Aryl hydrocarbon receptor activity in human breast milk and cryptorchidism: A case-control study within the prospective Norwegian HUMIS cohort.

BACKGROUND: The etiology of cryptorchidism remains poorly understood. Endocrine disrupting chemicals can impact estrogen signaling by interacting with aryl hydrocarbon receptor (AhR) activity. OBJECTIVE: To evaluate whether AhR activity in breast milk samples is associated with cryptorchidism. METHOD: We conducted a case-control study based on 199 mother-child pairs (n = 91 cases/108 controls) selected from the Norwegian Human Milk Study (2002-2009). We defined cases for cryptorchidism based on maternal reports at 1-, 6-, 12-, and 24- months after birth. Chemically- and biologically stable AhR activity (pg 2,3,7,8-TCDD equivalent (TEQ)/g lipid) was determined by DR- CALUX® assay in the mothers' milk collected at a median of 33 (10th-90th percentile: 18-57) days after delivery. We used multivariate logistic regression to compare AhR activity levels between cases and controls, and linear regression separately, to establish the relationship with the presence of 27 potential EDCs measured in breast milk and AhR activity. RESULTS: The average estimated daily intake (EDI) of dioxin and (dioxin-like (dl)-compounds via breast milk is 33.7 ± 17.9 pg TEQ/kg bodyweight per day among Norwegian children. There were no significant differences in AhR activation in breast milk samples between cases with cryptorchidism and controls. Among the 27 chemicals measured in breast milk, AhR activity was (borderline) significantly associated with all dl-PCBs, three non-dioxin-like (ndl)-PCBs (PCB-74, PCB-180, PCB-194) and two organochlorine pesticides (OCPs; HCB, ß-HCH). No associations between AhR activity and brominated flame retardants (PBDEs) or poly- and perfluoroalkyl substances (PFASs). CONCLUSION: No association between AhR activity and cryptorchidism was found among Norwegian boys. The average EDI of dioxin and dl-compounds in exclusively breastfed Norwegian infants remains above the safety threshold and, therefore requires further reduction measures. Consistent with a possible role in the observed AhR activity, all dl-PCBs were associated with AhR activity whereas the association was null for either PBDEs or PFASs.

Maternal body mass index, gestational weight gain, and the risk of overweight and obesity across childhood: An individual participant data meta-analysis.

BACKGROUND: Maternal obesity and excessive gestational weight gain may have persistent effects on offspring fat development. However, it remains unclear whether these effects differ by severity of obesity, and whether these effects are restricted to the extremes of maternal body mass index (BMI) and gestational weight gain. We aimed to assess the separate and combined associations of maternal BMI and gestational weight gain with the risk of overweight/obesity throughout childhood, and their population impact. METHODS AND FINDINGS: We conducted an individual participant data meta-analysis of data from 162,129 mothers and their children from 37 pregnancy and birth cohort studies from Europe, North America, and Australia. We assessed the individual and combined associations of maternal pre-pregnancy BMI and gestational weight gain, both in clinical categories and across their full ranges, with the risks of overweight/obesity in early (2.0-5.0 years), mid (5.0-10.0 years) and late childhood (10.0-18.0 years), using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal sociodemographic and lifestyle-related characteristics. We observed that higher maternal pre-pregnancy BMI and gestational weight gain both in clinical categories and across their full ranges were associated with higher risks of childhood overweight/obesity, with the strongest effects in late childhood (odds ratios [ORs] for overweight/obesity in early, mid, and late childhood, respectively: OR 1.66 [95% CI: 1.56, 1.78], OR 1.91 [95% CI: 1.85, 1.98], and OR 2.28 [95% CI: 2.08, 2.50] for maternal overweight; OR 2.43 [95% CI: 2.24, 2.64], OR 3.12 [95% CI: 2.98, 3.27], and OR 4.47 [95% CI: 3.99, 5.23] for maternal obesity; and OR 1.39 [95% CI: 1.30, 1.49], OR 1.55 [95% CI: 1.49, 1.60], and OR 1.72 [95% CI: 1.56, 1.91] for excessive gestational weight gain). The proportions of childhood overweight/obesity prevalence attributable to maternal overweight, maternal obesity, and excessive gestational weight gain ranged from 10.2% to 21.6%. Relative to the effect of maternal BMI, excessive gestational weight gain only slightly increased the risk of childhood overweight/obesity within each clinical BMI category (p-values for interactions of maternal BMI with gestational weight gain: p = 0.038, p < 0.001, and p = 0.637 in early, mid, and late childhood, respectively). Limitations of this study include the self-report of maternal BMI and gestational weight gain for some of the cohorts, and the potential of residual confounding. Also, as this study only included participants from Europe, North America, and Australia, results need to be interpreted with caution with respect to other populations. CONCLUSIONS: In this study, higher maternal pre-pregnancy BMI and gestational weight gain were associated with an increased risk of childhood overweight/obesity, with the strongest effects at later ages. The additional effect of gestational weight gain in women who are overweight or obese before pregnancy is small. Given the large population impact, future intervention trials aiming to reduce the prevalence of childhood overweight and obesity should focus on maternal weight status before pregnancy, in addition to weight gain during pregnancy.

