Maternal smoking during pregnancy and offspring risk of intellectual disability: a UK-based cohort study.

Background: Observational studies have described associations of maternal smoking during pregnancy with intellectual disability (ID) in the exposed offspring. Whether these results reflect a causal effect or unmeasured confounding is still unclear. Methods: Using a UK-based prospectively collected birth cohort (the Avon Longitudinal Study of Parents and Children) of 13,479 children born between 1991 and 1992, we assessed the relationship between maternal smoking at 18 weeks' gestation and offspring risk of ID, ascertained through multiple sources of linked information including primary care diagnoses and education records. Using confounder-adjusted logistic regression, we performed observational analyses and a negative control analysis that compared maternal with partner smoking in pregnancy under the assumption that if a causal effect were to exist, maternal effect estimates would be of greater magnitude than estimates for partner smoking if the two exposures suffer from comparable biases. Results: In observational analysis, we found an adjusted odds ratio for ID of 0.75 (95% CI = 0.49-1.13) for any maternal smoking and 0.97 (95% CI = 0.71-1.33) per 10-cigarette increase in number of cigarettes smoked per day. In negative control analysis, comparable effect estimates were found for any partner smoking (OR = 0.94; 95% CI = 0.63-1.40) and number of cigarettes smoked per day (OR = 0.94; 95% CI = 0.74-1.20). Conclusions: The results are not consistent with a causal effect of maternal smoking during pregnancy on offspring ID.

The Effect of Various Environmental Pollutants on the Reproductive Health in Children: A Brief Review of the Literature.

PURPOSE OF REVIEW: Environmental pollutants in air, water, soil, and food are a significant concern due to their potential adverse effects on fetuses, newborns, babies, and children. These chemicals, which pass to fetuses and babies through trans-placental transfer, breast milk, infant formula, dermal transfer, and non-nutritive ingestion, can cause health problems during childhood. This review aims to discuss how exposure to various environmental pollutants in early life stages can disrupt reproductive health in children. RECENT FINDINGS: Environmental pollutants can affect Leydig cell proliferation and differentiation, decreasing testosterone production throughout life. This may result in cryptorchidism, hypospadias, impaired semen parameters, and reduced fertility. Although many studies on female reproductive health cannot be interpreted to support causal relationships, exposure to pollutants during critical windows may subsequently induce female reproductive diseases, including early or delayed puberty, polycystic ovary syndrome, endometriosis, and cancers. There is growing evidence that fetal and early-life exposure to environmental pollutants could affect reproductive health in childhood. Although diet is thought to be the primary route by which humans are exposed to various pollutants, there are no adopted nutritional interventions to reduce the harmful effects of pollutants on children's health. Therefore, understanding the impact of environmental contaminants on various health outcomes may inform the design of future human nutritional studies.

Vaping during pregnancy: a systematic review of health outcomes.

INTRODUCTION: Smoking during pregnancy is harmful to maternal and child health. Vaping is used for smoking cessation but evidence on health effects during pregnancy is scarce. We conducted a systematic review of health outcomes of vaping during pregnancy. METHODS: We searched six databases for maternal/fetal/infant outcomes and vaping, including quantitative, English language, human studies of vaping during pregnancy, to November 10th, 2023. We assessed study quality with the Mixed-Methods Appraisal Tool. We focused on comparisons of exclusive-vaping with non-use of nicotine and tobacco products and with smoking. Presentation is narrative as the studies were of insufficient quality to conduct meta-analysis. RESULTS: We included 26 studies, with 765,527 women, with one randomised controlled trial (RCT) comparing vaping and nicotine replacement therapy for smoking cessation, 23 cohort studies and two case-control studies. While the RCT met 4/5 quality criteria, the quality of the cohort studies and case-control studies was poor; none adequately assessed exposure to smoking and vaping. For studies comparing exclusive-vaping with 'non-use', more reported no increased risk for vaping (three studies) than reported increased risk for maternal pregnancy/postpartum outcomes (one study) and for fetal and infant outcomes (20 studies no increased risk, four increased risk), except for birth-weight and neurological outcomes where two studies each observed increased and no increased risk. When the RCT compared non-users with those not smoking but vaping or using NRT, irrespective of randomisation, they reported no evidence of risk for vaping/NRT. For studies comparing exclusive-vaping and exclusive-smoking, most studies provided evidence for a comparable risk for different outcomes. One maternal biomarker study revealed a lower risk for vaping. For small-for-gestational-age/mean-birth-centile equal numbers of studies found lower risk for vaping than for smoking as found similar risk for the two groups (two each). CONCLUSIONS: While more studies found no evidence of increased risk of exclusive-vaping compared with non-use and evidence of comparable risk for exclusive-vaping and exclusive-smoking, the quality of the evidence limits conclusions. Without adequate assessment of exposure to vaping and smoking, findings cannot be attributed to behaviour as many who vape will have smoked and many who vape may do so at low levels. STUDY REGISTRATION: https://osf.io/rfx4q/ .

