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Structural and functional magnetic resonance imaging (MRI) studies have suggested a neuroanatomical basis that may underly attention-deficit–hyperactivity disorder (ADHD), but the anatomical ground truth remains unknown. In addition, the role of the white matter (WM) microstructure related to attention and impulsivity in a general pediatric population is still not well understood. Using a state-of-the-art structural connectivity pipeline based on the Brainnetome atlas extracting WM connections and its subsections, we applied dimensionality reduction techniques to obtain biologically interpretable WM measures. We selected the top 10 connections-of-interests (located in frontal, parietal, occipital, and basal ganglia regions) with robust anatomical and statistical criteria. We correlated WM measures with psychometric test metrics (Conner’s Continuous Performance Test 3) in 171 children (27 Dx ADHD, 3Dx ASD, 9–13 years old) from the population-based GESTation and Environment cohort. We found that children with lower microstructural complexity and lower axonal density show a higher impulsive behavior on these connections. When segmenting each connection in subsections, we report WM alterations localized in one or both endpoints reflecting a specific localization of WM alterations along each connection. These results provide new insight in understanding the neurophysiology of attention and impulsivity in a general population.

The apparent increase in the prevalence of the attention deficit hyperactivity disorder (ADHD) diagnosis raises many questions regarding the variability of the subjective diagnostic method. This comprehensive review reports findings in studies assessing white matter (WM) bundles in diffusion MRI and symptom severity in children with ADHD. These studies suggested the involvement of the connections between the frontal, parietal, and basal ganglia regions. This review discusses the limitations surrounding diffusion tensor imaging (DTI) and suggests novel imaging techniques allowing for a more reliable representation of the underlying biology. We propose a more inclusive approach to studying ADHD that includes known endophenotypes within the ADHD diagnosis. Aligned with the Research Domain Criteria Initiative, we also propose to investigate attentional capabilities and impulsive behaviours outside of the borders of the diagnosis. We support the existing hypothesis that ADHD originates from a developmental error and propose that it could lead to an accumulation in time of abnormalities in WM microstructure and pathways. Finally, state-of-the-art diffusion processing and novel artificial intelligence approaches would be beneficial to fully understand the pathophysiology of ADHD.

BACKGROUND: Prenatal exposure to persistent organic pollutants (POPs), widespread in North America, is associated with increased Attention Deficit/Hyperactivity Disorder (ADHD) symptoms and may be a modifiable risk for ADHD phenotypes. However, the effects of moderate exposure to POPs on task-based inhibitory control performance, related brain function, and ADHD-related symptoms remain unknown, limiting our ability to develop interventions targeting the neural impact of common levels of exposure. OBJECTIVES: The goal of this study was to examine the association between prenatal POP exposure and inhibitory control performance, neural correlates of inhibitory control and ADHD-related symptoms. METHODS: Prospective data was gathered in an observational study of Canadian mother-child dyads, with moderate exposure to POPs, including polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs), as part of the GESTation and the Environment (GESTE) cohort in Sherbrooke, Quebec, Canada. The sample included 87 eligible children, 46 with maternal plasma samples, functional magnetic resonance imaging (fMRI) data of Simon task performance at 9–11 years, and parental report of clinical symptoms via the Behavioral Assessment System for Children 3 (BASC-3). Simon task performance was probed via drift diffusion modeling, and parameter estimates were related to POP exposure. Simon task-based fMRI data was modeled to examine the difference in incongruent vs congruent trials in regions of interest (ROIs) identified by meta analysis. RESULTS: Of the 46 participants with complete data, 29 were male, and mean age was 10.42 ± 0.55 years. Increased POP exposure was associated with reduced accuracy (e.g. PCB molar sum rate ratio = 0.95; 95% CI [0.90, 0.99]), drift rate (e.g. for PCB molar sum β = −0.42; 95% CI [−0.77, −0.07]), and task-related brain activity (e.g. in inferior frontal cortex for PCB molar sum β = −0.35; 95% CI [−0.69, 0.02]), and increased ADHD symptoms (e.g. hyperactivity PCB molar sum β = 2.35; 95%CI [0.17, 4.53]), supporting the possibility that prenatal exposure to POPs is a modifiable risk for ADHD phenotypes. DISCUSSION: We showed that exposure to POPs is related to task-based changes in neural activity in brain regions important for inhibitory control, suggesting a biological mechanism underlying previously documented associations between POPs and neurobehavioral deficits found in ADHD phenotypes.

Evaluating in utero exposure to inorganic and multiclass organic contaminants is critical to better evaluate potential harmful effects on prenatal and postnatal development. The analysis of meconium, the first bowel discharge of the newborn, has been proposed as a non-invasive way to assess cumulative prenatal exposure. The aim of this study was to implement an analytical method for quantifying 72 targeted organic compounds, including pesticides, pharmaceutical compounds and daily life xenobiotics, in meconium in addition to selected elements (17 elements). We report initial monitoring results based on the analysis of 396 meconium samples from an Eastern Canada cohort (Quebec, Canada). Element contents in meconium were analyzed by mass spectrometry after digestion in nitric acid and peroxide. Targeted organic compounds were extracted and purified from meconium samples by a solid-liquid extraction followed by a dispersive-SPE purification before tandem mass spectrometry analysis. Concentrations of targeted elements were within the range of concentration reported in European and US studies but were lower than concentrations found in a developing country cohort (i.e., Pb, Cd). Out of the 72 targeted organic compounds, 31 were detected at least once and 30 were quantified. Compounds with the highest frequency of detection were caffeine, detected in all samples (from 2.80 to 6186 ng g(−1)), followed by acetaminophen detected in 53% of the samples (up to ~402 μg g(−1)) and methyl paraben detected in 20% of the samples (up to ~10 μg g(−1)). Pesticides were detected in low frequencies (< 2%) and low concentration (< 35 ng g(−1)). Results show that meconium can be used to monitor prenatal exposure of foetus to a wide array of inorganic and organic contaminants.

