Effects Of Prenatal Exposure Research Articles

Assessment of embryo morphology following perinatal exposure to aspirin, ibuprofen and paracetamol using whole embryo culture system

Background Recent evidence from a meta-analysis indicates that maternal prenatal exposure, single or repeated, to non-steroidal anti-inflammatory drugs (NSAIDs) or non-opioid painkillers, is associated with increased risk of cerebral palsy and cognitive-behavioral disorders in offspring. One potential route of action is interference with the neurulation process and hence early brain development. Objective To examine the effect of prenatal exposure to common NSAIDs and non-opioid drugs on neurulation using an in vitro whole embryo culture system. Methods Mouse embryos from in-bred Institute of Cancer Research albino strain mice were exteriorized on embryonic day 7.5 and cultured for 48 h in either 1 mL heat-inactivated rat serum + 0.1% dimethyl sulfoxide (“Control”) or 1 mL of rat serum supplemented with six increasing concentrations of laboratory-grade aspirin, paracetamol, and ibuprofen (“Experimental”). After culture, embryo morphological and developmental parameters were documented using standardized scoring systems at each dosage concentration. The assessed concentration in rat serum culture ranged from 1.23 to 13.57 mg/mL for aspirin and 0.06–4.93 mg/mL for paracetamol and ibuprofen. The equivalent respective human dosages were 600–6600 mg and 30–2400 mg. Results Between-group comparisons (“Control” vs “Experimental”) and post-hoc pair-wise tests, adjusted for multiple comparisons, indicating no statistically significant effect on crown-rump length (p > .21), head length (p > .28), somite number (p > .25), incidence of absent hindlimb buds (p > .18), yolk sac circulation score (p > .07) and posterior neuropore closure (p > .35) in the aspirin, paracetamol and ibuprofen experiments. All embryos had forelimb buds, closed anterior neuropores and none had neural tube defects. Conclusion This study has demonstrated that there are no safety concerns regarding high-dose aspirin, ibuprofen, and paracetamol on mice’s embryonic development.

Prenatal exposure to air pollution and the risk of macrosomia: Identifying windows of susceptibility

This study explores the effects of prenatal exposure to air pollution on the risk of macrosomia and its window of susceptibility.We conducted a retrospective cohort study utilizing records of birth certificates for all full-term live newborns born in Xi'an city, China from January 1, 2015, to December 31, 2018.Weekly- and trimester-specific exposures of PM2.5, PM10, NO2, and O3 during pregnancy were calculated by inverse distance weighting (IDW) based on their residences. Cox proportional hazard model and distributed lag models (DLMs) were performed to estimate the effects of air pollution exposure during pregnancy on macrosomia risk and its window of susceptibility.In total, 318,323 full-term newborns were identified, including 24,996 (7.8%) cases of macrosomia. An IQR increase in PM2.5 exposure (45.46 μg/m3) from the 33rd until the 37th weeks of gestation was positively associated with an elevated risk of macrosomia, with the strongest effect in the 37th weeks (HR = 1.007, 95%CI: 1.002–1.013). The window of susceptibility for NO2 exposure on macrosomia risk was in the 29th–35th gestational weeks, with the strongest effect in the 34th weeks (IQR = 21.96 μg/m3, HR = 1.006, 95%CI:1.000–1.013). For prenatal exposure to O3, 5th–24th weeks of gestation was identified as susceptible windows for elevated risk of macrosomia, with the strongest associations observed in the 15th weeks (IQR = 80.53 μg/m3, HR = 1.022, 95%CI: 1.011–1.033). However, we did not observe any associations between weekly exposure of PM10 and macrosomia.Our findings imply that the windows of susceptibility to PM2.5 and NO2 exposure on macrosomia are mainly in late pregnancy, whereas the windows of susceptibility to O3 exposure are in early and middle pregnancy.

Effects of prenatal exposure to abnormal rainfall on cognitive development in Vietnam

Effects of prenatal exposure to abnormal rainfall on cognitive development in Vietnam

Effects of Prenatal Electronic Cigarette Exposure On Foetal Development: a Review of the Literature.