Human Health Effects of Oral Exposure to Chromium: A Systematic Review of the Epidemiological Evidence.

The toxicity and carcinogenicity of hexavalent chromium via the inhalation route is well established. However, a scientific debate has arisen about the potential effects of oral exposure to chromium on human health. Epidemiological studies evaluating the connection between ingested chromium and adverse health effects on the general population are limited. In recent years, a wealth of biomonitoring studies has emerged evaluating the associations between chromium levels in body fluids and tissues and health outcomes. This systematic review brings together epidemiological and biomonitoring evidence published over the past decade on the health effects of the general population related to oral exposure to chromium. In total, 65 studies were reviewed. There appears to be an inverse association between prenatal chromium exposure and normal fetal development. In adults, parameters of oxidative stress and biochemical alterations increase in response to chromium exposure, while effects on normal renal function are conflicting. Risks of urothelial carcinomas cannot be overlooked. However, findings regarding internal chromium concentrations and abnormalities in various tissues and systems are, in most cases, controversial. Environmental monitoring together with large cohort studies and biomonitoring with multiple biomarkers could fill the scientific gap.

Developmental anaesthesia neurotoxicity in humans: finding the sweet spot?

A recent human epidemiological study in this issue of British Journal of Anaesthesia examined the association between anaesthesia exposure in pregnant women undergoing appendicectomy or cholecystectomy and the subsequent diagnosis of behavioural disorders in their offspring. When compared with unexposed children, prenatally exposed children had ∼30% greater likelihood of a diagnosis of disruptive or internalising behavioural disorders. Although these data are new and interesting, they should be interpreted with caution. Indeed, appendicitis and cholecystitis can produce acute and chronic systemic inflammation, and maternal immune activation can affect fetal neurodevelopment through inflammatory and epigenetic mechanisms. It is, therefore, possible that the findings are related to maternal and fetal inflammation than to anaesthesia exposure. As there is no causal evidence for the implication that anaesthesia and surgery induce such pathologies, it is unwise to consider alternative treatments when surgery is indicated in pregnant patients.

The epidemiology of cryptorchidism and potential risk factors, including endocrine disrupting chemicals.

Congenital cryptorchidism, also known as undescended testis, is the condition where one or both testes are not in place in the scrotum at birth and is one of the most common birth defects in boys. Temporal trends and geographic variation in the prevalence of cryptorchidism from 1% to 9% have been reported in prospective cohort studies. The testes develop in the abdominal cavity and descend to the scrotum in two phases, which should be completed by gestational week 35. Thus, the risk of cryptorchidism is higher in preterm boys. In many cases a spontaneous descent occurs during the first months of life during the surge of gonadotropins and testosterone. If not, the testis is usually brought down to the scrotum, typically by surgery, to increase future fertility chances and facilitate cancer surveillance. The increasing frequency of impaired semen quality and testicular cancer, with which cryptorchidism is associated, represents a concern for male reproductive health in general and a need to understand its risk factors. The risk of cryptorchidism is closely related to gestational factors (preterm birth, low birth weight and intrauterine growth restriction), and especially maternal smoking seems to be a risk factor. Evidence is accumulating that the increasing prevalence of cryptorchidism is also related to prenatal exposure to environmental chemicals, including endocrine disrupting compounds. This association has been corroborated in rodents and supported by ecological studies. Conducting human studies to assess the effect of endocrine disrupting chemicals and their interactions is, however, challenged by the widespread concomitant exposure of all humans to a wide range of chemicals, the combined effect of which and their interactions are highly complex.

Epigenetic regulation by KDM5A mediates the effects of prenatal PM2.5 exposure on hippocampal development and synaptic integrity through the Shh signaling pathway.

