Biomarkers of aging through the life course: A Recent Literature Update.

Purpose of review: The development of biomarkers of aging has greatly advanced epidemiological studies of aging processes. However, much debate remains on the timing of aging onset and the causal relevance of these biomarkers. In this review, we discuss the most recent biomarkers of aging that have been applied across the life course. Recent findings: The most recently developed aging biomarkers that have been applied across the life course can be designated into three categories: epigenetic clocks, epigenetic markers of chronic inflammation, and mitochondrial DNA copy number. While these have been applied at different life stages, the development, validation, and application of these markers has been largely centered on populations of older adults. Few studies have examined trajectories of aging biomarkers across the life course. As the wealth of molecular and biochemical data increases, emerging biomarkers may be able to capture complex and system-specific aging processes. Recently developed biomarkers include novel epigenetic clocks; clocks based on ribosomal DNA, transcriptomic profiles, proteomics, metabolomics, and inflammatory markers; clonal hematopoiesis of indeterminate potential gene mutations; and multi-omics approaches. Summary: Attention should be placed on aging at early and middle life stages to better understand trajectories of aging biomarkers across the life course. Additionally, novel biomarkers will provide greater insight into aging processes. The specific mechanisms of aging reflected by these biomarkers should be considered when interpreting results.

Evaluation of pediatric epigenetic clocks across multiple tissues.

BACKGROUND: Epigenetic clocks are promising tools for assessing biological age. We assessed the accuracy of pediatric epigenetic clocks in gestational and chronological age determination. RESULTS: Our study used data from seven tissue types on three DNA methylation profiling microarrays and found that the Knight and Bohlin clocks performed similarly for blood cells, while the Lee clock was superior for placental samples. The pediatric-buccal-epigenetic clock performed the best for pediatric buccal samples, while the Horvath clock is recommended for children's blood cell samples. The NeoAge clock stands out for its unique ability to predict post-menstrual age with high correlation with the observed age in infant buccal cell samples. CONCLUSIONS: Our findings provide valuable guidance for future research and development of epigenetic clocks in pediatric samples, enabling more accurate assessments of biological age.

Prenatal oxidative stress and rapid infant weight gain.

BACKGROUND AND OBJECTIVES: Infant weight patterns predict subsequent weight outcomes. Rapid infant weight gain, defined as a >0.67 increase in weight-for-age z-score (WAZ) between two time points in infancy, increases obesity risk. Higher oxidative stress, an imbalance between antioxidants and reactive oxygen species, has been associated with low birthweight and paradoxically also with later obesity. We hypothesized that prenatal oxidative stress may also be associated with rapid infant weight gain, an early weight pattern associated with future obesity. METHODS: Within the NYU Children's Health and Environment Study prospective pregnancy cohort, we analyzed associations between prenatal lipid, protein, and DNA urinary oxidative stress biomarkers and infant weight data. Primary outcome was rapid infant weight gain (>0.67 increase in WAZ) between birth and later infancy at the 8 or 12 month visit. Secondary outcomes included: very rapid weight gain (>1.34 increase in WAZ), low (<2500 g) or high (≥4000 g) birthweight, and low (< -1 WAZ) or high (>1 WAZ) 12 month weight. RESULTS: Pregnant participants consented to the postnatal study (n = 541); 425 participants had weight data both at birth and in later infancy. In an adjusted binary model, prenatal 8-iso-PGF2α, a lipid oxidative stress biomarker, was associated with rapid infant weight gain (aOR 1.44; 95% CI: 1.16, 1.78, p = 0.001). In a multinomial model using ≤0.67 change in WAZ as a reference group, 8-iso-PGF2α was associated with rapid infant weight gain (defined as >0.67 but ≤1.34 WAZ; aOR 1.57, 95% CI: 1.19, 2.05, p = 0.001) and very rapid infant weight gain (defined as >1.34 WAZ; aOR 1.33; 95% CI: 1.02, 1.72, p < 0.05) Secondary analyses detected associations between 8-iso-PGF2α and low birthweight outcomes. CONCLUSIONS: We found an association between 8-iso-PGF2α, a lipid prenatal oxidative stress biomarker, and rapid infant weight gain, expanding our understanding of the developmental origins of obesity and cardiometabolic disease.

Prenatal bisphenol A and S exposure and atopic disease phenotypes at age 6.

