Early Life Exposure Research Articles

Early-life exposure to tobacco, genetic susceptibility, and accelerated biological aging in adulthood.

Early-life tobacco exposure serves as a non-negligible risk factor for aging-related diseases. To understand the underlying mechanisms, we explored the associations of early-life tobacco exposure with accelerated biological aging and further assessed the joint effects of tobacco exposure and genetic susceptibility. Compared with those without in utero exposure, participants with in utero tobacco exposure had an increase in Klemera-Doubal biological age (KDM-BA) and PhenoAge acceleration of 0.26 and 0.49 years, respectively, but a decrease in telomere length of 5.34% among 276,259 participants. We also found significant dose-response associations between the age of smoking initiation and accelerated biological aging. Furthermore, the joint effects revealed that high-polygenic risk score participants with in utero exposure and smoking initiation in childhood had the highest accelerated biological aging. There were interactions between early-life tobacco exposure and age, sex, deprivation, and diet on KDM-BA and PhenoAge acceleration. These findings highlight the importance of reducing early-life tobacco exposure to improve healthy aging.

Persistent gene expression and DNA methylation alterations linked to carcinogenic effects of dichloroacetic acid.

Mechanistic understanding of transient exposures that lead to adverse health outcomes will enhance our ability to recognize biological signatures of disease. Here, we measured the transcriptomic and epigenomic alterations due to exposure to the metabolic reprogramming agent, dichloroacetic acid (DCA). Previously, we showed that exposure to DCA increased liver tumor incidence in B6C3F1 mice after continuous or early life exposures significantly over background level. Using archived formalin-fixed liver samples, we utilized modern methodologies to measure gene expression and DNA methylation levels to link to previously generated phenotypic measures. Gene expression was measured by targeted RNA sequencing (TempO-seq 1500+ toxicity panel: 2754 total genes) in liver samples collected from 10-, 32-, 57-, and 78-week old mice exposed to deionized water (controls), 3.5 g/L DCA continuously in drinking water ("Direct" group), or DCA for 10-, 32-, or 57-weeks followed by deionized water until sample collection ("Stop" groups). Genome-scaled alterations in DNA methylation were measured by Reduced Representation Bisulfite Sequencing (RRBS) in 78-week liver samples for control, Direct, 10-week Stop DCA exposed mice. Transcriptomic changes were most robust with concurrent or adjacent timepoints after exposure was withdrawn. We observed a similar pattern with DNA methylation alterations where we noted attenuated differentially methylated regions (DMRs) in the 10-week Stop DCA exposure groups compared to the Direct group at 78-weeks. Gene pathway analysis indicated cellular effects linked to increased oxidative metabolism, a primary mechanism of action for DCA, closer to exposure windows especially early in life. Conversely, many gene signatures and pathways reversed patterns later in life and reflected more pro-tumorigenic patterns for both current and prior DCA exposures. DNA methylation patterns correlated to early gene pathway perturbations, such as cellular signaling, regulation and metabolism, suggesting persistence in the epigenome and possible regulatory effects. Liver metabolic reprogramming effects of DCA interacted with normal age mechanisms, increasing tumor burden with both continuous and prior DCA exposure in the male B6C3F1 rodent model.

Early-life exposures and long-term health: adverse gestational environments and the programming of offspring renal and vascular disease.