Thyroid-stimulating hormone levels in newborns and early life exposure to endocrine-disrupting chemicals: analysis of three European mother-child cohorts.

BackgroundVarious studies have reported interactions between thyroid hormones and early life chemical exposure. Our objective was to analyze the associations between markers of endocrine-disrupting chemical exposure and thyroid function in newborns, determined through heel prick blood spots.MethodsThree European mother-child cohorts (FLEHSI-Belgium, HUMIS-Norway, and the PCB cohort-Slovakia. Total n=1,784) were pooled for the purpose of this study. Data on thyroid-stimulating hormone (TSH) were obtained from national neonatal screening registries, and samples of cord plasma and/or breast milk were collected to determine exposure to various chemicals. Multiple regression models were composed with exposure and cohort as fixed factors, and adjustments were made for a priori defined covariates.ResultsMedian TSH concentrations were 1, 1.10, and 2.76 mU/l for the Belgian, Norwegian, and Slovak cohorts, respectively. For polychlorinated biphenyl (PCB)-153 and dichlorodiphenyldichloroethylene (p,p'-DDE), children in the third exposure quartile had a 12-15% lower TSH at birth. Results remained unchanged after additional adjustment for birth weight and gestational weight gain. No effect on TSH was observed for the other compounds.ConclusionEarly life exposure to PCB-153 and p,p'-DDE impacts newborn TSH levels. Higher exposure levels were associated with 12-15% lower TSH levels.

Persistent Environmental Toxicants in Breast Milk and Rapid Infant Growth.

BACKGROUND/AIMS: Many environmental toxicants are passed to infants in utero and through breast milk. Exposure to toxicants during the perinatal period can alter growth patterns, impairing growth or increasing obesity risk. Previous studies have focused on only a few toxicants at a time, which may confound results. We investigated levels of 26 toxicants in breast milk and their associations with rapid infant growth, a risk factor for later obesity. METHODS: We used data from the Norwegian HUMIS study, a multi-center cohort of 2,606 mothers and newborns enrolled between 2002 and 2008. Milk samples collected 1 month after delivery from a subset of 789 women oversampled by overweight were analyzed for toxicants including polychlorinated biphenyls (PCBs), heavy metals, and pesticides. Growth was defined as change in weight-for-age z-score between 0 and 6 months among the HUMIS population, and rapid growth was defined as change in z-score above 0.67. We used a Bayesian variable selection method to determine the exposures that most explained variation in the outcome. Identified toxicants were included in logistic and linear regression models to estimate associations with growth, adjusting for maternal age, smoking, education, pre-pregnancy body mass index (BMI), gestational weight gain, parity, child sex, cumulative breastfeeding, birth weight, gestational age, and preterm status. RESULTS: Of 789 infants, 19.2% displayed rapid growth. The median maternal age was 29.6 years, and the median pre-pregnancy BMI was 24.0 kg/m2, with 45.3% of mothers overweight or obese. Rapid growers were more likely to be firstborn. Hexachlorobenzene, ß-hexachlorocyclohexane (ß-HCH), and PCB-74 were identified in the variable selection method. An interquartile range (IQR) increase in ß-HCH exposure was associated with a lower odds of rapid growth (OR 0.63, 95% CI 0.42-0.94). Newborns exposed to high levels of ß-HCH showed reduced infant growth (ß = -0.03, 95% CI -0.05 to -0.01 for IQR increase in breast milk concentration). No other significant associations were found. CONCLUSIONS: Our results suggest that early life ß-HCH exposure may be linked to slowed growth. Further research is warranted on the potential mechanism behind this association and the longer-term metabolic effects of perinatal ß-HCH exposure.

Novel application of statistical methods for analysis of multiple toxicants identifies DDT as a risk factor for early child behavioral problems.