Since their market launch in 2007, e-cigarettes gained popularity and were considered a relatively safe alternative to traditional cigarettes. Pregnant women and women of childbearing age in particular are increasingly turning to e-cigarettes. Little is known about the effects of prenatal exposure on the affected foetus. This paper aims to provide an overview of the current research on the effects of prenatal e-cigarette exposure on the foetus. Since studies in humans are lacking to date, this review refers only to animal and in vitro analyses. The PubMed and Web of Science databases were used for an extensive literature search. The search yielded N = 17 significant research papers. Possible sequelae resulting from prenatal exposure to traditional cigarettes were also seen in prenatal exposure to e-cigarettes. Prenatal e-cigarette exposure was found to be associated with increased DNA methylation overall, resulting in lower gene expression. This could adversely impact the development of affected children, especially in case of those genes relevant to their development. In mice, for example, this greatly reduced the cell vitality of neural and stem cells and increased cell death. Further, prenatal exposure to e-cigarettes resulted in numerous developmental disorders, such as malformations of facial morphology and lower birth weight. Moreover, in animal models the animals suffered from a deterioration of their short-term memory. Activity and cognitive flexibility increased, while anxiety behaviour decreased. It is clear that more research and especially studies of humans are needed on this issue. In addition, there is a need for more intense education of prenatal care professionals as well as women of childbearing age and during pregnancy.

Associations between a mixture of phenols and phthalates and child behaviour in a French mother-child cohort with repeated assessment of exposure.

Synthetic phenols and phthalates can interfere with biological pathways involved in brain development. Despite the high within-subject temporal variability of urinary concentrations observed for their metabolites, studies investigating effects of phenols and phthalates on child behaviour often relied on a limited number of spot biospecimens to assess exposure. Besides, the majority did not consider mixture effects. To study the combined effect of prenatal exposure to synthetic phenols and phthalates on child behaviour using repeated exposure measurements. We assessed concentrations of 12 phenols, 13 phthalate and 2 non-phthalate plasticizer metabolites in within-subject pools of multiple urine samples (median=21 samples per individual pool) collected at two distinct time points during pregnancy in 416 mother-child pairs from the French SEPAGES cohort. Child behaviour was evaluated at two years using the Child Behaviour Checklist 1.5-5 (CBCL). Associations between a mixture of biomarkers of exposure and externalizing and internalizing behaviour scores were studied using adjusted Weighted Quantile Sum (WQS) regressions with a repeated holdout validation (100 repetitions). The positive WQS indexes were associated with both the externalizing and internalizing behaviour scores in the whole population, indicating greater risk of behavioural problems. Stratification for child sex suggested stronger associations in girls than boys. On average, girls externalizing and internalizing scores increased by 3.67 points (95% CI: 1.24, 6.10) and 2.47 points (95%CI: 0.60, 4.33) respectively, for an increase of one tertile in the WQS index, compared with 1.70 points (95%CI: -0.42, 3.81) and 1.17 points (95%CI: -0.50, 2.84) in boys. Main contributors for the associations observed in girls were bisphenol A (weight of 18%), triclosan (17%) and monoethyl phthalate (MEP, 15%) for the externalizing score and MEP (19%), mono-benzyl phthalate (MBzP, 19%) and mono-n-butyl phthalate (MnBP, 16%) for the internalizing score. Our results suggest adverse associations between in utero exposure to a mixture of phenols and phthalates and child behaviour, mainly in girls. Public health consequences may be substantial due to the widespread exposure of the population to these compounds.

The sex-specific association of prenatal phthalate exposure with low birth weight and small for gestational age: A nationwide survey by the Taiwan Maternal and Infant Cohort Study (TMICS)

