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.

Association of maternal hypertensive disorders in pregnancy with infant neurodevelopment.

Inconsistent findings have been reported regarding the associations between hypertensive disorders in pregnancy (HDP) and infant neurodevelopment. Leveraging data from the Jiangsu Birth Cohort, in the present study, we re-visited such associations in one-year-old infants from 2576 singleton pregnancies and 261 twin pregnancies. We first assessed infant neurodevelopment by the Bayley Scales of Infant and Toddler Development Screening Test (the Third Edition), and then estimated its association with maternal HDP using general linear regression models and Poisson regression models. In singleton pregnancies, compared with mothers unexposed to HDP, infants born to mothers with chronic hypertension exhibited a lower score ( ß, -0.67; 95% confidence interval [CI], -1.19--0.15) and a higher risk of "non-optimal" gross motor development (risk ratio [RR], 2.21; 95% CI, 1.02-4.79); in twin pregnancies, infants born to mothers with HDP exhibited lower scores in cognition ( ß, -0.49; 95% CI, -0.96--0.01), receptive communication ( ß, -0.55; 95% CI, -1.03--0.06), and gross motor ( ß, -0.44; 95% CI, -0.86--0.03), and at a higher risk of "non-optimal" gross motor development (RR, 2.12; 95% CI, 1.16-3.88). These findings indicate that infants born to mothers with HDP may have inferior neurodevelopment outcomes at the age of one year.

Maternal exposure to fine particulate matter and brain-derived neurotrophic factor (BDNF) in the fetus: A prospective cohort study.

Maternal exposure to ambient fine particulate matter (PM2.5) during pregnancy has been associated with impaired neurobehavioral development in children. However, the specific mechanism remains unclear. Brain derived neurotrophic factor (BDNF) is an important growth factor in the nervous system. We evaluated the associations of maternal PM2.5 exposures with fetal BDNF in the umbilical cord blood in a prospective cohort study. A total of 711 eligible mother-infant pairs from the Shanghai Birth Cohort were included in the current study. Daily maternal exposures to ambient PM2.5 were assessed with a gap-filling approach at 1 * 1 km2 resolution based on self-reported home addresses. The concentrations of BDNF in the cord blood were measured by ELISA. A linear regression model was applied to evaluate the association of maternal ambient PM2.5 exposure with fetal BDNF level at birth. The median concentration of BDNF was 13,403 pg/ml. Vaginal deliveries and female infants had higher BDNF levels than cesarean deliveries and male infants. One natural log (ln) unit increase in maternal PM2.5 exposure during the second trimester was significantly associated with - 0.20 (95% CI: -0.36, -0.05) ln-unit decrease in BDNF level in all births. These effects were stronger and more significant in vaginal deliveries and in male infants. Our study suggests that BDNF in the cord blood may serve as a potential biomarker in assessing the neurodevelopmental effects of maternal PM2.5 exposure.

Prenatal Exposure to Legacy and Alternative Per- and Polyfluoroalkyl Substances and Neuropsychological Development Trajectories over the First 3 Years of Life.

The neurotoxic effects of prenatal exposure to per- and polyfluoroalkyl substances (PFAS) on offspring animals are well-documented. However, epidemiological evidence for legacy PFAS is inconclusive, and for alternative PFAS, it is little known. In this investigation, we selected 718 mother-child pairs from the Chinese Maoming Birth Cohort Study and measured 17 legacy and alternative PFAS in the third-trimester serum. Neuropsychological developments (communication, gross motor function, fine motor function, problem solving ability, and personal-social skills) were assessed at 3, 6, 12, 18, 24, and 36 months using the Ages and Stages Questionnaires 3rd edition. Trajectories of each subscale were classified into persistently low and persistently high groups via group-based trajectory modeling. Logistic regression and grouped weighted quantile sum were fitted to assess the potential effects of individual PFAS and their mixtures, respectively. Higher linear PFHxS levels were associated with elevated odds for the persistently low trajectories of communication (OR = 1.73; 95% CI: 1.12, 2.66) and problem solving ability (OR = 2.11; 95% CI: 1.14, 3.90). Similar findings were observed for linear PFOS, 1m-PFOS, PFDA, PFDoDA, PFUnDA, and legacy PFAS mixture. However, no association was observed for alternative PFAS and their mixture. We provided insights into the longitudinal links between prenatal legacy/alternative PFAS exposure and neuropsychological development trajectories over the first 3 years of life.

