Exposure to chlorpyrifos and pyrethroid insecticides and symptoms of Attention Deficit Hyperactivity Disorder (ADHD) in preschool children from the Odense Child Cohort.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is a common childhood psychiatric disorder with severe and lifelong impact on mental health and socioeconomic achievements. Environmental factors may play a role in the increasing incidens rates. Previous studies on associations between prenatal and childhood exposure to organophosphate and pyrethroid insecticides and ADHD symptoms have yielded mixed findings. OBJECTIVES: To investigate associations between prenatal and childhood exposure to chlorpyrifos and pyrethroids and ADHD symptoms in 5-year-old children from the Odense Child Cohort. METHODS: Spot urine samples from pregnant women in gestational week 28 (n = 614) and offspring at 5 years of age (n = 814) were collected and analyzed for the specific metabolite of chlorpyrifos, TCPY (3,5,6-trichloro-2-pyridinol), as well as the generic pyrethroid metabolite, 3-PBA (3-phenoxybenzoic acid). Offspring ADHD symptoms were assessed at age 5 years using the parent reported "ADHD scale" from the "Child Behavior Checklist 1½-5" (n = 1114). Associations between insecticide exposure variables and an ADHD score ≥90th percentile were analyzed using logistic regression for all children and stratified by sex. RESULTS: Most pregnant women had detectable concentrations of 3-PBA (93%) and TCPY (91%) with median concentrations of 0.20 µg/L and 1.62 µg/L, respectively. In children, 3-PBA and TCPY concentrations were detectable in 88% and 82% of the samples, and the median concentrations were 0.17 and 1.16 µg/L. No statistically significant associations were observed between insecticide metabolites and an ADHD score ≥90th percentile at age 5. CONCLUSION: In this relatively large Danish birth cohort study with mainly low dietary insecticide exposure, we found no statistically significant associations between prenatal or childhood exposure to chlorpyrifos or pyrethroids, and excess ADHD-symptom load, in 5-year-old children. Prospective studies with multiple urine samples across vulnerable windows of neurodevelopment is warranted to improve assessment of safe exposure levels, which is particularly relevant for pyrethroids, since their use is increasing.

Association between prenatal or early postnatal exposure to perfluoroalkyl substances and language development in 18 to 36-month-old children from the Odense Child Cohort.

BACKGROUND: Perfluoroalkyl substances (PFAS) are persistent chemicals used in everyday consumer products leading to ubiquitous human exposure. Findings of impaired neurodevelopment after prenatal exposure to PFAS are contradictory and few studies have assessed the impact of postnatal PFAS exposure. Language development is a good early marker of neurodevelopment but only few studies have investigated this outcome separately. We therefore investigated the association between prenatal and early postnatal PFAS exposure and delayed language development in 18 to 36-month-old Danish children. METHODS: The Odense Child Cohort is a large prospective cohort. From 2010 to 2012 all newly pregnant women residing in the Municipality of Odense, Denmark was invited to participate. Concentration of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) were assessed in maternal serum collected in the 1st trimester of pregnancy and in child serum at 18 months. Parents responded to the Danish adaption of the MacArthur-Bates Communicative Development Inventories (MB-CDI) when their child was between 18 and 36 months. Language scores were converted into sex and age specific percentile scores and dichotomized to represent language scores above or below the 15th percentile. We applied Multiple Imputation by Chained Equation and conducted logistic regressions investigating the association between prenatal and early postnatal PFAS exposure and language development adjusting for maternal age, pre-pregnancy BMI, education and respectively fish intake in pregnancy or childhood and duration of breastfeeding in early postnatal PFAS exposure models. RESULTS: We found no significant associations between neither prenatal nor early postnatal PFAS exposure and language development among 999 mother-child pairs. CONCLUSION: In this low-exposed cohort the finding of no association between early postnatal PFAS exposure and language development should be interpreted with caution as we were unable to separate the potential adverse effect of PFAS exposure from the well documented positive effect of breastfeeding on neurodevelopment. We, therefore, recommend assessment of child serum PFAS at an older age as development of the brain proceeds through childhood and even a small impact of PFAS on neurodevelopment would be of public health concern at population level due to the ubiquitous human exposure.

Quality of Life in the Danish Fontan Population is Unchanged Over the Past Decade-A Nationwide Longitudinal Study.

