Socioeconomic adversity, maternal nutrition, and the prenatal programming of offspring cognition and language at two years of age through maternal inflammation.

Increasing rates of child neurodevelopmental vulnerability are a significant public health challenge. The adverse effect of socioeconomic adversity on offspring cognition may be mediated through elevated prenatal maternal systemic inflammation, but the role of modifiable antecedents such as maternal nutrition has not yet been clarified. This study aimed to examine (1) whether prenatal factors, with an emphasis on maternal nutrition, were associated with prenatal maternal systemic inflammation at 28 weeks' gestation, including the metabolomic marker glycoprotein acetyls (GlycA); (2) the extent to which the association between prenatal maternal nutrition and child cognition and language at age two years was mediated by elevated maternal inflammation in pregnancy; (3) the extent to which the associations between prenatal socioeconomic adversity and child neurodevelopment were mediated through prenatal maternal nutrition and GlycA levels. We used a prospective population-derived pre-birth longitudinal cohort study, the Barwon Infant Study (Barwon region of Victoria, Australia), where 1074 mother-child pairs were recruited by 28 weeks' gestation using an unselected sampling frame. Exposures included prenatal factors such as maternal diet measured by a validated food frequency questionnaire at 28 weeks' gestation and dietary patterns determined by principal component analysis. The main outcome measures were maternal inflammatory biomarkers (GlycA and hsCRP levels) at 28 weeks' gestation, and offspring Bayley-III cognition and language scores at age two years. Results showed that the 'modern wholefoods' and 'processed' maternal dietary patterns were independently associated with reduced and elevated maternal inflammation respectively (GlycA or hsCRP p < 0.001), and also with higher and reduced offspring Bayley-III scores respectively (cognition p ≤ 0.004, language p ≤ 0.009). Associations between dietary patterns and offspring cognition and language were partially mediated by higher maternal GlycA (indirect effect: cognition p ≤ 0.036, language p ≤ 0.05), but were less evident for hsCRP. The maternal dietary patterns mediated 22 % of the association between socioeconomic adversity (lower maternal education and/or lower household income vs otherwise) and poorer offspring cognition (indirect effect p = 0.001). Variation in prenatal GlycA levels that were independent of these dietary measures appeared less important. In conclusion, modifiable prenatal maternal dietary patterns were associated with adverse child neurocognitive outcomes through their effect on maternal inflammation (GlycA). Maternal diet may partially explain the association between socioeconomic adversity and child neurocognitive vulnerability. Maternal diet-by-inflammation pathways are an attractive target for future intervention studies.

Infant inflammation predicts childhood emotional and behavioral problems and partially mediates socioeconomic disadvantage.

BACKGROUND: Emotional and behavioral problems (EBP) are common in children. Environmental factors like socioeconomic disadvantage influence EBP pathogenesis and can trigger inflammation. However, the link between early inflammation-EBP in children is unclear. We investigated the associations between i) infant inflammatory biomarkers and subsequent EBP and ii) early life environmental factors and EBP and assessed whether infant inflammation mediated these associations. METHODS: Inflammatory biomarkers glycoprotein acetyls (GlycA) and high-sensitivity C-reactive protein (hsCRP) were quantified at birth and 12 months in a population-derived birth cohort, the Barwon Infant Study. Early life factors including demographic, prenatal, and perinatal factors were collected from antenatal to the two-year period. Internalizing and externalizing problems at age two were measured by the Child Behavior Checklist. Prospective associations were examined by multivariable regression analyses adjusted for potential confounders. Indirect effects of early life factors on EBP through inflammation were identified using mediation analyses. RESULTS: Elevated GlycA levels at birth (GlycAbirth) were associated with greater internalizing problems at age two (ß = 1.32 per SD increase in GlycA; P = 0.001). Inflammation at birth had a stronger magnitude of effect with later EBP than at 12 months. GlycAbirth partially mediated the associations between lower household income (6%), multiparity (12%) and greater number of older siblings (13%) and EBP. Patterns were less evident for hsCRP or externalizing problems. CONCLUSIONS: GlycAbirth was positively associated with EBP at age two and partially mediated the association between several indicators of socioeconomic disadvantage and EBP. Prenatal and perinatal inflammation may be relevant to early neurodevelopment and emotional health.

Maternal inflammatory and omega-3 fatty acid pathways mediate the association between socioeconomic disadvantage and childhood cognition.