BACKGROUND AND AIM: 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...

Structured AbstractBackgroundAlthough we previously reported an association of prenatal acetaminophen exposure with more than two-fold increased odds of child ADHD, it is unknown whether prenatal acetaminophen is associated with adverse birth outcomes, and if birth outcomes may mediate the association of prenatal acetaminophen with ADHD.MethodsThis birth cohort from Sherbrooke, Québec, Canada, included 773 live births. Mothers with no thyroid disease enrolled at their first prenatal care visit or delivery. Acetaminophen was measured in meconium for 393 children at delivery. Physician diagnosis of ADHD was determined when children were 6-7 years old. We first tested associations of prenatal acetaminophen with birthweight, preterm birth, gestational age, and small and large for gestational age. Then we assessed whether these birth outcomes mediate the association of prenatal acetaminophen with ADHD. We imputed missing data via multiple imputation and used inverse probability weighting to account for confounding and selection bias.ResultsAcetaminophen was detected in 222 meconium samples (56.5%). Prenatal acetaminophen exposure was associated with decreased birthweight by 136 grams (β = -136; 95%CI [-229, - 43]), 20% increased weekly hazard of delivery (hazard ratio = 1.20; 95%CI [1.00, 1.43]), and over 60% decreased odds of being born large for gestational age (odds ratio = 0.38; 95%CI [0.20, 0.75]). There was no evidence for adverse birth outcomes mediating the association of prenatal acetaminophen with child ADHD.ConclusionsAlthough unobserved confounding and confounding by indication are possible, these results warrant further investigation into adverse perinatal effects of prenatal acetaminophen exposure.

Supplemental Digital Content is available in the text., Background: 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.

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 [β = −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.

Halogenated flame retardants (HFRs) market is continuously evolving and have moved from the extensive use of polybrominated diphenyl ether (PBDE) to more recent introduced mixtures such as Firemaster 550, Firemaster 680, DP-25, DP-35, and DP-515. These substitutes are mainly composed of non-PBDEs HFRs such as 2-ethyl-hexyl tetrabromobenzoate (TBB), bis(2-ethylhexyl) tetrabromophthalate (TBPH), 1,2-bis-(2,4,6-tribromophenoxy) ethane (BTBPE) and decabromodiphenyl ethane (DBDPE). Other HFRs commonly being monitored include Dechlorane Plus (DP), Dechlorane 602 (Dec602), Dechlorane 603 (Dec603), Dechlorane 604 (Dec604), 5,6-dibromo-1,10, 11, 12,13,13-hexachloro- 11-tricyclo[8.2.1.02,9]tridecane (HCDBCO) and 4,5,6,7-tetrabromo-1,1,3-trimethyl-3-(2,3,4,5-tetrabromophenyl)-2,3-dihydro-1H-indene (OBTMPI). This review aims at highlighting the advances in the past decade (2010–2020) on both the analytical procedures of HFRs in human bio-specimens using gas chromatography coupled with single quadrupole mass spectrometry and synthesizing the information on the levels of these HFRs in human samples. Human specimen included in this review are blood, milk, stool/meconium, hair and nail. The review summarizes the analytical methods, including extraction and clean-up techniques, used for measuring HFRs in biological samples, which are largely adopted from those for analysing PBDEs. In addition, new challenges in the analysis to include both PBDEs and a wide range of other HFRs are also discussed in this review. Review of the levels of HFRs in human samples shows that PBDEs are still the most predominant HFRs in many cases, followed by DP. However, emerging HFRs are also being detected in human despite of the fact that both their detection frequencies and levels are lower than PBDEs and DP. It is clearly demonstrated in this review that people working in the industry or living close to the industrial areas have higher HFR levels in their bodies.

Background Multiple studies have shown an association between prenatal acetaminophen exposure and attention-deficit hyperactivity disorder (ADHD), but questions remain due to a paucity of quantifia...

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 Universite de Sherbrooke in Sherbrooke, Quebec, 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.