Sex Discrepancy Observed for Gestational Metabolic Syndrome Parameters and Polygenic Risk Associated With Preschoolers' BMI Growth Trajectory: The Ma'anshan Birth Cohort Study.

Background: Few studies have investigated the associations of childhood growth trajectories with the prenatal metabolic risks of mothers and their interaction with children's genetic susceptibility. Objective: To investigate the effects of gestational metabolic syndrome (GMS) risks and children's polygenic risk scores (PRSs), and their interaction effect on the BMI trajectory and obesity risk of offspring from birth to 6 years of age. Methods: A total of 2,603 mother-child pairs were recruited from the Ma'anshan birth cohort (Anhui Province of China) study. Data on maternal prepregnancy obesity, gestational weight gain (GWG), gestational diabetes mellitus (GDM), and hypertensive disorders of pregnancy (HDP) were used to evaluate maternal GMS risk. In addition, 1,482 cord blood samples were used to genotype 11 candidate single-nucleotide polymorphisms (SNPs) to calculate children's PRSs. The latent class growth model using the longitudinal BMI-for-age z scores (BMIz) was applied to validly capture the BMIz growth trajectory. Results: Maternal GMS status was associated with higher BMIz scores and with an increased risk of overweight/obesity. Positive relationships were revealed between PRS and the risk of overweight/obesity among girls. Additionally, maternal GMS significantly interacted with the child's PRS on BMIz scores and the risk of overweight/obesity among girls. Hierarchical BMI trajectory graphs by different exposure groups showed consistent findings, and both boys' and girls' BMIz trajectories were divided into three groups. Among girls, the higher the GMS risk or PRS they had, the higher the probability of being in the high BMIz trajectory group. Conclusions: Maternal GMS status increased BMIz scores and the risk of obesity in both boys and girls and elevated the child's BMI trajectory from birth to 6 years of age among girls. PRSs were significantly associated with children's BMI trajectory and the risk of obesity and modified the associations between maternal GMS status and obesity biomarkers only among girls. Thus, regarding childhood obesity, steps should be taken to decrease maternal metabolic risks before and during pregnancy, and sex discrepancies should be noted to identify high-risk populations after birth to hierarchically manage them.

Lag associations of gestational phthalate exposure with maternal serum vitamin D levels: Repeated measure analysis.

Few studies have investigated the relationships between gestational phthalate exposure and maternal circulating vitamin D. In the Ma'anshan birth cohort, 3265 pregnant women were included. Each woman provided up to three urine and serum samples for measurement of phthalates and 25(OH)D and calcium, respectively. Linear mixed models were performed to analyse the association between phthalate metabolites and 25(OH)D and calcium. Stratified analyses of the relationship between phthalates and 25(OH)D by urine collection season were conducted. Finally, the post hoc lag effect of phthalate exposure on 25(OH)D was determined if longitudinal associations were significant. Some phthalate metabolites were associated with increased 25(OH)D but with decreased calcium. Furthermore, the relationship of phthalate exposure with 25(OH)D varied with urine collection season. Phthalate metabolites collected in summer and autumn were associated with an increase in 25(OH)D, while monobenzyl phthalate collected in winter and spring was inversely associated with 25(OH)D. Finally, high-molecular-weight phthalates had lag associations with 25(OH)D with a 1-trimester lag period. Low-molecular-weight phthalates exhibited lag associations with 25(OH)D with a 2-trimester lag period. In conclusion, the positive cross-sectional correlation between phthalate metabolites and 25(OH)D was partly affected by urine collection season. This study suggested that gestational phthalate exposure would have a lag association with maternal 25(OH)D levels.