BACKGROUND: Atopic disease may be influenced by prenatal and early life exposure to endocrine disrupting chemicals, including bisphenols, but results from epidemiological studies have been mixed. This study aimed to extend the epidemiological literature, hypothesizing that children with higher prenatal bisphenol exposure are more likely to have childhood atopic disease. METHODS: Urinary bisphenol A (BPA) and S (BPS) concentrations were measured in each trimester from 501 pregnant women in a multi-center, prospective pregnancy cohort. Ever asthma, current asthma, wheeze, and food allergy) were assessed at age six via standardized ISAAC questionnaire. We constructed generalized estimating equations to examine BPA and BPS exposure jointly at each trimester for each atopy phenotype. BPA was modeled as a log-transformed continuous variable, whereas BPS was modeled as detected versus not detected. We also modeled pregnancy-averaged BPA values and a categorical indicator for number of detectable BPS values over pregnancy (0-3) in logistic regression models. RESULTS: First trimester BPA was associated with inverse odds of food allergy among the entire study sample (OR = 0.78, 95% CI = 0.64-0.95, p = 0.01) and females only (OR = 0.69, 95% CI = 0.52-0.90, p = 0.006). The inverse relationship persisted in pregnancy-averaged models of BPA among females (OR = 0.56, 95% CI = 0.35-0.90, p = 0.006). Second trimester BPA was associated with greater odds of food allergy in the entire sample (OR = 1.27, 95% CI = 1.02-1.58, p = 0.03) and among males only (OR = 1.48, 95% CI = 1.02-2.14, p = 0.04). Odds of current asthma increased among males in the pregnancy-averaged BPS models (OR = 1.65, 95% CI = 1.01-2.69, p = 0.045). CONCLUSION: We saw opposite effects of BPA on food allergy that were trimester- and sex-specific. These divergent associations warrant further investigation. There is some evidence to suggest that prenatal BPS is associated with asthma among males, but further research is required in cohorts with a greater proportion of prenatal urine samples with detectable BPS to validate these results.

Fetal exposure to phthalates and bisphenols and DNA methylation at birth: the Generation R Study.

BACKGROUND: Phthalates and bisphenols are non-persistent endocrine disrupting chemicals that are ubiquitously present in our environment and may have long-lasting health effects following fetal exposure. A potential mechanism underlying these exposure-outcome relationships is differential DNA methylation. Our objective was to examine the associations of maternal phthalate and bisphenol concentrations during pregnancy with DNA methylation in cord blood using a chemical mixtures approach. METHODS: This study was embedded in a prospective birth cohort study in the Netherlands and included 306 participants. We measured urine phthalates and bisphenols concentrations in the first, second and third trimester. Cord blood DNA methylation in their children was processed using the Illumina Infinium HumanMethylation450 BeadChip using an epigenome-wide association approach. Using quantile g-computation, we examined the association of increasing all mixture components by one quartile with cord blood DNA methylation. RESULTS: We did not find evidence for statistically significant associations of a maternal mixture of phthalates and bisphenols during any of the trimesters of pregnancy with DNA methylation in cord blood (all p values > 4.01 * 10-8). However, we identified one suggestive association (p value < 1.0 * 10-6) of the first trimester maternal mixture of phthalates and bisphenols and three suggestive associations of the second trimester maternal mixture of phthalates and bisphenols with DNA methylation in cord blood. CONCLUSIONS: Although we did not identify genome-wide significant results, we identified some suggestive associations of exposure to a maternal mixture of phthalates and bisphenols in the first and second trimester with DNA methylation in cord blood that need further exploration in larger study samples.

Variability and correlations of synthetic chemicals in urine from a New York City-based cohort of pregnant women.

Fetal exposure to environmental chemicals has been associated with adverse health outcomes in children and later into adulthood. While several studies have examined correlations and variability of non-persistent chemical exposures throughout pregnancy, many do not capture more recent exposures, particularly in New York City. Our goal was to characterize exposure to phthalates, bisphenols, polycyclic aromatic hydrocarbons, and organophosphate pesticides among pregnant women residing in New York City who enrolled in the New York University Children's Health and Environment Study (NYU CHES) between 2016 and 2018. We measured urinary chemical metabolite concentrations in 671 women at early, mid, and late pregnancy (median 10.8, 20.8, and 29.3 weeks, respectively). We calculated Spearman correlation coefficients among chemical concentrations at each measurement time point. We compared changes in population-level urinary metabolites at each stage using paired Wilcoxon signed-rank tests and calculated intraclass correlation coefficients (ICCs) to quantify intra-individual variability of metabolites across pregnancy. Geometric means and ICCs were compared to nine other pregnancy cohorts that recruited women in 2011 or later as well as nationally reported levels from women of child-bearing age. Compared with existing cohorts, women in NYU CHES had higher geometric means of organophosphate pesticides (Σdiethylphosphates = 28.7 nmol/g cr, Σdimethylphosphates = 57.3 nmol/g cr, Σdialkyl phosphates = 95.9 nmol/g cr), bisphenol S (0.56 µg/g cr), and 2-naphthalene (8.98 µg/g cr). Five PAH metabolites and two phthalate metabolites increased between early to mid and early to late pregnancy at the population level. Spearman correlation coefficients for chemical metabolites were generally below 0.50. Intra-individual exposures varied over time, as indicated by low ICCs (0.22-0.88, median = 0.38). However, these ICCs were often higher than those observed in other pregnancy cohorts. These results provide a general overview of the chemical metabolites measured in NYU CHES in comparison to other contemporary pregnancy cohorts and highlight directions for future studies.

Persistent organic pollutant exposure and celiac disease: A pilot study.

