Publications by authors named "Anna-Maria Andersson"

164 Publications

Endocrine Disrupting Chemicals and Risk of Testicular Cancer A Systematic Review and Meta-analysis.

J Clin Endocrinol Metab 2021 Jul 16. Epub 2021 Jul 16.

Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.

The incidence of many hormone-dependent diseases, including testicular cancer, have sharply increased in all high-income countries during the 20th century. This is not fully explained by established risk factors. Concurrent, increasing exposure to antiandrogenic environmental endocrine disrupting chemicals (EDCs) in fetal life may partially explain this trend. This systematic review assessed available evidence regarding the association between environmental EDC exposure and risk of testicular cancer (seminomas and non-seminomas). Following PRISMA guidelines, a search of English peer-reviewed literature published prior to December 14 th, 2020, in the databases PubMed and Embase® was performed. Among the 279 identified records, 19 were eligible for quality assessment and 10 for further meta-analysis. The completeness of reporting was high across papers, but over 50% were considered subject to potential risk of bias. Mean age at diagnosis was 31.9 years. None considered effects of EDCs multipollutant mixtures. The meta-analyses showed that maternal exposure to combined EDCs was associated with a higher risk of testicular cancer in male offspring (summary RRs: 2.16, (95% CI:1.78-2.62); 1.93 (95% CI:1.49-2.48); 2.78 (95% CI:2.27-3.41) for all, seminoma, non-seminoma respectively). Similarly, high maternal exposures to grouped organochlorines and organo-halogens were associated with higher risk of seminoma and non-seminoma in the offspring. Summary estimates related to postnatal adult male EDC exposures were inconsistent.Maternal but not postnatal adult male, EDC exposures were consistently associated with a higher risk of testicular cancer, particularly risk of non-seminomas. However, the quality of studies was mixed and considering the fields complexity, more prospective studies of prenatal EDC multipollutant mixture exposures and testicular cancer are needed.
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http://dx.doi.org/10.1210/clinem/dgab523DOI Listing
July 2021

Cohort profile: The COPENHAGEN Minipuberty Study-A longitudinal prospective cohort of healthy full-term infants and their parents.

Paediatr Perinat Epidemiol 2021 Jun 22. Epub 2021 Jun 22.

Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen O, Denmark.

Background: The hypothalamic-pituitary-gonadal (HPG) axis governs sexual maturation and reproductive function in humans. In early postnatal life, it is transiently active during which circulating sex steroids reach adult levels. While this so-called minipuberty represents a universal phenomenon in infants of both sexes, its role for early maturation and growth remains incompletely understood.

Objectives: To provide normative data on auxology as well as serum and urinary hormone levels in healthy, full-term infants throughout the first year of life and to investigate associations of postnatal HPG axis dynamics as well as hormonal, genetic and environmental exposures with early genital development and growth.

Population: Healthy, Danish, full-term, singleton newborns including their parents.

Design: Single-centre, prospective, observational longitudinal pregnancy and birth cohort.

Methods: Newborns were followed with six repeated clinical examinations during a one-year follow-up period. An umbilical cord blood sample was drawn at birth. At each visit, infants underwent a clinical examination focusing on auxology and genital development. Further, blood (serum, plasma, DNA) and urine samples were collected at each visit. Mothers and fathers underwent a clinical examination and provided blood samples prior to and after birth. A subset of parents provided urine samples and breast milk samples. Pregnancy and obstetrical outcomes, and detailed parental questionnaires were compiled.

Preliminary Results: Between August 2016 and August 2018, 2481 women with singleton pregnancies were invited to participate of which 298, including their partners, were enrolled (12.0%). A total of 268 healthy, full-term newborns born appropriate for gestational age (AGA) were included at birth, 233 newborns participated in the postnatal follow-up period and 186 completed the one-year follow-up period (9.4% and 7.5%, respectively).

Conclusion: The COPENHAGEN Minipuberty Study provides detailed, longitudinal data on early genital development and growth including hormonal and genetic profiles and environmental exposure in healthy infants including additional data in their parents.
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http://dx.doi.org/10.1111/ppe.12777DOI Listing
June 2021

RUBIC (ReproUnion Biobank and Infertility Cohort): A binational clinical foundation to study risk factors, life course, and treatment of infertility and infertility-related morbidity.

Andrology 2021 Jun 10. Epub 2021 Jun 10.

Departments of Environmental Health and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Background: Infertility affects 15%-25% of all couples during their reproductive life span. It is a significant societal and public health problem with potential psychological, social, and economic consequences. Furthermore, infertility has been linked to adverse long-term health outcomes. Despite the advanced diagnostic and therapeutic techniques available, approximately 30% of infertile couples do not obtain a live birth after fertility treatment. For these couples, there are no further options to increase their chances of a successful pregnancy and live birth.

Objectives: Three overall questions will be studied: (1) What are the risk factors and natural life courses of infertility, early embryonic loss, and adverse pregnancy outcomes? (2) Can we develop new diagnostic and prognostic biomarkers for fecundity and treatment success? And (3) what are the health characteristics of women and men in infertile couples at the time of fertility treatment and during long-term follow-up?

Material And Methods: ReproUnion Biobank and Infertility Cohort (RUBIC) is established as an add-on to the routine fertility management at Copenhagen University Hospital Departments in the Capital Region of Denmark and Reproductive Medicine Centre at Skåne University Hospital in Sweden. The aim is to include a total of 5000 couples equally distributed between Denmark and Sweden. The first patients were enrolled in June 2020. All eligible infertile couples are prospectively asked to participate in the project. Participants complete an extensive questionnaire and undergo a physical examination and collection of biospecimens (blood, urine, hair, saliva, rectal swabs, feces, semen, endometrial biopsies, and vaginal swabs). After the cohort is established, the couples will be linked to the Danish and Swedish national registers to obtain information on parental, perinatal, childhood, and adult life histories, including disease and medication history. This will enable us to understand the causes of infertility and identify novel therapeutic options for this important societal problem.
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http://dx.doi.org/10.1111/andr.13063DOI Listing
June 2021

Possible Relevance of Soluble Luteinizing Hormone Receptor during Development and Adulthood in Boys and Men.

Cancers (Basel) 2021 Mar 16;13(6). Epub 2021 Mar 16.

Group of Skeletal, Mineral and Gonadal Endocrinology, University Department of Growth and Reproduction, Rigshospitalet, 2100 Copenhagen, Denmark.

Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) are agonists for the luteinizing hormone receptor (LHCGR) which regulates male reproductive function. LHCGR may be released into body fluids. We wish to determine whether soluble LHCGR is a marker for gonadal function. Cross-sectional, longitudinal, and intervention studies on 195 healthy boys and men and 396 men with infertility, anorchia, or Klinefelter Syndrome (KS) were used to correlate LHCGR measured in serum, seminal fluid, urine, and hepatic/renal artery and vein with gonadal function. LHCGR was determined in fluids from in vitro and in vivo models of human testicular tissue and cell lines, xenograft mouse models, and human fetal kidney and adrenal glands. Western blot showed LHCGR fragments in serum and gonadal tissue of similar size using three different antibodies. The LHCGR-ELISA had no species cross-reactivity or unspecific reaction in mouse serum even after human xenografting. Instead, sLHCGR was released into the media after the culture of a human fetal kidney and adrenal glands. Serum sLHCGR decreased markedly during puberty in healthy boys ( = 0.0001). In healthy men, serum sLHCGR was inversely associated with the Inhibin B/FSH ratio (β -0.004, = 0.027). In infertile men, seminal fluid sLHCGR was inversely associated with serum FSH (β 0.006, = 0.009), sperm concentration (β -3.5, = 0.003) and total sperm count (β -3.2, = 0.007). The injection of hCG lowered sLHCGR in serum and urine of healthy men ( < 0.01). In conclusion, sLHCGR is released into body-fluids and linked with pubertal development and gonadal function. Circulating sLHCGR in anorchid men suggests that sLHCGR in serum may originate from and possibly exert actions in non-gonadal tissues. (ClinicalTrials: NTC01411527, NCT01304927, NCT03418896).
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http://dx.doi.org/10.3390/cancers13061329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999540PMC
March 2021

Prenatal Exposure to Butyl Paraben Is Associated With Fat Percentage in 7-Year-Old Boys.

J Clin Endocrinol Metab 2021 Jun;106(7):e2633-e2638

Department of Clinical Pharmacology, Pharmacy and Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense, Denmark.

Context: Parabens are used as preservatives in consumer products but are suspected of having endocrine-disrupting properties. A recent study reported an association between in utero exposure to butyl paraben and overweight in childhood, with a stronger trend in girls.

Objective: We therefore studied the association between parabens in maternal urine in third trimester and fat percentage in children aged 7 years.

Design, Setting, And Participants: We used data from the Odense Child Cohort, a mother-child cohort with enrollment from 2010 to 2012, in which the children are followed. Paraben concentration was assessed in maternal urine at median gestational week 28.7 and body composition measured as total, gynoid, and android fat percentages assessed by dual X-ray absorptiometry in their children at age 7 years.

Main Outcome Measurements: Total, gynoid, and android fat percentages and z-score for body mass index.

Interventions: None.

Results: Paraben exposure was low. In multivariate linear regressions, detection of butylparaben in maternal urine was associated with an increase of 17% [95% confidence intervals (CI) 3.0%, 32%] in total body fat percentage and an increase of 23% (95% CI 5.1%, 43%) in android fat percentage in boys, compared to boys whose mother had no detectable butylparaben in urine. No significant associations between in utero exposure to methyl-, ethyl- or propyl parabens and body composition were found, and no significant associations were seen in girls.

Conclusion: Our findings suggest that parabens, which are believed to have low toxicity, may affect obesity development at vulnerable time periods during development.
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http://dx.doi.org/10.1210/clinem/dgab167DOI Listing
June 2021

Prenatal exposure to bisphenol A and autistic- and ADHD-related symptoms in children aged 2 and5 years from the Odense Child Cohort.

Environ Health 2021 03 12;20(1):24. Epub 2021 Mar 12.

Department of Clinical Pharmacology, Pharmacy and Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense, Denmark.

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.
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http://dx.doi.org/10.1186/s12940-021-00709-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955642PMC
March 2021

Free testosterone and cardiometabolic parameters in men: comparison of algorithms.

Endocr Connect 2021 Feb;10(2):220-229

Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Blegdamsvej, Copenhagen, Denmark.

Objective: Calculating the free testosterone level has gained increasing interest and different indirect algorithms have been suggested. The objective was to compare free androgen index (FAI), free testosterone estimated using the linear binding model (Vermeulen: cFTV) and the binding framework accounting for allosterically coupled SHBG monomers (Zakharov: cFTZ) in relation to cardiometabolic conditions.

Design: A prospective cohort study including 5350 men, aged 30-70 years, participating in population-based surveys (MONICA I-III and Inter99) from 1982 to 2001 and followed until December 2012 with baseline and follow-up information on cardiometabolic parameters and vital status.

Results: Using age-standardized hormone levels, FAI was higher among men with baseline cardiometabolic conditions, whereas cFTV and cFTZ levels were lower compared to men without these conditions as also seen for total testosterone. Men in highest quartiles of cFTV or cFTZ had lower risk of developing type 2 diabetes (cFTV: HR = 0.74 (0.49-1.10), cFTZ: HR = 0.59 (0.39-0.91)) than men in lowest quartile. In contrast, men with highest levels of FAI had a 74% (1.17-2.59) increased risk of developing type 2 diabetes compared to men in lowest quartile.

Conclusion: The association of estimated free testosterone and the studied outcomes differ depending on algorithm used. cFTV and cFTZ showed similar associations to baseline and long-term cardiometabolic parameters. In contrast, an empiric ratio, FAI, showed opposite associations to several of the examined parameters and may reflect limited clinical utility.
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http://dx.doi.org/10.1530/EC-20-0552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983478PMC
February 2021

Prenatal paraben exposure and anogenital distance and reproductive hormones during mini-puberty: A study from the Odense Child Cohort.

Sci Total Environ 2021 May 14;769:145119. Epub 2021 Jan 14.

Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark; International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark.

Background: Parabens are added to personal care products as antimicrobial preservatives. They have been suggested to have endocrine disrupting abilities. Prenatal exposure to parabens has been associated with reproductive endpoints including reduced male anogenital distance (AGD, distance from anus to genitals), which is sensitive to prenatal anti-androgenic exposure.

Objectives: To study the associations between maternal paraben concentrations in second trimester urine and AGD and reproductive hormone concentrations at 3 months of age in offspring.

Methods: Pregnant women from Odense, Denmark were included in early pregnancy from 2010 to 12, and their children are being followed up. Fasting spot urine samples from 536 pregnant women were analyzed for methylparaben (MeP), ethyl-paraben (EtP), iso-propylparaben (i-PrP), n-propylparaben (n-PrP), n-butylparaben (n-BuP) and benzylparaben (BzP) by liquid chromatography tandem mass spectrometry and thereafter osmolarity adjusted. Three months after expected date of birth, AGD was measured in 452 children, and serum concentrations of follicle stimulating hormone (FSH), luteinizing (LH), testosterone, dehydroepiandrosterone-sulphate (DHEAS), androstenedione and 17-hydroxyprogesterone (17-OHP) were measured in 198 children. Maternal paraben exposure was categorized into tertiles or below and above level of detection, and sex-stratified multiple linear regression analyses were performed with AGD or reproductive hormones as outcomes.

Results: Most pregnant women had low concentrations of parabens in urine, but 10% exceeded the threshold for adverse estrogenic effects. Higher maternal paraben exposure was associated with shorter AGD in male offspring and longer AGD in girls, although only significant for MeP in boys. In addition, FSH, LH, DHEAS, 17-OHP concentrations were lower in girls with high prenatal paraben exposure, whereas no consistent pattern was found in boys.