Background: Increasing evidence suggests that high exposure to manganese (Mn) may impair brain development. In Canada, Mn exposure comes from several environmental sources and the most common is drinking water. Our objective was to examine the relationship between blood Mn and psychomotor skills in school-aged children from the Eastern Townships, Qc, Canada. In addition, we examined the association of Mn with Attention-Deficit Hyperactivity Disorder (ADHD) diagnosis in our study group.Methods: Children were recruited at birth (through their mother) and followed prospectively. At 6-7 years of age, 210 children provided a blood sample for manganese testing and underwent a battery of neuropsychological tests. This battery assessed several major cognitive domains including general intelligence, attention and others via subtests from the Wechsler Intelligence Scale for Children – IV (WISC-IV), the Developmental NEuroPSYchological Assessment-II (NEPSYII) and the Test of Everyday Attention for Children (TEACH). Parents were asked if their child had ever received a physician diagnosis of ADHD. Blood was analysed by inductively coupled plasma mass spectrometry. Multivariate statistic modelling was used to control for potential confounding factors, including blood lead.Results: Median blood Mn was 9.9 µg/L (range 4.7 – 21.4 µg/L). The Design Copying – Fine motor score of the NEPSYII was positively associated with blood Mn (linear model β: 0.17 [95% Confidence Interval: 0.03 to 0.32]; adjusted model β: 0.16 [95% Confidence Interval 0.01 to 0.30]). Blood Mn was not associated with diagnosis of ADHD. Sex-stratified analyses indicated potential effect modification by child sex such that manganese had a beneficial association on the Score DT test (a measure of sustained attention), but only among boys (β: 0.29, [95% confidence interval: 0.098 to 0.49]) Conclusions: In agreement with studies from areas with similar environmental Mn levels, our study suggests that blood Mn level does not have wide-ranging associations with cognitive functions, psychomotor skills, or a diagnosis/suspicion of ADHD in school-aged children. To resolve the controversy about toxicity of environmental Mn on the developing brain, further studies should simultaneously focus on several biomarkers of Mn exposure, potential lifestyle protective factors, as well as brain imaging.

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

In Canada, the presence of pharmaceuticals and pesticides in municipal drinking water has been examined primarily in larger urban centres which draw their supplies from surface water. However, few studies have examined this issue in smaller and rural communities, which represent nearly one-third of the Canadian population and which draw their drinking water mainly from groundwater. This study presents a regional-scale assessment of the presence of these contaminants in the drinking waters of 17 smaller rural communities, compared with two larger urban communities, in south-central Quebec. From a total of 70 chemicals examined, 15 compounds (nine pharmaceuticals and six pesticides) were detected. The three most frequently detected contaminants were caffeine, atrazine and naproxen, respectively, in 29%, 24% and 21% of the samples. Detections reported here for the first time in Quebec drinking water include the known human carcinogen cyclophosphamide and the fungicide thiabendazole. Maximum concentrations of pharmaceuticals ranged from 30 to 1,848 ng L−1 and of pesticides from 21 to 856 ng L−1. This study provides direct evidence that drinking water in smaller, rural communities of Quebec, Canada, whether sourced from groundwater or surface water, can contain measurable levels of pharmaceuticals and pesticides, indicative of their susceptibility to source contamination.This article has been made Open Access thanks to the kind support of CAWQ/ACQE (https://www.cawq.ca).

Background Folates in their role as key one carbon donors, are essential for two major pathways: the synthesis of DNA and RNA precursors and DNA methylation. A growing body of evidence from epidemiological studies indicates a possible association between nutritional and functional deficiency in folates and Autism Spectrum Disorders (ASD). However, there are no available behavioral animal studies on periconceptional one‑carbon donor deficiency during gestation and the autistic phenotype. Objective The objective of this study was to determine if the periconceptional alteration of one‑carbon metabolism induced with a folate deficient diet would affect the behaviour of rat offspring. Methods Female Wistar rats were divided in two groups: control (basal diet, in compliance with standards of regular laboratory diets), or exposed during one month before breeding until Gestational Day 15 to a modified diet with no added folic acid (0.2 mg/kg of food), reduced choline (750 mg/kg of food), and added 1% SST (a non-absorbable antibiotic used to inhibit folate synthesis by gut bacteria). We administered behavioral tests to offspring, i.e., open field (P20), social interactions (P25), marble burying (P30), elevated plus maze (P35), and prepulse inhibition of the acoustic startle reflex (sensorimotor gating) (P45). Blood homocysteine levels were used to confirm the deficit in one‑carbon donors. Results Compared to controls, offspring with the periconceptional deficit in folate showed: (i) congenital body malformations; (ii) reduced social interactions, with a ~ 30% decrease in social sniffing behavior; (iii) reduced exploration of the open arm by 50% in the elevated plus maze test, indicating increased anxiety; (iv) a ~ 160% increased number of marbles buried, indicating repetitive behaviors; and (v) altered sensorimotor gating, with a global 50% decrease in startle inhibition. Conclusion Maternal periconceptional deficit in folate provokes alterations in the behavior of offspring relevant to the autistic-like phenotype.

Three hexachloronorbornene-based flame retardants and five polybrominated diphenyl ethers (PBDEs) were measured in 414 human plasma samples, (169 from children, 167 from mothers, and 78 from fathers), collected from 200 families between 2014 and 2016. The median concentration of ∑PBDEs (sum of BDE-47, -99, −100, −153 and −183) was 13.2 ng/g lipid for child, 9.03 ng/g lipid for mother and 12.7 ng/g lipid for father, respectively. Among the hexachloronorbornene-based flame retardants, Dec 602 was the most frequently detected chemical. Significant and positive correlations between the concentrations of PBDE congeners as well as between Dec 602 and Dec 603 were observed. Concentrations of PBDE congeners also showed significant and positive correlations in paired samples from family members (child-mother-father), while Dec 602 was the only hexachloronorbornene-based flame retardant whose concentrations correlated between family members, and only in mother-father paired samples. This is the largest study to date focusing on measuring and correlating HRFs in children and their parents living in the same household. The results convey important information on human exposure to measured HFRs, which can help researchers and regulators more clearly understand the influence of diet and the home environment.