According to the Developmental Origins of Health and Disease hypothesis, exposure to certain environmental influences during early life may be a key determinant of fetal development and short- and long-term offspring health. Indeed, adverse conditions encountered during the fetal, perinatal, and early childhood stages can alter normal development and growth, as well as put the offspring at elevated risk of developing long-term health conditions in adulthood, including chronic kidney disease and cardiovascular diseases. Of relevance in understanding the mechanistic basis of these long-term health conditions are previous findings showing low glomerular number in human intrauterine growth restriction and low birth weight-indicators of a suboptimal intrauterine environment. In different animal models, the main suboptimal intrauterine conditions studied relate to maternal dietary manipulations, poor micronutrient intake, prenatal ethanol exposure, maternal diabetes, glucocorticoid and chemical exposure, hypoxia, and placental insufficiency. These studies have demonstrated changes in kidney structure, glomerular endowment, and expression of key genes and signaling pathways controlling endocrine, excretion, and filtration function of the offspring. This review aims to summarize those studies to uncover the effects and mechanisms by which adverse gestational environments impact offspring renal and vascular health in adulthood. This is important for identifying agents and interventions that can prevent and mitigate the long-term consequences of an adverse intrauterine environment on the subsequent generation.NEW & NOTEWORTHY Human data and experimental animal data show that suboptimal environments during fetal development increase the risk of renal and vascular diseases in adult-life. This is related to permanent changes in kidney structure, function, and expression of genes and signaling pathways controlling filtration, excretion, and endocrine function. Uncovering the mechanisms by which offspring renal development and function is impacted is important for identifying ways to mitigate the development of diseases that strain health care services worldwide.

DETERMINANTS OF ADULT CARDIAC STRUCTURE: DEVELOPMENTAL INFLUENCE OF PHYSICAL ACTIVITY, SYSTOLIC BLOOD PRESSURE AND TV WATCHING

INTRODUCTION The impacts of health-related behaviours and risk factor exposures across childhood and adolescence on the adult heart are largely unexplored. We investigated whether early-life trajectories for physical activity (PA), sedentary behaviour and systolic blood pressure (SBP) are associated with cardiac structure in adulthood. METHODS Data collected throughout childhood and adolescence on PA, TV watching and SBP in a cohort study were used to develop antecedent trajectories. At age ∼29yrs, participants were invited to undergo an echocardiogram, to assess left ventricular mass (LVM), LV internal diameter (LVID) and LV wall thickness (LVWT). Analysis was performed between trajectories, separately by sex. RESULTS 723 participants were included. In males, LVM was greater in the antecedent High-PA trajectory (184.1±35.6g), compared to both Mid-PA (171.7±36.1g, P=0.014) and Low-PA (166.7±38.0g, P=0.021). This was related to greater LVID in High-PA compared to both Mid-PA (Δ1.3±0.5cm, P=0.018) and Low-PA (Δ1.3±0.8cm, P=0.087) groups; there were no differences in LVWT (all P>0.050). No differences were found in heart structure between PA trajectory groups in females (all P>0.050). For antecedent SBP, LVM was lower in both the Low-SBP (155.7±30.5g) and Normal-SBP groups (172.9±36.7g) compared to both High-normal (184.8±32.9g) and High-SBP (206.2±41.3g) in males (all P<0.001). This was primarily driven by larger LVWT in High-normal (Δ1.2±0.2g, P=0.001) and High-SBP groups (1.9±0.5g, P=0.001); no differences were observed for LVID (P=0.398). These findings for SBP were similar in females, with the highest SBP group having the greatest LVM and LVWT (all P<0.001). There were no significant impacts of antecedent TV trajectories on adult cardiac measures (all P>0.050). CONCLUSION Higher developmental SBP is associated with larger heart size and wall thickness in adulthood. Higher developmental PA levels are associated with larger cardiac chamber dimension in adult males, but not females. These findings suggest adult cardiac structure may be influenced by early-life risk factor exposures.

Associations between prenatal metal and metalloid mixtures in teeth and reductions in childhood lung function

BackgroundMetal(oid)s have been cross-sectionally associated with lung function outcomes in childhood but there is limited data on their combined effects starting in utero. Child sex may further modify these effects. ObjectiveExamine associations between in utero and early life exposure to metals assessed via novel dentine biomarkers and childhood lung function and explore effect modification by child sex. MethodsAnalyses included 291 children enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, a longitudinal birth cohort study in Mexico City. Weekly dentine levels of arsenic (As), cadmium (Cd), cobalt (Co), copper (Cu), manganese (Mn), nickel (Ni), and lead (Pb) were measured from 15 weeks pre-birth to 15 weeks post birth in deciduous children's teeth. Lung function was tested at ages 8–14 years and then modeled as age, height and sex adjusted z-scores. Associations were modeled using lagged weighted quantile sum (LWQS) regression to evaluate the potential for a time-varying mixture effect adjusting for maternal age and education at enrollment and exposure to environmental tobacco smoke in pregnancy. Models were also stratified by sex. ResultsWe identified a window of susceptibility at 12–15 weeks pre-birth in which the metal mixture was associated with lower FVC z-scores in children aged 8–14 years. Cd and Mn were the largest contributors to the mixture effect (70 %). There was also some evidence of effect modification by sex, in which the mean weights and weighted correlations over the identified window was more evident in males when compared to females. In the male stratum, Cd, Mn and additionally Pb also dominated the mixture association. ConclusionsPrenatal metal(oid) exposure was associated with lower lung function in childhood. These findings underscore the need to consider both mixtures and windows of susceptibility to fully elucidate effects of prenatal metal(oid) exposure on childhood lung function.