BACKGROUND: The aim of this study was to assess the association between postnatal exposure to multiple persistent organic pollutants (POPs) measured in breast milk samples and early behavioral problems using statistical methods to deal with correlated exposure data. METHODS: We used data from the Norwegian HUMIS study. We measured concentrations of 24 different POPs in human milk from 612 mothers (median collection time: 32 days after delivery), including 13 polychlorinated biphenyls (PCB) congeners, 6 polybrominated diphenyl ethers (PBDE) congeners and five organochlorine compounds. We assessed child behavioral problems at 12 and 24 months using the infant toddler symptom checklist (ITSC). Higher score in ITSC corresponds to more behavioral problems. First we performed principal component analysis (PCA). Then two variable selection methods, elastic net (ENET) and Bayesian model averaging (BMA), were applied to select any toxicants associated with behavioral problems. Finally, the effect size of the selected toxicants was estimated using multivariate linear regression analyses. RESULTS: p,p'-DDT was associated with behavioral problems at 12 months in all the applied models. Specifically, the principal component composed of organochlorine pesticides was significantly associated with behavioral problems and both ENET and BMA identified p,p'-DDT as associated with behavioral problems. Using a multiple linear regression model an interquartile increase in p,p'-DDT was associated with a 0.62 unit increase in ITSC score (95% CI 0.45, 0.79) at 12 months, corresponding to more behavioral problems. The association was modified by maternal education: the effect of p,p'-DDT was strongest in women with lower education (ß=0.59; 95%CI: 0.38, 0.81) compared to the mother with higher education (ß=0.14; 95%CI: -0.05, 0.34) (p-value for interaction=0.089). At 24 months, neither selection method consistently identified any toxicant associated with behavioral problems. CONCLUSION: Within a mixture of 24 toxicants measured in breast milk, p,p'-DDT was the single toxicant associated with behavioral problems at 12 months using different methods for handling numerous correlated exposures.

Novel developmental analyses identify longitudinal patterns of early gut microbiota that affect infant growth.

It is acknowledged that some obesity trajectories are set early in life, and that rapid weight gain in infancy is a risk factor for later development of obesity. Identifying modifiable factors associated with early rapid weight gain is a prerequisite for curtailing the growing worldwide obesity epidemic. Recently, much attention has been given to findings indicating that gut microbiota may play a role in obesity development. We aim at identifying how the development of early gut microbiota is associated with expected infant growth. We developed a novel procedure that allows for the identification of longitudinal gut microbiota patterns (corresponding to the gut ecosystem developing), which are associated with an outcome of interest, while appropriately controlling for the false discovery rate. Our method identified developmental pathways of Staphylococcus species and Escherichia coli that were associated with expected growth, and traditional methods indicated that the detection of Bacteroides species at day 30 was associated with growth. Our method should have wide future applicability for studying gut microbiota, and is particularly important for translational considerations, as it is critical to understand the timing of microbiome transitions prior to attempting to manipulate gut microbiota in early life.

Urinary phthalate/DINCH metabolites associations with kisspeptin and reproductive hormones in teenagers: A cross-sectional study from the HBM4EU aligned studies.

BACKGROUND: Exposure to phthalate/DINCH metabolites can induce human reproductive toxicity, however, their endocrine-disrupting mechanisms are not fully elucidated. OBJECTIVE: To investigate the association between concentrations of phthalate/DINCH metabolites, serum kisspeptin, and reproductive hormones among European teenagers from three of the HBM4EU Aligned Studies. METHODS: In 733 Belgian (FLEHS IV study), Slovak (PCB cohort follow-up), and Spanish (BEA study) teenagers, ten phthalate and two DINCH metabolites were measured in urine by high-performance liquid chromatography-tandem mass spectrometry. Serum kisspeptin (kiss54) protein, follicle-stimulating hormone (FSH), total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG) levels were measured by immunosorbent assays. Free Androgen Index (FAI) was calculated as a proxy of free testosterone. Adjusted sex-stratified linear regression models for individual studies, mixed effect models (LME) accounting for random effects for pooled studies, and g-computation and Bayesian kernel machine regression (BKMR) models for the phthalate/DINCH mixture were performed. RESULTS: The LME suggested that each IQR increase in ln-transformed levels of several phthalates was associated with lower kisspeptin [MnBP: %change (95%CI): -2.8 (-4.2;-0.4); MEHP: -1.4 (-3.4,0.2)] and higher FSH [∑DINP: 11.8 (-0.6;25.1)] levels in females from pooled studies. G-computation showed that the phthalates/DINCH mixture was associated with lower kisspeptin [-4.28 (-8.07;-0.34)] and higher FSH [22.13 (0.5;48.4)] also in females; BKMR showed similar although non-significant pattern. In males, higher phthalates metabolites [MEHP: -12.22 (-21.09;-1.18); oxo-MEHP: -12.73 (-22.34;-1.93)] were associated with lower TT and FAI, although higher DINCH [OH-MINCH: 16.31 (6.23;27.35), cx-MINCH: 16.80 (7.03;27.46), ∑DINCH: 17.37 (7.26;29.74)] were associated with higher TT levels. No mixture associations were found in males. CONCLUSION: We observed sex-specific associations between urinary concentrations of phthalate/DINCH metabolites and the panel of selected effect biomarkers (kisspeptin and reproductive hormones). This suggests that exposure to phthalates would be associated with changes in kisspeptin levels, which would affect the HPG axis and thus influence reproductive health. However, further research is needed, particularly for phthalate replacements such as DINCH.

Prenatal Exposure to Chemical Mixtures and Metabolic Syndrome Risk in Children.