Discussion: The endocrine disrupting abilities of parabens may affect humans at vulnerable time periods during development, which may have long term impact on reproductive function. This is the first study to find these associations in girls and our findings need confirmation.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145119DOI Listing
May 2021

Congenital Adrenal Hyperplasia in Children: A Pilot Study of Steroid Hormones Expressed as Sex- and Age-Related Standard Deviation Scores.

Horm Res Paediatr 2020 5;93(4):226-238. Epub 2020 Oct 5.

Department of Growth and Reproduction and International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Introduction: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease predominantly caused by 21-hydroxylase deficiency. Clinical management in children includes glucocorticoid and often mineralocorticoid treatment alongside monitoring outcomes such as an-thro-po-metry, pubertal status, blood pressure, and biochemistry.

Objective: The objective of this pilot study was to present the use of 17-hydroxyprogesterone (17-OHP) and androgen metabolites expressed as standard deviation (SD) scores rather than actual concentrations as a tool in the management of children with CAH as well as in research settings.

Methods: The study was a retrospective, longitudinal study that took place in a single, tertiary center and included 38 children and adolescents aged 3-18 years with CAH due to 21-hydroxylase deficiency. Biochemical measurements of 17-OHP, androstenedione, dehydroepiandrosterone-sulphate (DHEAS), and testosterone using liquid chromatography-tandem mass spectrometry were expressed as SD scores, and outcomes such as genotype, height, bone maturation, blood pressure, and treatment doses were extracted from patient files.

Results: The majority (86%) of CAH patients had 17-OHP measurements above +2 SD during standard hydrocortisone therapy, receiving an average daily hydrocortisone dose of 12.6 mg/m2. Androstenedione concentrations were mostly within ±2 SD, whereas DHEAS values were below -2 SD in 47% of patients.

Conclusions: Applying sex- and age-related SD scores to 17-OHP and androgen metabolite concentrations allows for monitoring of hydrocortisone treatment independent of age, sex, assay, and center. We propose that 17-OHP and androgen metabolites expressed as SD scores be implemented as a unifying tool that simplifies research and, in the future, also optimal management of treatment.
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http://dx.doi.org/10.1159/000509079DOI Listing
October 2020

Mass Spectrometry Supports That the Structure of Circulating Human Insulin-Like Factor 3 Is a Heterodimer.

Front Endocrinol (Lausanne) 2020 28;11:552. Epub 2020 Aug 28.

Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

The structure of the testicular peptide hormone insulin-like factor 3 (INSL3) has been the subject of discussion for more than a decade. Some studies support that the central C-domain of INSL3 is proteolytically removed and that INSL3 is secreted by the testicular Leydig cells into circulation as a small heterodimer consisting of an A- and a B-chain linked by two disulfide bridges. Other studies support that the INSL3 peptide remains uncleaved and that the predominant structure of circulating INSL3 is the larger pro-form. Furthermore, the structure of INSL3 could differ between species, and both structural forms of INSL3 could, in principle, be present in circulation. Recently, we have developed a mass spectrometry (MS)-based method for INSL3 in human serum that provides new information about the structure of circulating INSL3. Based on recent and newly presented data, we argue that in healthy men, the common, and probably the only, form of circulating INSL3 is the smaller AB heterodimer. For the first time, we demonstrate that the same analytical principle, with slight modifications, can also be applied to sera from other species, and we show that the INSL3 AB heterodimer is also present in serum from rodents. Improved understanding of the structure and biochemistry of circulating INSL3 could be valuable for the interpretation of INSL3 as a marker for reproductive and developmental disorders in humans and domesticated animals.
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http://dx.doi.org/10.3389/fendo.2020.00552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484738PMC
June 2021

The LH/FSH ratio is not a sex-dimorphic marker after infancy: data from 6417 healthy individuals and 125 patients with Differences of Sex Development.

Hum Reprod 2020 10;35(10):2323-2335

Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Study Question: What is the course of the LH/FSH ratio from infancy into adulthood in healthy individuals and in patients with Differences of Sex Development (DSD)?

Summary Answer: The LH/FSH ratio had a marked overlap between the sexes after infancy and onwards throughout adulthood in healthy individuals and it was not a marker of hypogonadism in DSD patients.

What Is Known Already: The LH/FSH ratio is a distinct marker of sex during minipuberty. No study has evaluated the LH/FSH ratio from infancy into adulthood.

Study Design, Size, Duration: This was a combined study of prospective longitudinal and cross-sectional cohorts of healthy individuals totaling 6417 males and females aged 0-80 years. Retrospective data from a single, tertiary center on 125 patients with DSD was also included.

Participants/materials, Setting, Methods: Based on the healthy males (n = 3144) and females (n = 3273) aged 0-80 years, reference ranges for LH, FSH and the LH/FSH ratio were established from infancy (after minipuberty) and onwards. LH, FSH, and the LH/FSH ratio in 125 patients with DSD not undergoing treatment were compared to the reference ranges. Included DSD diagnoses were: Klinefelter syndrome including mosaic variants (males: n = 14), Turner syndrome including mosaic variants without Y-chromosome material (females: n = 48), 45,X/46,XY mosaicism (males: n = 24 and females: n = 6), partial androgen insensitivity syndrome (males: n = 11), complete androgen insensitivity syndrome (females: n = 13) and anorchia (males: n = 9).

Main Results And The Role Of Chance: An overlap was observed in the LH/FSH ratio reference curves between males and females. However, when comparing the sexes at specific time points, the LH/FSH ratio was significantly higher in healthy males during childhood and adulthood and significantly higher in healthy females during puberty. When compared with healthy participants, male patients with anorchia and 45,X/46,XY mosaicism had significantly lower ratios, while patients with androgen insensitivity, regardless of sex, had significantly higher ratios.

Limitations, Reasons For Caution: The limitations of this study include that; (i) all healthy individuals were Caucasian, so conclusions may not apply to non-Caucasians; (ii) the calculated LH/FSH ratios were restricted to the specific analytical method used and may not be applicable to other laboratories; (iii) the samples from healthy individuals were stored for varying amounts of time up to 20 years which may affect the durability; and (iv) DSD diagnoses are heterogeneous thus making sturdy conclusions across diagnoses impossible.

Wider Implications Of The Findings: In this study of combined cohorts of healthy participants, the largest normative ranges of LH, FSH, and the LH/FSH ratio to date were created. These reference ranges provide the opportunity for clinical as well as research use for all three markers. However, the previously rather undescribed LH/FSH ratio was not a distinct marker of sex after infancy nor a new marker of hypogonadism. Although there were significant differences between subgroups of DSD patients compared to healthy controls, the clinical significance of the LH/FSH ratio after infancy lacked. However, it can be speculated whether there are other areas of clinical application not investigated in this article, for example as a marker of fertility in select patient groups. As gonadotropin assays are readily available and gonadotropin measurements are part of regular workups, the LH/FSH ratio can easily be explored in further research without additional costs.

