Time-varying associations of gestational and childhood triclosan with pubertal and adrenarchal outcomes in early adolescence.

Background: Triclosan is an endocrine-disrupting chemical, but associations with pubertal outcomes remain unclear. We examined associations of gestational and childhood triclosan with adolescent hormone concentrations and pubertal stage. Methods: We quantified urinary triclosan concentrations twice during pregnancy and seven times between birth and 12 years in participants recruited from Cincinnati, OH (2003-2006). We averaged concentrations across pregnancy and childhood and separately considered individual exposure periods in multiple informant models. At 12 years, we measured serum hormone concentrations (males [n = 72] and females [n = 84]-dehydroepiandrosterone-sulfate, luteinizing hormone, follicle-stimulating hormone; males-testosterone; females-estradiol). Also at age 12 years, participants self-reported physical development and menarchal timing. We estimated associations (95% confidence interval) of triclosan with hormone concentrations, more advanced physical development, and age at menarche. Results: For females, each doubling of childhood triclosan was associated with 16% lower estradiol concentrations (-29%, 0%), with stronger associations for measures closer to adolescence. We found suggestive evidence that higher triclosan at any age was associated with ~10% (for gestational triclosan: -18%, -2%) lower follicle-stimulating hormone concentrations among males and early postnatal (1-3 years) triclosan was associated with 63% (5%, 96%) lower odds of advanced pubic hair development in females. In multiple informant models, each doubling of gestational triclosan concentrations was associated with 5% (0%, 9%) earlier age at menarche, equivalent to 5.5 months. Conclusion: Gestational and childhood triclosan concentrations were related to some pubertal outcomes including hormone concentrations and age at menarche. Our findings highlight the relevance of elucidating potential sex-specific and time-dependent actions of triclosan.

Patterns of infant fecal metabolite concentrations and social behavioral development in toddlers.

BACKGROUND: Gut-derived metabolites, products of microbial and host co-metabolism, may inform mechanisms underlying children's neurodevelopment. We investigated whether infant fecal metabolites were related to toddler social behavior. METHODS: Stool samples collected from 6-week-olds (n = 86) and 1-year-olds (n = 209) in the New Hampshire Birth Cohort Study (NHBCS) were analyzed using nuclear magnetic resonance spectroscopy metabolomics. Autism-related behavior in 3-year-olds was assessed by caregivers using the Social Responsiveness Scale (SRS-2). To assess the association between metabolites and SRS-2 scores, we used a traditional single-metabolite approach, quantitative metabolite set enrichment (QEA), and self-organizing maps (SOMs). RESULTS: Using a single-metabolite approach and QEA, no individual fecal metabolite or metabolite set at either age was associated with SRS-2 scores. Using the SOM method, fecal metabolites of six-week-olds organized into four profiles, which were unrelated to SRS-2 scores. In 1-year-olds, one of twelve fecal metabolite profiles was associated with fewer autism-related behaviors, with SRS-2 scores 3.4 (95%CI: -7, 0.2) points lower than the referent group. This profile had higher concentrations of lactate and lower concentrations of short chain fatty acids than the reference. CONCLUSIONS: We uncovered metabolic profiles in infant stool associated with subsequent social behavior, highlighting one potential mechanism by which gut bacteria may influence neurobehavior. IMPACT: Differences in host and microbial metabolism may explain variability in neurobehavioral phenotypes, but prior studies do not have consistent results. We applied three statistical techniques to explore fecal metabolite differences related to social behavior, including self-organizing maps (SOMs), a novel machine learning algorithm. A 1-year-old fecal metabolite pattern characterized by high lactate and low short-chain fatty acid concentrations, identified using SOMs, was associated with social behavior less indicative of autism spectrum disorder. Our findings suggest that social behavior may be related to metabolite profiles and that future studies may uncover novel findings by applying the SOM algorithm.

Conceptualizing the Role of the Microbiome as a Mediator and Modifier in Environmental Health Studies: A Scoping Review of Studies of Triclosan and the Microbiome.