Importance: Prenatal exposure to ubiquitous endocrine-disrupting chemicals (EDCs) may increase the risk of metabolic syndrome (MetS) in children, but few studies have studied chemical mixtures or explored underlying protein and metabolic signatures. Objective: To investigate associations of prenatal exposure to EDC mixtures with MetS risk score in children and identify associated proteins and metabolites. Design, Setting, and Participants: This population-based, birth cohort study used data collected between April 1, 2003, and February 26, 2016, from the Human Early Life Exposome cohort based in France, Greece, Lithuania, Norway, Spain, and the UK. Eligible participants included mother-child pairs with measured prenatal EDC exposures and complete data on childhood MetS risk factors, proteins, and metabolites. Data were analyzed between October 2022 and July 2023. Exposures: Nine metals, 3 organochlorine pesticides, 5 polychlorinated biphenyls, 2 polybrominated diphenyl ethers (PBDEs), 5 perfluoroalkyl substances (PFAS), 10 phthalate metabolites, 3 phenols, 4 parabens, and 4 organophosphate pesticide metabolites measured in urine and blood samples collected during pregnancy. Main Outcomes and Measures: At 6 to 11 years of age, a composite MetS risk score was constructed using z scores of waist circumference, systolic and diastolic blood pressures, triglycerides, high-density lipoprotein cholesterol, and insulin levels. Childhood levels of 44 urinary metabolites, 177 serum metabolites, and 35 plasma proteins were quantified using targeted methods. Associations were assessed using bayesian weighted quantile sum regressions applied to mixtures for each chemical group. Results: The study included 1134 mothers (mean [SD] age at birth, 30.7 [4.9] years) and their children (mean [SD] age, 7.8 [1.5] years; 617 male children [54.4%] and 517 female children [45.6%]; mean [SD] MetS risk score, -0.1 [2.3]). MetS score increased per 1-quartile increase of the mixture for metals (ß = 0.44; 95% credible interval [CrI], 0.30 to 0.59), organochlorine pesticides (ß = 0.22; 95% CrI, 0.15 to 0.29), PBDEs (ß = 0.17; 95% CrI, 0.06 to 0.27), and PFAS (ß = 0.19; 95% CrI, 0.14 to 0.24). High-molecular weight phthalate mixtures (ß = -0.07; 95% CrI, -0.10 to -0.04) and low-molecular weight phthalate mixtures (ß = -0.13; 95% CrI, -0.18 to -0.08) were associated with a decreased MetS score. Most EDC mixtures were associated with elevated proinflammatory proteins, amino acids, and altered glycerophospholipids, which in turn were associated with increased MetS score. Conclusions and Relevance: This cohort study suggests that prenatal exposure to EDC mixtures may be associated with adverse metabolic health in children. Given the pervasive nature of EDCs and the increase in MetS, these findings hold substantial public health implications.

Chlorination by-products in tap water and semen quality in England and Wales.

OBJECTIVES: Disinfection by-products (DBPs) have been associated with adverse semen outcomes in laboratory animals, although the evidence for trihalomethanes (THMs) is limited. Three small epidemiological studies found little evidence for an association between DBPs and adverse semen outcomes in humans. Using data from a large case-referent study (Chemicals and Pregnancy Study, Chaps-UK), we investigated the association between total THM (TTHM), chloroform and total brominated THMs and sperm concentration, percent motile sperm and motile sperm concentration (MSC). METHODS: Chaps-UK recruited men from 13 fertility clinics in nine urban centres across England and Wales between 1999 and 2002. We linked modelled THM concentrations in water zones to semen quality data for 642 cases (men with low MSC) and 926 referents (other men investigated for infertility), based on the men's residence during semen sampling. We assessed risk of low MSC in relation to DBP exposure using continuous THM concentrations. A secondary analysis investigated continuous outcomes (MSC, sperm concentration and percent motile sperm). RESULTS: In the case-referent analysis there was little evidence of elevated risk associated with chloroform, total brominated THM or TTHM concentration after adjustment (OR per 10 µg/L TTHM 1.01; 95% CI 0.91 to 1.12). Similarly, there was no significant effect of THMs on the continuous outcomes. CONCLUSIONS: In the largest study to date on DBPs in public water supplies, and semen quality we found that concentrations of THMs were not associated with poor semen quality. Large-scale investigation of other DBPs (eg, haloacetic acids) and other semen quality parameters (eg, sperm morphology and/or sperm DNA integrity) is recommended.

Perinatal exposure to potential endocrine disrupting chemicals and autism spectrum disorder: From Norwegian birth cohort to zebrafish studies.