Study Funding/competing Interest(s): M.L.L. was funded by the Absalon Foundation. Cohort 1 was funded by the European Commission, through the Biomed 2 Program (BMH4-CT96-0314), Environmental Reproductive Health (QLK4-CT1999-01422) and EXPORED (QLK4-2001-00269), by the Danish Council for Independent Research (9700833 and 9700909), and by the Svend Andersens Foundation. Cohort 2 was funded by the Danish Environmental Research Program (96.01.015.16.05). Cohort 3 was funded by Kirsten and Freddy Johansens Foundation.

Trial Registration Number: NA.

Date Of First Patient’s Enrolment: June 1990 (the launch of the department from which this project stems).
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http://dx.doi.org/10.1093/humrep/deaa182DOI Listing
October 2020

Learning from previous work and finding synergies in the domains of public and environmental health: EU-funded projects BRIDGE Health and HBM4EU.

Arch Public Health 2020 10;78:78. Epub 2020 Sep 10.

German Environment Agency, Berlin, Germany.

Background: During the last decade, the European Union initiated several projects in the domains of public and environmental health. Within this framework, BRIDGE Health (Bridging Information and Data Generation for Evidence-based Health policy and Research) and HBM4EU (European human biomonitoring initiative) have been implemented. Whereas, the focus of BRIDGE Health was towards a sustainable and integrated health information system (HIS), the aim of HBM4EU is to improve evidence of the internal exposure of European citizens to environmental chemicals by human biomonitoring (HBM) and the impact of internal exposure on health. As both, environmental and public health determinants are important for health promotion, disease prevention and policy, BRIDGE Health and HBM4EU have overlapping aims and outcomes. In order to improve health information regarding public health and environmental health issues, best use and exchange of respective networks and project results is necessary.

Methods: Both projects have implemented health information (HI) and HBM tasks in order to provide adequate environmental and public health information of the European population. Synergies of the projects were identified in the working progress and because of overlapping networks and experts a focused analysis of both projects was envisaged. This paper elaborates on the aims and outcomes of both projects and the benefit of merging and channelling research results for the use of better health information and policy making that may be of relevance for any other project in these research fields.

Results: The need for focused exchanges and collaborations between the projects were identified and benefits of exchanges were highlighted for the specific areas of indicator development, linkage of data repositories and the combination of HBM studies and health examination surveys (HES). Further recommendations for a European wide harmonisation among different tasks in the fields of public health and environmental health are being developed.

Conclusions: Lessons learned from HBM4EU and BRIDGE Health show that continuous efforts must be undertaken, also by succeeding projects, to guarantee the exchange between public health and environmental health issues. Networks covering both are essential to provide better evidence of knowledge. The experiences from BRIDGE Health and HBM4EU give a valuable input for any future activity in these domains. Avoiding overlaps and streamlining further exchange of public health and environmental health contributes to best use of research results and allows to develop new strategies and tools for improvement of health information and thus enhances people's health and well-being.
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http://dx.doi.org/10.1186/s13690-020-00460-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488312PMC
September 2020

Maternal phthalate exposure associated with decreased testosterone/LH ratio in male offspring during mini-puberty. Odense Child Cohort.

Environ Int 2020 11 13;144:106025. Epub 2020 Aug 13.

Department of Environmental Medicine, University of Southern Denmark, Odense C, Denmark; Odense Child Cohort, Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense C, Denmark; OPEN Patient Data Exploratorive Network (OPEN), University of Southern, Odense C, Denmark. Electronic address:

Background: Phthalates are plastic softeners with anti-androgenic properties. Prenatal exposure has led to lower testosterone (T) levels and smaller testicles in adult rats. To our knowledge, no studies have examined associations between prenatal phthalate exposure and sex hormone concentrations in infants.

Objective: To study associations between phthalate exposure in Danish pregnant women and T, luteinizing hormone (LH), follicle stimulating hormone (FSH), Δ4-androstenedione (adion), 17α-hydroxyprogesterone (17-OHP) dehydroepiandrosterone sulfate (DHEAS) concentrations in their infants (N = 479) during mini-puberty.

Methods: Concentrations of 12 phthalate metabolites from six phthalate diesters were measured in urine samples collected from 2010 to 2012 from 479 pregnant women participating in the Odense Child Cohort at gestational week 28 (range 20.4-30.4). Serum T, LH, FSH, adion, 17-OHP, DHEAS, weight and height were measured approximately three months after expected date of birth. Associations between prenatal phthalate exposure and gonadotropin and androgen metabolite concentrations were estimated in boys and girls separately in adjusted linear regression models.

Results: T concentration was lower in boys prenatally exposed to phthalates. Maternal urinary concentrations of summed mono-iso-butyl and mono-n-butyl phthalate (∑MBP) and summed metabolites of di-iso-nonyl phthalate (∑DiNP) were associated with lower T/LH ratio in male offspring and a dose-response association was found. FSH was 14% (95% CI: 1; 25) lower among male offspring from mothers exposed to ∑DiNP in the highest compared to the lowest tertile. No association was found for girls.

Conclusion: Even in these low exposed children, we found a significant decrease in T/LH ratio during mini-puberty in boys prenatally exposed to phthalates, which may suggest impairment of Leydig cells. The children will be followed as they approach adrenarche and pubarche in order to assess if long-term adverse effects persist.
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http://dx.doi.org/10.1016/j.envint.2020.106025DOI Listing
November 2020

Using assessment criteria for pesticides to evaluate the endocrine disrupting potential of non-pesticide chemicals: Case butylparaben.

Environ Int 2020 11 6;144:105996. Epub 2020 Aug 6.

Division of Diet, Disease Prevention and Toxicology, National Food Institute, Technical University of Denmark, Kongens Lyngby, Denmark.

Regulation of chemicals with endocrine disrupting properties depend on the use of the chemical rather than its intrinsic properties. Within the EU, the only criteria currently in place for identifying an endocrine disrupting chemical (EDC) are those developed for biocidal and plant protection products. We argue that ECHA/EFSA guidance for assessing endocrine disrupting properties of biocidal and plant protection products can be applied to all chemicals independent of their intended use. We have assessed the REACH-registered compound butylparaben (CAS 94-36-8), a preservative used primarily in cosmetics. Based on scientific evidence of adverse reproductive effects and endocrine activity, the open literature suggest that butylparaben is an EDC. By applying the ECHA/EFSA guidance for pesticides and biocides, we identify butylparaben as a compound with endocrine disrupting properties. Even though available data is markedly different from that for biocides and pesticides, it was possible to reach this conclusion. More generally, we propose that the ECHA/EFSA guidance can and should be used for identification of EDC regardless of their intended application.
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http://dx.doi.org/10.1016/j.envint.2020.105996DOI Listing
November 2020

Physiologically based kinetic (PBK) modelling and human biomonitoring data for mixture risk assessment.

Environ Int 2020 10 4;143:105978. Epub 2020 Aug 4.