Poor cognitive outcomes in early childhood predict poor educational outcomes and diminished health over the life course. We sought to investigate (i) whether maternal metabolites predict child cognition, and (ii) if maternal metabolomic profile mediates the relationship between environmental exposures and child cognition. Metabolites were measured using nuclear magnetic resonance-based metabolomics in pregnant women from a population-derived birth cohort. Child cognition was measured at age 2 years. In 662 mother-child pairs, elevated inflammatory markers (ß = -2.62; 95% CI -4.10, -1.15; P = 0.0005) and lower omega-3 fatty acid-related metabolites (ß = 0.49; 95% CI 0.09, 0.88; P = 0.02) in the mother were associated with lower child cognition and partially mediated the association between lower child cognition and multiple risk factors common to socioeconomic disadvantage. Modifying maternal prenatal metabolic pathways related to inflammation and omega-3 fatty acids may offset the adverse associations between prenatal risk factors related to socioeconomic disadvantage and low child cognition.

Shortened Infant Telomere Length Is Associated with Attention Deficit/Hyperactivity Disorder Symptoms in Children at Age Two Years: A Birth Cohort Study.

Environmental factors can accelerate telomere length (TL) attrition. Shortened TL is linked to attention deficit/hyperactivity disorder (ADHD) symptoms in school-aged children. The onset of ADHD occurs as early as preschool-age, but the TL-ADHD association in younger children is unknown. We investigated associations between infant TL and ADHD symptoms in children and assessed environmental factors as potential confounders and/or mediators of this association. Relative TL was measured by quantitative polymerase chain reaction in cord and 12-month blood in the birth cohort study, the Barwon Infant Study. Early life environmental factors collected antenatally to two years were used to measure confounding. ADHD symptoms at age two years were evaluated by the Child Behavior Checklist Attention Problems (AP) and the Attention Deficit/Hyperactivity Problems (ADHP). Associations between early life environmental factors on TL or ADHD symptoms were assessed using multivariable regression models adjusted for relevant factors. Telomere length at 12 months (TL12), but not at birth, was inversely associated with AP (ß = -0.56; 95% CI (-1.13, 0.006); p = 0.05) and ADHP (ß = -0.66; 95% CI (-1.11, -0.21); p = 0.004). Infant secondhand smoke exposure at one month was independently associated with shorter TL12 and also higher ADHD symptoms. Further work is needed to elucidate the mechanisms that influence TL attrition and early neurodevelopment.

Buy-now-pay-later: Hazards to human and planetary health from plastics production, use and waste.

More than 8 billion tonnes of plastic were produced between 1950 and 2015, that is 1 tonne for every man, woman and child on our planet. Global plastic production has been growing exponentially with an annual growth rate of 8.4% since 1950, equating to approximately 380 million tonnes per annum. A further 50 kg of plastic is now being produced for each person every year with production continuing to accelerate. Here, we discuss the human and planetary health hazards of all that plastic. We consider each step in the journey of these complex and pervasive industrial materials: from their synthesis predominantly from fossil fuel feedstocks, through an often-brief consumer use as plastic products, and onto waste streams as fuel, permanent landfill or as unmanaged waste in our environment, food, air and bodies.

Pre-school child blood lead levels in a population-derived Australian birth cohort: the Barwon Infant Study.

OBJECTIVES: To investigate blood lead levels in an Australian birth cohort of children; to identify factors associated with higher lead levels. DESIGN, SETTING: Cross-sectional study within the Barwon Infant Study, a population birth cohort study in the Barwon region of Victoria (1074 infants, recruited June 2010 - June 2013). Data were adjusted for non-participation and attrition by propensity weighting. PARTICIPANTS: Blood lead was measured in 523 of 708 children appraised in the Barwon Infant Study pre-school review (mean age, 4.2 years; SD, 0.3 years). MAIN OUTCOME MEASURE: Blood lead concentration in whole blood (µg/dL). RESULTS: The median blood lead level was 0.8 µg/dL (range, 0.2-3.7 µg/dL); the geometric mean blood lead level after propensity weighting was 0.97 µg/dL (95% CI, 0.92-1.02 µg/dL). Children in houses 50 or more years old had higher blood lead levels (adjusted mean difference [AMD], 0.13 natural log units; 95% CI, 0.02-0.24 natural log units; P = 0.020), as did children of families with lower household income (per $10 000, AMD, -0.035 natural log units; 95% CI, -0.056 to -0.013 natural log units; P = 0.002) and those living closer to Point Henry (inverse square distance relationship; P = 0.002). Associations between hygiene factors and lead levels were evident only for children living in older homes. CONCLUSION: Blood lead levels in our pre-school children were lower than in previous Australian surveys and recent surveys in areas at risk of higher exposure, and no children had levels above 5 µg/dL. Our findings support advice to manage risks related to exposure to historical lead, especially in older houses.