BACKGROUND: The etiology of autism spectrum disorder (ASD) is multifactorial, involving genetic and environmental contributors such as endocrine-disrupting chemicals (EDCs). OBJECTIVE: To evaluate the association between perinatal exposure to 27 potential EDCs and ASD among Norwegian children, and to further examine the neurodevelopmental toxicity of associated chemicals using zebrafish embryos and larvae. METHOD: 1,199 mothers enrolled in the prospective birth-cohort (HUMIS, 2002-2009) study. Breastmilk levels of 27 chemicals were measured: polychlorinated biphenyls, organochlorine pesticides, polybrominated diphenyl ethers, and perfluoroalkyl substances as a proxy for perinatal exposure. We employed multivariable logistic regression to determine association, utilized elastic net logistic regression as variable selection method, and conducted an in vivo study with zebrafish larvae to confirm the neurodevelopmental effect. RESULTS: A total of 20 children had specialist confirmed diagnosis of autism among 1,199 mother-child pairs in this study. ß-Hexachlorocyclohexane (ß-HCH) was the only chemical associated with ASD, after adjusting for 26 other chemicals. Mothers with the highest levels of ß-HCH in their milk had a significant increased risk of having a child with ASD (OR = 1.82, 95 % CI: 1.20, 2.77 for an interquartile range increase in ln-transformed ß-HCH concentration). The median concentration of ß-HCH in breast milk was 4.37 ng/g lipid (interquartile range: 2.92-6.47), and the estimated daily intake (EDI) for Norwegian children through breastfeeding was 0.03 µg/kg of body weight. The neurodevelopmental and social behavioral effects of ß-HCH were established in zebrafish embryos and larvae across various concentrations, with further analysis suggesting that perturbation of dopaminergic neuron development may underlie the neurotoxicity associated with ß-HCH. CONCLUSIONS: Prenatal exposure to ß-HCH was associated with an increased risk of specialist-confirmed diagnoses of ASD among Norwegian children, and the EDI surpasses the established threshold. Zebrafish experiments confirm ß-HCH neurotoxicity, suggesting dopaminergic neuron disruption as a potential underlying mechanism.

PFAS and Phthalate/DINCH Exposure in Association with Age at Menarche in Teenagers of the HBM4EU Aligned Studies.

Early puberty has been found to be associated with adverse health outcomes such as metabolic and cardiovascular diseases and hormone-dependent cancers. The decrease in age at menarche observed during the past decades has been linked to an increased exposure to endocrine-disrupting compounds (EDCs). Evidence for the association between PFAS and phthalate exposure and menarche onset, however, is inconsistent. We studied the association between PFAS and phthalate/DINCH exposure and age at menarche using data of 514 teenagers (12 to 18 years) from four aligned studies of the Human Biomonitoring for Europe initiative (HBM4EU): Riksmaten Adolescents 2016-2017 (Sweden), PCB cohort (follow-up; Slovakia), GerES V-sub (Germany), and FLEHS IV (Belgium). PFAS concentrations were measured in blood, and phthalate/DINCH concentrations in urine. We assessed the role of each individual pollutant within the context of the others, by using different multi-pollutant approaches, adjusting for age, age- and sex-standardized body mass index z-score and household educational level. Exposure to di(2-ethylhexyl) phthalate (DEHP), especially mono(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), was associated with an earlier age at menarche, with estimates per interquartile fold change in 5OH-MEHP ranging from -0.34 to -0.12 years in the different models. Findings from this study indicated associations between age at menarche and some specific EDCs at concentrations detected in the general European population, but due to the study design (menarche onset preceded the chemical measurements), caution is needed in the interpretation of causality.

PFAS association with kisspeptin and sex hormones in teenagers of the HBM4EU aligned studies.

Exposure to Perfluoroalkyl acids (PFAS) can impair human reproductive function, e.g., by delaying or advancing puberty, although their mechanisms of action are not fully understood. We therefore set out to evaluate the relationship between serum PFAS levels, both individually and as a mixture, on the Hypothalamic-Pituitary-Gonadal (HPG) axis by analyzing serum levels of reproductive hormones and also kisspeptin in European teenagers participating in three of the HBM4EU Aligned Studies. For this purpose, PFAS compounds were measured in 733 teenagers from Belgium (FLEHS IV study), Slovakia (PCB cohort follow-up), and Spain (BEA study) by high performance liquid chromatography-tandem mass spectrometry (HPLC/MS) in laboratories under the HBM4EU quality assurance quality control (QA/QC) program. In the same serum samples, kisspeptin 54 (kiss-54) protein, follicle-stimulating hormone (FSH), total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG) levels were also measured using immunosorbent assays. Sex-stratified single pollutant linear regression models for separate studies, mixed single pollutant models accounting for random effects for pooled studies, and g-computation and Bayesian kernel machine regression (BKMR) models for the mixture of the three most available (PFNA, PFOA, and PFOS) were fit. PFAS associations with reproductive markers differed according to sex. Each natural log-unit increase of PFOA, PFNA, and PFOS were associated with higher TT [18.41 (6.18; 32.31), 15.60 (7.25; 24.61), 14.68 (6.18; 24.61), respectively] in girls, in the pooled analysis (all studies together). In males, G-computation showed that PFAS mixture was associated with lower FSH levels [-10.51 (-18.81;-1.36)]. The BKMR showed the same patterns observed in G-computation, including a significant increase on male Kiss-54 and SHBG levels. Overall, effect biomarkers may enhance the current epidemiological knowledge regarding the adverse effect of PFAS in human HPG axis, although further research is warranted.