The Taiwan Maternal and Infant Cohort Study (TMICS) was launched with the aim to assess the effects of prenatal exposure to phthalic acid esters (PAEs) on infant health. A total of 1102 pregnant women were enrolled in this study from 2012 to 2015. All participants completed a structured questionnaire, and provided urine specimens. The urinary concentrations of PAE metabolites in the third trimester were measured using liquid chromatography-electrospray ionization tandem mass spectrometry. Generalized additive model-penalized regression splines and logistic regression models were employed to determine the risk for low birth weight (LBW) or small for gestational age (SGA) among pregnant women exposed to PAEs. After adjustments for other covariates, each incremental unit of ln-transformed mono-n-butyl phthalate (MnBP) for pregnant women increased the odds of SGA in male neonates by 1.44 (95% CI: 0.92–2.23). An inverse association between SGA and maternal MnBP exposure level was observed in female neonates. An increase in one ln-transformed MnBP concentration unit decreased the risk of female SGA to 0.50 (95% CI: 0.24–0.97). In the penalized regression splines, increased risks of LBW/SGA in male neonates were presented while pregnant women exposed to increased MnBP levels. However, an association in the opposite direction was observed between maternal MnBP and LBW or SGA for male and female neonates.This study indicated that high maternal MnBP exposure in the third trimester was associated with LBW or SGA for male infants. Adverse effects on susceptible populations exposed to high levels of PAEs should be of concern.

Antioxidant effect of vitamin E on diphenylamine-induced hepato-renal oxidative stress and structural changes in rat fetuses

To date, studies on the effects of prenatal exposure to diphenylamine on developing fetuses are sparse. Therefore, further investigation is required to determine the potential prenatal hazard of this compound and to introduce possible treatment for these hazards. This study aimed to assess the biochemical, histopathological, and ultrastructural changes induced by diphenylamine in the developing liver and kidney of rat fetuses and the role of vitamin E in alleviating these changes. Fifty pregnant rats were divided equally into five groups, the group I was administrated distilled water, group II was administrated corn oil, group III was administrated 100 mg/kg/b.wt. vitamin E, group IV was administrated approximately 400 mg/kg/b.wt diphenylamine and group V was administrated diphenylamine + vitamin E at the above-mentioned doses from the 6th to 15th day of pregnancy. Diphenylamine induced undesirable histopathological and ultrastructural changes in the fetal liver and kidney. These changes were in the form of vacuolation, congestions of central veins, hemorrhage, leucocytic infiltration, degenerated cytoplasm, pyknotic nuclei, and swollen mitochondria and rER of hepatocytes. While the degenerative changes in the kidney were represented by degenerated brush border, lumen dilation, tubular hyalinization, vacuolation, degenerated nuclei, and mitochondria. Also, there was a significant decrease in the antioxidant enzymes i.e., superoxide dismutase and catalase, and a significant increase in reactive oxygen radicals and malondialdehyde. Treatment with vitamins E after diphenylamine restored all biochemical, histopathological, and ultrastructural damage cited above. In conclusion, vitamin E has antioxidant effects which could be able to antagonize diphenylamine prenatal toxicity.

Effects of Prenatal Exposure to Titanium Dioxide Nanoparticles on DNA Methylation and Gene Expression Profile in the Mouse Brain.

Background and Objectives: Titanium dioxide nanoparticles (TiO2-NP) are important materials used in commercial practice. Reportedly, TiO2-NP exposure during pregnancy can affect the development of the central nervous system in mouse offspring; however, the underlying mechanism remains unknown. In the present study, we investigated the impact of prenatal TiO2-NP exposure on global DNA methylation and mRNA expression patterns in the brains of neonatal mice. Materials and Methods: Pregnant C57BL/6J mice were intratracheally administered a TiO2-NP suspension (100 μg/mouse) on gestational day 10.5, and brains were collected from male and female offspring at day 1 postpartum. After extraction of methylated DNA by immunoprecipitation, the DNA methylation profile was analyzed using a mouse CpG island microarray. Total RNA was obtained, and mRNA expression profiles were comprehensively assessed using microarray analysis. Results: Among genes in the CpG island microarray, DNA methylation was increased in 614 and 2,924 genes and decreased in 6,220 and 6,477 genes in male and female offspring, respectively. Combined with mRNA microarray analysis, 88 and 89 genes were upregulated (≥1.5-fold) accompanied by demethylation of CpG islands, whereas 13 and 33 genes were downregulated (≤0.67-fold) accompanied by methylation of CpG islands in male and female offspring mice, respectively. Gene Set Enrichment Analysis (GSEA) revealed that these genes were enriched in gene ontology terms related to the regulation of transcription factors, cell proliferation, and organism development. Additionally, MeSH terms related to stem cells and morphogenesis were enriched. Conclusion: Prenatal TiO2-NP exposure induced genome-wide alterations in DNA methylation and mRNA expression in the brains of male and female offspring. Based on GSEA findings, it can be speculated that prenatal TiO2-NP exposure causes adverse effects on brain functions by altering the DNA methylation state of the fetal brain, especially neural stem cells, resulting in the subsequent abnormal regulation of transcription factors that modulate development and differentiation.