Knowledge about health-related quality of life (HRQoL) over time in Fontan patients is sparse. We aimed to describe HRQoL over a ten-year period in a population-based Fontan cohort. Further, we compared HRQoL in Fontan patients with the general population. In 2011, Danish Fontan patients were invited to participate in a nationwide study assessing HRQoL. Depending on age, 152 participants filled out either the Pediatric Quality of Life Inventory or the 36-Item Short Form Health Survey. After a decade, patients from the initial study were invited to participate in a follow-up study. All were given the same questionnaire as in the first study, plus the 12-Item Short Form Health Survey (SF-12) as part of the Danish National Health Survey. HRQoL over time was described, and SF-12 scores were compared with the general population. A total of 109 Fontan patients completed the questionnaires in both studies. The mean patient age was 14.9 ± 6.6 years and 25.6 ± 6.5 years respectively. Despite an increase in complications, HRQoL did not decrease during the study period. Physical HRQoL scores were lower than mental HRQoL scores at both time points. The SF-12 physical component score was significantly lower in Fontan patients than in the general population (median score 52 vs. 56, p < 0.001), while the SF-12 mental component score was comparable (median score 51 vs. 50, p = 0.019). HRQoL remained stable over a ten-year period in a contemporary Danish Fontan cohort. Still, the physical HRQoL remained significantly lower than that of the general population.

Opposing roles of the entero-pancreatic hormone urocortin-3 in glucose metabolism in rats.

AIM/HYPOTHESIS: Urocortin-3 (UCN3) is a glucoregulatory peptide produced in the gut and pancreatic islets. The aim of this study was to clarify the acute effects of UCN3 on glucose regulation following an oral glucose challenge and to investigate the mechanisms involved. METHODS: We studied the effect of UCN3 on blood glucose, gastric emptying, glucose absorption and secretion of gut and pancreatic hormones in male rats. To supplement these physiological studies, we mapped the expression of UCN3 and the UCN3-sensitive receptor, type 2 corticotropin-releasing factor receptor (CRHR2), by means of fluorescence in situ hybridisation and by gene expression analysis. RESULTS: In rats, s.c. administration of UCN3 strongly inhibited gastric emptying and glucose absorption after oral administration of glucose. Direct inhibition of gastrointestinal motility may be responsible because UCN3's cognate receptor, CRHR2, was detected in gastric submucosal plexus and in interstitial cells of Cajal. Despite inhibited glucose absorption, post-challenge blood glucose levels matched those of rats given vehicle in the low-dose UCN3 group, because UCN3 concomitantly inhibited insulin secretion. Higher UCN3 doses did not further inhibit gastric emptying, but the insulin inhibition progressed resulting in elevated post-challenge glucose and lipolysis. Incretin hormones and somatostatin (SST) secretion from isolated perfused rat small intestine was unaffected by UCN3 infusion; however, UCN3 infusion stimulated secretion of somatostatin from delta cells in the isolated perfused rat pancreas which, unlike alpha cells and beta cells, expressed Crhr2. Conversely, acute antagonism of CRHR2 signalling increased insulin secretion by reducing SST signalling. Consistent with these observations, acute drug-induced inhibition of CRHR2 signalling improved glucose tolerance in rats to a similar degree as administration of glucagon-like peptide-1. UCN3 also powerfully inhibited glucagon secretion from isolated perfused rat pancreas (perfused with 3.5 mmol/l glucose) in a SST-dependent manner, suggesting that UCN3 may be involved in glucose-induced inhibition of glucagon secretion. CONCLUSIONS/INTERPRETATION: Our combined data indicate that UCN3 is an important glucoregulatory hormone that acts through regulation of gastrointestinal and pancreatic functions.

De Novo Missense Variants in FBXW11 Cause Diverse Developmental Phenotypes Including Brain, Eye, and Digit Anomalies.

The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11 variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling. FBXW11 encodes an F-box protein, part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degradation and thus fundamental to many protein regulatory processes. FBXW11 targets include ß-catenin and GLI transcription factors, key mediators of Wnt and Hh signaling, respectively, critical to digital, neurological, and eye development. Structural analyses indicate affected residues cluster at the surface of the loops of the substrate-binding domain of FBXW11, and the variants are predicted to destabilize the protein and/or its interactions. In situ hybridization studies on human and zebrafish embryonic tissues demonstrate FBXW11 is expressed in the developing eye, brain, mandibular processes, and limb buds or pectoral fins. Knockdown of the zebrafish FBXW11 orthologs fbxw11a and fbxw11b resulted in embryos with smaller, misshapen, and underdeveloped eyes and abnormal jaw and pectoral fin development. Our findings support the role of FBXW11 in multiple developmental processes, including those involving the brain, eye, digits, and jaw.