European Commission, Joint Research Centre (JRC), Ispra, Italy. Electronic address:

Human biomonitoring (HBM) data can provide insight into co-exposure patterns resulting from exposure to multiple chemicals from various sources and over time. Therefore, such data are particularly valuable for assessing potential risks from combined exposure to multiple chemicals. One way to interpret HBM data is establishing safe levels in blood or urine, called Biomonitoring Equivalents (BE) or HBM health based guidance values (HBM-HBGV). These can be derived by converting established external reference values, such as tolerable daily intake (TDI) values. HBM-HBGV or BE values are so far agreed only for a very limited number of chemicals. These values can be established using physiologically based kinetic (PBK) modelling, usually requiring substance specific models and the collection of many input parameters which are often not available or difficult to find in the literature. The aim of this study was to investigate the suitability and limitations of generic PBK models in deriving BE values for several compounds with a view to facilitating the use of HBM data in the assessment of chemical mixtures at a screening level. The focus was on testing the methodology with two generic models, the IndusChemFate tool and High-Throughput Toxicokinetics package, for two different classes of compounds, phenols and phthalates. HBM data on Danish children and on Norwegian mothers and children were used to evaluate the quality of the predictions and to illustrate, by means of a case study, the overall approach of applying PBK models to chemical classes with HBM data in the context of chemical mixture risk assessment. Application of PBK models provides a better understanding and interpretation of HBM data. However, the study shows that establishing safety threshold levels in urine is a difficult and complex task. The approach might be more straightforward for more persistent chemicals that are analysed as parent compounds in blood but high uncertainties have to be considered around simulated metabolite concentrations in urine. Refining the models may reduce these uncertainties and improve predictions. Based on the experience gained with this study, the performance of the models for other chemicals could be investigated, to improve the accuracy of the simulations.
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http://dx.doi.org/10.1016/j.envint.2020.105978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684529PMC
October 2020

Levels of endocrine-disrupting chemicals are associated with changes in the peri-pubertal epigenome.

Endocr Connect 2020 Aug;9(8):845-857

Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Puberty marks a transition period, which leads to the attainment of adult sexual maturity. Timing of puberty is a strongly heritable trait. However, large genetic association studies can only explain a fraction of the observed variability and striking secular trends suggest that lifestyle and/or environmental factors are important. Using liquid-chromatography tandem-mass-spectrometry, we measured endocrine-disrupting chemicals (EDCs; triclosan, bisphenol A, benzophenone-3, 2,4-dichlorophenol, 11 metabolites from 5 phthalates) in longitudinal urine samples obtained biannually from peri-pubertal children included in the COPENHAGEN puberty cohort. EDC levels were associated with blood DNA methylation profiles from 31 boys and 20 girls measured both pre- and post-pubertally. We found little evidence of single methylation sites that on their own showed association with urinary excretion levels of EDCs obtained either the same-day or measured as the yearly mean of dichotomized EDC levels. In contrast, methylation of several promoter regions was found to be associated with two or more EDCs, overlap with known gene-chemical interactions, and form a core network with genes known to be important for puberty. Furthermore, children with the highest yearly mean of dichotomized urinary phthalate metabolite levels were associated with higher promoter methylation of the thyroid hormone receptor interactor 6 gene (TRIP6), which again was mirrored by lower circulating TRIP6 protein levels. In general, the mean TRIP6 promoter methylation was mirrored by circulating TRIP6 protein levels. Our results provide a potential molecular mode of action of how exposure to environmental chemicals may modify pubertal development.
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http://dx.doi.org/10.1530/EC-20-0286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487188PMC
August 2020

Testicular microlithiasis on scrotal ultrasound in 4850 young men from the general population: associations with semen quality.

Andrology 2020 11 16;8(6):1736-1743. Epub 2020 Jul 16.

Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark.

Background: Testicular microlithiasis (TM) is sometimes found on scrotal ultrasound. The prevalence seems higher in populations of men with testicular dysfunction, and TM may be a risk factor for testicular germ cell neoplasia in situ in men with additional risk factors. The association between TM and testicular function is controversial, especially in incidentally found TM.

Objectives: To determine the frequency of TM in young men from the general population, and associations between TM, semen quality, and reproductive hormones.

Materials And Methods: A cross-sectional study of 4850 Danish men, median age 19 years. Testicular pattern, including the presence of TM, was assessed by ultrasound examination. Participants provided a questionnaire, one semen sample, and one blood sample. Semen variables and serum reproductive hormones were analyzed as outcomes using multivariable regression analysis to determine associations with TM.

Results: TM was detected in 53 men (1%), of which 19 (36%) were unilateral and 34 (64%) were bilateral cases. A history of cryptorchidism was associated with presence of TM. Bilateral TM was associated with slightly lower testicular volume, sperm concentration, and total sperm count. TM was not significantly associated with serum testosterone or other reproductive hormones.

Discussion And Conclusion: TM is rare in men from the general population and is associated with lower sperm count if bilateral, although effect sizes were small. Current European guidelines do not recommend any follow-up in cases of TM with no other risk factors for testicular cancer. We suggest that men with incidentally found bilateral TM may be offered a semen analysis, but analysis of reproductive hormones seems unnecessary.
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http://dx.doi.org/10.1111/andr.12854DOI Listing
November 2020

Use of e-cigarettes associated with lower sperm counts in a cross-sectional study of young men from the general population.

Hum Reprod 2020 07;35(7):1693-1701

Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark.

Study Question: Are use of e-cigarettes and snuff associated with testicular function as previously shown for conventional cigarettes and marijuana?

Summary Answer: Use of e-cigarettes is associated with reduced semen quality but not with higher serum testosterone level as observed for conventional cigarette use. Snuff use was not associated with markers of testicular function.

What Is Known Already: Cigarette smoking has previously been associated with higher testosterone levels and impaired semen quality, whereas it is unresolved whether use of e-cigarettes or snuff influence the testicular function.

Study Design, Size, Duration: This cross-sectional population-based study included 2008 men with information on cigarette and marijuana use (enrolled between 2012 and 2018), among whom 1221 men also had information on e-cigarette and snuff use (enrolled between 2015 and 2018).

Participants/materials, Setting, Methods: Men (median age 19.0 years) from the general population provided a semen and blood sample and filled out a questionnaire on lifestyle including information on smoking behaviour. Associations between different types of smoking (e-cigarettes, snuff, marijuana and cigarettes) and reproductive hormones (total and free testosterone, sex hormone-binding globulin, LH, oestradiol and ratios of inhibin B/FSH, testosterone/LH and free testosterone/LH) and semen parameters (total sperm count and sperm concentration) were examined using multiple linear regression analyses adjusted for relevant confounders.

Main Results And The Role Of Chance: Approximately half of the men (52%) were cigarette smokers, 13% used e-cigarettes, 25% used snuff and 33% used marijuana. Users of e-cigarettes and marijuana were often also cigarette smokers. Compared to non-users, daily e-cigarette users had significantly lower total sperm count (147 million vs 91 million) as did daily cigarette smokers (139 million vs 103 million), in adjusted analyses. Furthermore, significantly higher total and free testosterone levels were seen in cigarette smoking men (6.2% and 4.1% higher total testosterone and 6.2% and 6.2% higher free testosterone in daily smokers and occasional smokers, respectively, compared to non-smoking men), but not among e-cigarette users. Daily users of marijuana had 8.3% higher total testosterone levels compared to non-users. No associations were observed for snuff in relation to markers of testicular function.