Alpha lipoic acid ameliorates detrimental effects of maternal lipopolysaccharides exposure on prefrontal white matter in adult male offspring rats

BackgroundActivation of the maternal immune system by lipopolysaccharide (LPS) increases the production of proinflammatory cytokines, free radicals, and reactive oxygen species (ROS), all of which play a significant role in the pathogenesis of many offspring neurodevelopmental disorders. Alpha Lipoic Acid (ALA) is a natural compound that has anti-inflammatory and antioxidant properties. This study was performed to assess the effect of prenatal exposure to LPS on the prefrontal white matter of rat offspring and evaluate the potential protective effects of ALA co-administration during pregnancy. MethodsPregnant Wistar rats were randomly divided into six groups (n = 6 each group): (1) control, (2) received LPS (100 μg/kg, intraperitoneally (IP) on gestational day 9.5 (GD 9.5), (3) received ALA (20 mg/kg) from GD1 to GD11, (4) LPS+ALA received LPS on GD9.5 and ALA from GD1 to GD11, (5 and 6) received LPS and ALA vehicle respectively. In each group, 21-day old male offspring (2 male pups from each mother) was harvested, and then their prefrontal white matter was separated and prepared for the ultrastructural, stereological, and molecular assays. ResultsIn utero exposure to LPS led to a significant decrease in nerve cell counts, ultrastructural alterations in myelinated axons, and abnormal changes in genes expression of Sox10,Olig1,yrf,Wnt in the prefrontal of the rat offspring. Co-administration of ALA resulted in amelioration of those abnormal changes in the LPS rat offspring. ConclusionThe findings of our preclinical study, explore that prenatal ALA treatment efficiently protects the nervous system against LPS induced abnormal changes in the offspring.

Effects of Prenatal Phthalate Exposure and Childhood Exercise on Maternal Behaviors in Female Rats at Postpartum: A Role of Oxtr Methylation in the Hypothalamus.

Both the detrimental effect of prenatal exposure to di-(2-ethylhexyl)-phthalate (DEHP) and the beneficial effects of physical exercise on brain functions have been reported. The oxytocin pathway has been implicated in the onset of maternal behaviors. Epigenetic modification of the oxytocin receptor gene (OXTR) through DNA methylation has been associated with the pathogenesis of neuropsychiatric disorders. The purpose of this study was to investigate the effects of prenatal DEHP exposure on oxytocin-regulated maternal behaviors and to examine the protective effect of exercise. Pregnant rats (F0) were fed with vehicle or DEHP during gestation and the offspring females (F1) were assessed for their maternal behaviors by pup retrieval test at postpartum. The results showed that reduced pup retrieval activities without significant alteration of stress responses were observed in the prenatally DEHP-exposed females. Prenatal DEHP exposure decreased the expressions of oxytocin, Oxtr mRNA, and oxytocin receptor, and increased Oxtr methylation in the hypothalamus of postpartum female rats. There were no significant effects of exercise on behavioral, biochemical, and epigenetic measurements. These results suggest that prenatal DEHP exposure has a long-term adverse effect on maternal behaviors; Oxtr hyper-methylation may be a potential epigenetic mechanism for this alteration, which cannot be prevented by physical exercise during childhood.