Background The PrePulse Inhibition (PPI) of the acoustic startle reflex is a neurobehavioral test frequently used in neurodevelopmental studies. Most PPI studies have used rodent models of schizophrenia; however, the currently used data analysis method does not take into account the variability present in autistic preclinical models. New method We propose a new data modelling approach for PPI data obtained from animals exposed to valproic acid or endocrine disruptors, using mixed modeling; and a new calculation of inhibition of the acoustic startle, which takes into account the habituation phenomenon. Results Habituation, or possibly exhaustion, occurred in all groups. The classic method of calculation of inhibition analysed with ANOVA indicated no group or sex effect for the overall inhibition of startle. In contrast, when analysed using mixed models, group and sex effects were observed. In addition, using the new method of calculation, both statistical analyses showed a sex effect, with females having decreased global inhibition but no group effect. ANOVA generated more false positive results for PPI in relation to prepulse intensities. Comparison with existing method The current classic method of analysis of PPI test is a calculation of inhibition based on average startle amplitude throughout the test session and a statistical ANOVA analysis. This method does not take into account habituation/exhaustion and within-subject and −group variability. Conclusions The results of this study demonstrate that use of ANOVA analysis leads to misinterpretation of PPI data in autistic preclinical models and we propose a new data analysis adapted to these models.

In previous studies, the total content of urinary phthalate metabolites was commonly used to evaluate human exposure to phthalates. However, phthalate metabolites are mainly present in urine in two forms, conjugated and free. These metabolite forms in urine are more relevant to the biotransformation pathways of the phthalates in humans. Therefore, the concentration of these forms is more relevant to exposure related health outcomes than total content. In this study, instead of measuring total content, the free- and conjugated-form concentrations of phthalate metabolites in the urine of fertile and infertile men were measured. The main metabolites in urine of both groups are monoethyl phthalate (MEP) and the di-(2-ethylhexyl) phthalate (DEHP) metabolites. The geometric means of their both conjugated- and free-forms in the infertile group were higher than in the fertile group, specifically, 24.3 and 43.4 μg/g creatinine vs 8.5 and 28.9 μg/g creatinine, respectively, for MEP, and 50.0 and 9.1 μg/g creatinine vs 39.1 and 8.4 μg/g creatinine, respectively for total DEHP metabolites. We investigated the correlations of free- and conjugated-form phthalate metabolite concentrations between the infertile and fertile group as well as among different phthalate metabolites. The results showed that there was a statistically significant difference between the infertile and fertile group for monobenzyl phthalate (MBzP) in both free-form and conjugated-form. However, there was only a statistically significant difference between the two groups for conjugated-form MEP and MEHP, and no statistically significant difference between the two groups for free-form MEP and MEHP. The results of the Pearson correlation test revealed that the correlations between DEHP metabolites and the correlations between mid-sized phthalate metabolites (mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP) and mono-benzyl phthalate (MBzP)) were stronger than between these two clusters of metabolites. This study is the first attempt to examine possible effects of conjugated-form concentrations of phthalate metabolites on human fertility. The results of this study suggest that conjugated-form and free-form concentrations of urinary phthalate metabolites may be appropriate biomarkers for assessing human exposure to phthalates and association with health outcomes.

BACKGROUND: The gut microbiome is influenced by early-life exposures, but—despite potentially enormous implications for child health—is understudied in environmental epidemiology. This pilot study is one of the first to explore in utero exposures and long-term gut microbiome profiles. We examined the association between exposure to polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) during pregnancy and the mid-childhood gut microbiome. METHODS: We measured levels of PBDE-47, −99, −100, and −153 and PCB-138, −153, and −180 in maternal plasma during early pregnancy (n=18) and at delivery (n=25) in women of European descent who breastfed the child participant of the Gestation and Environment cohort in Sherbrooke, Québec (recruited 2007–2009). Bacteria in the mid-childhood (6–8 years) fecal microbiome were detected with 16S rRNA sequencing. To test for differences at the taxon level, we used the Microbiome Comprehensive Association Mapping algorithm. RESULTS: Early pregnancy PCB-153, −180, and the sum of PCBs (Σ(3)PCB) concentrations were associated with a higher relative abundance of Propionibacteriales and Propionibacteriaceae in mid-childhood. Higher PCB-180 and Σ(3)PCB were associated with higher relative abundance of Bacillales Family XI. Higher PBDE-99 exposure was associated with a decrease in uncultured bacteria within the Ruminococcaceae NK4A214 group and PBDE-47 was associated with differences in Ruminococcus 2. These taxon-level changes did not result in differences in within- or between-subject diversity. Exposures at delivery were not associated with differences in taxa. CONCLUSIONS: Prenatal exposure to PCBs and PBDEs is associated with mid-childhood gut microbiome profiles. Larger studies are needed to confirm these results and explore health implications.