Prenatal environmental exposure could be an essential health risk factor associated with neurodevelopmental disorders in offspring. However, the exact mechanisms underlying the impact of prenatal PM2.5 exposure on offspring cognition remain unclear. In our recent study using a PM2.5 exposed pregnant mouse model, we observed significant synaptic dysfunction in the hippocampi of the offspring. Concurrently, the epigenetic regulator of KDM5A and the Shh signaling pathway exhibited decreased activities. Significantly, changes in hippocampal KDM5A and Shh levels directly correlated with PM2.5 exposure intensity. Subsequent experiments revealed a marked reduction in the expression of Shh signaling and related synaptic proteins when KDM5A was silenced in cells. Notably, the effects of KDM5A deficiency were reversed significantly with the supplementation of a Shh activator. Furthermore, our findings indicate that Shh activation significantly attenuates PM2.5-induced synaptic impairments in hippocampal neurons. We further demonstrated that EGR1, a transcriptional inhibitor, plays a direct role in KDM5A's regulation of the Shh pathway under conditions of PM2.5 exposure. Our results suggest that the KDM5A's inhibitory regulation on the Shh pathway through the EGR1 gene is a crucial epigenetic mechanism underlying the synaptic dysfunction in hippocampal neurons caused by maternal PM2.5 exposure. This emphasizes the role of epigenetic regulations in neurodevelopmental disorders caused by environmental factors.

Prenatal diethylhexylphthalate exposure disturbs adult Leydig cell function via epigenetic downregulation of METTL4 expression in male rats.

Prenatal exposure to diethylhexyl phthalate (DEHP) has been linked with a decline in testosterone levels in adult male rats, but the underlying mechanism remains unclear. We investigated the potential epigenetic regulation, particularly focusing on N6-methyladenosine (m6A) modification, as a possible mechanism. Dams were gavaged with DEHP (0, 10, 100, and 750 mg/kg/day) from gestational day 14 to day 21. The male offspring were examined at the age of 56 days. Prenatal DEHP administration at 750 mg/kg/day caused a decline in testosterone concentrations, an elevation in follicle-stimulating hormone, a downregulated expression of CYP11A1 HSD3B2, without affecting Leydig cell numbers. Interestingly, Methyltransferase Like 4 (METTL4), an m6A methyltransferase, was downregulated, while there were no changes in METTL3 and METTL14. Moreover, CYP11A1 showed m6A reduction in response to prenatal DEHP exposure. Additionally, METTL4 expression increased postnatally, peaking in adulthood. Knockdown of METTL4 resulted in the downregulation of CYP11A1 and HSD3B2 and an increase in SCARB1 expression. Furthermore, the increase in autophagy protection in adult Leydig cells induced by prenatal DEHP exposure was not affected by 3-methyladenosine (3MA) treatment, indicating a potential protective role of autophagy in response to DEHP exposure. In conclusion, prenatal DEHP exposure reduces testosterone by downregulating CYP11A1 and HSD3B2 via m6A epigenetic regulation and induction of autophagy protection in adult Leydig cells as a response to DEHP exposure.

Activated fibroblasts modify keratinocyte stem niche through TET1 and IL-6 to promote their rapid transformation in a mouse model of prenatal arsenic exposure.

Early life exposure to environmental pollutants such as arsenic (As) can increase the risk of cancers in the offspring. In an earlier study, we showed that only prenatal As exposure significantly increases epidermal stem cell proliferation and accelerates skin tumorigenesis in BALB/c mouse offspring. In the present work, we have examined the role of As-conditioned dermal fibroblasts (DFs) in creating pro-tumorigenic niches for Keratinocyte stem cells (KSCs) in the offspring. DFs isolated from prenatally exposed animals showed increased levels of activation markers (α-SMA, Fibronectin, Collagen IV), induction of ten-eleven translocation methylcytosine dioxygenase 1(TET1), and secreted high levels of niche modifying IL-6. This led to enhanced proliferation, migration, and survival of KSCs. Increased IL-6 production in As-conditioned fibroblast was driven through TET1 mediated 5-mC to 5-hmC conversion at -698/-526 and -856/-679 region on its promoter. IL-6 further acted through downstream activation of JAK2-STAT3 signaling, promoting epithelial-to-mesenchymal transition (EMT) in KSCs. Inhibition of pSTAT3 induced by IL-6 reduced the EMT process in KSCs resulting in a significant decrease in their proliferation, migration, and colony formation. Our results indicate that IL-6 produced by prenatally conditioned fibroblasts plays a major role in regulating the KSC niche and promoting skin tumor development in As-exposed offspring.