In Utero Exposure to Mercury Is Associated With Increased Susceptibility to Liver Injury and Inflammation in Childhood.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of liver disease in children. Mercury (Hg), a ubiquitous toxic metal, has been proposed as an environmental factor contributing to toxicant-associated fatty liver disease. We investigated the effect of prenatal exposure to Hg on childhood liver injury by combining epidemiological results from a multicenter mother-child cohort with complementary in vitro experiments on monocyte cells that are known to play a key role in liver immune homeostasis and NAFLD. We used data from 872 mothers and their children (median age, 8.1years; interquartile range [IQR], 6.5-8.7) from the European Human Early-Life Exposome cohort. We measured Hg concentration in maternal blood during pregnancy (median, 2.0μg/L; IQR, 1.1-3.6). We also assessed serum levels of alanine aminotransferase (ALT), a common screening tool for pediatric NAFLD, and plasma concentrations of inflammation-related cytokines in children. We found that prenatal Hg exposure was associated with a phenotype in children that was characterized by elevated ALT (≥22.1 U/L for females and ≥25.8 U/L for males) and increased concentrations of circulating IL-1β, IL-6, IL-8, and TNF-α. Consistently, inflammatory monocytes exposed in vitro to a physiologically relevant dose of Hg demonstrated significant up-regulation of genes encoding these four cytokines and increased concentrations of IL-8 and TNF-α in the supernatants. These findings suggest that developmental exposure to Hg can contribute to inflammation and increased NAFLD risk in early life.

Prenatal Exposure to General Anesthesia and Childhood Behavioral Deficit

(Anaesthesia. 2020;75:1424–1427) (Anesth Analg. 2021. doi: 10.1213/ANE.0000000000005389. Epub ahead of print) While the US Food and Drug Administration has issued a warning about the neurodevelopmental effects of anesthetic drugs in the third trimester of pregnancy and children under the age of 3, no clinical study has evaluated long-term neurodevelopmental outcomes following prenatal exposure to anesthetics. Since anesthetic drugs cross the placenta and the brain is particularly vulnerable in the prenatal period, it is plausible that prenatal anesthetic exposure could lead to adverse neurodevelopmental effects. This study examined the effects of prenatal exposure to general anesthetic agents and neuropsychological and behavioral survey scores at age 10.

Prenatal Exposure to Perfluoroalkyl Substances and Mental Health in Childhood

BACKGROUND AND AIM: Epidemiological studies have evaluated the effect of prenatal exposure to perfluoroalkyl substances (PFAS) on neurobehavioral and cognitive endpoints in childhood, but a research focus on mental health is lacking. We evaluated the associations between prenatal PFAS exposure and mental health including depressive symptoms, physical or emotional stress, and psychosis-like experience in children at age 11. METHODS: Using pooled samples in the Danish National Birth Cohort established between 1996 and 2002 (N=2,250), we estimated the associations between concentrations of six types of PFAS in maternal plasma (median, 8 gestational weeks) and child self-report mental health outcomes using validated questionnaires. Binary classifications (with or without moderate/severe symptoms) for each of the outcomes and continuous outcome variables were analyzed. We used unconditional logistic regressions to estimate the adjusted odds ratio (OR) and 95% confidence interval (CI) for the binary outcomes according to log2-transformed PFAS concentrations and PFAS tertiles. PFAS mixture by using the weighted-quantile-sum index was conducted. Analyses were repeated using negative binomial regressions for continuous count outcome variables. Sex-specific analyses were conducted. RESULTS:The highest exposure tertile for perfluorooctanoic acid (OR=1.34, 95% CI: 1.06, 1.71), perfluorohexane sulfonate (OR=1.43, 95% CI: 1.06, 1.92) and perfluoroheptane sulfonate (OR=1.37, 95% CI: 1.02, 1.84) were associated with elevated physical or emotional stress in childhood. The WQS index for PFAS mixture was also positively associated with stress in childhood (OR=1.21, 95% CI: 1.05, 1.40). There were no consistent associations found for these PFAS compounds and depressive symptoms or psychosis-like experience. Findings from negative binomial regressions were similar. There were also no apparent differences in analyses stratified by sex. CONCLUSIONS:Higher prenatal levels of three PFAS compounds and PFAS mixtures might influence physical and emotional stress in childhood. More research of fetal exposures to environmental pollutants and mental health risk in the offspring would be needed. KEYWORDS: PFAS, Mental health outcomes, Children's environmental health, Environmental epidemiology

Effects of prenatal exposure to air pollution on toddler neurodevelopment and effect modification by ambient temperature