Association between prenatal exposure to perfluoroalkyl substances and respiratory tract infections in preschool children.

BACKGROUND: Prenatal exposure to perfluoroalkyl substances (PFAS) is considered to affect adversely the immune function. However, the effect of prenatal PFAS exposure on respiratory tract infections (RTIs) in children is unclear. Thus, we evaluated whether cord blood PFAS levels were associated with RTI in the first 5 years of life. METHODS: The Shanghai Prenatal Cohort is an on-going birth cohort, which included all the mothers during pregnancy. Children were followed by paediatricians once a year after birth. The levels of 10 PFAS in cord blood were tested using liquid chromatography-mass spectrometry. RTIs were diagnosed based on face-to-face interviews with the parents and review of medical records. Immunoglobulin G (IgG) and immunoglobulin E (IgE) levels, as biomarkers of humoral immunity, were assessed using enzyme-linked immunosorbent assay at age 5 years. Multivariable logistic and linear regression models were applied to study the association between prenatal PFAS exposure and RTIs. RESULTS: A total of 743 children completed the follow-up, 344 of them had detail information of cord blood PFAS, IgG, and IgE concentrations. Eight PFAS were detected in more than 90% of the cord blood samples, except for perfluoroheptanoic acid (PFHpA) and perfluorooctane sulfonamide (FOSA). During the 5-year follow-up period, the frequency of RTIs increased with age, reaching a peak at age 4. Moreover, 20.6% of the children were diagnosed with recurrent RTIs. Children with recurrent RTIs had higher prenatal perfluorobutane sulfonic acid (PFBS) concentration. Higher prenatal PFBS concentration was positively associated with total RTI frequency (ß = 6.05, 95% CI [0.84, 11.26]) in first 5 years of life and negatively associated with IgG level (ß = -0.82, 95% CI [-1.67, -0.01]) at age 5. CONCLUSIONS: Children with higher prenatal PFBS were more vulnerable to RTIs in early life, which may be attributed to immunosuppression of IgG production. These findings need to be further verified in larger prospective studies.

Maternal psychosocial stress and children's ADHD diagnosis: a prospective birth cohort study.

Objective: Examine the association of mothers' psychosocial stressors before and during pregnancy with their children's diagnosis of attention deficit hyperactivity disorder (ADHD). Methods: This study included 2140 mother-child pairs who had at least one postnatal pediatric visit at the Boston Medical Center between 2003 and 2015. Child ADHD was determined via International Classification of Diseases, Ninth Revision (ICD-9) codes documented in electronic medical records. Latent factors of maternal stress and social support and measures of the physical home environment and psychosocial adversities were constructed using exploratory factor analysis. The association between the latent factors and child ADHD diagnosis was examined using multiple logistic regression, controlling for known risk factors for ADHD. Results: Children were 1.45 (95% CI: 1.06, 1.99) and 3.03 (95% CI: 2.19, 4.20) times more likely to receive an ADHD diagnosis if their mother experienced a major stressful event during pregnancy or reported a high level of perceived stress, respectively. The number of family adversities increases the risk of ADHD diagnosis [second quartile: OR = 1.90; CI (1.31, 2.77); third quartile: OR = 1.96 CI (1.34, 2.88); fourth quartile: OR = 2.89 CI (2.01, 4.16)] compared to first quartile. Conclusions: In this prospective, predominantly urban, low-income, minority birth cohort, mothers' psychosocial stress before and during pregnancy appears to be an independent risk factor for the development of ADHD in their children.

Down syndrome as risk factor for respiratory syncytial virus hospitalization: A prospective multicenter epidemiological study.