Prenatal arsenic exposure alters keratinocyte stem cell fate through persistent activation of IGF2R-MAPK cascade leading to aggravated skin carcinogenesis in mice offspring.

Chronic exposure to arsenic (As) promotes skin carcinogenesis in humans and potentially disturbs resident stem cell dynamics, particularly during maternal and early life exposure. In the present study, we demonstrate how only prenatal arsenic exposure disturbs keratinocyte stem cell (KSC) conditioning using a BALB/c mice model. Prenatal As exposure alters the normal stemness (CD34, KRT5), differentiation (Involucrin), and proliferation (PCNA) program in skin of offspring with progression of age as observed at 2, 10, and 18 weeks. Primary KSCs isolated from exposed animal at Day-2 showed increased survival (Bax:Bcl-xL, TUNEL assay), proliferation (BrdU), and differentiation (KRT5, Involucrin) potential through the activation of pro-carcinogenic IGF2R-MAPK cascade (IGF2R-G(α)q-MEK1-ERK1/2). This was associated with reduced enrichment of histone H3K27me3 and its methylase, EZH2 along with increased binding of demethylase, KDM6A at Igf2r promoter. Altered KSCs conditioning through disturbed Igf2r imprint contributed to impaired proliferation and differentiation and an aggravated tumor response in offspring.

Behavioural disorders after prenatal exposure to anaesthesia for maternal surgery.

BACKGROUND: The association between prenatal exposure to general anaesthesia for maternal surgery during pregnancy and subsequent risk of disruptive or internalising behavioural disorder diagnosis in the child has not been well-defined. METHODS: A nationwide sample of pregnant women linked to their liveborn infants was evaluated using the Medicaid Analytic eXtract (MAX, 1999-2013). Multivariate matching was used to match each child prenatally exposed to general anaesthesia owing to maternal appendectomy or cholecystectomy during pregnancy with five unexposed children. The primary outcome was diagnosis of a disruptive or internalising behavioural disorder in children. Secondary outcomes included diagnoses for a range of other neuropsychiatric disorders. RESULTS: We matched 34,271 prenatally exposed children with 171,355 unexposed children in the database. Prenatally exposed children were more likely than unexposed children to receive a diagnosis of a disruptive or internalising behavioural disorder (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.23-1.40). For secondary outcomes, increased hazards of disruptive (HR, 1.32; 95% CI, 1.24-1.41) and internalising (HR, 1.36; 95% CI, 1.20-1.53) behavioural disorders were identified, and also increased hazards of attention-deficit/hyperactivity disorder (HR, 1.32; 95% CI, 1.22-1.43), behavioural disorders (HR, 1.28; 95% CI, 1.14-1.42), developmental speech or language disorders (HR, 1.16; 95% CI, 1.05-1.28), and autism (HR, 1.31; 95% CI, 1.05-1.64). CONCLUSIONS: Prenatal exposure to general anaesthesia is associated with a 31% increased risk for a subsequent diagnosis of a disruptive or internalising behavioural disorder in children. Caution is advised when making any clinical decisions regarding care of pregnant women, as avoidance of necessary surgery during pregnancy can have detrimental effects on mothers and their children.

Neonatal outcomes and follow-up of children born to women with pregnancy-associated cancer: a prospective observational study.

BACKGROUND: During the last decade, there has been a growing number of cases of children born from pregnancy-associated cancer (PAC), however there are currently insufficient data on the follow up to be observed in this category of newborns. Objective of the study was to evaluate the neonatal outcomes of infants born to mother with PAC, the potential adverse effect of chemotherapy during pregnancy and the risk of metastasis to the fetus. METHODS: Maternal clinical data and neonatal outcomes of child born to mothers diagnosed with PAC were collected; infants were divided into those were and were not exposed to chemotherapy during fetal life and their outcomes were compered. RESULTS: A total of 37 newborn infants from 36 women with PAC were analyzed. Preterm delivery occurred in 83.8% of the cases. No significant differences in neonatal outcomes were found between infants who were and were not exposed to chemotherapy during pregnancy. The median follow-up period was 12 months. CONCLUSIONS: PAC treatment during the second or third trimester does not seem to be dangerous for the fetus, however infants born from PAC must be carefully evaluated for to rule out the consequences of chemotherapy and exclude the presence of metastasis. Long-term follow-up, especially in children exposed to chemotherapy, should be encouraged to obtain relevant data on long-term toxicity.