BACKGROUND AND AIM: To evaluate the impacts of prenatal exposure to ambient SO2 and NO2 on toddler neurodevelopment and the effect modification by ambient temperature. METHODS: A prospective birth-cohort study was conducted from 2010 to 2012 in Shanghai and 223 mother-child pairs were followed-up until 24-36 months postpartum. Daily concentrations of SO2 and NO2 and daily average temperature were obtained for each woman based on the district where she lived during pregnancy and toddler neurodevelopment was assessed at 24-36 months old. Distributed-lag-nonlinear-models (DLNMs) were used to assess the effects of weekly air pollution exposure and the interactions between prenatal air pollution and temperature on toddler neurodevelopment. RESULTS:Each 10 μg/m3 increase in SO2 had negative associations with gross motor during gestational weeks 1 to 16 with developmental quotients (DQs) changing from -0.26% to -0.14%, with fine motor from week 25 to 34 with DQs changing from -0.23% to -0.13%, and with adaptive behavior from week 7 to 27 with DQs changing from -0.14% to -0.09%. Each 10 μg/m3 increase in NO2 had negative associations with gross motor from week 28 to 36 with DQs changing from -0.38% to -0.14%, and with fine motor from week 25 to 36 with DQs changing from -0.54% to -0.13%. The cumulative effects for a 10 μg/m3 increase in SO2 induced changes of -4.7% (95% CI: -8.4 to -0.9%) for gross motor and -3.7% (95% CI: -6.6% to -0.7%) for adaptive behavior. We found interactions between low SO2 and high temperature on gross motor (-11.3%, 95%CI:-21.3 to -0.04%) and adaptive behavior DQs (-12.5%, 95%CI:-18.9 to -5.7%), and interactions between low NO2 and high temperature on gross motor (-23.2%, 95%CI: -39.9 to -1.7%). CONCLUSIONS:Prenatal exposure to ambient SO2 and NO2 in specific time windows could impair toddler neurodevelopment and high temperature may aggravate the neurotoxicity induced at low pollution levels. KEYWORDS: Air pollution, Temperature, Neurodevelopmental outcomes

Prenatal exposure to toxicants and child language development in the Norwegian Mother, Father and Child Cohort Study (MoBa)

BACKGROUND AND AIM: Prenatal toxicant exposures have been associated with increased risk of language difficulties in children. Much of this work has yet to explore which toxicant among correlated exposures might be most influential; therefore, we examined the effect of prenatal exposure to phthalates, organophosphate esters (OPEs), and organophosphorous pesticides (OPPs) on children’s language development from toddlerhood to the preschool period. METHODS: The study included 1022 pregnant women that were selected from the MoBa cohort run by the Norwegian Institute of Public Health. Prenatal concentrations of toxicant metabolites (6 phthalates, 4 OPEs, and 6 dialkylphosphate pesticides) were measured in maternal urine collected at 17 weeks gestation. Children’s language was assessed with parent report on the Ages and Stages Questionnaire at 18 months, and teacher report on the Child Development Inventory at preschool age. We used structural equation models to account for multiple exposures on each developmental outcome separately and also ran multigroup analyses to examine potential child sex differences. RESULTS:Prenatal low molecular weight phthalates were associated with better language development at 18 months (β=.08, 95% CI: 0.01, 0.14); however, they were associated with more adverse language development in the preschool period (β=-.11, 95% CI: -0.22, 0.00). OPPs were associated with worse language development at 18 months (β=-.09, 95% CI: -0.16, -0.02), and a slight negative association in preschool (β=-.10, 95% CI: -0.21, 0.01). High molecular weight phthalates and organophosphate esters were not associated with language development at either age, nor were there differences by child sex for any toxicant. Follow-up analyses will consider developmental trajectories. CONCLUSIONS:In models accounting for mixed exposures, we found that prenatal toxicants were associated with language development in a potentially age-dependent manner, but that did not vary by child sex. Differences in associations by child age may reflect patterns of brain development in early life. KEYWORDS: pesticides, phthalates, neurodevelopmental outcomes, mixtures analysis

Nitrate in Danish household tap water and the risk of small-for-gestational-age, 1991-2015