PURPOSE OF REVIEW: Triclosan is an endocrine-disrupting antimicrobial additive that is suspected of contributing to antibiotic resistance and altering the microbiome. In this scoping review, we summarize what is known about the association between triclosan exposure and the microbiome using evidence from in vivo and epidemiologic studies. RECENT FINDINGS: Our review includes 11 rodent studies, seven fish studies, and five human studies. Evidence from animal studies suggests that triclosan decreases the diversity of the microbiome, although only one epidemiologic study agreed. Most studies suggest that triclosan alters the microbial community beta diversity, but disagree on which taxa contributed to compositional differences. Taxa in the Bacteroidetes, Firmicutes, and Proteobacteria may be more influenced by triclosan than those in other phyla. Studies on triclosan and the microbiome were scarce and were inconclusive as to the effects of triclosan on the microbiome. Additional research is needed to clarify windows of heightened susceptibility of the microbiome to triclosan. We recommend guidelines for future microbiome research in environmental health to increase comparability across studies.

Bacterial Modification of the Association Between Arsenic and Autism-Related Social Behavior Scores.

Arsenic is related to neurodevelopmental outcomes and is associated with the composition of the gut microbiome. Data on the modifying role of the microbiome are limited. We probed suggestive relationships between arsenic and social behaviors to quantify the modifying role of the infant gut microbiome. We followed children for whom arsenic concentrations were quantified in 6-week-old toenail clippings. Scores on the Social Responsiveness Scale (SRS-2), which measures autism-related social behaviors, were provided by caregivers when the child was approximately 3 years of age. Metagenomic sequencing was performed on infant stools collected at 6 weeks and 1 year of age. To evaluate modification by the top ten most abundant species and functional pathways, we modeled SRS-2 total T-scores as a function of arsenic concentrations, microbiome features dichotomized at their median, and an interaction between exposure and the microbiome, adjusting for other trace elements and sociodemographic characteristics. As compared to the standardized population (SRS-2 T-scores = 50), participants in our study had lower SRS-2 scores (n = 78, mean = 44, SD = 5).The relative abundances of several functional pathways identified in 6-week stool samples modified the arsenic-SRS-2 association, including the pathways of valine and isoleucine biosynthesis; we observed no association among those with high relative abundance of each pathway [ß = - 0.67 (95% CI - 1.46, 0.12)], and an adverse association [ß = 1.67 (95% CI 0.3, 3.04), pinteraction= 0.05] among infants with low relative abundance. Our findings indicate the infant gut microbiome may alter neurodevelopmental susceptibility to environmental exposures.

Early-life exposure to per- and polyfluoroalkyl substances and infant gut microbial composition.

Human milk is rich in essential nutrients and immune-activating compounds but is also a source of toxicants including per- and polyfluoroalkyl substances (PFAS). Evidence suggests that immune-related effects of PFAS may, in part, be due to alterations of the microbiome. We aimed to identify the association between milk PFAS exposure and the infant gut microbiome. Methods: PFAS [perfluorooctane sulfonic acid (PFOS) and perfluorooctanoate (PFOA)] were quantified in milk from ~6 weeks postpartum using high-performance liquid chromatography with tandem mass spectrometry. A molar sum (ΣPFAS) was calculated. Caregivers collected infant stool samples at 6 weeks (n = 116) and/or 1 year postpartum (n = 119). Stool DNA underwent metagenomic sequencing. We estimated the association of PFAS with diversity and relative abundances of species with linear regression. Single- and multi-PFAS models adjusted for potential confounders in complete case analyses and with imputed missing covariate data for 6-week and 1-year microbiomes separately. We assessed sensitive populations with stratification. Results: PFOS and PFOA were detected in 94% and 83% of milk samples, respectively. PFOS was associated with increased diversity at 6 weeks among infants fed exclusively human milk [ß = 0.24 per PFOS doubling, (95% CI = 0.03, 0.45), P = 0.03] and born to primiparous mothers [ß = 0.37 (0.06, 0.67), P = 0.02]. Estimates were strongest in multi-PFAS models and among complete cases. ΣPFAS was associated with Bacteroides vulgatus relative abundance at 1 year [(ß = -2.34% per doubling (-3.63, -1.05), FDR q = 0.099]. Conclusions: PFAS may increase infant gut microbiome diversity and alter the relative abundance of biologically relevant bacteria. Additional analyses may identify related health outcomes.