The ICRP, MELODI, and ALLIANCE workshop on effects of ionizing radiation exposure in offspring and next generations: a summary of discussions.

PURPOSE: Task Group 121 - Effects of ionizing radiation exposure in offspring and next generations - is a task group under the Committee 1 of the International Commission on Radiological Protection (ICRP), approved by the Main Commission on 18th November 2021. The main goals of Task Group 121 are to (1) review and update the scientific literature of relevance to radiation-related effects in the offspring of parent(s) exposed to ionizing radiation in both human and non-human biota; (2) to assess preconceptional and intrauterine effects of radiation exposure and related morbidity and mortality; and, (3) to provide advice about the level of evidence and how to consider these preconceptional and postconceptional effects in the system of radiological protection for humans and non-human biota. METHODS: The Task Group is reviewing relevant literature since Publication 90 'Biological effects after prenatal irradiation (embryo and fetus)' (2003) and will include radiation-related effects on future generations in humans, animals, and plants. This review will be conducted to account for the health effects on offspring and subsequent generations in the current system of radiological protection. Radiation detriment calculation will also be reviewed. Finally, preliminary recommendations will be made to update the integration of health effects in offspring and next generations in the system of radiological protection. RESULTS: A Workshop, jointly organized by ICRP Task Group 121 and European Radiation Protection Research Platforms MELODI and ALLIANCE was held in Budapest, Hungary, from 31st May to 2nd June 2022. Participants discussed four important topics: (1) hereditary and epigenetic effects due to exposure of the germ cell line (preconceptional exposure), (2) effects arising from exposure of the embryo and fetus (intrauterine exposure), (3) transgenerational effects on biota, and (4) its potential impact on the system of radiological protection. CONCLUSIONS: Based on the discussions and presentations during the breakout sessions, newer publications, and gaps on the current scientific literature were identified. For instance, there are some ongoing systematic reviews and radiation epidemiology reviews of intrauterine effects. There are newer methods of Monte Carlo simulation for fetal dosimetry, and advances in radiation genetics, epigenetics, and radiobiology studies. While the current impact of hereditary effects on the global detriment was reported as small, the questions surrounding the effects of radiation exposure on offspring and the next generation are crucial, recurring, and with a major focus on exposed populations. This article summarizes the workshop discussions, presentations, and conclusions of each topic and introduces the special issue of the International Journal of Radiation Biology resulting from the discussions of the meeting.

Prenatal Substance Use Among Young Pregnant Sexual Minority People.

Purpose: Sexual minority (SM) youth have higher rates of substance use and pregnancy but are absent from the prenatal substance use literature. We modeled the impact of SM identity and syndemic factors on prenatal substance use among 14- to 21-year-olds. Methods: Pregnant people completed an online survey (n = 357). Prenatal substance use was regressed on SM identity, controlling for other syndemic factors (e.g., depressive symptoms, intimate partner violence) and household substance use. Results: Pregnant SM participants (n = 125) were primarily bisexual and were more likely to use tobacco and illicit drugs than heterosexual participants (n = 232). The association between SM identity and prenatal tobacco use was not attenuated by syndemic factors, prenatal cannabis use, or household tobacco use. Conclusion: SM people need increased support for smoking cessation to redress health inequities in tobacco use, prevent prenatal exposures to tobacco, and limit the long-term consequences of tobacco use on health.

Anthropometrics of neonates born to mothers with PCOS with metformin or placebo exposure in utero.