Maternal Limosilactobacillus reuteri rescues social and emotional recognition behavior in an environmental mouse model of autism

Introduction: Polybrominated diphenyl ethers (PBDEs) are thyroid disrupting chemicals with adverse neurodevelopmental effects in children. Our group has previously shown that PBDEs produce autism (ASD)-like traits (Kozlova et al. 2022 Arch Tox; PMID: 34687351) in combination with reduced hypothalamic oxytocin expression in developmentally exposed female mice offspring. Limosilactobacillus reuteri (LR) is a beneficial probiotic that can increase oxytocin and thyroid hormones (THs) in other ASD mouse models. Therefore, we hypothesized that LR would ameliorate PBDE-induced deficits in social behavior, oxytocin and thyroid status. Methods: C57BL/6N dams (n=8/group) were dosed with a commercial mixture of PBDE congeners, DE-71, at 0.1 mg/kg/d (DE-71), or corn oil vehicle control (VEH/CON) during preconception, gestation and lactation). Dams were gavaged with L. reuteri (LR) ATCC-PTA-6475 at 107-108 CFU/mL (gift of Biogaia, Sweden). Cohort 1 pups (C1) received LR via dam until weaning (PND 21). Cohort 2 pups (C2) continued to receive gavage of LR post-weaning, daily, through 6 mo of age. Results: Fecal microbiome analysis confirmed colonization of LR in dams after 25 doses and their offspring at postnatal day 22 and 40. Beta diversity PCoA using unweighted Unifrac revealed differences in microbial communities in 6 month old female (p<.05-.01) and male offspring (apparent) between DE-71 and VEH/CON (C2). LR treatment normalized DE-71-induced abnormal social novelty preference (30 min retention) in adult male (p<.01) and females (p<.05) and long-term social recognition memory (24 h retention) in adult C2 females (p<.001). Using an emotional recognition task DE-71-exposed C2 male and female offspring were unable to distinguish between emotional state of stimulus mice but LR supplementation normalized the DE-71-induced deficits in C2 males (p<.01) and females (p<.05). On a marble burying test DE-71 exposed offspring showed abnormally elevated scores compared to VEH/CON, which were normalized by LR treatment only in C1 females (p<.05). In females, maternal LR treatment ameliorated DE-71-induced locomotor hyperactivity in C1. Since social behavior involves discrimination between social odors we also investigated the effects of DE-71 and LR treatment on olfactory discrimination ability. LR treatment ameliorated DE-71 effects compared to VEH/CON, i.e., reduced dishabituation from social odor 1 to 2 in males and female (p<.0001). Single molecule in situ hybridization performed on paraventricular hypothalamic nucleus (PVN) sections revealed upregulation of thyroid hormone transporter monocarboxylate transporter 8 (Mct8) and downregulation of iodothyronine deiodinase 3 (Dio3) on oxytocin-positive neurons in DE-71 vs VEH/CON in C2 females. Dio3 expression was normalized in DE-71+LR. Conclusions: These results indicate that early life exposure to PBDEs alters thyroid hormone system genes in PVN neurons that express oxytocin, suggesting that PBDEs may alter ASD-relevant behavior via brain thyroid signaling. In addition, maternal LR supplementation provides normalization in a sex-dependent manner. This work is supported by a Danone North America Gut Microbiome, Yogurt and Probiotics Fellowship Grant and a University of California President's Pre-Professoriate Fellowship to E.V.K and an NIH/NIGMS R35GM124724 to A.H. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Prenatal and postnatal early life exposure to greenness and particulate matter of different size fractions in relation to childhood rhinitis - A multi-center study in China

