White matter microstructural variability linked to differential attentional skills and impulsive behavior in a pediatric population.

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.

Establishing non-fasting reference values for plasma lipids levels based on age, sex, and puberty stage in a French-Canadian pediatric population.

BACKGROUND: Dyslipidemias, including familial hypercholesterolemia (FH), are a significant risk factor for cardiovascular diseases. FH is a genetic disorder resulting in elevated levels of low-density lipoprotein cholesterol (LDL-C) and an increased probability of early cardiovascular disorders. Heterozygous familial hypercholesterolemia (HeFH) is the most common form, affecting approximately 1 in 250 individuals worldwide, with a higher prevalence among the French-Canadian population. Childhood is a critical period for screening risk factors, but the recommendation for non-fasting screening remains controversial due to a lack of specific reference values for this state. This study aims to establish reference values for lipid levels in non-fasting children from Sherbrooke, Quebec, Canada, that will be specific for sex, age, and pubertal stages. METHODS: Blood samples and corresponding anthropometric data were collected from 356 healthy children aged from 6 to 13. They were categorized either into two age groups: Cohort 6-8 and Cohort 9-13, or into pubertal stages. Reference values, specifically the 2.5th, 5th, 10th, 50th, 90th, 95th, and 97.5th percentiles were determined using the CLSI C28-A3 guidelines. RESULTS: Lipid profiles did not significantly differ between sexes, except for higher levels of high-density lipoprotein (HDL-C) in boys within Cohort 6-8. HDL-C levels significantly increased, while LDL-C and non-HDL-C levels significantly decreased in both sexes with age. Non-fasting age- and pubertal stages-specific reference values were established. CONCLUSION: This study established reference intervals for lipid markers in non-fasting state within the pediatric French-Canadian population. These findings could be used in dyslipidemia screening in daily practice.

Characterization of childhood exposure to environmental contaminants using stool in a semi-urban middle-class cohort from eastern Canada.

Children are exposed to various environmental organic and inorganic contaminants with effects on health outcomes still largely unknown. Many matrices (e.g., blood, urine, nail, hair) have been used to characterize exposure to organic and inorganic contaminants. The sampling of feces presents several advantages; it is non-invasive and provides a direct evaluation of the gut microbiome exposure to contaminants. The gut microbiome is a key factor in neurological development through the brain-gut axis. Its composition and disturbances can affect the neurodevelopment of children. Characterization of children exposure to contaminants is often performed on vulnerable populations (e.g., from developing countries, low-income neighborhoods, and large urban centers). Data on the exposure of children from middle-class, semi-urban, and mid-size populations to contaminants is scarce despite representing a significant fraction of the population in North America. In this study, 73 organics compounds from different chemical classes and 22 elements were analyzed in 6 years old (n = 84) and 10 years old (n = 119) children's feces from a middle-class, semi-urban, mid-size population cohort from Eastern Canada. Results show that 67 out of 73 targeted organics compounds and all elements were at least detected in one child's feces. Only caffeine (97% & 80%) and acetaminophen (28% & 48%) were detected in more than 25% of the children's feces, whereas all elements besides titanium were detected in more than 50% of the children.

The relationship between persistent organic pollutants and Attention Deficit Hyperactivity Disorder phenotypes: Evidence from task-based neural activity in an observational study of a community sample of Canadian mother-child dyads.

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 ß = -0.42; 95% CI [-0.77, -0.07]), and task-related brain activity (e.g. in inferior frontal cortex for PCB molar sum ß = -0.35; 95% CI [-0.69, -0.02]), and increased ADHD symptoms (e.g. hyperactivity PCB molar sum ß = 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.

Learning from Sisyphus: time to rethink our current, ineffective strategy on neurodevelopmental environmental toxicants.

BACKGROUND: The overwhelming number of potentially toxic chemicals in consumer products and in our daily environment makes it unrealistic to carry out in-depth analyses of each product with the objective of banning and eliminating toxic chemicals from our environment. OBJECTIVES: To present the challenges that environmental toxicology and epidemiology are currently facing in the context of ubiquitous chemical pollution. DISCUSSION: We propose a realistic and pragmatic approach to this Herculean problem.