INTRODUCTION: Fetal growth may be affected by both maternal polycystic ovary syndrome (PCOS) and metformin therapy. Here, we explore the effect of intrauterine metformin exposure on birth anthropometrics of infants born to women with PCOS. We also investigated whether the effect of metformin on birth anthropometrics is modified by maternal pre-pregnancy body mass index, PCOS hyperandrogenic phenotype, serum androgen levels, preconception use of metformin and offspring sex. Additionally, we assessed newborn anthropometrics in relation to a national reference population. MATERIAL AND METHODS: Individual data from three randomized controlled triasl were pooled. The randomized controlled trials investigated the effects of metformin in pregnant women with PCOS. In all, 397 and 403 were randomized to the metformin and placebo groups, respectively. A Scandinavian growth reference was used to calculate sex and gestational age adjusted z-scores. Linear regression models were used to estimate the effect of metformin on offspring z-scores of head circumference, birth length, birthweight, placental weight, body mass index, ponderal index and birthweight:placental weight ratio. S-testosterone, s-androstenedione, and s-sex-hormone binding globulin from four timepoints in pregnancy were analyzed. RESULTS: Compared with the PCOS-placebo group, newborns in the PCOS-metformin group had larger head circumference (head circumference z-score: mean difference = 0.25, 95% CI = 0.11- 0.40). This effect of metformin on head circumference z-score was particularly observed among offspring of overweight/obese mothers and mothers with hyperandrogenic PCOS-phenotype. We observed no difference in other anthropometric measures between the metformin and placebo groups or any clear interaction between maternal androgen levels and metformin. Newborns in the PCOS-placebo group were shorter than in the reference population (birth length z-score: mean = -0.04, 95% CI = -0.05 to -0.03), but head circumference and birthweight were similar. CONCLUSIONS: Larger head circumference was observed at birth in metformin-exposed offspring of mothers with PCOS. PCOS-offspring were also shorter, with a similar birthweight to the reference population, indirectly indicating higher weight-to-height ratio at birth.

Investigating the associations between prenatal exposure to substances and intergenerational maltreatment and symptoms of psychopathology for adolescent girls from families with low income.

BACKGROUND: Adolescent girls whose families experience poverty are more vulnerable to psychopathology, and it is vital to investigate biopsychosocial factors contributing to mental health functioning. OBJECTIVE: To test associations between prenatal exposure to substances, intergenerational maltreatment, and adolescent mental health symptoms. PARTICIPANTS AND SETTING: Baseline data were used from a randomized controlled trial testing the efficacy of Interpersonal Psychotherapy (IPT-A) for depression among girls with and without maltreatment exposure. Adolescents (Aged 13-16; 63.5 % Black/African-American, 21.0 % White, 15.57 % other racial identity; 12.57 % Latina/x) were recruited from families experiencing financial adversity (income <200 % poverty threshold). METHODS: Adolescent maltreatment status was determined by using multiple sources (child protective service records, parental report, and adolescent report). Mothers reported on prenatal substance exposure, experiences of maltreatment in their own childhood, and rated adolescent internalizing and externalizing symptoms. Latent Class Analysis was used to determine common patterns of prenatal substance exposure (tobacco, alcohol, marijuana, and cocaine). Structural Equation Modeling was used to evaluate associations between maltreatment in two generations, prenatal exposure to substances, and adolescent mental health symptoms. RESULTS: Two profiles of prenatal substance exposure emerged: one typified by low substance exposure (92.8 %), and one with moderate to high substance exposure (7.2 %). Both prenatal substance exposure and maternal history of maltreatment were associated with adolescent maltreatment, which in turn, was associated with greater adolescent externalizing symptoms. Parental history of maltreatment was directly associated with greater adolescent internalizing symptoms. CONCLUSION: Prenatal exposure to substances and intergenerational maltreatment each confer risk for mental health symptoms in adolescent girls.

Associations of cord plasma per- and polyfluoroakyl substances (PFAS) with neonatal and child body composition and adiposity: The GUSTO study.

BACKGROUND: The influence of prenatal exposure to per- and poly- fluoroalkyl substances (PFAS) on birth size and offspring adiposity is unclear, especially for the newer, shorter-chained replacement PFAS. METHODS: In the GUSTO multi-ethnic Singaporean mother-offspring cohort, 12 PFAS were measured in 783 cord plasma samples using ultra-performance-liquid chromatography-tandem-mass-spectrometer (UPLC-MS/MS). Outcomes included offspring anthropometry, other indicators of body composition/metabolic health, and MRI-derived abdominal adiposity (subset) at birth and 6 years of age. PFAS were modeled individually, in categories of long-chain and short-chain PFAS, and as scores of three principal components (PC) derived using PC analysis (PC1, PC2, and PC3 reflect predominant exposure patterns to "very-long-PFAS", "long-PFAS", and "short-PFAS", respectively). Associations with outcomes were assessed using multivariable linear regressions, adjusted for important covariates such as maternal sociodemographic and lifestyle factors. RESULTS: Overall, cord PFAS levels showed either no or positive associations (mostly for long-chain PFAS) with birth weight, length and head circumference. In general, PFAS were associated with higher neonatal abdominal adiposity, driven by shorter-chain PFAS. Perfluoroheptanoic acid (PFHpA) was associated with higher volumes of superficial subcutaneous adipose tissue (sSAT) (3.75 [1.13, 6.37] mL per SD increase in PFAS) and internal adipose tissue (IAT) (1.39 [0.41, 2.38] mL). Higher levels of perfluorobutanesulfonic acid (PFBS), short-chain PFAS, and PC3 were associated with higher IAT volume (ß range 1.22-1.41 mL/SD, all P < 0.02), especially in girls. Higher PC3 score was additionally associated with higher sSAT (3.12 [0.45, 5.80] mL) volume. At age 6 years, most observed associations did not persist. No consistent associations were observed between PFAS and whole-body adiposity measures. CONCLUSIONS: Fetal exposure to emerging short-chain PFAS was associated with higher abdominal adiposity at birth but not at age 6 years. Further research is needed to replicate the findings and to determine if these effects may reappear beyond early childhood. Population exposure to newer PFAS and consequent health impact must be monitored.