Early life microbial exposure, child neurocognition and behaviour at 2 years of age: A birth cohort study.

AIM: To investigate the relationship between factors which influence external microbial exposures (FEMEs), previously identified to be protective or to increase the risk of the development of allergic disease, and cognition and behaviour in infants 2 years of age in an Australian population. METHOD: The Barwon Infant Study is a birth cohort (n = 1074) in Victoria, Australia. Comprehensive questionnaire, clinical and biological measures were collected at multiple time oints. Multiple linear regression was used to evaluate the associations between 56 FEMEs and 3 outcomes; cognition (Bayley Scales of Infant and Toddler Development (BAYLEY-III)) (n = 667, mean (standard deviation) age = 2.45 (0.14) years), internalising and externalising behaviour (Child Behavior Checklist) (n = 666, mean (standard deviation) age = 2.45 (0.14) years). RESULTS: Overall, there were no consistent patterns or dose response found within an outcome nor across all three outcomes, although there was some evidence for individual associations. Breastfeeding and child care were associated with higher cognitive scores (adjusted mean difference (95% confidence interval) = 3.20 (0.23-6.17) and 0.68 (0.12-1.24), respectively), and increasing sibling number was associated with lower internalising behaviour (adjusted mean difference (95% confidence interval) = -4.13 (-6.34, -1.91)). CONCLUSION: In contrast to allergic disease, there was an absence of epidemiological evidence to support the association between these FEMEs and cognition and behaviour. Direct investigations into the relationship between exposures which influence gut-microbial composition and cognition and behaviour are now needed.

Diagnosing autism: Contemporaneous surveys of parent needs and paediatric practice.

AIM: Concurrence between parents' information needs and clinicians' practice when diagnosing autism is unknown but may influence families' uptake of management and adjustment. We aimed to compare parents' experience and preferences with paediatrician report of (i) diagnosis delivery and (ii) information given at diagnosis and identify types and usefulness of resources accessed by families post-diagnosis. METHODS: The design used for the study are parent and paediatrician surveys. Participants are parents of children aged 1.5-18 years, diagnosed with autism between 01 January 2010 and 30 September 2012 and their paediatricians who are members of the Australian Paediatric Research Network. Study-designed quantitative and qualitative questions about diagnosis delivery and information given at diagnosis (written and spoken vs. neither) and parent perceived importance and harms of information accessed post-diagnosis. RESULTS: Paediatricians (53/198 (27%)) identified 1127 eligible families, of whom 404 (36%) participated. Parents were more likely to report receiving adequate time to discuss diagnosis than paediatricians (71 vs. 51%). Parents (98%) rated information about accessing allied health professionals and the meaning of diagnosis as most important, yet paediatricians offered written or spoken information about each infrequently (allied health: 22%; diagnosis: 42%). Post-diagnosis, allied health was the most important source of information (83%). Harmful resources conveyed helplessness or non-evidenced-based therapies, but few parents (14%) reported this. CONCLUSIONS: Parents want more information than can be conveyed in a single diagnostic consultation. Developing a tailored 'autism action plan' with written materials could improve parents' understanding of and satisfaction with children's autism diagnoses.

Diagnosing autism: Australian paediatric research network surveys.

AIM: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with reported prevalence of more than 1/100. In Australia, paediatricians are often involved in diagnosing ASD and providing long-term management. However, it is not known how paediatricians diagnose ASD. This study aimed to investigate whether the way Australian paediatricians diagnose ASD is in line with current recommendations. METHODS: Members of the Australian Paediatric Research Network were invited to answer questions about their ASD diagnostic practice in a multi-topic survey and also as part of a study about parents needs around the time of a diagnosis of ASD. RESULTS: The majority of the 124 paediatricians who responded to the multi-topic survey and most who responded to the parent needs survey reported taking more than one session to make a diagnosis of ASD. Most paediatricians included information from preschool, child care or school when making a diagnosis, and over half included information from speech pathology or psychology colleagues more than 50% of the time. The main reasons for not including assessment information in the diagnostic process were service barriers such as no regular service available or long waiting lists. More than 70% reported ordering audiology and genetic tests more than half of the time. CONCLUSION: Not all paediatricians are following current recommendations for diagnosing ASD more than 50% of the time. While there are good reasons why current diagnostic approaches may fall short of expected standards, these need to be overcome to ensure diagnostic validity and optimal services for all children and their families.