Acetaminophen is the only over-the-counter pain reliever that is not contraindicated during pregnancy, but recent studies have questioned whether acetaminophen is safe for the fetus, particularly the developing brain. This prospective birth cohort study probed the previously observed association between in utero exposure to acetaminophen and neurodevelopment by using concentrations of acetaminophen measured in meconium, which more objectively captures exposure of the fetus than maternal report. Exposure, measured by liquid chromatography coupled with tandem mass spectrometry, was categorized into nondetection, low detection, and high detection levels. At age 6–8 years, children completed a set of subtests from the Wechsler Intelligence Scale for Children, 4th edition. Additionally, this study examined potential effect modification by child sex on the association between acetaminophen exposure and neurodevelopment. In fully adjusted models, in utero exposure to acetaminophen was not statistically significantly associated with decreased scores on any of the examined subtests in all children combined (n = 118). The effect of in utero acetaminophen exposure on the Coding subtest was marginally significantly different among boys and girls, with girls performing significantly better on the task with higher levels of acetaminophen compared with girls with undetectable levels of exposure (β(girls, low) = 2.83 [0.97, 4.70], β(girls, high) = 1.95 [−0.03, 3.93], β(boys, low) = .02 [−1.78, 1.81], β(boys, high) = −.39 [−2.09, 1.31], p(interaction) = .06). Effect modification by child sex was not observed on other subtests. These results do not support prior reports of adverse neurodevelopmental effects of in utero exposure to acetaminophen.

International audience; Polybrominated diphenyl ethers (PBDEs) are known endocrine disrupting chemicals used commonly as flame retardants in everything from electronics to furniture. Exposure to PBDEs during early development has been linked to neurodevelopmental delays. Despite mounting evidence of neurological harm from PBDE exposure, the molecular mechanisms underlying these effects on brain function remain unknown. We examined the effects of perinatal exposure to BDE-47, the most biologically active and prevalent BDE congener in North America, on epigenetic patterns in the frontal lobe of Wistar rats. Dams were gavaged with BDE-47 (0.002 and 0.2 mg/kg body weight) at gestation days 9 and 16, and postnatal days 1, 8, and 15. Frontal lobes from offspring at postnatal day 41 were collected to measure 5-methylcytosine (5mC) in mitochondrial cytochrome c oxidase genes (Mt-co1,Mt-co2, and Mt-co3), global nuclear 5-hydroxymethylcytosine (5hmC) content, 5mC in repetitive elements L1Rn, and 5mC in nuclear genes (Bdnf, Crhr1, Mc2r, Nr3c1, and Snca) related to behavioral and brain functions in the nuclear genome. We observed a significant decrease in %5mC in Mt-co2 (difference from control=-0.68%, p=0.01 at the 0.2 mg/kg BDE-47). 5mC in repetitive elements L1Rn decreased at 0.002 mg/kg BDE-47 (difference=-1.23%, p=0.02). Decreased nuclear 5mC was observed in Bdnf and Nr3c1 in BDE-47 exposed rats. However, we did not observe significant effects of PBDE toxicity on DNA methylation patterns for the majority of genes in the brain.

We have examined several emerging brominated flame retardants (BFRs) including 2-ethyl-1-hexyl-2,3,4,5-tetrabromobenzoate (TBB), bis(2-ethylhexyl) tetrabromophthalate (TBPH), 1,2-bis(2,4,6-tribromophenoxy) ethane (BTBPE), 4,5,6,7-tetrabromo-1,1,3-trimethyl-3-(2,3,4,5-tetrabromophenyl)-indane (OBIND), and decabromodiphenyl ethane (DBDPE) in paired human maternal serum (n = 102) and breast milk (n = 105) collected in 2008-2009 in the Sherbrooke region in Canada. Three legacy BFRs were also included in the study for comparison: decabromobiphenyl (BB-209), 2,2',4,4',5,5'-hexabromobiphenyl (BB-153), and 2,2',4,4',5,5'-hexabromodiphenyl ethers (BDE-153). TBB, BB-153, and BDE-153 had detection frequencies greater than 55% in both serum and milk samples. Their lipid weight (lw) adjusted median concentrations (ng g(-1) lw) in serum and milk were 1.6 and 0.41 for TBB, 0.48 and 0.31 for BB-153, and 1.5 and 4.4 for BDE-153, respectively. The detection frequencies for the other BFRs measured in serum and milk were 16.7% and 32.4% for TBPH, 3.9% and 0.0% for BTBPE, 2.0% and 0.0% for BB-209, 9.8% and 1.0% for OBIND, and 5.9% and 8.6% for DBDPE. The ratio of TBB over the sum of TBB and TBPH (fTBB) in serum (0.23) was lower than that in milk (0.46), indicating TBB has a larger tendency than TBPH to be redistributed from blood to milk. Overall, these data confirm the presence of non-PBDE BFRs in humans, and the need to better understand their sources, routes of exposure, and potential human health effects.