Celiac disease affects approximately 1% of the population worldwide. Little is known about environmental factors that may modulate risk in genetically susceptible populations. Persistent organic pollutants (POPs) are known endocrine disruptors and, given the interplay between the endocrine and immune systems, are plausible contributors to celiac disease. The current study aims to elucidate the association between POPs and celiac disease. We conducted a single-site pilot study of 88 patients recruited from NYU Langone's Hassenfeld Children's Hospital outpatient clinic, 30 of which were subsequently diagnosed with celiac disease using standard serology and duodenal biopsy examination. Polybrominated diphenyl ether (PBDEs), perfluoroalkyl substances (PFASs), and p,p'-dichlorodiphenyldichloroethylene (DDE) and HLA-DQ genotype category were measured in blood serum and whole blood, respectively. Multivariable logistic regressions were used to obtain odds ratios for celiac disease associated with serum POP concentrations. Controlling for sex, race, age, BMI, and genetic susceptibility score, patients with higher serum DDE concentrations had 2-fold higher odds of celiac disease (95% CI: 1.08, 3.84). After stratifying by sex, we found higher odds of celiac disease in females with serum concentrations of DDE (OR = 13.0, 95% CI = 1.54, 110), PFOS (OR = 12.8, 95% CI = 1.17, 141), perfluorooctanoic acid (OR = 20.6, 95% CI = 1.13, 375) and in males with serum BDE153, a PBDE congener (OR = 2.28, 95% CI = 1.01, 5.18). This is the first study to report on celiac disease with POP exposure in children. These findings raise further questions of how environmental chemicals may affect autoimmunity in genetically susceptible individuals.

Trends in neurodevelopmental disability burden due to early life chemical exposure in the USA from 2001 to 2016: A population-based disease burden and cost analysis.

Endocrine disrupting chemicals are known to cause neurodevelopmental toxicity through direct and indirect pathways. In this study we used data from the National Health and Nutrition Examination Surveys, along with known exposure-disease relationships, to quantify the intellectual disability burden attributable to in utero exposure to polybrominated diphenyl ethers (PBDEs), organophosphates, and methylmercury and early life exposure to lead. We also estimated the cost of the IQ points lost and cases of intellectual disability. PBDE exposure was the greatest contributor to intellectual disability burden, resulting in a total of 162 million IQ points lost and over 738,000 cases of intellectual disability. This was followed by lead, organophosphates, and methylmercury. From 2001 to 2016, IQ loss from PBDEs, methylmercury, and lead have decreased or remained stagnant. Organophosphate exposure measurements were only available up to 2008 but did show an increase in organophosphate-attributable IQ loss. Although most of these trends show benefit for children's neurodevelopmental health, they may also point towards the use of potentially harmful substitutions for chemicals that are being phased out.

Serum perfluoroalkyl substances and lung function in adolescents exposed to the World Trade Center disaster.

The effects of childhood exposure to perfluoroalkyl substances (PFASs) on lung function remain mostly unknown. Previous research indicates that children living or going to school near the World Trade Center (WTC) disaster were exposed to high levels of PFASs, among other toxic chemicals. To explore the effects of PFAS exposure on lung function, we measured serum PFASs in a cohort of children from the WTC Health Registry and a matched control group. Perfluorooctanesulfonate had the highest median concentrations in both groups (WTCHR = 3.72 ng/mL, Comparison = 2.75 ng/mL), while the lowest median concentrations were seen for perfluoroundecanoic acid (WTCHR = 0.12 ng/mL, Comparison = 0.01 ng/mL). Lung function outcomes were measured by spirometry, plethysmography, and oscillometry. Asthma diagnosis and serum eosinophil count were also recorded. We examined the relationships of each PFAS with lung function parameters and eosinophil count using linear regressions. Odds ratios for asthma were obtained for each PFAS using logistic regression. The effect of total PFASs on these outcomes was also assessed. All regression models were adjusted for sex, race/ethnicity, age, body mass index (BMI) and tobacco smoke exposure. We found that serum PFASs were not statistically associated with the measured lung function parameters, asthma diagnosis, or eosinophil count in this cohort (p < 0.05). These findings highlight the need for more longitudinal studies to explore the long-term effects of childhood PFAS exposure on lung function past adolescence and early adulthood.

Impact of housing instability on child behavior at age 7.

Housing instability is a thought to be a major influence on children's healthy growth and development. However, little is known about the factors that influence housing instability, limiting the identification of effective interventions. The goals of this study were to 1) explore factors, including material hardship, satisfaction with living conditions and housing disrepair, that predict housing instability (total number of moves that a child experienced in the first seven years); and 2) examine the relationship between housing instability and child behavior at age 7, measured by the Child Behavior Checklist. We analyzed these associations among children enrolled in the Columbia Center for Children's Environmental Health (CCCEH) Mothers and Newborns study. In our analysis, we found that housing disrepair predicted residential change after 3 years of age, but not before. Persistent material hardship over the seven-year time period from pregnancy through age 7 was associated with increased number of moves. Children who experienced more than three moves in the first 7 years had significantly more thought- and attention-related problems compared to children who experienced less than 3 moves over the same time period. Children who experienced more than 3 moves also had higher total and internalizing problem behavior scores, although these differences were not statistically significant. We conclude that housing instability is significantly associated with problem behavior in early childhood and that interventions to reduce socioeconomic strain may have the greatest impact in breaking the cycle of children's environmental health disparities related to housing instability.