Pyrethroids and developmental neurotoxicity - A critical review of epidemiological studies and supporting mechanistic evidence.

BACKGROUND: Pyrethroid metabolites are widely detectable in urine from the general population, including pregnant women and children. Pyrethroids are neurotoxic and suggested endocrine disruptors. Exposure during vulnerable developmental time windows may have long-term impacts on neurodevelopment. OBJECTIVE: To evaluate the epidemiological evidence for neurodevelopmental effects related to prenatal and childhood pyrethroid exposure in a systematic review and to assess biological plausibility by evaluating mechanistic evidence. METHODS: We searched PubMed and Web of Science up to September 1, 2021 and included original studies published in English in which pyrethroid exposure was measured or estimated during pregnancy or childhood and associations with neurodevelopmental outcomes in the children were investigated. The Navigation Guide Systematic Review Methodology was used to evaluate the epidemiological evidence. For mechanistic evidence, we focused on relevant key events (KEs) suggested in Adverse Outcome Pathways (AOPs) using the OECD-supported AOP-wiki platform. A systematic search combining the KEs with pyrethroids, including 26 individual compounds, was performed in the ToxCast database. RESULTS: Twenty-five epidemiological studies met the inclusion criteria, 17 presented findings on prenatal exposure, 10 on childhood exposure and two on both exposure windows. The overall body of evidence was rated as "moderate quality" with "sufficient evidence" for an association between prenatal pyrethroid exposure and adverse neurodevelopment. For childhood exposure, the overall rating was "low quality" with "limited evidence" because of cross-sectional study design. Regarding mechanistic evidence, we found that pyrethroids are able to interfere with neurodevelopmental KEs included in established AOPs for adverse neurodevelopmental. The evidence was strongest for interference with thyroid hormone (TH) function. CONCLUSION: Pyrethroids are probably human developmental neurotoxicants and adverse impacts of pyrethroid exposure on neurodevelopment are likely at exposure levels occurring in the general population. Preventive measures to reduce exposure among pregnant women and children are warranted.

AOP4EUpest: mapping of pesticides in adverse outcome pathways using a text mining tool.

MOTIVATION: Exposure to pesticides may lead to adverse health effects in human populations, in particular vulnerable groups. The main long-term health concerns are neurodevelopmental disorders, carcinogenicity as well as endocrine disruption possibly leading to reproductive and metabolic disorders. Adverse outcome pathways (AOP) consist in linear representations of mechanistic perturbations at different levels of the biological organization. Although AOPs are chemical-agnostic, they can provide a better understanding of the Mode of Action of pesticides and can support a rational identification of effect markers. RESULTS: With the increasing amount of scientific literature and the development of biological databases, investigation of putative links between pesticides, from various chemical groups and AOPs using the biological events present in the AOP-Wiki database is now feasible. To identify co-occurrence between a specific pesticide and a biological event in scientific abstracts from the PubMed database, we used an updated version of the artificial intelligence-based AOP-helpFinder tool. This allowed us to decipher multiple links between the studied substances and molecular initiating events, key events and adverse outcomes. These results were collected, structured and presented in a web application named AOP4EUpest that can support regulatory assessment of the prioritized pesticides and trigger new epidemiological and experimental studies. AVAILABILITY AND IMPLEMENTATION: http://www.biomedicale.parisdescartes.fr/aop4EUpest/home.php. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Urinary metabolites of non-persistent pesticides and serum hormones in Spanish adolescent males.