Five hexachloronorbornene-based flame retardants, Dechlorane Plus (DP), Dechlorane 602 (Dec 602), Dechlorane 603 (Dec 603), Dechlorane 604 (Dec 604) and hexachlorocyclopentadienyl-dibromocyclooctane (HCDBCO), were measured in human milk and maternal serum. Dec 602, Dec 603 and HCDBCO were detected in both sample matrices with detection frequencies over 60%. Dec 604 was not detected in serum and only detected in 4.8% of milk samples. DP was present in over 77–87% of serum and 40–50% of milk samples. DP levels found in this study were lower than those reported in two Chinese studies. The ratio of the two DP isomers found in human samples (fanti-DP = 0.8) remained similar to the ratio reported in the DP technical mixture. Levels of Dec 602 and Dec 603 in serum were correlated. Levels of Dec 602 and HCBDCO were also correlated in serum samples as well as in milk samples. These biomonitoring results have provided baseline information about the presence of these flame retardants in nursing women in Canada, which can be used for estimating human exposure to these chemicals. Keywords: Flame retardants, Human data, Milk and serum, GC/MS

Thyroid hormones play a critical role in the growth of many organs, especially the brain. Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) interact with the thyroid pathway and may disturb neurodevelopment. This prospective study was designed to examine associations between maternal blood PBDEs and PCBs in early pregnancy and levels of thyroid hormones in maternal and umbilical-cord blood. Levels of low-brominated PBDEs, 3 PCB congeners, total and free thyroid hormones (triiodothyronine (T3) and thyroxine (T4)), thyroid-stimulating hormone, thyroid peroxidase antibodies, iodine, selenium, and mercury were measured in 380 pregnant women in the first trimester who were recruited at the University Hospital Center of Sherbrooke (Quebec, Canada) between September 2007 and December 2008. Thyroid hormone levels were also assessed at delivery and in cord blood (n = 260). Data were analyzed on both a volume basis and a lipid basis. At less than 20 weeks of pregnancy, no relationship was statistically significant in volume-based analysis. In lipid-based models, an inverse association between maternal PBDEs and total T3 and total T4 and a direct association with free T3 and free T4 were observed. At delivery, in both analyses, we observed negative associations between maternal total T4, free T3, cord-blood free T4, and PBDEs and between maternal free T3 and PCBs. Our results suggest that exposure to PBDEs and PCBs in pregnancy may interfere with thyroid hormone levels.

Background A growing body of evidence indicates that gut microbiota characteristics may be closely related to mental dysfunctions. However, no studies have investigated fetal brain development in relation to the maternal gut microbiota, despite the extensive use of antibiotics in obstetric practice. Objective To determine how periconceptional exposure to SuccinylSulfaThiazole (SST), a non-absorbable antibiotic, can affect behavior in rat offspring. This antibiotic drug has previously been shown to substantially perturb the gut microbiota in rats following a 28-day exposure. Methods Female Wistar rats were divided in two groups: control, or exposed during one month before breeding until gestational day 15 to a diet containing 1% SST. We administered behavioral tests to offspring, i.e., open field (post-natal day 20), social interactions (P25), marble burying (P30), elevated plus maze (P35), and prepulse inhibition of the acoustic startle reflex (sensory gating) (P45). Results Both male and female offspring exposed peri-conceptionally to SST showed reduced social interactions, with a decrease of about half in time spent in social interactions compared to controls, reduced exploration of the open arm by 20% in the elevated plus maze test indicating increased anxiety and altered sensorimotor gating, with a 1.5–2-fold decrease in startle inhibition. Conclusion Maternal periconceptional exposure to SST provokes alterations in offspring behavior in the absence of maternal infection. Because we administered SST, a non-absorbable antibiotic, only to the dam, we conclude that these neurobehavioral alterations in the offspring are related to maternal gut microbiota alterations.

The prevention of neurodevelopmental disorders (NDD) of prenatal origin suffers from the lack of objective tools for early detection of susceptible individuals and the long time lag, usually in years, between the neurotoxic exposure and the diagnosis of mental dysfunction. Human data on the effects of alcohol, lead, and mercury and experimental data from animals on developmental neurotoxins and their long-term behavioral effects have achieved a critical mass, leading to the concept of the Developmental Origin of Health and Disease (DOHaD). However, there is currently no way to evaluate the degree of brain damage early after birth. We propose that extracellular vesicles (EVs) and particularly exosomes, released by brain cells into the fetal blood, may offer us a non-invasive means of assessing brain damage by neurotoxins. We are inspired by the strategy applied by Alan Turing (a cryptanalyst working for the British government), who created a first computer to decrypt German intelligence communications during World War II. Given the growing evidence that microRNAs (miRNAs), which are among the molecules carried by EVs, are involved in cell-cell communication, we propose that decrypting messages from EVs can allow us to detect damage thus offering an opportunity to cure, reverse, or prevent the development of NDD. This review summarizes recent findings on miRNAs associated with selected environmental toxicants known to be involved in the pathophysiology of NDD.

Background Polybrominated diphenyl ethers are known endocrine disrupting environmental contaminants used as flame retardants. Their levels have increased in humans over the last ten years, raising concerns about their consequences on human health. Some animal studies suggest that PBDEs can affect fetal growth; however, the results of human studies are contradictory. This study evaluates the association between the most common PBDEs in maternal blood measured in early pregnancy and birth weight. Methods BDE-47, BDE-99, BDE-100 and BDE-153 levels were measured in 349 women during their first prenatal care visit at the University Hospital Center of Sherbrooke (Quebec, Canada). Birth weight and relevant medical information were collected from medical records. In contrast with previous studies, we examined the full range of clinical risk factors known to affect fetal growth as potential confounders, as well as other environmental pollutants that are likely to interact with fetal growth (polychlorinated biphenyls (PCBs), mercury, lead, cadmium and manganese). Results There was no statistically significant relationship between PBDE levels in early pregnancy and birth weight in both unadjusted and multivariate regression models. Conclusions Our results suggest that PBDEs in early pregnancy have little or no direct impact on birth weight, at least at the levels of exposure in our population. Electronic supplementary material The online version of this article (doi:10.1186/s12940-016-0134-z) contains supplementary material, which is available to authorized users.