BACKGROUND AND AIM: Findings from studies examining the effects of prenatal exposure to nitrate from drinking water on fetal growth have been inconsistent, small, and mostly ecologic in nature. The aim of this study was to assess maternal exposure to nitrate (NO₃⁻) in drinking water and small-for-gestational-age in a large population-based cohort. METHODS: Exposure estimates from each maternal address during pregnancy were obtained from a national public and private water monitoring database. We linked these individual household nitrate concentrations with individual-level birth registry data to create a cohort of 1,078,892 singleton live births in Denmark to Danish-born parents during 1991–2015. Exposures were modeled as log-transformed continuous estimates and categorically. Small-for-gestational-age was defined as the lightest 10% of infants at birth per sex and gestational week. Multivariable logistic regression with generalized estimating equations was used to assess associations and account for the non-independence of siblings. National register-based data were used to adjust for sex, birth year, birth order, and maternal age, smoking, education, income, and employment status at the individual level. RESULTS:In this cohort, the median nitrate concentration was 1.9 mg/L NO₃⁻. An increased risk of small-for-gestational-age was observed when comparing half the European Union standard (25 mg/L NO₃⁻) to 1 mg/L NO₃⁻ [OR: 1.03 (95% CI: 1.01, 1.05)] and in categorical analyses, except for the highest category (25 mg/L NO₃⁻) compared to the referent (2 mg/L NO₃⁻), possibly due to small numbers. CONCLUSIONS:In this nationwide study spanning 25 years, we found that nitrate in maternal household tap water during pregnancy was associated with an increased risk of her child being born small-for-gestational-age. While the increased risk may be small at an individual level, given the widespread presence of nitrate in drinking water it is important on a global scale. When evaluating nitrate regulations, policymakers should focus on health impacts at levels below current standards. KEYWORDS: Big data, Birth outcomes, Children's environmental health, Environmental epidemiology, International collaboration, Water quality

The Associations of Prenatal Exposure to Dioxins and Dioxin-Like Polychlorinated Biphenyls with Neurodevelopment at 6 Months of Age: Multi-pollutant Approaches

BACKGROUND AND AIM: Prenatal exposure to endocrine disrupting chemicals, including polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (DL-PCBs), has been hypothesized to have detrimental impact on neurodevelopment. However, the effect of prenatal exposure to dioxin and DL-PCB mixtures on neurodevelopment remains largely inconclusive. Therefore, we aimed to elucidate the associations of in utero exposure to a dioxin and DL-PCB mixture with infant neurodevelopment by applying novel multi-pollutant methods. METHODS: The concentrations of individual dioxin and DL-PCB isomers were measured in maternal peripheral blood during pregnancy in the Sapporo cohort, Hokkaido Study on Environment and Children’s Health. The mental and psychomotor development of the study participants’ six-month-old infants were assessed using the Bayley Scales of Infant Development-2nd Edition (n=210). To determine both the joint and individual associations of prenatal exposure to dioxin and DL-PCB mixtures with infant neurodevelopment, Bayesian Kernel Machine Regression (BKMR) and quantile-based g-computation models were performed. RESULTS:Suggestive, but not significant, inverse associations were observed between prenatal exposure to a dioxin and DL-PCB mixture, and infant psychomotor development in the both BKMR and quantile g-computation models. In contrast, we found no association of dioxin and DL-PCB mixtures with mental development. These mixture methods consistently indicated 2,3,7,8-TCDD and 23'44'55'-HxCB(#167) as the most influential dioxin and DL-PCB congener on mental and psychomotor development, respectively. When group-specific posterior inclusion probabilities were evaluated, BKMR revealed in utero exposure to PCDFs and mono-ortho DL-PCBs as the more important contributing factors to early mental and psychomotor development, respectively, compared with the other dioxin or DL-PCB groups. No evidence of non-linear relationships or interactions among the chemical mixtures was detected. CONCLUSIONS:Employing the novel statistical methods for chemical mixture analysis, we demonstrated limited evidence of inverse associations of prenatal exposure to dioxins and DL-PCBs with infant psychomotor development, but not with mental development. KEYWORDS: Chemical mixtures, Dioxins, Polychlorinated biphenyls, Neurological development, Bayesian Kernel Machine Regression, Quantile g-computation

Effects of prenatal exposure to phthalates and Hexamoll® DINCH derived from urinary untargeted metabolomics analysis

BACKGROUND AND AIM: Phthalates and their substitute Hexamoll® DINCH® are a group of plasticisers with a production volume of millions of tons per year found in daily use products. There is a societ...