Cross-sectional associations between exposure to per- and polyfluoroalkyl substances and body mass index among European teenagers in the HBM4EU aligned studies.

Per- and polyfluoroalkyl substances (PFAS) are widespread pollutants that may impact youth adiposity patterns. We investigated cross-sectional associations between PFAS and body mass index (BMI) in teenagers/adolescents across nine European countries within the Human Biomonitoring for Europe (HBM4EU) initiative. We used data from 1957 teenagers (12-18 yrs) that were part of the HBM4EU aligned studies, consisting of nine HBM studies (NEBII, Norway; Riksmaten Adolescents 2016-17, Sweden; PCB cohort (follow-up), Slovakia; SLO CRP, Slovenia; CROME, Greece; BEA, Spain; ESTEBAN, France; FLEHS IV, Belgium; GerES V-sub, Germany). Twelve PFAS were measured in blood, whilst weight and height were measured by field nurse/physician or self-reported in questionnaires. We assessed associations between PFAS and age- and sex-adjusted BMI z-scores using linear and logistic regression adjusted for potential confounders. Random-effects meta-analysis and mixed effects models were used to pool studies. We assessed mixture effects using molar sums of exposure biomarkers with toxicological/structural similarities and quantile g-computation. In all studies, the highest concentrations of PFAS were PFOS (medians ranging from 1.34 to 2.79 µg/L). There was a tendency for negative associations with BMI z-scores for all PFAS (except for PFHxS and PFHpS), which was borderline significant for the molar sum of [PFOA and PFNA] and significant for single PFOA [ß-coefficient (95% CI) per interquartile range fold change = -0.06 (-0.17, 0.00) and -0.08 (-0.15, -0.01), respectively]. Mixture assessment indicated similar negative associations of the total mixture of [PFOA, PFNA, PFHxS and PFOS] with BMI z-score, but not all compounds showed associations in the same direction: whilst [PFOA, PFNA and PFOS] were negatively associated, [PFHxS] associated positively with BMI z-score. Our results indicated a tendency for associations of relatively low PFAS concentrations with lower BMI in European teenagers. More prospective research is needed to investigate this potential relationship and its implications for health later in life.

Predictors of Human Milk Fatty Acids and Associations with Infant Growth in a Norwegian Birth Cohort.

Triglyceride-bound fatty acids constitute the majority of lipids in human milk and may affect infant growth. We describe the composition of fatty acids in human milk, identify predictors, and investigate associations between fatty acids and infant growth using data from the Norwegian Human Milk Study birth cohort. In a subset of participants (n = 789, 30% of cohort), oversampled for overweight and obesity, we analyzed milk concentrations of detectable fatty acids. We modelled percent composition of fatty acids in relation to maternal body mass index, pregnancy weight gain, parity, smoking, delivery mode, gestational age, fish intake, and cod liver oil intake. We assessed the relation between fatty acids and infant growth from 0 to 6 months. Of the factors tested, excess pregnancy weight gain was positively associated with monounsaturated fatty acids and inversely associated with stearic acid. Multiparity was negatively associated with monounsaturated fatty acids and n-3 fatty acids while positively associated with stearic acid. Gestational age was inversely associated with myristic acid. Medium-chain saturated fatty acids were inversely associated with infant growth, and mono-unsaturated fatty acids, particularly oleic acid, were associated with an increased odds of rapid growth. Notably, excessive maternal weight gain was associated with cis-vaccenic acid, which was further associated with a threefold increased risk of rapid infant growth (OR = 2.9, 95% CI 1.2-6.6), suggesting that monounsaturated fatty acids in milk may play a role in the intergenerational transmission of obesity.

Anti-androgenic compounds in breast milk and cryptorchidism among Norwegian boys in the HUMIS birth cohort.

The prevalence of cryptorchidism has increased over the past decades, yet its origins remain poorly understood. Testis descent is dependent on androgens and likely affected by endocrine disrupting compounds (EDCs), targeting the androgen receptor (AR). We investigated the association between anti-androgenic activity, not derived from natural hormones, in maternal breast milk and impaired testis descent among boys. We performed a case-control study based on 199 breast milk samples from 94 mothers of cryptorchid boys and 105 random non-cryptorchid boys participating in the Norwegian HUMIS (Human Milk Study) cohort. For each participant, apolar, and polar fractions were extracted, and combined to reconstitute a mixture. Anti-androgenic activity was measured in all three fractions using the human cell-based in vitro anti-AR CALUX® assay and expressed in µg of flutamide equivalent, a well-known antiandrogen. Results from fraction analyses were compared among boys with cryptorchidism and controls using multiple logistic regression, controlling for appropriate confounders identified using a directed acyclic graph. Children's daily exposure to anti-androgenic EDCs through breastfeeding was estimated to 78 µg flutamide eq./kg of body weigh/day. The activity was higher in the polar fraction (1.48 ± 1.37 µg flutamide eq./g of milk) mainly representing non-persistent chemicals, in contrast to other fractions. However, the activity in the polar extracts was decreased when in mixtures with the apolar fraction, indicating synergistic interactions. No significant difference in the activity was observed according to cryptorchid status for polar, apolar or mixed breast milk fractions. The study showed anti-androgenic activity in nearly all human milk samples, and at levels higher than the advisory threshold. However, no significant association was observed between cryptorchidism and antiandrogenic activity measured in either polar, apolar, or mixture fractions derived from breast milk.