Limitations, Reasons For Caution: We cannot exclude that our results can be influenced by residual confounding by behavioural factors not adjusted for. The number of daily e-cigarette users was limited and findings should be replicated in other studies.

Wider Implications Of The Findings: This is the first human study to indicate that not only cigarette smoking but also use of e-cigarettes is associated with lower sperm counts. This could be important knowledge for men trying to achieve a pregnancy, as e-cigarettes are often considered to be less harmful than conventional cigarette smoking.

Study Funding/competing Interest(s): Funding was received from the Danish Ministry of Health (1-1010-308/59), the Independent Research Fund Denmark (8020-00218B), ReproUnion (20200407) and the Research Fund of the Capital Region of Denmark (A6176). The authors have nothing to disclose.

Trial Registration Number: NA.
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http://dx.doi.org/10.1093/humrep/deaa089DOI Listing
July 2020

Predicting Transdermal Uptake of Phthalates and a Paraben from Cosmetic Cream Using the Measured Fugacity.

Environ Sci Technol 2020 06 2;54(12):7471-7484. Epub 2020 Jun 2.

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27516, United States.

Transdermal uptake models compliment in vitro and in vivo experiments in assessing risk of environmental exposures to semivolatile organic compounds (SVOCs). A key parameter for mechanistic models is the chemical driving force for mass transfer from environmental media to human skin. In this research, we measure this driving force in the form of fugacity for chemicals in cosmetic cream and use it to model uptake from cosmetics as a surrogate for condensed environmental media. A simple cosmetic cream, containing no target analytes, was mixed with diethyl phthalate (DEP), di--butyl phthalate (DnBP), and butyl paraben (BP) and diluted to make creams with concentrations ranging from 0.025% to 6%. The fugacity, relative to the pure compound, was measured using solid-phase micro extraction (SPME). We found that the relationship between the concentration and fugacity is highly nonlinear. The relative fugacity of the chemicals for a 2% w/w formulation was used in a diffusion-based model to predict transdermal uptake of each chemical and was compared with excretion data from a prior human subject study with the same formulation. Dynamic simulations of excretion are generally consistent with the results of the human subject experiment but sensitive to the input parameters, especially the time between cream application and showering.
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http://dx.doi.org/10.1021/acs.est.0c01503DOI Listing
June 2020

Evaluation of Serum Insulin-like Factor 3 Quantification by LC-MS/MS as a Biomarker of Leydig Cell Function.

J Clin Endocrinol Metab 2020 06;105(6)

Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1210/clinem/dgaa145DOI Listing
June 2020

Maternal phthalate exposure and asthma, rhinitis and eczema in 552 children aged 5 years; a prospective cohort study.

Environ Health 2020 03 13;19(1):32. Epub 2020 Mar 13.

Department of Environmental Medicine, Institute of Public Health, University of Southern Denmark, J.B. Winsløwsvej 17A, 5000, Odense, Denmark.

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 and di-2-ethylhexyl phthalate metabolite (ΣDEHP) 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 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.
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http://dx.doi.org/10.1186/s12940-020-00586-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069194PMC
March 2020

Impacts of food contact chemicals on human health: a consensus statement.

Environ Health 2020 03 3;19(1):25. Epub 2020 Mar 3.

Department of Biology, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.

Food packaging is of high societal value because it conserves and protects food, makes food transportable and conveys information to consumers. It is also relevant for marketing, which is of economic significance. Other types of food contact articles, such as storage containers, processing equipment and filling lines, are also important for food production and food supply. Food contact articles are made up of one or multiple different food contact materials and consist of food contact chemicals. However, food contact chemicals transfer from all types of food contact materials and articles into food and, consequently, are taken up by humans. Here we highlight topics of concern based on scientific findings showing that food contact materials and articles are a relevant exposure pathway for known hazardous substances as well as for a plethora of toxicologically uncharacterized chemicals, both intentionally and non-intentionally added. We describe areas of certainty, like the fact that chemicals migrate from food contact articles into food, and uncertainty, for example unidentified chemicals migrating into food. Current safety assessment of food contact chemicals is ineffective at protecting human health. In addition, society is striving for waste reduction with a focus on food packaging. As a result, solutions are being developed toward reuse, recycling or alternative (non-plastic) materials. However, the critical aspect of chemical safety is often ignored. Developing solutions for improving the safety of food contact chemicals and for tackling the circular economy must include current scientific knowledge. This cannot be done in isolation but must include all relevant experts and stakeholders. Therefore, we provide an overview of areas of concern and related activities that will improve the safety of food contact articles and support a circular economy. Our aim is to initiate a broader discussion involving scientists with relevant expertise but not currently working on food contact materials, and decision makers and influencers addressing single-use food packaging due to environmental concerns. Ultimately, we aim to support science-based decision making in the interest of improving public health. Notably, reducing exposure to hazardous food contact chemicals contributes to the prevention of associated chronic diseases in the human population.
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http://dx.doi.org/10.1186/s12940-020-0572-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053054PMC
March 2020

Use of stored serum in the study of time trends and geographical differences in exposure of pregnant women to phthalates.

Environ Res 2020 05 7;184:109231. Epub 2020 Feb 7.

Department of Growth and Reproduction and International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen, Denmark.

Background: Exposure to some phthalate diesters has been associated with adverse reproductive health outcomes in both rodents and humans indicative of anti-androgenic effects. Exposure during sensitive periods of development, such as prenatally, is of particular concern.

Objectives: We wished to investigate whether phthalate metabolites measured in maternal serum samples from historical birth cohorts can be used to assess prenatal exposure. Further, we aimed to study temporal and geographical trends in phthalate exposure across three different birth cohorts.

Methods: We compared phthalate metabolite levels in maternal serum samples from an Australian (1989-91) and a Danish (1997-2001) birth cohort with levels in serum and urine samples from a recent Danish birth cohort (2012-14). Samples were analysed for 32 phthalate metabolites from 15 phthalate diesters by isotope-diluted liquid chromatography-tandem mass spectrometry (LC-MS/MS). Correlations between metabolites were tested by Spearman rank correlation test, and differences between the cohorts were tested by Mann-Whitney U test.

Results: Overall, we observed large variations in serum phthalate metabolite levels between individuals. Secondary metabolites of di-(2-ethyl-hexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DiNP) in serum were weakly to moderately and positively correlated to the levels measured in urine, and secondary metabolites of DEHP were also moderately to strongly and significantly correlated in serum. Correlations with mono-(2-ethyl-hexyl) phthalate (MEHP) and mono-iso-nonyl phthalate (MiNP), the two primary metabolites of DEHP and DiNP, were inconsistent, and we found indications of sample contamination. We observed some significant differences in phthalate metabolite levels between the three cohorts with generally higher levels in the older birth cohorts.