Early life programming as a target for prevention of child and adolescent mental disorders.

This paper concerns future policy development and programs of research for the prevention of mental disorders based on research emerging from fetal and early life programming. The current review offers an overview of findings on pregnancy exposures such as maternal mental health, lifestyle factors, and potential teratogenic and neurotoxic exposures on child outcomes. Outcomes of interest are common child and adolescent mental disorders including hyperactive, behavioral and emotional disorders. This literature suggests that the preconception and perinatal periods offer important opportunities for the prevention of deleterious fetal exposures. As such, the perinatal period is a critical period where future mental health prevention efforts should be focused and prevention models developed. Interventions grounded in evidence-based recommendations for the perinatal period could take the form of public health, universal and more targeted interventions. If successful, such interventions are likely to have lifelong effects on (mental) health.

Chocolate frogs do not increase completion of parent survey: randomised study.

Four months into a year-long, national survey assessing parents' experiences of a child's diagnosis of autism spectrum disorder, our response fraction was only 23%. We aimed to determine whether including a chocolate incentive in the postal survey would increase the response fraction. Families enrolled between 15 March and 25 May 2012 were randomised to receive a chocolate frog versus no chocolate frog. Both groups received a written reminder and replacement survey 2 weeks after the survey was posted and up to two telephone reminders thereafter. We analysed the effect of the incentive using χ(2) tests for the categorical response variable and t-tests for the continuous reminder and length of response variables at the end of (i) randomisation and (ii) the study (1 November 2012). A total of 137 families were randomised in the 6-week period. Parents who received an incentive were more likely to return a completed survey in the 6 weeks than those who did not (21% vs. 6%, P = 0.009). This effect faded by the end of the study (53% vs. 42%, P = 0.4). There were no differences between groups at either follow-up in the number of reminders that parents received or the number of days it took parents to return the survey. Including a chocolate-based incentive does not significantly increase response rate in a postal survey over and above standard reminder techniques like posting follow-up survey packs or phoning families.

An Umbrella Review of Meta-Analyses Evaluating Associations between Human Health and Exposure to Major Classes of Plastic-Associated Chemicals.