Association between cumulative maternal exposures related to inflammation and child attention-deficit/hyperactivity disorder: A cohort study.

BACKGROUND: Preclinical studies suggest synergistic effects of maternal inflammatory exposures on offspring neurodevelopment, but human studies have been limited. OBJECTIVES: To examine the cumulative association and potential interactions between seven maternal exposures related to inflammation and child attention-deficit/hyperactivity disorder (ADHD). METHODS: We conducted a population-based cohort study of children born from July 2001 to December 2011 in New South Wales, Australia, and followed up until December 2014. Seven maternal exposures were identified from birth data and hospital admissions during pregnancy: autoimmune disease, asthma, hospitalization for infection, mood or anxiety disorder, smoking, hypertension, and diabetes. Child ADHD was identified from stimulant prescription records. Multivariable Cox regression assessed the association between individual and cumulative exposures and ADHD and potential interaction between exposures, controlling for potential confounders. RESULTS: The cohort included 908,770 children, one-third (281,724) with one or more maternal exposures. ADHD was identified in 16,297 children (incidence 3.5 per 1000 person-years) with median age of 7 (interquartile range 2) years at first treatment. Each exposure was independently associated with ADHD, and risk increased with additional exposures: one exposure (hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.54, 1.65), two exposures (HR 2.25, 95% CI 2.13, 2.37), and three or more exposures (HR 3.28, 95% CI 2.95, 3.64). Positive interaction was found between smoking and infection. The largest effect size was found for cumulative exposure of asthma, infection, mood or anxiety disorder, and smoking (HR 6.12, 95% CI 3.47, 10.70). CONCLUSIONS: This study identifies cumulative effects of multiple maternal exposures related to inflammation on ADHD, most potentially preventable or modifiable. Future studies should incorporate biomarkers of maternal inflammation and consider gene-environment interactions.

Prenatal exposure to per- and polyfluoroalkyl substances and DNA methylation in the placenta: A prospective cohort study.

Epidemiological studies regarding the relationship between per- and polyfluoroalkyl substances (PFAS) and DNA methylation were limited. We investigated the associations of maternal PFAS concentrations with placental DNA methylation and examined the mediating role of methylation changes between PFAS and infant development. We measured the concentrations of 11 PFAS in maternal plasma during early pregnancy and infant development at six months of age. We analyzed genome-wide DNA methylation in 16 placental samples using reduced representation bisulfite sequencing. Additionally, we measured DNA methylation levels using bisulfite amplicon sequencing in 345 mother-infant pairs for five candidate genes, including carbohydrate sulfotransferase 7 (CHST7), fibroblast growth factor 13 (FGF13), insulin receptor substrate 4 (IRS4), paired like homeobox 2Ap (PHOX2A), and plexin domain containing 1 (PLXDC1). We found that placental DNA methylation profiles related to PFOA mainly enriched in angiogenesis and neuronal signaling pathways. PFOA was associated with hypomethylation of IRS4 and PLXDC1, and PFNA was associated with PLXDC1 hypomethylation. There were positive associations of CHST7 methylation with PFTrDA and IRS4 methylation with PFDoA and PFTrDA. PLXDC1 hypomethylation mediated the association between PFOA and suspected developmental delay in infants. Future studies with larger sample sizes are warranted to confirm these findings.