OBJECTIVE: To assess the relationship of urinary concentrations of ethylenethiourea (ETU), the main degradation product of ethylene bis-dithiocarbamate fungicides, 3-phenoxybenzoic acid (3-PBA), a common metabolite of many pyrethroids, and 1-naphthol (1N), a metabolite of the carbamate insecticide carbaryl, with hormone concentrations in adolescent males; and to examine interactions between pesticide metabolites and polymorphisms in xenobiotic metabolizing enzymes, including CYP2C19 and CYP2D6, in relation to hormone concentrations. METHODS: A cross-sectional study was conducted in 134 males from the Spanish Environment and Childhood (INMA)-Granada cohort. Urine and serum samples were collected from participants during the same clinical visit at the age of 15-17 years. First morning urine void was analyzed for concentrations of ETU, 3-PBA, and 1N. Serum was analyzed for concentrations of reproductive hormones (testosterone, 17ß-estradiol [E2], dehydroepiandrosterone sulfate [DHEAS], sex hormone binding globulin [SHBG], luteinizing hormone [LH], follicle stimulating hormone [FSH], anti-Müllerian hormone [AMH], and prolactin), thyroid hormones (free thyroxine [FT4], total triiodothyronine [TT3], and thyroid stimulating hormone [TSH]), insulin growth factor 1 (IGF-1), adrenocorticotropic hormone (ACTH), and cortisol. CYP2C19 G681A and CYP2D6 G1846A polymorphisms were determined in blood from 117 participants. Multiple linear regression, interaction terms, and stratified analyses were performed. RESULTS: Urinary ETU was detected in 74.6% of participants, 1N in 38.1%, and 3-PBA in 19.4%. Positive associations between detectable 3-PBA and TT3 and between detectable 1N and DHEAS were found, and marginally-significant associations of 1N with reduced E2 and FSH were observed. Poor CYP2C19 and CYP2D6 metabolizers (GA and AA genotype carriers) showed a greater increase in DHEAS for detected versus undetected 1N compared with GG genotype carriers. Poor CYP2D6 metabolizers (1846 GA and AA genotypes) evidenced increased cortisol for detected versus undetected ETU. CONCLUSIONS: The associations observed between urinary pesticide metabolites and altered thyroid and reproductive hormones are novel and should be verified in studies with larger sample size. Further research on gene-environment interactions is warranted to establish individual susceptibility to pesticides and the risk of adverse health effects.

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.

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).

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.

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.

Maternal urinary concentrations of pyrethroid and chlorpyrifos metabolites and attention deficit hyperactivity disorder (ADHD) symptoms in 2-4-year-old children from the Odense Child Cohort.

BACKGROUND: Pyrethroids and chlorpyrifos are widely used insecticides, but the potential impact of prenatal exposure on child neurodevelopment has only been addressed in few longitudinal studies. OBJECTIVES: To investigate associations between prenatal exposure to pyrethroids and chlorpyrifos and traits of ADHD in 2-4-year-old children. METHODS: Metabolites of chlorpyrifos and pyrethroids were measured in maternal urine collected at gestational week 28 among 1207 women from the Odense Child Cohort. Of these, 948 completed the Child Behavior Check List for ages 1.5-5 years (CBCL: 1½-5). Negative binomial and logistic regression models were used to estimate relative differences in ADHD problem scores (CBCL: 1½-5 subscale) expressed as the ratio of expected scores between exposure groups and the odds (OR) of scoring equal to or above the 90th percentile in relation to maternal urinary metabolite concentrations (continuous ln2-transformed or categorized into tertiles). The analyses were adjusted for maternal education level, parental psychiatric diagnosis, child age and sex. RESULTS: The chlorpyrifos metabolite, 3,5,6-trichloro-2-pyridinol (TCPY), the generic pyrethroid metabolite, 3-phenoxybenzoic acid (3-PBA), and the metabolite of trans-isomers of permethrin, cypermethrin, and cyfluthrin, trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (trans-DCCA), were detected in 90%, 94%, and 11%, respectively, of the urine samples. Each doubling in maternel 3-PBA concentration was associated with a 3% increase in the ADHD score (Ratio: 1.03 (95% CI: 1.00,1.07)) and a 13% higher odds of having a ADHD score ≥ the 90th percentile (OR: 1.13 (1.04,1.38)). Similar associations were seen for 3-PBA as categorical variable (p-trend=0.052 in negative binimoal regression, p-trend=0.007 in logistic regression). Furthermore, concurrent concentrations of 3-PBA and TCPY above their medians were associated with higher ADHD score (Ratio: 1.20 (1.04, 1.38)) and higher odds of scoring ≥ the 90th percentile (OR: 1.98 (1.26, 3.11)). Maternal trans-DCCA above the detection level increased the odds of ADHD symptoms (OR: 1.76 (1.08, 2.86)). The associations were not modified by sex. CONCLUSIONS: Prenatal exposure to pyrethroids was associated with ADHD related traits at 2-4 years of age. Considering the widespread use of pyrethroids these results are of concern.

Prenatal bisphenol A exposure is associated with language development but not with ADHD-related behavior in toddlers from the Odense Child Cohort.