BACKGROUND: Respiratory syncytial virus (RSV) infection in childhood, particularly in premature infants, is associated with significant morbidity and mortality. OBJECTIVES: To compare the hospitalization rates due to RSV infection and severity of disease between infants with and without Down syndrome (DS) born at term and without other associated risk factors for severe RSV infection. PATIENTS/METHODS: In a prospective multicentre epidemiological study, 93 infants were included in the DS cohort and 68 matched by sex and data of birth (±1 week) and were followed up to 1 year of age and during a complete RSV season. RESULTS: The hospitalization rate for all acute respiratory infection was significantly higher in the DS cohort than in the non-DS cohort (44.1% vs 7.7%, P<.0001). Hospitalizations due to RSV were significantly more frequent in the DH cohort than in the non-DS cohort (9.7% vs 1.5%, P=.03). RSV prophylaxis was recorded in 33 (35.5%) infants with DS. The rate of hospitalization according to presence or absence of RSV immunoprophylaxis was 3.0% vs 15%, respectively. CONCLUSIONS: Infants with DS showed a higher rate of hospitalization due to acute lower respiratory tract infection and RSV infection compared to non-DS infants. Including DS infants in recommendations for immunoprophylaxis of RSV disease should be considered.

Early pregnancy maternal and fetal angiogenic factors and fetal and childhood growth: the Generation R Study.

STUDY QUESTION: What are the effects of maternal and fetal soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) concentrations on fetal and childhood growth patterns? SUMMARY ANSWER: An angiogenic profile that is characterized by both low early pregnancy maternal sFlt-1 and PlGF concentrations and higher sFlt-1 concentrations, lower PlGF concentrations or a higher sFlt-1:PlGF ratio in umbilical cord blood is associated with a reduced fetal and childhood growth. WHAT IS KNOWN ALREADY: An imbalance in maternal and fetal sFlt-1 and PlGF concentrations has been suggested to affect pregnancy outcomes. However, their effects on longitudinal fetal and childhood growth remain largely unknown. STUDY DESIGN, SIZE, DURATION: This study was performed in 5980 mothers and 4108 of their children, participating in the Generation R Study; a population-based prospective cohort study from fetal life onwards in Rotterdam, the Netherlands (2001-2005). PARTICIPANTS/MATERIALS, SETTING, METHODS: Blood samples were obtained from mothers in early and mid-pregnancy and from the umbilical vein at delivery. Fetal and childhood growth characteristics (weight and length) were measured repeatedly by ultrasound and physical examinations until the age of 6 years. We assessed the associations of maternal and fetal angiogenic factors with fetal and childhood growth using repeated measurement regression models. Logistic regression models were used to determine associations between angiogenic factors and small for gestational age at birth (SGA). MAIN RESULTS AND THE ROLE OF CHANCE: Compared with early pregnancy maternal sFlt-1 concentrations in the lowest quintile, early pregnancy maternal sFlt-1 concentrations in the highest quintile were associated with a higher fetal weight growth resulting in a higher birthweight (difference in birthweight 0.33 standard deviation score (SDS); 95% Confidence Interval (CI) 0.25-0.41), a lower risk of SGA (Odds Ratio (OR) 0.36; 95% CI 0.27-0.48) and a subsequent higher weight growth until the age of 6 years. Early pregnancy maternal PlGF concentrations in the lowest quintile were associated with a reduced weight growth pattern resulting in a smaller birthweight (difference in birthweight -0.34 SDS; 95% CI -0.44, -0.25), an increased risk of SGA (OR 3.48; 95% CI 2.39-5.08) and a lower weight growth throughout childhood. An early pregnancy maternal sFlt-1:PlGF ratio in the highest quintile was associated with a higher fetal weight growth pattern from 30 weeks onwards, resulting in a higher weight at birth (difference in birthweight 0.09 SDS; P-value <0.05), which remained present until the age of 2 years. Newborns with higher umbilical cord sFlt-1 concentrations, lower PlGF concentrations or a higher sFlt-1:PlGF ratio showed a lower fetal and childhood weight growth from 30 weeks gestation onwards until the age of 6 years (P-value <0.05). Similar patterns were observed in relation to fetal and childhood length growth. LIMITATIONS, REASONS FOR CAUTION: The study is an observational study. Therefore, no causal relationships can be established. WIDER IMPLICATIONS OF THE FINDINGS: Both a maternal and fetal angiogenic imbalance may affect fetal and childhood growth. Changes in angiogenic profiles may be involved in the pathways linking fetal growth restriction with the long-term risk of vascular disease in adulthood. STUDY FUNDING/COMPETING INTERESTS: The first phase of the Generation R Study is made possible by financial support from The Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam, and the Netherlands Organization for Health Research and Development (ZonMw 21000074). V.W.V.J. received additional grants from the Netherlands Organization for Health Research and Development (ZonMw VIDI). M.I.B.-B. is financially supported by the Bo Hjelt foundation (grant 2009). The authors have no competing interests.