Assessing the role of the gut microbiome at the interface between environmental chemical exposures and human health: Current knowledge and challenges.

The explosion of microbiome research over the past decade has shed light on the various ways that external factors interact with the human microbiome to drive health and disease. Each individual is exposed to more than 300 environmental chemicals every day. Accumulating evidence indicates that the microbiome is involved in the early response to environmental toxicants and biologically mediates their adverse effects on human health. However, few review articles to date provided a comprehensive framework for research and translation of the role of the gut microbiome in environmental health science. This review summarizes current evidence on environmental compounds and their effect on the gut microbiome, discusses the involved compound metabolic pathways, and covers environmental pollution-induced gut microbiota disorders and their long-term outcomes on host health. We conclude that the gut microbiota may crucially mediate and modify the disease-causing effects of environmental chemicals. Consequently, gut microbiota needs to be further studied to assess the complete toxicity of environmental exposures. Future research in this field is required to delineate the key interactions between intestinal microbiota and environmental pollutants and further to elucidate the long-term human health effects.

In Utero Exposure to Caffeine and Acetaminophen, the Gut Microbiome, and Neurodevelopmental Outcomes: A Prospective Birth Cohort Study.

Pregnant individuals are exposed to acetaminophen and caffeine, but it is unknown how these exposures interact with the developing gut microbiome. We aimed to determine whether acetaminophen and/or caffeine relate to the childhood gut microbiome and whether features of the gut microbiome alter the relationship between acetaminophen/caffeine and neurodevelopment. Forty-nine and 85 participants provided meconium and stool samples at 6-7, respectively, for exposure and microbiome assessment. Fecal acetaminophen and caffeine concentrations were quantified, and fecal DNA underwent metagenomic sequencing. Caregivers and study staff assessed the participants' motor and cognitive development using standardized scales. Prenatal exposures had stronger associations with the childhood microbiome than concurrent exposures. Prenatal acetaminophen exposure was associated with a trend of lower gut bacterial diversity in childhood [ß = -0.17 Shannon Index, 95% CI: (-0.31, -0.04)] and was marginally associated with differences in the relative abundances of features of the gut microbiome at the phylum (Firmicutes, Actinobacteria) and gene pathway levels. Among the participants with a higher relative abundance of Proteobacteria, prenatal exposure to acetaminophen and caffeine was associated with lower scores on WISC-IV subscales. Acetaminophen during bacterial colonization of the naïve gut is associated with lasting alterations in childhood microbiome composition. Future studies may inform our understanding of downstream health effects.

Contribution of gut bacteria to arsenic metabolism in the first year of life in a prospective birth cohort.

Gut bacteria are at the interface of environmental exposures and their impact on human systems, and may alter host absorption, metabolism, and excretion of toxic chemicals. We investigated whether arsenic-metabolizing bacterial gene pathways related to urinary arsenic concentrations. In the New Hampshire Birth Cohort Study, urine and stool samples were obtained at six weeks (n = 186) and one year (n = 190) of age. Inorganic arsenic (iAs), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), and arsenobetaine (AsB) were quantified in infant urine samples using high-performance liquid chromatography with inductively coupled plasma mass spectrometry. Total arsenic exposure (tAs) was summarized as Σ(iAs, MMA, DMA) and log2-transformed. Fecal microbial DNA underwent metagenomic sequencing and the relative abundance of bacterial gene pathways were grouped as KEGG Orthologies (KOs) using BioBakery algorithms. Arsenic metabolism KOs with >80% prevalence were log2-transformed and modeled continuously using linear regression, those with <10% were not evaluated and those with 10-80% prevalence were analyzed dichotomously (detect/non-detect) using logistic regression. In the first set of models, tAs was regressed against KO relative abundance or detection adjusting for age at sample collection and child's sex. Effect modification by delivery mode was assessed in stratified models. In the second set of models, the association between the relative abundance/detection of the KOs and arsenic speciation (%iAs, %MMA, %DMA) was quantified with linear regression. Urinary tAs was associated with the increased relative abundance/detection odds of several arsenic-related KOs, including K16509, an arsenate reductase transcriptional regulator, with stronger associations among six-week-olds than one-year-olds. K16509 was also associated with decreased %MMA and increased %DMA at six weeks and one year. Notably, many associations were stronger among operatively-delivered than vaginally-delivered infants. Our findings suggest associations between arsenic-metabolizing bacteria in the infant gut microbiome and urinary arsenic excretion.