Background: Epidemiological research investigating the impact of exposure to plastics, and plastic-associated chemicals, on human health is critical, especially given exponentially increasing plastic production. In parallel with increasing production, academic research has also increased exponentially both in terms of the primary literature and ensuing systematic reviews with meta-analysis. However, there are few overviews that capture a broad range of chemical classes to present a state of play regarding impacts on human health. Methods: We undertook an umbrella review to review the systematic reviews with meta-analyses. Given the complex composition of plastic and the large number of identified plastic-associated chemicals, it was not possible to capture all chemicals that may be present in, and migrate from, plastic materials. We therefore focussed on a defined set of key exposures related to plastics. These were microplastics, due to their ubiquity and potential for human exposure, and the polymers that form the matrix of consumer plastics. We also included plasticisers and flame retardants as the two classes of functional additive with the highest concentration ranges in plastic. In addition, we included bisphenols and per- and polyfluoroalkyl substances (PFAS) as two other major plastic-associated chemicals with significant known exposure through food contact materials. Epistemonikos and PubMed were searched for systematic reviews with meta-analyses, meta-analyses, and pooled analyses evaluating the association of plastic polymers, particles (microplastics) or any of the selected groups of high-volume plastic-associated chemicals above, measured directly in human biospecimens, with human health outcomes. Results: Fifty-two systematic reviews were included, with data contributing 759 meta-analyses. Most meta-analyses (78%) were from reviews of moderate methodological quality. Across all the publications retrieved, only a limited number of plastic-associated chemicals within each of the groups searched had been evaluated in relevant meta-analyses, and there were no meta-analyses evaluating polymers, nor microplastics. Synthesised estimates of the effects of plastic-associated chemical exposure were identified for the following health outcome categories in humans: birth, child and adult reproductive, endocrine, child neurodevelopment, nutritional, circulatory, respiratory, skin-related and cancers. Bisphenol A (BPA) is associated with decreased anoclitoral distance in infants, type 2 diabetes (T2D) in adults, insulin resistance in children and adults, polycystic ovary syndrome, obesity and hypertension in children and adults and cardiovascular disease (CVD); other bisphenols have not been evaluated. Phthalates, the only plasticisers identified, are associated with spontaneous pregnancy loss, decreased anogenital distance in boys, insulin resistance in children and adults, with additional associations between certain phthalates and decreased birth weight, T2D in adults, precocious puberty in girls, reduced sperm quality, endometriosis, adverse cognitive development and intelligence quotient (IQ) loss, adverse fine motor and psychomotor development and elevated blood pressure in children and asthma in children and adults. Polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) but not other flame retardants, and some PFAS were identified and are all associated with decreased birth weight. In general populations, PCBs are associated with T2D in adults and endometriosis, bronchitis in infants, CVD, non-Hodgkin's lymphoma (NHL) and breast cancer. In PCB-poisoned populations, exposure is associated with overall mortality, mortality from hepatic disease (men), CVD (men and women) and several cancers. PBDEs are adversely associated with children's cognitive development and IQ loss. PBDEs and certain PFAS are associated with changes in thyroid function. PFAS exposure is associated with increased body mass index (BMI) and overweight in children, attention deficit hyperactive disorder (ADHD) in girls and allergic rhinitis. Potential protective associations were found, namely abnormal pubertal timing in boys being less common with higher phthalate exposure, increased high-density lipoprotein (HDL) with exposure to mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) and reduced incidence of chronic lymphocytic lymphoma (a subtype of NHL) with PCB exposure. Conclusions: Exposure to plastic-associated chemicals is associated with adverse outcomes across a wide range of human health domains, and every plastic-associated chemical group is associated with at least one adverse health outcome. Large gaps remain for many plastic-associated chemicals. Recommendations: For research, we recommend that efforts are harmonised globally to pool resources and extend beyond the chemicals included in this umbrella review. Priorities for primary research, with ensuing systematic reviews, could include micro- and nanoplastics as well as emerging plastic-associated chemicals of concern such as bisphenol analogues and replacement plasticisers and flame retardants. With respect to chemical regulation, we propose that safety for plastic-associated chemicals in humans cannot be assumed at market entry. We therefore recommend that improved independent, systematic hazard testing for all plastic-associated chemicals is undertaken before market release of products. In addition because of the limitations of laboratory-based testing for predicting harm from plastic in humans, independent and systematic post-market bio-monitoring and epidemiological studies are essential to detect potential unforeseen harms.

Impacts associated with the plastic polymers polycarbonate, polystyrene, polyvinyl chloride, and polybutadiene across their life cycle: A review.

Polymers are the main building blocks of plastic, with the annual global production volume of fossil carbon-based polymers reaching over 457 million metric tons in 2019 and this figure is anticipated to triple by 2060. There is potential for environmental harm and adverse human health impacts associated with plastic, its constituent polymers and the chemicals therein, at all stages of the plastic life cycle, from extraction of raw materials, production and manufacturing, consumption, through to ultimate disposal and waste management. While there have been considerable research and policy efforts in identifying and mitigating the impacts associated with problematic plastic products such as single-use plastics and hazardous chemicals in plastics, with national and/or international regulations to phase out their use, plastic polymers are often overlooked. In this review, the polymer dimension of the current knowledge on environmental release, human exposure and health impacts of plastic is discussed across the plastic life cycle, including chemicals used in production and additives commonly used to achieve the properties needed for applications for which the polymers are generally used. This review focuses on polycarbonate, polystyrene, polyvinyl chloride, and polybutadiene, four common plastic polymers made from the hazardous monomers, bisphenol, styrene, vinyl chloride and 1,3-butadiene, respectively. Potential alternative polymers, chemicals, and products are considered. Our findings emphasise the need for a whole system approach to be undertaken for effective regulation of plastics whereby the impacts of plastics are assessed with respect to their constituent polymers, chemicals, and applications and across their entire life cycle.

Blueprint for the design, construction, and validation of a plastic and phthalate-minimised laboratory.