A case-cohort study of perinatal exposure to potential endocrine disrupters and the risk of cryptorchidism in the Norwegian HUMIS study.

BACKGROUND: Exposure to endocrine-disrupting chemicals (EDCs) during the critical period of testicular descent may increase the risk of cryptorchidism and male fertility. OBJECTIVE: To investigate 27 potential EDCs measured in breast milk as a proxy for perinatal exposure and the risk of cryptorchidism in a prospective cohort. METHOD: The Norwegian Human Milk Study (2002-2009) enrolled 2606 mother-infant pairs, of which 1326 were mother-son pairs. In a case-cohort design, we studied 641 male infants who had 27 EDCs already quantified in milk samples: 5 organochlorine pesticides, 14 polychlorinated biphenyls (PCBs), 6 brominated flame retardants, and 2 poly- and perfluoroalkyl substances. We defined cases of congenital, recurrent, persistent and ever-reported cryptorchidism based on questionnaires mothers completed when children were 1, 6, 12 and 24 months old. Variable selection via elastic net logistic regression identified the best cryptorchidism predictors while multivariable logistic regression models determined their effect estimates. RESULTS: The prevalence of reported congenital cryptorchidism was 6.1%, with half spontaneously descending within six months of birth, after which prevalence stabilized between 2.2 and 2.4%. The ever-reported prevalence of cryptorchidism at 1, 6, 12, or 24 months was 12.2%. Elastic net models identified PCB-74 (OR = 1.31, 95% CI: 1.001-1.703), PCB-114 (OR = 1.36, 95% CI: 1.05-1.77), PCB-194 (OR = 1.28, 95% CI: 1.03-1.53) and ß-HCH (OR = 1.26, 95% CI: 1.03-1.53 (per interquartile range increase in concentration of EDCs) as best predictors of congenital cryptorchidism. No EDCs were selected for either recurrent or persistent cryptorchidism, and only PCB-194 was selected by elastic net for ever-reported cryptorchidism (OR = 1.23, 95% CI: 1.01-1.51), in contrast to unpenalized multivariable logistic regression, where most of the individual congeners of PCBs showed significant associations. CONCLUSION: In the largest multi-pollutant analysis to date considering potential confounding from co-exposure to other chemicals, perinatal exposure to PCB-74, PCB-114, PCB-194 and ß-HCH were associated with increased odds of congenital cryptorchidism. Many PCBs may falsely be associated with cryptorchidism when assessed individually, due to confounding by highly correlated chemicals. Experimental studies are warranted to confirm our findings.

Maternal seafood intake during pregnancy, prenatal mercury exposure and child body mass index trajectories up to 8 years.

BACKGROUND: Maternal seafood intake during pregnancy and prenatal mercury exposure may influence children's growth trajectories. METHODS: This study, based on the Norwegian Mother, Father and Child Cohort Study (MoBa), includes 51 952 mother-child pairs recruited in pregnancy during 2002-08 and a subsample (n = 2277) with maternal mercury concentrations in whole blood. Individual growth trajectories were computed by modelling based on child's reported weight and length/height from 1 month to 8 years. We used linear mixed-effects regression analysis and also conducted discordant-sibling analysis. RESULTS: Maternal lean fish was the main contributor to total seafood intake in pregnancy and was positively but weakly associated with child body mass index (BMI) growth trajectory. Higher prenatal mercury exposure (top decile) was associated with a reduction in child's weight growth trajectory, with the estimates ranging from -130 g [95% Confidence Intervals (CI) = -247, -12 g] at 18 months to -608 g (95% CI = -1.102, -113 g) at 8 years. Maternal fatty fish consumption was positively associated with child weight and BMI growth trajectory, but only in the higher mercury-exposed children (P-interaction = 0.045). Other seafood consumption during pregnancy was negatively associated with child weight growth compared with no intake, and this association was stronger for higher mercury-exposed children (P-interaction = 0.004). No association was observed between discordant maternal seafood intake and child growth in the sibling analysis. CONCLUSIONS: Within a population with moderate seafood consumption and low mercury exposure, we found that maternal seafood consumption in pregnancy was associated with child growth trajectories, and the direction of the association varied by seafood type and level of prenatal mercury exposure. Prenatal mercury exposure was negatively associated with child growth. Our findings on maternal seafood intake are likely non-causal.