Monitoring of prenatal exposure to organic and inorganic contaminants using meconium from an Eastern Canada cohort.

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 analysed 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.

Maternal levels of endocrine disruptors, polybrominated diphenyl ethers, in early pregnancy are not associated with lower birth weight in the Canadian birth cohort GESTE.

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.

Measurements of selected brominated flame retardants in nursing women: implications for human exposure.

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.

Indoor environment, physiological factors, and diet as predictors of halogenated flame retardant levels in stool and plasma of children from a Canadian cohort.

Exposure to halogenated flame retardants (HFRs) has been associated with various adverse effects on human health. Human exposure to HFRs mainly occurs through diet, ingesting contaminated dust, and inhaling contaminated air. Understanding and characterizing the variables linked to these exposure pathways is essential for developing effective risk assessment and mitigation strategies. We investigated indoor environment quality, physiological factors, and diet as potential predictors of HFRs concentration in children's plasma and stool. A selected number of HFRs, including polybrominated diphenyl ethers (PBDEs), Dechlorane-like compounds, and emerging halogenated flame retardants, were measured in children from eastern Quebec (Canada). Information on indoor environment quality, physiological factors, and diet was obtained through self-report questionnaires. Our results show that lower brominated compounds, which are more volatile, were primarily correlated to indoor environment quality. Notably, the use of air purifiers was associated with lower BDE47 and BDE100 levels in blood and newer residential buildings were associated with higher concentrations of BDE47. A significant seasonal variation was found in stool samples, with higher levels of lower brominated PBDEs (BDE47 and BDE100) in samples collected during summer. No association between household income or maternal education degree and HFRs was found. Among emerging compounds, Dec602 and Dec603 were associated with the most variables, including the use of air dehumidifiers, air conditioning, and air purifiers, and the child's age and body fat percentage.

Maternal and cord-blood thyroid hormone levels and exposure to polybrominated diphenyl ethers and polychlorinated biphenyls during early pregnancy.

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.

Complementarity of plasma and stool for the characterization of children's exposure to halogenated flame retardants: Update on analytical methods and application to a Canadian cohort.

Sixteen halogenated flame retardants including Polybrominated diphenyl ethers (PBDEs), Dechlorane-like compounds, and emerging halogenated flame retardants were measured in stool and plasma samples from children aged 8.9-13.8 years old. Samples were obtained from a Canadian cohort investigating the effect of contaminants on children's neurodevelopment in the Estrie region, Québec, Canada. The method for stool analysis developed for this study showed good recovery for all targeted compounds (73%-93%) with associated relative standard deviation (RSD) in the range of 16.0%-30.7% for most compounds except for the thermosensitive BDE209, OBTMBI, and BTBPE, which showed slightly higher RSD, i.e., 49.3%, 37.2%, and 34.9% respectively. Complementarity investigation of stool and blood samples allowed us to better characterize human exposure to these halogenated flame retardants. Exposure patterns differed significantly between stool and blood, notably in the relative abundance of BDE47, BDE100, BDE99, and BDE153 and the detection frequencies of BDE209, syn-DP, anti-DP, and DBDPE. There was no correlation between the two matrices' PBDEs concentration levels except for BDE153 (rho = 0.44, p < 0.01). Our results indicate that future epidemiological studies may benefit from the use of stool as a complementary matrix to blood, especially investigations into chemical impacts on the gut microbiome. Results also revealed that children from the GESTE cohort, an Eastern Canadian semi-rural cohort, are exposed to both historical and emergent flame retardants.

Better characterization of attention and hyperactivity/impulsivity in children with ADHD: The key to understanding the underlying white matter microstructure.

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.

Association of Prenatal Acetaminophen Exposure Measured in Meconium With Adverse Birth Outcomes in a Canadian Birth Cohort.