The impact of early life exposure to residential greenness on childhood rhinitis and its interaction with particulate matter (PM) of different size fractions remain inconsistent. Herein, we recruited 40,486 preschool children from randomly selected daycare centers in 7 cities in China from 2019 to 2020, and estimated exposure to residential greenness by the normalized difference vegetation index (NDVI) with a 500 m buffer. Exposure to ambient PM (PM1, PM2.5, and PM10) was evaluated using a satellite-based prediction model (daily, at a resolution of 1 km × 1 km). By mixed-effect logistic regression, NDVI values during pregnancy, in the first (0–1 year old) and the second (1–2 years old) year of life were negatively associated with lifetime rhinitis (LR) and current rhinitis (CR) (P < 0.001). PM in the same time windows was associated with increased risks of LR and CR in children, with smaller size fraction of PM showing greater associations. The negative associations between prenatal and postnatal NDVI and LR and CR in preschool children remained robust after adjusting for concomitant exposure to PM, whereas the associations of postnatal NDVI and rhinitis showed significant interactions with PM. At lower levels of PM, postnatal NDVI remained negatively associated with rhinitis and was partly mediated by PM (10.0–40.9 %), while at higher levels of PM, the negative associations disappeared or even turned positive. The cut-off levels of PM were identified for each size fraction of PM. In conclusion, prenatal exposure to greenness had robust impacts in lowering the risk of childhood rhinitis, while postnatal exposure to greenness depended on the co-exposure levels to PM. This study revealed the complex interplay of greenness and PM on rhinitis in children. The exposure time window in prenatal or postnatal period and postnatal concomitant PM levels played important roles in influencing the associations between greenness, PM and rhinitis.

Killing Prescriptions Softly: Low Emission Zones and Child Health from Birth to School

We examine the persistence of the impact of early-life exposure to air pollution on children’s health from birth to school enrollment using administrative public health insurance records covering one-third of all children in Germany. For identification, we exploit air quality improvements caused by Low Emission Zones, a policy imposing driving restrictions on emission-intensive vehicles. Our results indicate that children exposed to cleaner air in utero and their first year of life require less medication for at least five years. The initially latent health response materializes only gradually, leaving important but subtle health benefits undetected in common measures of infant health. (JEL I12, I13, J13, Q51, Q53, R48)

Fetal and Infancy Exposure to Phenols, Parabens, and Phthalates and Anthropometric Measurements up to 36 Months, in the Longitudinal SEPAGES Cohort.

Endocrine-disrupting chemicals may play a role in adiposity development during childhood. Until now literature in this scope suffers from methodologic limitations in exposure assessment using one or few urine samples and missing assessment during the infancy period. We investigated the associations between early-life exposure to quickly metabolized chemicals and post-natal growth, relying on repeated within-subject urine collections over pregnancy and infancy. We studied the associations of four phenols, four parabens, seven phthalates, and one nonphthalate plasticizer from weekly pooled urine samples collected from the mother during second and third trimesters (median 18 and 34 gestational weeks, respectively) and infant at 2 and 12 months of age, and child growth until 36 months. We relied on repeated measures of height, weight and head circumference from study visits and the child health booklet to predict growth outcomes at 3 and 36 months using the Jenss-Bayley nonlinear mixed model. We assessed associations with individual chemicals using adjusted linear regression and mixtures of chemicals using a Bayesian kernel machine regression model. The unipollutant analysis revealed few associations. Bisphenol S (BPS) at second trimester was positively associated with all infant growth parameters at 3 and 36 months, with similar patterns between exposure at third trimester and all infant growth parameters at 3 months. Mono-n-butyl phthalate (MnBP) at 12 months was positively associated with body mass index (BMI), weight, and head circumference at 36 months. Mixture analysis revealed positive associations between exposure at 12 months and BMI and weight at 36 months, with MnBP showing the highest effect size within the mixture. This study suggests that exposure in early infancy may be associated with increased weight and BMI in early childhood, which are risk factors of obesity in later life. Furthermore, this study highlighted the impact of BPS, a compound replacing bisphenol A, which has never been studied in this context. https://doi.org/10.1289/EHP13644.