Micro and nanosized plastics (MNPs), and a range of associated additive chemicals, have become pervasive contaminants that humans and the environment are exposed to everyday. However, one of the principal challenges in their analysis is adequate strategies to minimise background contamination. Here a blueprint for a specialised plastics and additive-minimised clean room laboratory built for this purpose is presented. Common laboratory construction materials (n = 23) were tested, including acoustic baffles, ceiling materials, floor materials, glazing rubber, and silicone sealant. The % polymer content ranged from 2-76% w/w while the sum concentration of six phthalates ranged from 0.81 (0.73-0.86) to 21000 (15000-27000) mg/kg, assigning many of these materials as inappropriate for use in a clean room environment. The final design of the laboratory consisted of three interconnected rooms, operated under positive pressure with the inner rooms constructed almost entirely of stainless steel. Background concentrations of MNPs and phthalates in the new laboratory were compared to two Physical Containment Level 2 (PC2) laboratory environments, with concentrations of MNPs reduced by > 100 times and phthalates reduced by up to 120 times. This study reports the first known clean room of its kind and provides a blueprint for reference and use by future plastics research.

Genome-Wide Analyses of Vocabulary Size in Infancy and Toddlerhood: Associations With Attention-Deficit/Hyperactivity Disorder, Literacy, and Cognition-Related Traits.

BACKGROUND: The number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors. Here, we performed a meta-genome-wide association study of vocabulary acquisition and investigated polygenic overlap with literacy, cognition, developmental phenotypes, and neurodevelopmental conditions, including attention-deficit/hyperactivity disorder (ADHD). METHODS: We studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 children of European descent. Meta-analyses were performed for early-phase expressive (infancy, 15-18 months), late-phase expressive (toddlerhood, 24-38 months), and late-phase receptive (toddlerhood, 24-38 months) vocabulary. Subsequently, we estimated single nucleotide polymorphism-based heritability (SNP-h2) and genetic correlations (rg) and modeled underlying factor structures with multivariate models. RESULTS: Early-life vocabulary size was modestly heritable (SNP-h2 = 0.08-0.24). Genetic overlap between infant expressive and toddler receptive vocabulary was negligible (rg = 0.07), although each measure was moderately related to toddler expressive vocabulary (rg = 0.69 and rg = 0.67, respectively), suggesting a multifactorial genetic architecture. Both infant and toddler expressive vocabulary were genetically linked to literacy (e.g., spelling: rg = 0.58 and rg = 0.79, respectively), underlining genetic similarity. However, a genetic association of early-life vocabulary with educational attainment and intelligence emerged only during toddlerhood (e.g., receptive vocabulary and intelligence: rg = 0.36). Increased ADHD risk was genetically associated with larger infant expressive vocabulary (rg = 0.23). Multivariate genetic models in the ALSPAC (Avon Longitudinal Study of Parents and Children) cohort confirmed this finding for ADHD symptoms (e.g., at age 13; rg = 0.54) but showed that the association effect reversed for toddler receptive vocabulary (rg = -0.74), highlighting developmental heterogeneity. CONCLUSIONS: The genetic architecture of early-life vocabulary changes during development, shaping polygenic association patterns with later-life ADHD, literacy, and cognition-related traits.

Male autism spectrum disorder is linked to brain aromatase disruption by prenatal BPA in multimodal investigations and 10HDA ameliorates the related mouse phenotype.

Male sex, early life chemical exposure and the brain aromatase enzyme have been implicated in autism spectrum disorder (ASD). In the Barwon Infant Study birth cohort (n = 1074), higher prenatal maternal bisphenol A (BPA) levels are associated with higher ASD symptoms at age 2 and diagnosis at age 9 only in males with low aromatase genetic pathway activity scores. Higher prenatal BPA levels are predictive of higher cord blood methylation across the CYP19A1 brain promoter I.f region (P = 0.009) and aromatase gene methylation mediates (P = 0.01) the link between higher prenatal BPA and brain-derived neurotrophic factor methylation, with independent cohort replication. BPA suppressed aromatase expression in vitro and in vivo. Male mice exposed to mid-gestation BPA or with aromatase knockout have ASD-like behaviors with structural and functional brain changes. 10-hydroxy-2-decenoic acid (10HDA), an estrogenic fatty acid alleviated these features and reversed detrimental neurodevelopmental gene expression. Here we demonstrate that prenatal BPA exposure is associated with impaired brain aromatase function and ASD-related behaviors and brain abnormalities in males that may be reversible through postnatal 10HDA intervention.

Increased maternal non-oxidative energy metabolism mediates association between prenatal di-(2-ethylhexyl) phthalate (DEHP) exposure and offspring autism spectrum disorder symptoms in early life: A birth cohort study.