The mediating role of deviant peers on the link between depressed mood and harmful drinking.

PURPOSE: One's peer group can have a strong impact on depressed mood and harmful drinking in adolescence. It remains unclear whether affiliation with deviant peers explains the link between these traits. Our study aims to (1) explore the developmental relationship between harmful drinking and depressed mood in adolescence and (2) establish to which extent affiliation with deviant peers explains this relationship. METHODS: A total of 4,863 adolescents from the Avon Longitudinal Study of Parents and Children were assessed between the ages of 14 and 16 years. Harmful drinking was established using age-appropriate measures: the Semi-Structured Assessment for the Genetics of Alcoholism in mid-adolescence (age, 14 years) and the Alcohol Use Disorders Identification Test in late adolescence (age, 16 years). Depressed mood was measured by the Short Mood and Feelings Questionnaire at both ages. Affiliation with deviant peers was assessed at the age of 15 years. RESULTS: Harmful drinking at the age of 14 years predicted depressed mood 2 years later. This association was explained by affiliation with deviant peers and remained present even after adjustment for earlier depressed mood. Depressed mood at the age of 14 years predicted harmful drinking at the age of 16 years via affiliation with deviant peers; however, this indirect effect disappeared when adjusting for adolescents' earlier harmful alcohol use (age, 14 years). No gender differences were observed. CONCLUSIONS: Adolescents who engage in early harmful drinking and subsequently become affiliated with a deviant peer group may be at particular risk of later depressed mood.

Sexual orientation and alcohol problem use among U.K. adolescents: an indirect link through depressed mood.

BACKGROUND AND AIMS: Sexual minority adolescents are more likely to engage in alcohol use than their heterosexual counterparts; however, the underlying reasons remain unclear and longitudinal research is limited. Owing to evidence that this group also experiences greater depressive symptoms than their peers, we aimed to (i) assess to what extent depressed mood explains the increased likelihood of engaging in alcohol use among sexual minority adolescents, and (ii) explore potential gender-specific patterns. DESIGN: Structural equation modelling was used to test the indirect relationship between sexual orientation and alcohol use through depressed mood, with heterosexuals as the reference group. SETTINGS AND PARTICIPANTS: A total of 3710 adolescents (12% sexual minority), from the Avon Longitudinal Study of Parents and Children (ALSPAC) study, assessed between the ages of 15 and 18 years. MEASUREMENTS: Sexual orientation was assessed at age 15, while alcohol use was measured using the Alcohol Use Disorders Identification Test (AUDIT) at age 18. Depressed mood was indexed by the Short Mood and Feelings Questionnaire (SMFQ) at age 16. FINDINGS: Sexual minority adolescents were more likely to engage in alcohol problem use compared to their heterosexual counterparts [Btotal = 0.12, 95% confidence interval (CI) = 0.04-0.20, P = 0.003]. Depressed mood explained 21% of the link between sexual orientation and alcohol use after adjustment for covariates and earlier measures (Z = 3.2, P = 0.001). No gender differences were observed. CONCLUSIONS: A higher prevalence of alcohol problem use in adolescents who are gay, lesbian or bisexual is partly explained by increased rates of depression in this group.