The Developing Microbiome From Birth to 3 Years: The Gut-Brain Axis and Neurodevelopmental Outcomes.

The volume and breadth of research on the role of the microbiome in neurodevelopmental and neuropsychiatric disorders has expanded greatly over the last decade, opening doors to new models of mechanisms of the gut-brain axis and therapeutic interventions to reduce the burden of these outcomes. Studies have highlighted the window of birth to 3 years as an especially sensitive window when interventions may be the most effective. Harnessing the powerful gut-brain axis during this critical developmental window clarifies important investigations into the microbe-human connection and the developing brain, affording opportunities to prevent rather than treat neurodevelopmental disorders and neuropsychiatric illness. In this review, we present an overview of the developing intestinal microbiome in the critical window of birth to age 3; and its prospective relationship with neurodevelopment, with particular emphasis on immunological mechanisms. Next, the role of the microbiome in neurobehavioral outcomes (such as autism, anxiety, and attention-deficit hyperactivity disorder) as well as cognitive development are described. In these sections, we highlight the importance of pairing mechanistic studies in murine models with large scale epidemiological studies that aim to clarify the typical health promoting microbiome in early life across varied populations in comparison to dysbiosis. The microbiome is an important focus in human studies because it is so readily alterable with simple interventions, and we briefly outline what is known about microbiome targeted interventions in neurodevelopmental outcomes. More novel examinations of known environmental chemicals that adversely impact neurodevelopmental outcomes and the potential role of the microbiome as a mediator or modifier are discussed. Finally, we look to the future and emphasize the need for additional research to identify populations that are sensitive to alterations in their gut microbiome and clarify how interventions might correct and optimize neurodevelopmental outcomes.

Associations of Childhood and Perinatal Blood Metals with Children's Gut Microbiomes in a Canadian Gestation Cohort.

BACKGROUND: The gut microbiome is important in modulating health in childhood. Metal exposures affect multiple health outcomes, but their ability to modify bacterial communities in children is poorly understood. OBJECTIVES: We assessed the associations of childhood and perinatal blood metal levels with childhood gut microbiome diversity, structure, species, gene family-inferred species, and potential pathway alterations. METHODS: We assessed the gut microbiome using 16S rRNA gene amplicon sequencing and shotgun metagenomic sequencing in stools collected from 6- to 7-year-old children participating in the GESTation and Environment (GESTE) cohort study. We assessed blood metal concentrations [cadmium (Cd), manganese (Mn), mercury (Hg), lead (Pb), selenium (Se)] at two time points, namely, perinatal exposures at delivery (N=70) and childhood exposures at the 6- to 7-y follow-up (N=68). We used multiple covariate-adjusted statistical models to determine microbiome associations with continuous blood metal levels, including linear regression (Shannon and Pielou alpha diversity indexes), permutational multivariate analysis of variance (adonis; beta diversity distance matrices), and multivariable association model (MaAsLin2; phylum, family, species, gene family-inferred species, and pathways). RESULTS: Children's blood Mn and Se significantly associated with microbiome phylum [e.g., Verrucomicrobiota (coef=-0.305, q=0.031; coef=0.262, q=0.084, respectively)] and children's blood Mn significantly associated with family [e.g., Eggerthellaceae (coef=-0.228, q=0.052)]-level differences. Higher relative abundance of potential pathogens (e.g., Flavonifractor plautii), beneficial species (e.g., Bifidobacterium longum, Faecalibacterium prausnitzii), and both potentially pathogenic and beneficial species (e.g., Bacteriodes vulgatus, Eubacterium rectale) inferred from gene families were associated with higher childhood or perinatal blood Cd, Hg, and Pb (q<0.1). We found significant negative associations between childhood blood Pb and acetylene degradation pathway abundance (q<0.1). Finally, neither perinatal nor childhood metal concentrations were associated with children's gut microbial inter- and intrasubject diversity. DISCUSSION: Our findings suggest both long- and short-term associations between metal exposure and the childhood gut microbiome, with stronger associations observed with more recent exposure. Future epidemiologic analyses may elucidate whether the observed changes in the microbiome relate to children's health. https://doi.org/10.1289/EHP9674.