Effects of parental childhood cultural health environment on children’s influenza and COVID-19 vaccination status

Most studies examining factors associated with pediatric influenza (flu) and coronavirus disease (COVID-19) vaccination uptake focus on parental demographics. We examined whether the childhood cultural health environment (CHE) of parents (measured by self-reported regular attendance at doctor and dentist visits during childhood) was associated with flu and COVID-19 vaccination of their children. Using 2023 survey data from 397 US parents and causal inference methods, we estimated the average causal effect of parental CHE on flu vaccination rates (0.16 [95 % confidence interval: 0.06,0.27]) and COVID-19 (0.14 [95 % confidence interval: 0.04,0.24]), indicating that if all parents had attended regular doctor/dentist visits as children, flu and COVID-19 vaccination rates in children would be 16 % and 14 % higher, respectively, than if none had. Our findings suggest that early life exposure to medical and dental care has significant and lasting effects on the health of individuals and families.

Examining the associations between microglia genetic capacity, early life exposures and white matter development at the level of the individual

There are inter-individual differences in susceptibility to the influence of early life experiences for which the underlying neurobiological mechanisms are poorly understood. Microglia play a role in environmental surveillance and may influence individual susceptibility to environmental factors. As an index of neurodevelopment, we estimated individual slopes of mean white matter fractional anisotropy (WM-FA) across three time-points (age 4.5, 6.0, and 7.5 years) for 351 participants. Individual variation in microglia reactivity was derived from an expression-based polygenic score(ePGS) comprised of Single Nucleotide Polymorphisms (SNPs) functionally related to the expression of microglia-enriched genes.A higher ePGS denotes an increased genetic capacity for the expression of microglia-related genes, and thus may confer a greater capacity to respond to the early environment and to influence brain development. We hypothesized that this ePGS would associate with the WM-FA index of neurodevelopment and moderate the influence of early environmental factors.Our findings show sex dependency, where a significant association between WM-FA and microglia ePGS was only obtained for females.We then examined associations with perinatal factors known to decrease (optimal birth outcomes and familial conditions) or increase (systemic inflammation) the risk for later mental health problems.In females, individuals with high microglia ePGS showed a negative association between systemic inflammation and WM-FA and a positive association between more advantageous environmental conditions and WM-FA. The microglia ePGS in females thus accounted for variations in the influence of the quality of the early environment on WM-FA.Finally, WM-FA slopes mediated the association of microglia ePGS with interpersonal problems and social hostility in females. Our findings suggest the genetic capacity for microglia function as a potential factor underlying differential susceptibility to early life exposuresthrough influences on neurodevelopment.

Early life ambient air pollution, household fuel use, and under-5 mortality in Ghana

IntroductionEnvironmental exposures, such as ambient air pollution and household fuel use affect health and under-5 mortality (U5M) but there is a paucity of data in the Global South. This study examined early-life exposure to ambient particulate matter with a diameter of 2.5 µm or less (PM2.5), alongside household characteristics (including self-reported household fuel use), and their relationship with U5M in the Navrongo Health and Demographic Surveillance Site (HDSS) in northern Ghana. MethodsWe employed Satellite-based spatiotemporal models to estimate the annual average PM2.5 concentrations with the Navrongo HDSS area (1998 to 2016). Early-life exposure levels were determined by pollution estimates at birth year. Socio-demographic and household data, including cooking fuel, were gathered during routine surveillance. Cox proportional hazards models were applied to assess the link between early-life PM2.5 exposure and U5M, accounting for child, maternal, and household factors. FindingsWe retrospectively studied 48,352 children born between 2007 and 2017, with 1872 recorded deaths, primarily due to malaria, sepsis, and acute respiratory infection. Mean early-life PM2.5 was 39.3 µg/m3, and no significant association with U5M was observed. However, Children from households using “unclean” cooking fuels (wood, charcoal, dung, and agricultural waste) faced a 73 % higher risk of death compared to those using clean fuels (adjusted HR = 1.73; 95 % CI: 1.29, 2.33). Being born female or to mothers aged 20–34 years were linked to increased survival probabilities. InterpretationThe use of “unclean” cooking fuel in the Navrongo HDSS was associated with under-5 mortality, highlighting the need to improve indoor air quality by introducing cleaner fuels.