Bisphenol A (BPA) is a non-persistent chemical with endocrine disrupting abilities widely used in a variety of consumer products. The fetal brain is particularly sensitive to chemical exposures due to its rapid growth and complexity. Some studies have reported associationbetween maternal BPA exposure and behavior but few have assessed impact on cognitive development, and to our knowledge no studies have specifically assessed the impact on language development. We therefore assessed whether maternal urinary BPA concentration during pregnancy was associated with language development and attention-deficit and hyperactivity disorder (ADHD) symptoms in offspring aged 18-36 months in the prospective Odense Child Cohort. BPA was analyzed in 3rd trimester maternal fasting urine spot samples. Language development was addressed among 535 children using the Danish adaptation of the MacArthur-Bates Communicative Development Inventories at median age 21 months; ADHD traits were assessed by parents of 658 children using the Child Behavior Checklist for ages 1½-5 years at mean age 2.7 years. Associations were assessed using logistic regression models comparing children below the 15th percentile score for language and above the 85 percentiles score for ADHD with the other children while stratifying by sex and adjusting for maternal education, duration of breastfeeding and maternal urine phthalates. BPA was detected in 85.3% of the urine samples (median 1.2 ng/ml). Boys of mothers with BPA exposure in the highest tertile had an odds ratio of 3.70 (95% CI 1.34-10.21) of being in the lowest 15th percentile of vocabulary score compared to boys of mothers within the lowest tertile of BPA exposure after adjustment, whereas no association was found in girls. No clear dose-response relationship between maternal BPA and ADHD scores above the 85th percentile was found for either sex. Since early language development is a predictor of future reading skills and educational success, more epidemiological studies assessing BPA exposure and language skills are needed to confirm our findings.

Prenatal pesticide exposure associated with glycated haemoglobin and markers of metabolic dysfunction in adolescents.

BACKGROUND: Pesticide exposure has been associated with increased risk of diabetes mellitus in adults, but potential effects of prenatal exposure on glucose regulation have not been investigated. The aim of this study was to investigate if maternal occupational pesticide exposure in pregnancy was associated with glycated haemoglobin A1c (HbA1c) in adolescents and whether an association was modified by sex and paraoxonase-1 (PON1) Q192R polymorphism. METHODS: A prospective cohort study of children whose mothers were either occupationally exposed or unexposed to pesticides in early pregnancy. At age 10-to-16 years, the children (n = 168) underwent clinical examinations including pubertal stage assessment (accepted by 141 children) and blood sampling. PON1 Q192R genotype was available for 139 children and 103 mothers. The main outcome measure was HbA1c but other relevant biomarkers were also included. RESULTS: Prenatal pesticide exposure was associated with a 5.0% (95% confidence interval: 1.8; 8.2) higher HbA1c compared to unexposed children after adjustment for confounders. After stratification, the association remained significant for girls (6.2% (1.6; 11.1)) and if the child or the mother had the PON1 192R-allele (6.1% (1.6; 10.8) and 7.1% (2.0; 12.6), respectively). Besides, an exposure-related increase was seen for the leptin-to-adiponectin ratio, for plasminogen activator inhibitor type-1 in girls, and for interleukin-6 in children whose mothers had the R-allele. CONCLUSION: Prenatal pesticide exposure was associated with higher HbA1c and changes in related biomarkers in adolescents. Our results suggest an adverse effect on glucose homeostasis and support previous findings from this cohort of an exposure-associated metabolic risk profile with higher susceptibility related to female sex and the PON1 192R-allele.

Maternal use of mild analgesics during pregnancy associated with reduced anogenital distance in sons: a cohort study of 1027 mother-child pairs.