Sex-specific relationships of the infant microbiome and early-childhood behavioral outcomes.

BACKGROUND: A link between the gut microbiome and behavior is hypothesized, but most previous studies are cross-sectional or in animal models. The modifying role of host sex is poorly characterized. We aimed to identify sex-specific prospective associations between the early-life gut microbiome and preschool-age neurobehavior. METHODS: In a prospective cohort, gut microbiome diversity and taxa were estimated with 16S rRNA sequencing at 6 weeks, 1 year, and 2 years. Species and gene pathways were inferred from metagenomic sequencing at 6 weeks and 1 year. When subjects were 3 years old, parents completed the Behavioral Assessment System for Children, second edition (BASC-2). A total of 260 children contributed 523 16S rRNA and 234 metagenomics samples to analysis. Models adjusted for sociodemographic characteristics. RESULTS: Higher diversity at 6 weeks was associated with better internalizing problems among boys, but not girls [ßBoys = -1.86 points/SD Shannon diversity; 95% CI (-3.29, -0.42), pBoys = 0.01, ßGirls = 0.22 (-1.43, 1.87), pGirls = 0.8, pinteraction = 0.06]. Among other taxa-specific associations, Bifidobacterium at 6 weeks was associated with Adaptive Skills scores in a sex-specific manner. We observed relationships between functional features and BASC-2 scores, including vitamin B6 biosynthesis pathways and better Depression scores. CONCLUSIONS: This study advances our understanding of microbe-host interactions with implications for childhood behavioral health. IMPACT: This is one of the first studies to examine the early-life microbiome and neurobehavior, and the first to examine prospective sex-specific associations. Infant and early-childhood microbiomes relate to neurobehavior including anxiety, depression, hyperactivity, and social behaviors in a time- and sex-specific manner. Our findings suggest future studies should evaluate whether host sex impacts the relationship between the gut microbiome and behavioral health outcomes.

Dietary fat intake during early pregnancy is associated with cord blood DNA methylation at IGF2 and H19 genes in newborns.

Maternal fat intake during pregnancy affects fetal growth, but mechanisms underlying this relationship are unclear. We performed an exploratory study of the associations of fat consumption during pregnancy with cord blood DNA methylation of the insulin-like growth factor 2 (IGF2) and H19 genes. We used data from 96 uncomplicated full-term pregnancies of mothers of whom majority had normal body mass index (BMI) (66%) in Project Viva, a prospective pre-birth cohort. We assessed maternal diet with validated food frequency questionnaires during the first and second trimesters and measured DNA methylation in segments of the IGF2- and H19-differentially methylated regions (DMRs) by pyrosequencing DNA extracted from umbilical cord blood samples. Mean (SD) age was 32.8 (4.1) years and prepregnancy BMI was 24.0 (4.4) kg/m2 . Mean DNA methylation was 56.3% (3.9%) for IGF2-DMR and 44.6% (1.9%) for H19-DMR. Greater first trimester intake of omega-6 polyunsaturated fat (effect per 1% of calories at the expense of carbohydrates) was associated with lower DNA methylation of IGF2-DMR (-1.2%; 95% confidence interval [CI]: -2.2%, -0.2%) and higher DNA methylation at H19-DMR (0.8%; 95% CI: 0.3%, 1.3%). On the other hand, greater first trimester intake of omega-3 polyunsaturated fat was associated with lower DNA methylation of the H19-DMR (-4.3%; 95% CI: -7.9%, -0.8%). We did not find significant associations of IGF2 and H19 methylation with IGF2 cord blood levels. Our findings suggest that early prenatal fat intake (omega-3, omega-6, and saturated fatty acids) may influence DNA methylation at the IGF2 and H19 locus, which could impact fetal development and long-term health.

The association between prenatal concentrations of polybrominated diphenyl ether and child cognitive and psychomotor function.