Lantana macrophylla Schauer (Verbenaceae) a medicinal plant used to treat menstrual and respiratory disorders was investigated. The ethanolic extract from leaves was subjected to phytochemical and biological analysis. BeWo and JEG-3 cells were used to evaluate human chorionic gonadotropin hormone (hCG) production, syncytial formation, Ca2+ uptake and Ca2+ handling protein expression. The cAMP production and the mitogen-activated protein kinases (MAPKs) phosphorylation were also investigated. Phytochemical analysis yield three triterpenes: oleanolic, ursolic and latonolic acid. Viability assay showed no significant cytotoxic effect. A significant decrease in hCG production but not a disturbance on BeWo cell fusion were observed. The cAMP pathway was not affected by L. macrophylla extract alone; although the cAMP production inducted by forskolin was diminished. Both ERK1/2 and p38 MAPKs pathways were activated. Increased intracellular Ca2+ concentration ([Ca2+]i) was observed after 24 h treatment in a time and dose dependent manner; however only L. macrophylla at 10 μg/mL induced increased [Ca2+]i after 10 min treatment. CaBP28K and PMCA1/4 were modulated at protein and mRNA levels, respectively. This study showed for the first time the effect of triterpenoids from L. macrophylla leaves on trophoblasts-like cells and indicates a potential toxic effect of this plant in the placental development and fetal growth.

Flame retardant dechlorane plus (DP) and several polybrominated diphenylether (PBDE) congeners have been measured in 87 human milk samples collected in two Canadian cities: Kingston and Sherbrooke. The levels of PBDEs in human milk (mean (median), ng g−1 lipid weight=10 (5.9), 4.1 (2.8), 3.0 (1.6), 5.12 (1.6), and 15 (ND) for BDE-47, BDE-99, BDE-100, BDE-153, and BDE-209, respectively) were comparable to those reported in Europe, U.S.A. and China. The levels of DP, with a mean value of 0.98 ng g−1 and a median value of 0.60 ng g−1 (lipid weight), were two to ten times lower than those of concurrently measured major PBDEs including BDE-209. While there is little difference in the levels of measured contaminants in milk samples collected from the two cities, the contaminants levels in human milk show, indicated by Principal Components Analysis, that DP, deca-BDE, and penta-BDE come from three distinct sources. The mean and median isomer ratio values of DP in milk were 0.67 and 0.69, respectively, very similar to that of DP commercial products. Keywords: Dechlorane plus, Human milk, PBDEs, GC/MS, Environmental analysis, Biomonitoring

Key clinical message The objective of our case report was to raise awareness of the neurotoxic potential of levofloxacin in naïve patients. In patients with severe infections and comorbidities, it would be difficult to discriminate the neurotoxic effects of levofloxacin from those of the medical condition itself. Thus, health professionals should be aware of the early onset CNS effects of levofloxacin in naïve patients.

Genipa americana L. (Rubiaceae) is a fruit tree and a traditional medicine used to treat anemia, icterus, asthma, and liver and spleen problems. The aim of the present study was to verify the effect of G. americana fruit ethanolic extract on the mechanism for proliferation and differentiation of trophoblast-like cells. Qualitative analysis of G. americana fruit extract was performed, and BeWo cells, a well-established placental choriocarcinoma cell line that can undergo differentiation, were used to analyze cell viability and proliferation. Methods consisted of cytotoxic and proliferation measurement, detection of release of human chorionic gonadotrophins, cell fusion observation, and evaluation of cell-signaling pathways (production of cyclic adenosine monophosphate and phosphorylation of mitogen-activated protein kinases [MAPKs]). A stock solution of the extract was diluted in Ham's F-12 medium with 10% fetal bovine serum at concentrations ranging from 50 to 1000 μg/mL. Cells treated with dimethylsulfoxide, forskoline, and MAPK inhibitors (PD98059 or SB203580) were used as a control. Forskoline was used to induce the differentiation state in BeWo cells. Phytoanalysis indicated the presence of steroids only. Results showed that the G. americana fruit extract did not cause any cytotoxicity or interference in cell differentiation. However, a significant antiproliferative state related to inhibition and reactivation of ERK1/2 and p38 MAPK in BeWo cells was seen. These results suggest that steroids from G. americana may affect placental cell regulation.

Background Polybrominated diphenyl ethers are known to be endocrine disruptors and may affect male reproduction. This exploratory study investigated semen parameters and serum thyroid hormones in relation to serum PBDE, PCBs and p-p ′ DDE in adult men. Methods Fifty-two men were recruited in a fertility clinic. Semen counts were done for each participant. Serum thyroid hormone and PBDE, PCB and p-p ′ DDE levels were measured. Sociodemographic questionnaire were administered to each participant and all medical data were obtained from medical record. Results Semen mobility was negatively related to BDE-47, BDE-100 and ΣBDE. No relations were observed with other semen parameters. Thyroxin levels were negatively associated to serum BDE-47, BDE-99, ΣBDE and p-p ′ DDE and positively related to ΣPCB. No relations were observed between T3, TSH and any of the chemicals measured. Conclusion These findings increased the evidence that PBDE may interfere with semen quality and thyroid status in general population.