Prenatal phthalate exposure has previously been linked to the development of autism spectrum disorder (ASD). However, the underlying biological mechanisms remain unclear. We investigated whether maternal and child central carbon metabolism is involved as part of the Barwon Infant Study (BIS), a population-based birth cohort of 1,074 Australian children. We estimated phthalate daily intakes using third-trimester urinary phthalate metabolite concentrations and other relevant indices. The metabolome of maternal serum in the third trimester, cord serum at birth and child plasma at 1 year were measured by nuclear magnetic resonance. We used the Small Molecule Pathway Database and principal component analysis to construct composite metabolite scores reflecting metabolic pathways. ASD symptoms at 2 and 4 years were measured in 596 and 674 children by subscales of the Child Behavior Checklist and the Strengths and Difficulties Questionnaire, respectively. Multivariable linear regression analyses demonstrated (i) prospective associations between higher prenatal di-(2-ethylhexyl) phthalate (DEHP) levels and upregulation of maternal non-oxidative energy metabolism pathways, and (ii) prospective associations between upregulation of these pathways and increased offspring ASD symptoms at 2 and 4 years of age. Counterfactual mediation analyses indicated that part of the mechanism by which higher prenatal DEHP exposure influences the development of ASD symptoms in early childhood is through a maternal metabolic shift in pregnancy towards non-oxidative energy pathways, which are inefficient compared to oxidative metabolism. These results highlight the importance of the prenatal period and suggest that further investigation of maternal energy metabolism as a molecular mediator of the adverse impact of prenatal environmental exposures such as phthalates is warranted.

The plastic health map: A systematic evidence map of human health studies on plastic-associated chemicals.

BACKGROUND: The global production and use of plastic materials has increased dramatically since the 1960s and there is increasing evidence of human health impacts related to exposure to plastic-associated chemicals. There is, however, no comprehensive, regulatory, post-market monitoring for human health effects of plastic-associated chemicals or particles and it is unclear how many of these have been investigated for effects in humans, and therefore what the knowledge gaps are. OBJECTIVE: To create a systematic evidence map of peer-reviewed human studies investigating the potential effects of exposure to plastic-associated particles/chemicals on health to identify research gaps and provide recommendations for future research and regulation policy. METHODS: Medline and Embase databases were used to identify peer-reviewed primary human studies published in English from Jan 1960 - Jan 2022 that investigated relationships between exposures to included plastic-associated particles/chemicals measured and detected in bio-samples and human health outcomes. Plastic-associated particles/chemicals included are: micro and nanoplastics, due to their widespread occurrence and potential for human exposure; polymers, the main building blocks of plastic; plasticizers and flame retardants, the two most common types of plastic additives with the highest concentration ranges in plastic materials; and bisphenols and per- or polyfluoroalkyl substances, two chemical classes of known health concern that are common in plastics. We extracted metadata on the population and study characteristics (country, intergenerational, sex, age, general/special exposure risk status, study design), exposure (plastic-associated particle/chemical, multiple exposures), and health outcome measures (biochemical, physiological, and/or clinical), from which we produced the interactive database 'Plastic Health Map' and a narrative summary. RESULTS: We identified 100,949 unique articles, of which 3,587 met our inclusion criteria and were used to create a systematic evidence map. The Plastic Health Map with extracted metadata from included studies are freely available at https://osf.io/fhw7d/ and summary tables, plots and overall observations are included in this report. CONCLUSIONS: We present the first evidence map compiling human health research on a wide range of plastic-associated chemicals from several different chemical classes, in order to provide stakeholders, including researchers, regulators, and concerned individuals, with an efficient way to access published literature on the matter and determine knowledge gaps. We also provide examples of data clusters to facilitate systematic reviews and research gaps to help direct future research efforts. Extensive gaps are identified in the breadth of populations, exposures and outcomes addressed in studies of potential human health effects of plastic-associated chemicals. No studies of the human health effects of micro and/or nanoplastics were found, and no studies were found for 26/1,202 additives included in our search that are of known hazard concern and confirmed to be in active production. Few studies have addressed recent "substitution" chemicals for restricted additives such as organophosphate flame retardants, phthalate substitutes, and bisphenol analogues. We call for a paradigm shift in chemical regulation whereby new plastic chemicals are rigorously tested for safety before being introduced in consumer products, with ongoing post-introduction biomonitoring of their levels in humans and health effects throughout individuals' life span, including in old age and across generations.