Previous studies suggest a negative association between prenatal polybrominated diphenyl ethers (PBDEs) exposure and child cognitive and psychomotor development. However, the timing of the relationship between PBDE exposure and neurodevelopment is still unclear. We examined the association between PBDE concentration at two different prenatal times (early and late pregnancy) and cognitive function in children 6-8 years of age. METHODS: Eight hundred pregnant women were recruited between 2007 and 2009 from Sherbrooke, Canada. Four PBDE congeners (BDE-47, -99, -100, and -153) were measured in maternal plasma samples collected during early pregnancy (12 weeks of gestation) and at delivery. At 6-8 years of age, 355 children completed a series of subtests spanning multiple neuropsychologic domains: verbal and memory skills were measured using the Wechsler Intelligence Scale for Children, Fourth Edition; visuospatial processing using both Wechsler Intelligence Scale for Children, Fourth Edition and Neuropsychological Assessment second edition; and attention was assessed through the Test of Everyday Attention for Children. Additionally, parents completed subtests from the Developmental Coordination Disorder Questionnaire to measure child motor control. We used linear regression and quantile g-computation models to estimate associations of PBDE congener concentrations and psychologic test scores. RESULTS: In our models, no significant associations were detected between PBDE mixture and any of the child psychologic scores. BDE-99 concentration at delivery was nominally associated with higher scores on short-term and working memory while a decrease in spatial perception and reasoning was nominally associated with higher BDE-100 concentration at delivery. CONCLUSION: Overall, our results did not show a significant association between PBDEs and child cognitive and motor development.

Infant Feeding Alters the Longitudinal Impact of Birth Mode on the Development of the Gut Microbiota in the First Year of Life.

Cesarean-delivered (CD) infants harbor a distinct gut microbiome from vaginally delivered (VD) infants, however, during infancy, the most important driver of infant gut microbial colonization is infant feeding. Earlier studies have shown that breastfeeding is associated with higher levels of health-promoting bacteria such and Bifidobacterium and Bacteroides via modulation of the immune system, and production of metabolites. As the infant gut matures and solid foods are introduced, it is unclear whether longer duration of breast feeding restore loss of beneficial taxa within the intestinal microbiota of operatively delivered infants. Within the New Hampshire Birth Cohort Study, we evaluated the longitudinal effect of delivery mode and infant feeding on the taxonomic composition and functional capacity of developing gut microbiota in the First year of life. Microbiota of 500 stool samples collected between 6 weeks and 12 months of age (from 229 infants) were characterized by 16S ribosomal RNA sequencing. Shotgun metagenomic sequencing was also performed on 350 samples collected at either 6 weeks or 12 months of age. Among infant participants, 28% were cesarean-delivered (CD) infants and most (95%) initiated breastfeeding within the first six months of life, with 26% exclusively breastfed and 69% mixed-fed (breast milk and formula), in addition to complementary foods by age 1. Alpha (within-sample) diversity was significantly lower in CD infants compared to vaginally delivered (VD) infants (P < 0.05) throughout the study period. Bacterial community composition clustering by both delivery mode and feeding duration at 1 year of age revealed that CD infants who were breast fed for < 6 months were more dissimilar to VD infants than CD infants who breast fed for ≥ 6 months. We observed that breastfeeding modified the longitudinal impact of delivery mode on the taxonomic composition of the microbiota by 1 year of age, with an observed increase in abundance of Bacteroides fragilis and Lactobacillus with longer duration of breastfeeding among CD infants while there was an increase in Faecalibacterium for VD infants. Our findings confirm that duration of breastfeeding plays a critical role in restoring a health-promoting microbiome, call for further investigations regarding the association between breast milk exposure and health outcomes in early life.

Prospective associations of the infant gut microbiome and microbial function with social behaviors related to autism at age 3 years.

The hypothesized link between gut bacteria and autism spectrum disorder (ASD) has been explored through animal models and human studies with microbiome assessment after ASD presentation. We aimed to prospectively characterize the association between the infant/toddler gut microbiome and ASD-related social behaviors at age 3 years. As part of an ongoing birth cohort gut bacterial diversity, structure, taxa, and function at 6 weeks (n = 166), 1 year (n = 158), 2 years (n = 129), and 3 years (n = 140) were quantified with 16S rRNA gene and shotgun metagenomic sequencing (n = 101 six weeks, n = 103 one year). ASD-related social behavior was assessed at age 3 years using Social Responsiveness Scale (SRS-2) T-scores. Covariate-adjusted linear and permutation-based models were implemented. Microbiome structure at 1 year was associated with SRS-2 total T-scores (p = 0.01). Several taxa at 1, 2, and 3 years were associated with SRS-2 performance, including many in the Lachnospiraceae family. Higher relative abundance of Adlercreutzia equolifaciens and Ruminococcus torques at 1 year related to poorer SRS-2 performance. Two functional pathways, L-ornithine and vitamin B6 biosynthesis, were associated with better social skills at 3 years. Our results support potential associations between early-childhood gut microbiome and social behaviors. Future mechanistic studies are warranted to pinpoint sensitive targets for intervention.