BDE-47 is the most prevalent congener of polybrominated diphenyl ethers, which are widely used flame retardants, and is known for endocrine and behavioral disrupting properties in animals. Transient effect on spontaneous motor activity in rats following perinatal exposure to BDE-47 at low doses, relevant to human exposure, was reported in our previous study. The objective of this study was to screen for the long-term effects on gene expression in the brain of rats perinatally exposed to BDE-47. Wistar dams were exposed to BDE-47 (0.002 and 0.2 mg kg−1 body weight) from gestation day 15 to postnatal day (PND) 20. Total RNA was extracted from the whole brain at PND10 and the brain frontal lobes at PND41 and hybridized to whole-genome RNA expression microarrays. The genes, differentially expressed 1.5-fold, were analyzed with the DAVID bioinformatics resources for cluster and gene-term enrichment. At PND41, clusters of genes involved in nerve impulse transmission, nervous system development and functioning, and core biosynthetic process were altered, including several downregulated genes of cation channels. Representation of LINE1 RNA was decreased significantly. Altered expression of genes involved in neurodevelopment occured at least 3 weeks after the last exposure and the behavioral manifestation of low dose BDE-47 toxicity. Copyright © 2011 John Wiley & Sons, Ltd.

Hypericum perforatum L., known as St. John's wort (SJW), is widely used in human therapeutics for wound healing and to treat depression; however, its recommendation during pregnancy is controversial. Hypericin, a polycyclic quinone isolated from this plant, has been studied and used to standardize the plant extracts. The objective of the present study was to examine the effect of SJW and hypericin on in vitro placental Ca(2+) transport. Cell viability, human chorionic gonadotrophin (hCG) production, Ca(2+) uptake, and Ca(2+) transport proteins expression analysis were conducted using the JEG-3 cell line. Toxicity of SJW was seen at high concentrations (or=150 microg/mL), but no effect on hCG production was observed using SJW (25 microg/mL) or hypericin (7.5 and 75 ng/mL). The results showed that cells treated with both SJW and hypericin exhibited increased intracellular Ca(2+) concentration after long-term (24-hour) but not short-term (10-minute) period incubation. A significant decrease in translationally controlled tumor protein Ca(2+) handling protein was seen only with SJW-treated cells. Hypericin increased the protein expression of the transient receptor potential vanilloid 6 Ca(2+) channel and 28-kDa calcium-binding protein and decreased that of plasma membrane Ca(2+)-ATPase 1/4. In conclusion, SJW and hypericin can increase the trophoblast internal Ca(2+) concentration through regulating the protein expression of the Ca(2+) transport system, and their intake during pregnancy is still a point of concern.

Preeclampsia (PE) is characterized by maternal hypertension, proteinuria, oedema and, in 30% of cases, by intrauterine growth retardation. Causes are still unknown; however, epidemiological and clinical studies have suggested alterations in maternal calcium metabolism. We suggested that in PE, calcium transport by the syncytiotrophoblast (ST) is disturbed. From total placental tissues, we studied the expression of: calcium channels (TRPV5, TRPV6 [transient receptor potential vanilloid]), calcium binding proteins (CaBP-9K, CaBP-28K), plasma membrane calcium ATPase (PMCA)1,2,3,4 pumps, ATP synthase, genes implicated in Ca2+ release [inositol-1,4,5-triphosphate receptor (IP3R)1,2,3; Ryanodine receptor (RyR)1,2,3] and replenishment (SERCA1,2,3 [sarcoendoplasmic reticulum Ca2+ ATPases]) from endoplasmic reticulum, channels implicated in mitochondrial Ca2+ accumulation (VDAC1,2,3 [voltage-dependent anion channels]) and a marker of oxidative stress (hOGG1 [Human 8-oxoguanine-DNA glycosylase 1]), as well as the influence of these variations on calcium transport in primary ST cultures. The mRNA and protein levels were thereby examined by real-time PCR and Western blot analysis, respectively, in two different groups of pregnant women with similar gestational age: a normal group (n= 16) and a PE group (n= 8), diagnosed by a clinician. Our study showed a significant decrease in calcium transport by the ST cultured from preeclamptic placentas. We found a significant (P < 0.05) decrease in mRNA levels of TRPV5, TRPV6, CaBP-9K, CaBP-28K, PMCA1, PMCA4, ATP synthase, IP3R1, IP3R2, RyR1, RyR2 and RyR3 in PE group compared to normal one. We also noted a significant decrease in protein levels of TRPV5, TRPV6, CaBP-9K, CaBP-28K and PMCA1/4 in PE group. In contrast, SERCA1, SERCA2, SERCA3, VDAC3 and hOGG1 mRNA expressions were significantly increased in PE placentas. Calcium homeostasis and transport through placenta is compromised in preeclamptic pregnancies and it appears to be affected by a lack of ATP and an excess of oxidative stress.