STUDY QUESTION: Is maternal use of mild analgesics in pregnancy associated with anogenital distance (AGD)-the distance from the anus to the genitals-in the offspring? SUMMARY ANSWER: Maternal use of mild analgesics [especially simultaneous use of paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs)] during pregnancy was associated with a shorter AGD in boys whereas no effect was found in girls. WHAT IS KNOWN ALREADY: Mild analgesics including paracetamol (acetaminophen) and NSAIDs (e.g. ibuprofen and acetyl salicylic acid) have endocrine disrupting properties and in utero exposure reduces AGD in male rats. In humans, maternal exposure has been associated with cryptorchidism and hypospadias in male offspring but no studies have examined AGD. STUDY DESIGN, SIZE, DURATION: A prospective birth cohort study. Between 2010 and 2012, 2500 pregnant women were recruited from the Odense Child Cohort. Children were examined 3 months after the expected date of birth. PARTICIPANTS/MATERIALS, SETTING, METHODS: Pregnant women were asked about use of medication including mild analgesics (paracetamol and NSAID) during pregnancy at recruitment (gestational age (GA) week 10-27) and at GA week 28. AGD and penile width were measured 3 months after expected date of birth by trained personnel. A total of 1027 women answered both questionnaires and their children were examined. Associations between prenatal exposure to mild analgesics and AGD and penile width were estimated using multivariable linear regression adjusting for age and weight-for-age SD score. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 40% of the women reported use of paracetamol and/or NSAIDs (4.4%) during the first 28 weeks of pregnancy. Exposure to analgesics during pregnancy was associated with a reduced AGD in boys, although statistically significant only for NSAIDs. The association was significant among 20 boys exposed to both paracetamol and NSAIDs (AGD -4.1 mm; CI 95%: -6.4; -1.7). Maternal intake of analgesics did not show any clear association with AGD in female offspring. No effect on penile width was found. LIMITATIONS REASONS FOR CAUTION: Only 27 boys and 18 girls were exposed to NSAIDs and most of them were also exposed to paracetamol. This makes it impossible to distinguish between exposures to NSAIDs alone and a potential mixture effect. Moreover, use of mild analgesics was self-reported up to 2 months after intake, which could have caused misclassification of exposure but is probably not associated with AGD as this was unknown to the women at time of reply to the questionnaire thereby underestimating the association. Confounding by indication may also explain our findings, as the condition for which the analgesic was taken may be associated with a reduction in AGD, rather than the use of the analgesic medication. This is the first study to report such an association in humans and further studies are needed to confirm our findings. WIDER IMPLICATIONS OF THE FINDINGS: A negative association was observed between exposure to analgesics during pregnancy and AGD in boys, suggesting disruption of androgen action. The health implications of a shorter AGD are still uncertain, but in cross-sectional studies among adult men a shorter AGD is associated with poorer semen quality and lower testosterone. As 41% of the women used these painkillers the finding are of public health importance and pregnant women should be advised about the potentially harmful effects of painkiller use. STUDY FUNDING/COMPETING INTERESTS: The study was funded by the Danish Environmental Protection Agency by way of the Center on Endocrine Disruptors Danish Center for Hormone Disrupting Chemicals, the Danish Foundation for Scientific Innovation and Technology (09-067180), the Danish Research Council (4004-00352B_FSS), Novo Nordic Foundation (NNF15OC0017734), Ronald McDonald Children Foundation, K.A. Rohde's and wife's Foundation, Odense University Hospital and Region of Southern Denmark, Municipality of Odense, the Danish Council for Strategic Research, Program Commission on Health, Food and Welfare (2101-08-0058), Odense University Hospital Research Foundation and Odense Patient data Exploratory Network (OPEN). The authors declare they have no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

Human health implications of organic food and organic agriculture: a comprehensive review.

This review summarises existing evidence on the impact of organic food on human health. It compares organic vs. conventional food production with respect to parameters important to human health and discusses the potential impact of organic management practices with an emphasis on EU conditions. Organic food consumption may reduce the risk of allergic disease and of overweight and obesity, but the evidence is not conclusive due to likely residual confounding, as consumers of organic food tend to have healthier lifestyles overall. However, animal experiments suggest that identically composed feed from organic or conventional production impacts in different ways on growth and development. In organic agriculture, the use of pesticides is restricted, while residues in conventional fruits and vegetables constitute the main source of human pesticide exposures. Epidemiological studies have reported adverse effects of certain pesticides on children's cognitive development at current levels of exposure, but these data have so far not been applied in formal risk assessments of individual pesticides. Differences in the composition between organic and conventional crops are limited, such as a modestly higher content of phenolic compounds in organic fruit and vegetables, and likely also a lower content of cadmium in organic cereal crops. Organic dairy products, and perhaps also meats, have a higher content of omega-3 fatty acids compared to conventional products. However, these differences are likely of marginal nutritional significance. Of greater concern is the prevalent use of antibiotics in conventional animal production as a key driver of antibiotic resistance in society; antibiotic use is less intensive in organic production. Overall, this review emphasises several documented and likely human health benefits associated with organic food production, and application of such production methods is likely to be beneficial within conventional agriculture, e.g., in integrated pest management.

Prenatal exposure to antifungal medication may change anogenital distance in male offspring: a preliminary study.

