long CAG repeats (CAG ≥24) had lower levels of SHBG (88 vs 125 nmol/L) (P < .05) and a nonsignificant trend toward higher median skinfold thickness (41 vs 31 mm) (P = .06) compared with boys with an average number of CAG repeats (CAG 21-23). In contrast, the inverse association was observed at puberty (at 12 years of age) in boys with short CAG repeats (CAG 17-20) (P < .05). Serum levels of LH and testosterone (at 12 years) were significantly higher in boys with long CAG repeats compared with boys with an average number of CAG repeats (P = .05).Conclusion:The observed associations between AR (CAG)n and peripubertal fat accumulation and serum SHBG concentrations indicate that this genetic polymorphism may influence the androgen-dependent fine-tuning of metabolic and reproductive factors at a young age.
The Journal of clinical endocrinology and metabolism 02/2013; · 6.50 Impact Factor