Early Life Exposures and the Development of the Infant Gut Microbiome: A Review

The influence of the intestinal microbiota on metabolic, nutritional, and immunological processes is widely reported. With increasing literature associating altered microbial compositions with adverse health outcomes, it is important to understand how early life exposures may impact the development of gut microbial colonization and subsequent risk of altered metabolic and immune regulation. The purpose of this review is to describe factors in the maternal prenatal and perinatal period that may impact the intestinal microbiome over the first 2 years of life. A comprehensive search of MEDLINE, EMBASE, and the Cochrane Library using Medical Subject Headings (MeSH) and keywords for studies reporting on determinants of gut microbiota in infants (0 to 24 months) born at full term was conducted. Articles using culture techniques were included but not those that exclusively used molecular techniques that lacked sensitivity. Each citation title and abstract was independently assessed for inclusion for full text review. Findings related to the maternal prenatal period, mode of birthing, infant diet and antibiotics were included. Bifidobacteria and Bacteroides abundance were consistently greater in the first weeks of life in children born vaginally, and increased Bacteroides presence persisted throughout the first year. Bifidobacteria abundance was greater in breastfed children. Introduction of solid food was associated with greater presence of bacteria of the Firmicutes phylum. Although these studies advance our knowledge of how exposures in prenatal, intrapartum, and early life may impact colonization, larger studies with longitudinal follow-up are needed to improve our understanding of how perturbations may contribute to early origins of disease. This article has been peer reviewed.

Post-traumatic growth in later-life cognitive function? Evidence from the 1976 Great Tangshan Earthquake.

This study aimed to explore the long-term impacts of exposure to earthquake in adolescence on later-life cognitive function in China. Data were from the 2015 China Health and Retirement Longitudinal Study (CHARLS). Our analytical sample comprised 4394 participants aged 49 to 78 from two birth cohorts born between 1937 and 1966: exposed cohort during adolescence (born between 1952 and 1966), and non-exposed cohort during adolescence (born between 1937 and 1951). We defined earthquake exposure as the exposure severity of the 1976 Great Tangshan Earthquake (GTE). We selected community environmental characteristics as our key moderators. A difference-in-differences (DID) method was employed to estimate the long-term impact of the GTE on later-life cognitive function. We found that exposure to the earthquake during adolescence resulted in higher scores of later-life cognitive function (for males: β = 2.18; 95% CI: 0.70-3.66; for females: β = 1.22; 95% CI: 0.11-2.33). For males, this impact was moderated by community environmental characteristics including the old-age allowance program (β = 3.07; 95% CI: 1.94-4.19) and the condition of basic community infrastructures (β = 1.52; 95% CI: 0.84-2.19). Our study supports the post-traumatic growth theory. This finding suggest that individuals with early-life traumatic exposure need to be focused on. Additionally, improving the conditions of community infrastructures and establishing a community environment with comfort and security may be pretty important for promoting cognitive function and post-traumatic growth.

The Impact of the Aryl Hydrocarbon Receptor on Antenatal Chemical Exposure-Induced Cardiovascular-Kidney-Metabolic Programming.

Early life exposure lays the groundwork for the risk of developing cardiovascular-kidney-metabolic (CKM) syndrome in adulthood. Various environmental chemicals to which pregnant mothers are commonly exposed can disrupt fetal programming, leading to a wide range of CKM phenotypes. The aryl hydrocarbon receptor (AHR) has a key role as a ligand-activated transcription factor in sensing these environmental chemicals. Activating AHR through exposure to environmental chemicals has been documented for its adverse impacts on cardiovascular diseases, hypertension, diabetes, obesity, kidney disease, and non-alcoholic fatty liver disease, as evidenced by both epidemiological and animal studies. In this review, we compile current human evidence and findings from animal models that support the connection between antenatal chemical exposures and CKM programming, focusing particularly on AHR signaling. Additionally, we explore potential AHR modulators aimed at preventing CKM syndrome. As the pioneering review to present evidence advocating for the avoidance of toxic chemical exposure during pregnancy and deepening our understanding of AHR signaling, this has the potential to mitigate the global burden of CKM syndrome in the future.