Mixture effects of prenatal exposure to per- and polyfluoroalkyl substances and polybrominated diphenyl ethers on maternal and newborn telomere length

BACKGROUND AND AIM: Per- and polyfluoroalkyl substances (PFAS) and polybrominated diphenyl ethers (PBDEs) are endocrine disrupting chemicals associated with reproductive toxicity and adverse health outcomes, including certain cancers. PFAS and PBDEs may affect health through alternations in telomere length. We examined joint associations between prenatal exposure to PFAS, PBDEs, and maternal and newborn telomere length using mixture analyses, to characterize effects of cumulative environmental chemical exposures. METHODS: Study participants were enrolled in the Chemicals in Our Bodies study, a demographically diverse cohort of pregnant women and children in San Francisco, CA. Seven PFAS (ng/mL) and four PBDEs (ng/g lipid) were measured in second trimester maternal serum. Telomere length (T/S ratio) was measured in delivery cord blood of 292 newborns and 110 second trimester maternal whole blood samples. Quantile g-computation was used to assess the joint associations between groups of PFAS and PBDEs and newborn and maternal telomere length. Groups considered were: (1) all PFAS and PBDEs combined, (2) PFAS, and (3) PBDEs. Maternal and newborn telomere length were modeled as separate outcomes. RESULTS:T/S ratios in newborn cord and maternal whole blood were moderately correlated (Spearman ρ= 0.31). In mixtures analyses, a simultaneous one quartile increase in all PFAS and PBDEs was associated with a small increase in newborn (mean change per quartile increase =0.03, 95% confidence interval [CI]=-0.03, 0.08) and maternal telomere length (mean change per quartile increase =0.03 (95% CI=-0.03, 0.09). When restricted to maternal-fetal paired samples (N=76), increasing all PFAS and PBDEs combined was associated with a strong, positive increase in newborn telomere length (mean change per quartile increase=0.16, 95% CI=0.03, 0.28). These associations were primarily driven by PFAS (mean change per quartile increase= 0.11 [95% CI=0.01, 0.22]). CONCLUSIONS:Our findings show that PFAS and PBDEs may be positively associated with newborn telomere length. KEYWORDS: Per- and poly-fluoroalkyl substances, Polybrominated diphenyl ethers, telomere, exposure mixture

Individual and joint effects of prenatal green spaces and PM2.5 exposure on BMI Z-score of children: a birth cohort study

BACKGROUND AND AIM: Few studies examined the association of prenatal exposure to green spaces with children’s body mass index (BMI) Z-score, and no study evaluated the joint effect of prenatal green spaces and PM2.5 exposure on children’s BMI Z-score. We aimed to assess the individual and joint effect of prenatal green spaces and PM2.5 exposure on BMI Z-score of children. METHODS: The study was based on a birth cohort (2014-2017) in Beijing, China, in which 13,688 mother and their children were included. We estimated prenatal exposure to green spaces by calculating averaged normalized difference vegetation index with 500m buffers (NDVI-500), and prenatal PM2.5 exposure based on maternal residential addresses. Weight and height were measured at approximately 2 years old. We calculated BMI Z-score and defined overweight and obesity based on the WHO Standards. Generalized linear regression was used to examine the individual and joint effects of prenatal NDVI-500 and PM2.5 exposure on children’s BMI Z-score and overweight or obesity. RESULTS:A 0.1 increase in prenatal NDVI-500 exposure and a 10 µg/m3 decrease in PM2.5 were associated with 0.192 [95% confidence interval (95%CI): 0.158, 0.225] and 0.020 (95%CI: 0.001,0.040) increase of children’s BMI Z-score, respectively. Compared with exposed to low-level NDVI-500 and high-level PM2.5, the BMI Z-score was higher in children whose mother exposed to high-level of NDVI-500 (greater than median) and low-level PM2.5 (not greater than median) [β:0.163 (95%CI: 0.117, 0.209), Pinteraction=0.025]. We did not observe significant associations of NDVI-500 and PM2.5 with the risk of overweight or obesity. CONCLUSIONS:The study suggested the beneficial effect of prenatal exposure to green spaces on children’s growth and its interaction with PM2.5. The findings call for developing public health policy to improve green infrastructure and control PM2.5 concentrations, in order to promote children’s growth. KEYWORDS: Prenatal exposure, green spaces, PM2.5, body mass index, children, growth