Background: The small number of studies examining the association of prenatal acetaminophen with birth outcomes have all relied on maternal self-report. It remains unknown whether prenatal acetaminophen exposure measured in a biological specimen is associated with birth outcomes. Objectives: To investigate the association of acetaminophen measured in meconium with birthweight, gestational age, preterm birth, size for gestational age, gestational diabetes, preeclampsia, and high blood pressure. Methods: This birth cohort from Sherbrooke, QC, 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. We tested associations of prenatal acetaminophen with birthweight, preterm birth, gestational age, small and large for gestational age, gestational diabetes, preeclampsia, and high blood pressure. We imputed missing data via multiple imputation and used inverse probability weighting to account for confounding and selection bias. Results: Acetaminophen was detected in 222 meconium samples (56.5%). Prenatal acetaminophen exposure was associated with decreased birthweight by 136 g (ß = -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]). Prenatal acetaminophen was not associated with small for gestational age, preterm birth, or any pregnancy complications. Conclusion: Prenatal acetaminophen was associated with adverse birth outcomes. Although unobserved confounding and confounding by indication are possible, these results warrant further investigation into adverse perinatal effects of prenatal acetaminophen exposure.

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.

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.

Delayed response in the rat frontal lobe transcriptome to perinatal exposure to the flame retardant BDE-47.

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.

Does 2,2',4,4'-tetrabromodiphenyl ether interact directly with thyroid receptor?

2,2',4,4'-Tetrabromodiphenyl ether (BDE-47) is a flame-retardant chemical appearing at increasing concentrations and frequency in the environment and human samples. A number of health effects of exposure to BDE-47 have been observed, thyroid disruption being the most sensitive. Our objective was to examine BDE-47 interaction with thyroid receptor beta (TRß). We used a variety of approaches, including in vitro binding assays, luciferase reporter-gene transcriptional assays, and analysis of expression of thyroid responsive genes in rat offspring exposed perinatally to BDE-47. We found that BDE-47 alone or in mixture with 2,2',4,4',5-pentabromodiphenyl ether (BDE-99), 2,2',4,4',6-pentabromodiphenyl ether (BDE-100), and 2,2',4,4',5,5'-hexabromodiphenyl ether (BDE-153) does not compete with [(125)I]T(3) for TRß-binding even at 4000 fold higher concentrations. Also, BDE-47 does not affect thyroid responsive genes through TRß in in vitro studies of transcription regulation. A subset of thyroid responsive genes were significantly differentially expressed in liver and frontal lobe brain samples of exposed pups, however, the action of BDE-47 was neither agonistic or antagonistic to that of thyroid hormone. We conclude that BDE-47 does not interact directly with TRß1 nor does it influence its transcriptional activity. Developmental exposure of rats to BDE-47 leads to differential expression of thyroid responsive genes in liver and brain due to unknown mechanism.

A review on the analytical procedures of halogenated flame retardants by gas chromatography coupled with single quadrupole mass spectrometry and their levels in human samples.

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.

In Utero Exposure to Persistent Organic Pollutants and Childhood Lipid Levels.

Animal studies have shown that developmental exposures to polybrominated diphenyl ethers (PBDE) permanently affect blood/liver balance of lipids. No human study has evaluated associations between in utero exposures to persistent organic pollutants (POPs) and later life lipid metabolism. In this pilot, maternal plasma levels of PBDEs (BDE-47, BDE-99, BDE-100, and BDE-153) and polychlorinated biphenyls (PCB-138, PCB-153, and PCB-180) were determined at delivery in participants of GESTation and Environment (GESTE) cohort. Total cholesterol (TCh), triglycerides (TG), low- and high-density lipoproteins (LDL-C and HDL-C), total lipids (TL), and PBDEs were determined in serum of 147 children at ages 6-7. General linear regression was used to estimate the relationship between maternal POPs and child lipid levels with adjustment for potential confounders, and adjustment for childhood POPs. In utero BDE-99 was associated with lower childhood levels of TG (p = 0.003), and non-significantly with HDL-C (p = 0.06) and TL (p = 0.07). Maternal PCB-138 was associated with lower childhood levels of TG (p = 0.04), LDL-C (p = 0.04), and TL (p = 0.02). Our data indicate that in utero exposures to POPs may be associated with long lasting decrease in circulating lipids in children, suggesting increased lipid accumulation in the liver, a mechanism involved in NAFLD development, consistent with previously reported animal data.

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.