Association of Prenatal Acetaminophen Exposure Measured in Meconium With Risk of Attention-Deficit/Hyperactivity Disorder Mediated by Frontoparietal Network Brain Connectivity.

Importance: Despite evidence of an association between prenatal acetaminophen exposure and attention-deficit/hyperactivity disorder (ADHD) in offspring, the drug is not contraindicated during pregnancy, possibly because prior studies have relied on maternal self-report, failed to quantify acetaminophen dose, and lacked mechanistic insight. Objective: To examine the association between prenatal acetaminophen exposure measured in meconium (hereinafter referred to as meconium acetaminophen) and ADHD in children aged 6 to 7 years, along with the potential for mediation by functional brain connectivity. Design, Setting, and Participants: This prospective birth cohort study from the Centre Hospitalier Université de Sherbrooke in Sherbrooke, Québec, Canada, included 394 eligible children, of whom 345 had meconium samples collected at delivery and information on ADHD diagnosis. Mothers were enrolled from September 25, 2007, to September 10, 2009, at their first prenatal care visit or delivery and were followed up when children were aged 6 to 7 years. When children were aged 9 to 11 years, resting-state brain connectivity was assessed with magnetic resonance imaging. Data for the present study were collected from September 25, 2007, to January 18, 2020, and analyzed from January 7, 2019, to January 22, 2020. Exposures: Acetaminophen levels measured in meconium. Main Outcomes and Measures: Physician diagnosis of ADHD was determined at follow-up when children were aged 6 to 7 years or from medical records. Resting-state brain connectivity was assessed with magnetic resonance imaging; attention problems and hyperactivity were assessed with the Behavioral Assessment System for Children Parent Report Scale. Associations between meconium acetaminophen levels and outcomes were estimated with linear and logistic regressions weighted on the inverse probability of treatment to account for potential confounders. Causal mediation analysis was used to test for mediation of the association between prenatal acetaminophen exposure and hyperactivity by resting-state brain connectivity. Results: Among the 345 children included in the analysis (177 boys [51.3%]; mean [SD] age, 6.58 [0.54] years), acetaminophen was detected in 199 meconium samples (57.7%), and ADHD was diagnosed in 33 children (9.6%). Compared with no acetaminophen, detection of acetaminophen in meconium was associated with increased odds of ADHD (odds ratio [OR], 2.43; 95% CI, 1.41-4.21). A dose-response association was detected; each doubling of exposure increased the odds of ADHD by 10% (OR, 1.10; 95% CI, 1.02-1.19). Children with acetaminophen detected in meconium showed increased negative connectivity between frontoparietal and default mode network nodes to clusters in the sensorimotor cortices, which mediated an indirect effect on increased child hyperactivity (14%; 95% CI, 1%-26%). Conclusions and Relevance: Together with the multitude of other cohort studies showing adverse neurodevelopment associated with prenatal acetaminophen exposure, this work suggests caution should be used in administering acetaminophen during pregnancy. Research into alternative pain management strategies for pregnant women could be beneficial.

Methylparaben in meconium and risk of maternal thyroid dysfunction, adverse birth outcomes, and Attention-Deficit Hyperactivity Disorder (ADHD).