Early Life Exposure to Perfluoroalkyl Substances (PFAS) and ADHD: A Meta-Analysis of Nine European Population-Based Studies.

INTRODUCTION: To date, the evidence for an association between perfluoroalkyl substances (PFAS) exposure and attention deficit and hyperactivity disorder (ADHD) is inconclusive. OBJECTIVE: We investigated the association between early life exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), and ADHD in a collaborative study including nine European population-based studies, encompassing 4,826 mother-child pairs. METHODS: Concentrations of PFOS and PFOA were measured in maternal serum/plasma during pregnancy, or in breast milk, with different timing of sample collection in each cohort. We used a validated pharmacokinetic model of pregnancy and lactation to estimate concentrations of PFOS and PFOA in children at birth and at 3, 6, 12, and 24 months of age. We classified ADHD using recommended cutoff points for each instrument used to derive symptoms scores. We used multiple imputation for missing covariates, logistic regression to model the association between PFAS exposure and ADHD in each study, and combined all adjusted study-specific effect estimates using random-effects meta-analysis. RESULTS: A total of 399 children were classified as having ADHD, with a prevalence ranging from 2.3% to 7.3% in the studies. Early life exposure to PFOS or PFOA was not associated with ADHD during childhood [odds ratios (ORs) ranging from 0.96 (95% CI: 0.87, 1.06) to 1.02 (95% CI: 0.93, 1.11)]. Results from stratified models suggest potential differential effects of PFAS related to child sex and maternal education. CONCLUSION: We did not identify an increased prevalence of ADHD in association with early life exposure to PFOS and PFOA. However, stratified analyses suggest that there may be an increased prevalence of ADHD in association with PFAS exposure in girls, in children from nulliparous women, and in children from low-educated mothers, all of which warrant further exploration. https://doi.org/10.1289/EHP5444.

Endocrine disruptors in the workplace, hair spray, folate supplementation, and risk of hypospadias: case-control study.

BACKGROUND: Hypospadias is one of the most common urogenital congenital anomalies affecting baby boys. Prevalence estimates in Europe range from 4 to 24 per 10,000 births, depending on definition, with higher rates reported from the United States. Relatively little is known about potential risk factors, but a role for endocrine-disrupting chemicals (EDCs) has been proposed. OBJECTIVE: Our goal was to elucidate the risk of hypospadias associated with occupational exposure of the mother to endocrine-disruptor chemicals, use of folate supplementation during pregnancy, and vegetarianism. DESIGN: We designed a case-control study of 471 hypospadias cases referred to surgeons and 490 randomly selected birth controls, born 1 January 1997-30 September 1998 in southeast England. Telephone interviews of mothers elicited information on folate supplementation during pregnancy and vegetarianism. We used a job exposure matrix to classify occupational exposure. RESULTS: In multiple logistic regression analysis, there were increased risks for self-reported occupational exposure to hair spray [exposed vs. nonexposed, odds ratio (OR) = 2.39; 95% confidence interval (CI), 1.40-4.17] and phthalate exposure obtained by a job exposure matrix (OR = 3.12; 95% CI, 1.04-11.46). There was a significantly reduced risk of hypospadias associated with of folate use during the first 3 months of pregnancy (OR = 0.64; 95% CI, 0.44-0.93). Vegetarianism was not associated with hypospadias risk. CONCLUSIONS: Excess risks of hypospadias associated with occupational exposures to phthalates and hair spray suggest that antiandrogenic EDCs may play a role in hypospadias. Folate supplementation in early pregnancy may be protective.

Health impacts of long-term exposure to disinfection by-products in drinking water in Europe: HIWATE.

There appears to be very good epidemiological evidence for a relationship between chlorination by-products, as measured by trihalomethanes (THMs), in drinking water and bladder cancer, but the evidence for other cancers, including colorectal cancer appears to be inconclusive and inconsistent. There appears to be some evidence for a relationship between chlorination by-products, as measured by THMs, and small for gestational age (SGA)/intrauterine growth retardation (IUGR) and preterm delivery, but evidence for other outcomes such as low birth weight (LBW), stillbirth, congenital anomalies and semen quality appears to be inconclusive and inconsistent.The overall aim of the HIWATE study is to investigate potential human health risks (e.g. bladder and colorectal cancer, premature births, SGA, semen quality, stillbirth, congenital anomalies) associated with long-term exposure to low levels of disinfectants (such as chlorine) and DBPs occurring in water for human consumption and use in the food industry. The study will comprise risk-benefit analyses including quantitative assessments of risk associated with microbial contamination of drinking water versus chemical risk and will compare alternative treatment options. The outcome will be improved risk assessment and better information for risk management. The work is divided into different topics (exposure assessment, epidemiology, risk assessment and management) and studies.