Elemental composition of toxic and essential elements in rice-based baby foods from the United States and other countries: A probabilistic risk analysis

Consumption of rice-based foods provides essential nutrients required for infants and toddlers’ growth. However, they could contain toxic and excess essential elements that may affect human health. The study aims to determine the composition of rice-based baby foods in the USA and outside and conduct a multiple-life stages probabilistic exposure and risk assessment of toxic and essential elements in children. Elemental concentrations were measured using Inductively Coupled Plasma Mass Spectrometry (ICP-MS) in thirty-three rice-based baby foods. This includes 2 infant formulas, 11 rice baby cereals, and 20 rice snacks produced primarily in the United States, China, and other countries. A probabilistic risk assessment was conducted to assess risks of adverse health effects. Results showed that infant formula had higher median concentrations of selenium (Se), copper (Cu), zinc (Zn), sodium (Na), magnesium (Mg), calcium (Ca), and potassium (K) compared to rice baby cereal and rice snacks. On the contrary, rice snacks had the highest median concentration of Arsenic (As) (127 μg/kg) while rice baby cereals showed the highest median concentration of Cd (7 μg/kg). A higher lifetime estimated daily intake was observed for samples manufactured in the USA compared to those from China and other countries. Hazard quotient (HQ < 1) values were suggestive of minimal adverse health effects. However, lifetime carcinogenic risk analysis based on total As indicated an unacceptable cancer risk (>1E-04). These findings show a need for ongoing monitoring of rice-based foods consumed by infants and toddlers as supplementary and substitutes for breast milk or weaning food options. This can be useful in risk reduction and mitigation of early life exposure to improve health outcomes.

Environmental Exposures and Pediatric Cardiology: A Scientific Statement From the American Heart Association.

Environmental toxicants and pollutants are causes of adverse health consequences, including well-established associations between environmental exposures and cardiovascular diseases. Environmental degradation is widely prevalent and has a long latency period between exposure and health outcome, potentially placing a large number of individuals at risk of these health consequences. Emerging evidence suggests that environmental exposures in early life may be key risk factors for cardiovascular conditions across the life span. Children are a particularly sensitive population for the detrimental effects of environmental toxicants and pollutants given the long-term cumulative effects of early-life exposures on health outcomes, including congenital heart disease, acquired cardiac diseases, and accumulation of cardiovascular disease risk factors. This scientific statement highlights representative examples for each of these cardiovascular disease subtypes and their determinants, focusing specifically on the associations between climate change and congenital heart disease, airborne particulate matter and Kawasaki disease, blood lead levels and blood pressure, and endocrine-disrupting chemicals with cardiometabolic risk factors. Because children are particularly dependent on their caregivers to address their health concerns, this scientific statement highlights the need for clinicians, research scientists, and policymakers to focus more on the linkages of environmental exposures with cardiovascular conditions in children and adolescents.

Early-life house dust mite aeroallergen exposure augments cigarette smoke-induced myeloid inflammation and emphysema in mice