BACKGROUND: Parabens, which are used as a preservative in foods and personal care products, are detected in nearly 100% of human urine samples. Exposure to parabens is associated with DNA damage, male infertility, and endocrine disruption in adults, but the effects of prenatal exposure are unclear. In part, this is due to inadequate assessment of exposure in maternal urine, which may only reflect maternal rather than fetal exposure. To address this gap, we examined the association of prenatal methylparaben measured in meconium with preterm birth, gestational age, birthweight, maternal thyroid hormones, and child Attention-Deficit Hyperactivity Disorder (ADHD) at 6-7 years. DESIGN: Data come from the GESTation and the Environment (GESTE) prospective observational pregnancy cohort in Sherbrooke, Quebec, Canada. Participants were 345 children with data on ADHD among 394 eligible pregnancies in women age ≥18 years with no known thyroid disease before pregnancy and meconium collected at delivery. Methylparaben was measured in meconium. Birthweight, gestational age, and maternal thyroid hormones at <20 weeks gestation were measured at the Centre Hospitalier Universitaire de Sherbrooke. Preterm birth was defined as vaginal birth before the 37th week of gestation. Physician diagnosis of ADHD was determined at a scheduled cohort follow-up when children were 6-7 years old or from medical records. Associations between meconium methylparaben and outcomes were estimated with logistic and linear regressions weighted on the inverse probability of exposure to account for potential confounders, including child sex, familial income, maternal education, pre-pregnancy body mass index, age, and smoking and alcohol consumption during pregnancy. RESULTS: Methylparaben was detected in 65 meconium samples (19%), 33 children were diagnosed with ADHD (10%), and 13 children were born preterm (4%). Meconium methylparaben was associated with preterm birth (odds ratio [OR] = 4.81; 95% CI [2.29, 10.10]), decreased gestational age (beta [ß] = -0.61 weeks; 95% CI [-0.93, -0.29]) and birthweight (ß = -0.12 kg; 95% CI [-0.21, -0.03]), altered maternal TSH (relative concentration [RC] = 0.76; 95% CI [0.58, 0.99]), total T3 (RC = 0.84; 95% CI [0.75, 0.96]) and total T4 (RC = 1.10; 95% CI [1.01, 1.19]), maternal hypothyroxinemia (OR = 2.50, 95% CI [1.01, 6.22]), and child ADHD at age of 6-7 (OR = 2.33, 95% CI [1.45, 3.76]). The effect of meconium methylparaben on ADHD was partially mediated by preterm birth (20% mediation) and birthweight (13% mediation). CONCLUSIONS: Meconium methylparaben was associated with preterm birth, decreased gestational age and birthweight, maternal thyroid hormone dysfunction, and child ADHD. Parabens are a substantial health concern if causally related to these adverse outcomes.

Nutrient-toxic element mixtures and the early postnatal gut microbiome in a United States longitudinal birth cohort.

BACKGROUND: The infant microbiome contributes to health status across the lifespan, but environmental factors affecting microbial communities are poorly understood, particularly when toxic and essential elements interact. OBJECTIVE: We aimed to identify the associations between a spectrum of other early-postnatal nutrient or toxic elemental exposures measured and the infant gut microbiome. METHODS: Our analysis included 179 six-week-old infants from the New Hampshire Birth Cohort Study. Eleven elements were measured in infant toenail clippings. The gut microbiome was assessed using 16S rRNA V4-V5 hypervariable region targeted sequencing. Multivariable zero-inflated logistic normal regression (MZILN) was used to model the association between element concentrations and taxon relative abundance. To explore interactive and nonlinear associations between the exposures and specific taxa we employed Bayesian Kernel Machine Regression (BKMR). Effect modification by delivery mode, feeding mode, peripartum antibiotic exposure, and infant sex was assessed with stratified models. RESULTS: We found a negative association between arsenic and microbial diversity in the full population that was accentuated among infants exposed to peripartum antibiotics. Arsenic, cadmium, copper, iron, lead, manganese, nickel, selenium, tin, and zinc were each associated with differences in at least one taxon in the full study population, with most of the related taxa belonging to the Bacteroides and Lactobacillales. In stratified analyses, mercury, in addition to the other elements, was associated with specific taxa. Bifidobacterium, which associated negatively with zinc in MZILN and BKMR models, had a quadratic association with arsenic concentrations. These associations varied with the concentration of the other element. CONCLUSIONS: Early postnatal toxic and nutrient elemental exposures are associated with differences in the infant microbiome. Further research is needed to clarify the whether these alterations are a biomarker of exposure or if they have implications for child and lifelong health.