BACKGROUND: Vaginal candidiasis is frequent among pregnant women and it is treated with anti-fungal medication (conazoles). Conazoles have anti-androgenic properties and prenatal exposure in rodents is associated with a shorter (less masculine) anogenital distance (AGD) in male offspring. To our knowledge this has never been studied in humans. METHOD: In the Odense Child Cohort pregnant women residing in Odense municipality, Denmark, were recruited at gestational age 8-16 weeks between 2010 and 2012. Of the eligible 2421 mother-child pairs, 812 mother-son pairs were included. Questionnaire data on medicine use were collected in first and third trimester and physical examination at age 3 month was performed. Ano-scrotal distance; measured from the centre of anus to the posterior base of scrotum (AGDas). Ano-cephalad distance; measured from the centre of anus to the cephalad insertion of the penis (AGDap) and penile width; measured at the base of the penis. RESULTS: Eighty seven women had used antifungal medicine during pregnancy. Maternal use of oral fluconazole (n = 4) was associated with a 6.4 mm shorter AGDas (95% CI: -11.9;-0.9) in the male offspring. Use of antifungal vaginal tablets (n = 21), was associated with a non-significantly shorter AGDas (-1.9 mm; 95% CI: -4.3; 0.5) whereas exposure to vaginal cream (n = 23) was not associated to AGDas. Use of antifungal medicine in the window of genital development between 8 and 14 weeks of gestation was associated with a larger reduction in AGDas than exposure outside this window. Antifungal medicine intake was not associated with AGDap and penil width. CONCLUSION: Our preliminary findings prompted us to hypothesize that maternal use of conazole antifungal medication during pregnancy may affect the masculinization of male offspring. If confirmed, pregnant women should be advised to use antifungal medicine with caution.

Prenatal exposure to persistent organochlorine pollutants is associated with high insulin levels in 5-year-old girls.

BACKGROUND: Several persistent organochlorine pollutants (POPs) possess endocrine disrupting abilities, thereby potentially leading to an increased risk of obesity and metabolic diseases, especially if the exposure occurs during prenatal life. We have previously found associations between prenatal POP exposures and increased BMI, waist circumference and change in BMI from 5 to 7 years of age, though only among girls with overweight mothers. OBJECTIVES: In the same birth cohort, we investigated whether prenatal POP exposure was associated with serum concentrations of insulin and leptin among 5-year-old children, thus possibly mediating the association with overweight and obesity at 7 years of age. METHODS: The analyses were based on a prospective Faroese Birth Cohort (n=656), recruited between 1997 and 2000. Major POPs, polychlorinated biphenyls (PCBs), p,p'-dichlorodiphenyldichloroethylene (DDE) and hexachlorobenzene (HCB), were measured in maternal pregnancy serum and breast milk. Children were followed-up at the age of 5 years where a non-fasting blood sample was drawn; 520 children (273 boys and 247 girls) had adequate serum amounts available for biomarker analyses by Luminex® technology. Insulin and leptin concentrations were transformed from continuous to binary variables, using the 75th percentile as a cut-off point. Multiple logistic regression was used to investigate associations between prenatal POP exposures and non-fasting serum concentrations of insulin and leptin at age 5 while taking into account confounders. RESULTS: Girls with highest prenatal POP exposure were more likely to have high non-fasting insulin levels (PCBs 4th quartile: OR=3.71; 95% CI: 1.36, 10.01. DDE 4th quartile: OR=2.75; 95% CI: 1.09, 6.90. HCB 4th quartile: OR=1.98; 95% CI: 1.06, 3.69) compared to girls in the lowest quartile. No significant associations were observed with leptin, or among boys. A mediating effect of insulin or leptin on later obesity was not observed. CONCLUSION: These findings suggest, that for girls, prenatal exposure to POPs may play a role for later development of metabolic diseases by affecting the level of insulin.

Communities of reflection in nurse education programs: A qualitative multi-methods study.