Conclusion: Based on comparison across two older birth cohorts and a recent cohort, our results support the concept that historical biobanked serum samples may be used for assessment of prenatal exposure to phthalates when using serum levels of the monoesters of the low-molecular weight (LMW) phthalates and the secondary metabolites of the high-molecular weight (HMW) phthalates. Serum phthalate measurements are, however, not suitable for human biomonitoring and should only be used to exploit historical samples from cohorts, where urine samples were not collected. Our findings suggest that phthalate exposure may have decreased over time from the early 1990s to the 2010s.
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http://dx.doi.org/10.1016/j.envres.2020.109231DOI Listing
May 2020

Prenatal exposure to perfluorodecanoic acid is associated with lower circulating concentration of adrenal steroid metabolites during mini puberty in human female infants. The Odense Child Cohort.

Environ Res 2020 03 31;182:109101. Epub 2019 Dec 31.

Department of Environmental Medicine, University of Southern Denmark, J.B. Winsløws Vej 17A, 5000, Odense C, Denmark; Odense Child Cohort, Hans Christian Andersen Children's Hospital, Odense University Hospital, Søndre Blvd. 29, 5000, Odense C, Denmark; Odense Patient Data Explorative Network (OPEN), University of Southern, J. B. Winsløws Vej 9a, Odense C, Denmark.

Background: Fetal programming of the endocrine system may be affected by exposure to perfluoroalkyl substances (PFAAs), as they easily cross the placental barrier. In vitro studies suggest that PFAAs may disrupt steroidogenesis. "Mini puberty" refers to a transient surge in circulating androgens, androgen precursors, and gonadotropins in infant girls and boys within the first postnatal months. We hypothesize that prenatal PFAA exposure may decrease the concentrations of androgens in mini puberty.

Objectives: To investigate associations between maternal serum PFAA concentrations in early pregnancy and serum concentrations of androgens, their precursors, and gonadotropins during mini puberty in infancy.

Methods: In the prospective Odense Child Cohort, maternal pregnancy serum concentrations of five PFAAs: Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were measured at median gestational week 12 (IQR: 10, 15) in 1628 women. Among these, offspring serum concentrations of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEAS), androstenedione, 17-hydroxyprogesterone (17-OHP), testosterone, luteinizing (LH) and follicle stimulating hormones (FSH) were measured in 373 children (44% girls; 56% boys) at a mean age of 3.9 (±0.9 SD) months. Multivariate linear regression models were performed to estimate associations.

Results: A two-fold increase in maternal PFDA concentration was associated with a reduction in DHEA concentration by -19.6% (95% CI: -32.9%, -3.8%) in girls. In girls, also, the androstenedione and DHEAS concentrations were decreased, albeit non-significantly (p < 0.11), with a two-fold increase in maternal PFDA concentration. In boys, no significant association was found between PFAAs and concentrations of androgens, their precursors, and gonadotropins during mini puberty.

Conclusion: Prenatal PFDA exposure was associated with significantly lower serum DHEA concentrations and possibly also with lower androstenedione and DHEAS concentrations in female infants at mini puberty. The clinical significance of these findings remains to be elucidated.
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http://dx.doi.org/10.1016/j.envres.2019.109101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117803PMC
March 2020

UV filters in matched seminal fluid-, urine-, and serum samples from young men.

J Expo Sci Environ Epidemiol 2021 03 12;31(2):345-355. Epub 2020 Feb 12.

Department of Growth and Reproduction and International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

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 Ca channel and thereby potentially interfere with the fertilisation process.
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http://dx.doi.org/10.1038/s41370-020-0209-3DOI Listing
March 2021

Associations of Fish Oil Supplement Use With Testicular Function in Young Men.

JAMA Netw Open 2020 01 3;3(1):e1919462. Epub 2020 Jan 3.

Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Importance: Many young men have poor semen quality, and the causes are often unknown. Supplement intake of ω-3 polyunsaturated fatty acid has been found to improve semen quality among men with infertility, but the association with semen quality among healthy men is unknown.

Objective: To determine if intake of ω-3 fatty acid supplements is associated with testicular function as measured by semen quality and reproductive hormone levels among healthy men.

Design, Setting, And Participants: This cross-sectional study included young Danish men from the general population recruited between January 1, 2012, and December 31, 2017, at compulsory examinations to determine their fitness for military service. Young unselected men were approached after the examination and invited to participate in a study of reproductive function, regardless of their fitness for military service. Data analysis was conducted from September 1, 2018, to June 30, 2019.

Exposures: Intake of supplements, including fish oil, during the past 3 months.

Main Outcomes And Measures: Semen quality, measured as volume, concentration, total sperm count, percentage of morphologically normal spermatozoa, and motility, and serum reproductive hormone levels, measured as follicle-stimulating hormone, luteinizing hormone, testosterone, free testosterone, and inhibin B levels.

Results: Among 1679 young Danish men (median [interquartile range] age, 18.9 [18.7-19.4] years) recruited to participate, 98 men (5.8%) reported use of fish oil supplements during the past 3 months, of whom 53 (54.1%) reported intake on 60 or more days. After adjustment and compared with men with no supplement intake, men with fish oil supplement intake on fewer than 60 days had semen volume that was 0.38 (95% CI, -0.03 to 0.80) mL higher, and men with fish oil supplement intake on 60 or more days had semen volume that was 0.64 (95% CI, 0.15 to 1.12) mL higher (P for trend < .001). Similarly, testicular size in men with supplement intake on fewer than 60 days was 0.8 (95% CI, -0.2 to 1.9) mL larger and in men with fish oil supplement intake on 60 or more days was 1.5 (95% CI, 0.2 to 2.8) mL larger compared with men with no supplement intake (P for trend = .007). After adjustment, men with fish oil supplement intake had a 20% (95% CI, 9%-31%) lower follicle-stimulating hormone level and 16% (95% CI, 8%-24%) lower luteinizing hormone level compared with men with no supplement intake. There were no associations of intake of other supplements with measures of testicular function.

Conclusions And Relevance: These findings suggest that intake of fish oil supplements was associated with better testicular function, which is less likely to be due to confounding by indication, as no associations of intake of other supplements with testicular function were found. This cross-sectional study did not examine the actual content of ω-3 fatty acids in the supplements; therefore, these findings need confirmation in well-designed randomized clinical trials among unselected men.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.19462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991322PMC
January 2020

Sex-specific Estrogen Levels and Reference Intervals from Infancy to Late Adulthood Determined by LC-MS/MS.

J Clin Endocrinol Metab 2020 03;105(3)

Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Context: The lack of sensitive and robust analytical methods has hindered the reliable quantification of estrogen metabolites in subjects with low concentrations.

Objective: To establish sex-specific reference ranges for estrone (E1) and estradiol (E2) throughout life and to evaluate sex-differences using the state-of-the-art liquid chromatography tandem mass spectrometry (LC-MS/MS) method for quantification of E1, E2, and estriol (E3).

Design: LC-MS/MS method development and construction of estrogen reference ranges.

Settings: Population-based cross-sectional cohorts from the greater Copenhagen and Aarhus areas.

Participants: Healthy participants aged 3 months to 61 years (n = 1838).