BackgroundLongitudinal studies have identified childhood asthma as a risk factor for obstructive pulmonary disease (COPD) and asthma-COPD overlap (ACO) where persistent airflow limitation can develop more aggressively. However, a causal link between childhood asthma and COPD/ACO remains to be established. Our study aimed to model the natural history of childhood asthma and COPD and to investigate the cellular/molecular mechanisms that drive disease progression.MethodsAllergic airways disease was established in three-week-old young C57BL/6 mice using house dust mite (HDM) extract. Mice were subsequently exposed to cigarette smoke (CS) and HDM for 8 weeks. Airspace enlargement (emphysema) was measured by the mean linear intercept method. Flow cytometry was utilised to phenotype lung immune cells. Bulk RNA-sequencing was performed on lung tissue. Volatile organic compounds (VOCs) in bronchoalveolar lavage-fluid were analysed to screen for disease-specific biomarkers.ResultsChronic CS exposure induced emphysema that was significantly augmented by HDM challenge. Increased emphysematous changes were associated with more abundant immune cell lung infiltration consisting of neutrophils, interstitial macrophages, eosinophils and lymphocytes. Transcriptomic analyses identified a gene signature where disease-specific changes induced by HDM or CS alone were conserved in the HDM-CS group, and further revealed an enrichment of Mmp12, Il33 and Il13, and gene expression consistent with greater expansion of alternatively activated macrophages. VOC analysis also identified four compounds increased by CS exposure that were paradoxically reduced in the HDM-CS group.ConclusionsEarly-life allergic airways disease worsened emphysematous lung pathology in CS-exposed mice and markedly alters the lung transcriptome.

Sensitivity analysis for matched observational studies with continuous exposures and binary outcomes

Summary Matching is one of the most widely used study designs for adjusting for measured confounders in observational studies. However, unmeasured confounding may exist and cannot be removed by matching. Therefore, a sensitivity analysis is typically needed to assess a causal conclusion’s sensitivity to unmeasured confounding. Sensitivity analysis frameworks for binary exposures have been well-established for various matching designs and are commonly used in various studies. However, unlike the binary exposure case, there still lacks valid and general sensitivity analysis methods for continuous exposures, except in some special cases such as pair matching. To fill this gap in the binary outcome case, we develop a sensitivity analysis framework for general matching designs with continuous exposures and binary outcomes. First, we use probabilistic lattice theory to show our sensitivity analysis approach is finite-population- exact under Fisher’s sharp null. Second, we prove a novel design sensitivity formula as a powerful tool for asymptotically evaluating the performance of our sensitivity analysis approach. Third, to allow effect heterogeneity with binary outcomes, we introduce a framework for conducting asymptotically exact inference and sensitivity analysis on generalized attributable effects with binary outcomes via mixed- integer programming. Fourth, for the continuous outcomes case, we show that conducting an asymptotically exact sensitivity analysis in matched observational studies when both the exposures and outcomes are continuous is generally NP-hard, except in some special cases such as pair matching. As a real data application, we apply our new methods to study the effect of early-life lead exposure on juvenile delinquency. An implementation of the methods in this work is available in the R package doseSens.

Early life exposure to secondhand tobacco smoke and eating behaviors at age 12 years

BackgroundPrenatal or early childhood secondhand tobacco smoke (SHS) exposure increases obesity risk. However, the potential mechanisms underlying this association are unclear, but obesogenic eating behaviors are one pathway that components of SHS could perturb. Our aim was to assess associations of prenatal and early childhood SHS exposure with adolescent eating behaviors.MethodsData came from a prospective pregnancy and birth cohort (N = 207, Cincinnati, OH). With multiple informant models, we estimated associations of prenatal (mean of 16 and 26 weeks of gestation maternal serum cotinine concentrations) and early childhood cotinine (average concentration across ages 12, 24, 36, and 48 months) with eating behaviors at age 12 years (Child Eating Behaviors Questionnaire). We tested whether associations differed by exposure periods and adolescent’s sex. Models adjusted for maternal and child covariates.ResultsWe found no statistically significant associations between cotinine measures and adolescent’s eating behaviors. Yet, in females, prenatal cotinine was associated with greater food responsiveness (β: 0.23; 95% CI: 0.08, 0.38) and lower satiety responsiveness (β: -0.14; 95% CI: -0.26, -0.02); in males, prenatal and postnatal cotinine was related to lower food responsiveness (prenatal: β: -0.25; 95% CI: -0.04, -0.06; postnatal: β: -0.36; 95% CI: -0.06, -0.11). No significant effect modification by sex or exposure window was found for other eating behaviors.ConclusionPrenatal and early childhood SHS exposures were not related to adolescent’s eating behavior in this cohort; however, biological sex may modify these associations.