BACKGROUND: Nursing students often face challenges reconciling theoretical concepts with clinical realities. This study examines a novel concept 'Communities of Reflection' designed and tested to enhance coherency between theory and practice. The concept involves reflection groups comprising students, preceptors, and faculty during clinical placements. AIM: To examine the meaning of 'Communities of Reflection' regarding the coherency between theory and practice as perceived by the involved participants. METHOD: A qualitative multi-methods approach involved nursing students, preceptors, and faculty members who participated in 'Communities of Reflection.' Data collection methods included interviews, focus groups, written reflections, and observations. FINDINGS: The content analysis revealed that 'Communities of Reflection' facilitate a shared engagement in nursing, fostering a deeper level of reflection. Creating a safe space and embracing vulnerability are key aspects of this shared engagement. CONCLUSION: 'Communities of Reflection' offer a valuable framework for promoting coherency between theory and practice. It appears to be crucial to students' outcomes that a well-established, equitable theory-practice partnership is the solid foundation, acknowledging that emotions can serve as a catalyst for the development of professional expertise.

Prenatal exposure to pyrethroids and chlorpyrifos and IQ in 7-year-old children from the Odense Child Cohort.

BACKGROUND: Organophosphates and pyrethroids are two major groups of insecticides used for crop protection worldwide. They are neurotoxicants and exposure during vulnerable windows of brain development may have long-term impact on human neurodevelopment. Only few longitudinal studies have investigated associations between prenatal exposure to these substances and intelligence quotient (IQ) at school age in populations with low, mainly dietary, exposure. OBJECTIVE: To investigate associations between maternal urinary concentrations of insecticide metabolites at gestational week 28 and IQ in offspring at 7-years of age. MATERIALS AND METHODS: Data was derived from the Odense Child Cohort (OCC). Metabolites of chlorpyrifos (TCPy) and pyrethroids (3-PBA, cis- and trans-DCCA, 4-F-3PBA, cis-DBCA) were measured in maternal urine collected at gestational week (GW) 28. An abbreviated version of the Danish Wechsler Intelligence Scale for Children fifth edition (WISC-V) consisting of four subtests to estimate full scale IQ (FSIQ) was administered by trained psychologists. Data were analyzed by use of multiple linear regression and adjusted for confounders. RESULTS: 812 mother/child-pairs were included. Median concentrations were 0.21 µg/L for 3-PBA, 1.67 µg/L for TCPy and the mean IQ for children were 99.4. Null association between maternal 3-PBA and child IQ at 7 years was seen, but with trends suggesting an inverse association. There was a significant association for maternal TCPy and child IQ at mid-level exposure. Trans-DCCA above the level of detection (LOD) was also associated with slightly lower child IQ, but the association was also not statistically significant. CONCLUSIONS: We found no significant associations between maternal 3-PBA metabolites and child IQ at 7 years, but with trends suggesting an inverse association. A non-significant trend between maternal TCPy exposure and child IQ in 7-year-children was seen even in this low exposed population. Given the widespread exposure and increasing use of insecticides, this should be elaborated in future studies.

Pulmonary Valve Replacement in Tetralogy of Fallot: Procedural Volume and Durability of Bioprosthetic Pulmonary Valves.

BACKGROUND: Robust data on changes in pulmonary valve replacement (PVR) procedural volume and predictors of bioprosthetic pulmonary valve (BPV) durability in patients with tetralogy of Fallot (TOF) are scarce. OBJECTIVES: This study sought to assess temporal trends in PVR procedural volume and BPV durability in a nationwide, retrospective TOF cohort. METHODS: Data were obtained from patient records. Robust linear regression was used to assess temporal trends in PVR procedural volume. Piecewise exponential additive mixed models were used to estimate BPV durability, defined as the time from implantation to redo PVR with death as a competing risk, and to assess risk factors for reduced durability. RESULTS: In total, 546 PVR were performed in 384 patients from 1976 to 2021. The annual number of PVR increased from 0.4 to 6.0 per million population (P < 0.001). In the last decade, the transcatheter PVR volume increased by 20% annually (P < 0.001), whereas the surgical PVR volume did not change significantly. The median BPV durability was 17 years (Q1: 10-Q3: 10 years-not applicable). There was no significant difference in the durability of different BPV after adjustment for confounders. Age at PVR (HR: 0.78 per 10 years from <1 year; 95% CI: 0.63-0.96; P = 0.02) and true inner valve diameter (9-17 mm vs 18-22 mm HR: 0.40; 95% CI: 0.22-0.73; P = 0.003 and 18-22 mm vs 23-30 mm HR: 0.59; 95% CI: 0.25-1.39; P = 0.23) were associated with reduced BPV durability in multivariate models. CONCLUSIONS: The PVR procedural volume has increased over time, with a greater increment in transcatheter than surgical PVR during the last decade. Younger patient age at PVR and a smaller true inner valve diameter predicted reduced BPV durability.