Results: An isotope diluted LC-MS/MS method was developed and validated for measurements of serum E1, E2, and E3. Limits of detections (LODs) were 3 pmol/L (E1), 4 pmol/L (E2), and 12 pmol/L (E3), respectively. This sensitive method made it possible to differentiate between male and female concentration levels of E1 and E2 in children. In girls, E2 levels ranged from
Conclusion: Reference ranges of simultaneous quantification of E1 and E2 by this novel specific and highly sensitive LC-MS/MS method provide an invaluable tool in clinical practice and in future research studies.
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http://dx.doi.org/10.1210/clinem/dgz196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007877PMC
March 2020

Changes in urinary excretion of phthalates, phthalate substitutes, bisphenols and other polychlorinated and phenolic substances in young Danish men; 2009-2017.

Int J Hyg Environ Health 2020 01 25;223(1):93-105. Epub 2019 Oct 25.

Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Denmark; International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Denmark.

During the past two decades human exposure to bisphenol A (BPA) and phthalates such as di-iso-butyl phthalate (DiBP), di-n-butyl phthalate (DnBP), butylbenzyl phthalate (BBzP) and di-(2-ethyl-hexyl) phthalate (DEHP) has received substantial interest due to widespread population exposures and potential endocrine disrupting effects. Therefore, these chemicals have gradually been restricted and phased out through legislation. However, humans are still exposed to a wide range of other less studied phthalates, phthalate substitutes and BPA analogues as well as other polychlorinated and phenolic substances. In this study, we investigated human exposure to these chemicals over the past decade. Three hundred urine samples collected in 2009, 2013 and 2017 (100 samples each year) from young Danish men of the general population, participating in a large on-going cross-sectional study, were selected for the present time trend study. The urinary concentration of metabolites of 15 phthalates, di-2-ethylhexyl terephthalate (DEHTP) and di-iso-nonyl-cyclohexane-1,2-dicarboxylate (DINCH), seven bisphenols including BPA, bisphenol S (BPS) and bisphenol F (BPF), as well as triclosan, triclocarban, benzophenone-3, three chlorophenols and two phenylphenols were analyzed by two new sensitive LC-MS/MS methods developed and validated for the present study. A significant decrease in urinary concentrations over time was observed for the majority of the chemicals. Median concentrations of BPA and the metabolites of DiBP, DnBP, BBzP and DEHP were more than halved from 2009 to 2017. Similar decreases were observed for triclosan and the chloro- and phenylphenols. In contrast, metabolites of the two phthalate substitutes DEHTP and DINCH increased more than 20 and 2 times, respectively. The potential BPA substitutes; BPS and BPF also increased, but only slightly. Despite these new exposure patterns, the exposure to the old well-known chemicals, such as DiBP, DnBP, BBzP, DEHP and BPA was still higher in 2017 compared to the exposure level of the new substitutes such as DEHTP, DINCH, BPS and BPF. A significant decrease in internal exposure to most of the common phthalates and BPA over the past decade was observed, reflecting market changes and regulatory measures implemented in EU. Despite increasing exposures to some of the known phthalate substitutes and BPA analogues, the total amount of each measured chemical group (original and substitute analytes combined) was lower in the more recently collected samples. This indicates only partial direct substitution or substitution by chemicals not covered in this approach, or a general decline in the exposure to these chemical/product groups over the last decade.
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http://dx.doi.org/10.1016/j.ijheh.2019.10.002DOI Listing
January 2020

A European inter-laboratory trial to evaluate the performance of three serological methods for diagnosis of Mycoplasma bovis infection in cattle using latent class analysis.

BMC Vet Res 2019 Oct 25;15(1):369. Epub 2019 Oct 25.

Université de Lyon, Anses, Laboratoire de Lyon, UMR Mycoplasmoses des ruminants, Lyon, France.

Background: Mycoplasma bovis (M. bovis) is an emerging bovine pathogen, leading to significant economic losses in the livestock industry worldwide. Infection can result in a variety of clinical signs, such as arthritis, pneumonia, mastitis and keratoconjunctivitis, none of which are M. bovis-specific. Laboratory diagnosis is therefore important. Serological tests to detect M. bovis antibodies is considered an effective indicator of infection in a herd and often used as a herd test. Combined with clinical judgement, it can also be used to implement control strategies and/or to estimate the disease prevalence within a country. However, due to lack of harmonisation of approaches to testing, and serological tests used by different laboratories, comparisons of prevalence data between countries is often difficult. A network of researchers from six European countries designed and participated in an inter-laboratory trial, with the aim of evaluating the sensitivity (Se) and specificity (Sp) of two commercially available ELISA tests (ID Screen® ELISA (IDvet) and BIO K302 ELISA (BIO-X Diagnostics)) for diagnosis of M. bovis infection. Each laboratory received a blinded panel of bovine sera and tested independently, according to manufacturer's instructions. Western blot analyses (WB) performed by one of the participating laboratories was used as a third diagnostic test in the statistical evaluation of Se and Sp values using latent class analysis.

Results: The Se of WB, the ID Screen® ELISA and the BIO K302 ELISA were determined to be 91.8, 93.5 and 49.1% respectively, and corresponding Sp of the three tests were 99.6, 98.6 and 89.6%, respectively.

Conclusions: The present study is, to our knowledge, the first to present an inter-laboratory comparison of the BIO K302 ELISA and the ID Screen® ELISA. Based on our results, the ID Screen® ELISA showed high consistency with WB and performed with higher precision and accuracy than the BIO K302 ELISA.
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http://dx.doi.org/10.1186/s12917-019-2117-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814985PMC
October 2019

Efferocytosis of Apoptotic Neutrophils Enhances Control of Mycobacterium tuberculosis in HIV-Coinfected Macrophages in a Myeloperoxidase-Dependent Manner.

J Innate Immun 2020 27;12(3):235-247. Epub 2019 Jun 27.

Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden,

Tuberculosis remains a big threat, with 1.6 million deaths in 2017, including 0.3 million deaths among patients with HIV. The risk of developing active disease increases considerably during an HIV coinfection. Alveolar macrophages are the first immune cells to encounter the causative agent Mycobacterium tuberculosis, but during the granuloma formation other cells are recruited in order to combat the bacteria. Here, we have investigated the effect of efferocytosis of apoptotic neutrophils by M. tuberculosis and HIV-coinfected macrophages in a human in vitro system. We found that the apo-ptotic neutrophils enhanced the control of M. tuberculosis in single and HIV-coinfected macrophages, and that this was dependent on myeloperoxidase (MPO) and reactive oxygen species in an autophagy-independent manner. We show that MPO remains active in the apoptotic neutrophils and can be harnessed by infected macrophages. In addition, MPO inhibition removed the suppression in M. tuberculosis growth caused by the apoptotic neutrophils. Antimycobacterial components from apoptotic neutrophils could thus increase the microbicidal activity of macrophages during an M. tuberculosis/HIV coinfection. This cooperation between innate immune cells could thereby be a way to compensate for the impaired adaptive immunity against M. tuberculosis seen during a concurrent HIV infection.
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http://dx.doi.org/10.1159/000500861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267674PMC
July 2021
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