Faculty Bibliography

An important goal of environmental health research is to assess risks posed by mixtures of environmental exposures. Studies in different fields often group exposures based on their shared biological features. However, such grouping information has not been widely utilized in population-based environmental mixtures analyses due to the lack of appropriate statistical tools. Inspired by data from the National Health and Nutrition Examination Survey (NHANES), we propose a semiparametric multiple-index interaction model (MIIM) to explore the impact of three groups of persistent organic pollutants (POPs) on leukocyte telomere length (LTL). MIIM effectively addresses the challenge of high dimensionality by summarizing exposures into group-level indices, while allowing for nonlinear effects and interactions among exposures through these group indices. This formulation provides interpretable insights into both overall group effects and between-group interactions on the outcome, and allows for identification of key contributors within each group. MIIM can be applied to different types of health outcomes, including continuous, binary, and survival outcomes. We conducted Monte Carlo simulation studies to evaluate the performance of MIIM under various scenarios with high-dimensional and correlated exposure mixtures and illustrated its application to the NHANES data. By bridging biological insights with population-based epidemiological data, MIIM serves as a translational tool to explore the effects of environmental mixtures on health outcomes.

MOTIVATION/BACKGROUND:Large-scale prospective cohort studies collect longitudinal biospecimens alongside time-to-event outcomes to investigate biomarker dynamics in relation to disease risk. The nested case-control (NCC) design provides a cost-effective alternative to full cohort biomarker studies while preserving statistical efficiency. Despite advances in joint modeling for longitudinal and time-to-event outcomes, few approaches address the unique challenges posed by NCC sampling, non-normally distributed biomarkers, and competing survival outcomes. RESULTS:Motivated by the TEDDY study, we propose "JM-NCC", a joint modeling framework designed for NCC studies with competing events. It integrates a generalized linear mixed-effects model for potentially non-normally distributed biomarkers with a cause-specific hazard model for competing risks. Two estimation methods are developed. fJM-NCC leverages NCC sub-cohort longitudinal biomarker data and full cohort survival and clinical metadata, while wJM-NCC uses only NCC sub-cohort data. Both simulation studies and an application to TEDDY microbiome dataset demonstrate the robustness and efficiency of the proposed methods. AVAILABILITY/BACKGROUND:Software is available at https://github.com/Zhaoyn-oss/JMNCC and archived on Zenodo at https://zenodo.org/records/18199759 (DOI: 10.5281/zenodo.18199759). SUPPLEMENTARY INFORMATION/BACKGROUND:Supplementary data are available at Bioinformatics online.

BACKGROUND:Exposure to particulate matter (PM) is a significant public health concern associated with respiratory, cardiovascular, and metabolic diseases. Oxidative stress is a key biological mechanism mediating the harmful effects of PM exposure. However, a comprehensive review of relating PM exposure to omics layers of oxidative stress has been lacking. We aimed to systematically review the current evidence on the associations between PM exposure and the multi-omics signatures of oxidative stress. METHODS:We conducted a systematic review of studies published between January 2021 and March 2024 in PubMed and Web of Science, following a registered protocol (PROSPERO ID: CRD42024617742). Eligible studies assessed the impact of PM exposure on oxidative stress-related omics in adult human populations. Data on exposure assessment, study characteristics, and omics outcomes were extracted, and the risk of bias was evaluated using the Newcastle-Ottawa Scale and Cochrane's. RESULTS:Seventy-seven studies were included. PM exposure was consistently associated with oxidative stress markers across multiple omics platforms. Studies on the analytes showed that PM was associated with an increase in oxidative markers. Metabolomics studies revealed alterations in pro-oxidant metabolites (e.g., eicosanoids, ceramides) and disruptions in antioxidant pathways (e.g., glutathione, vitamin C, and E metabolism). PM exposure was also linked to changes in energy metabolism, fatty acid oxidation, and detoxification pathways. Genomics studies reported differential methylation in genes involved in oxidative stress and inflammation. Microbiome studies suggest that PM exposure alters the composition of gut and nasal microbiota, favoring a pro-oxidative profile. However, some studies reported no significant associations, highlighting heterogeneity in findings. CONCLUSION/CONCLUSIONS:Our systematic review demonstrates that PM exposure affects multiple molecular pathways related to oxidative stress across diverse omics platforms. These findings highlight the complex responses to PM, underscoring the need for integrative multi-omics approaches to fully understand the health impacts of air pollution.

OBJECTIVE:To examine associations between oxidative stress and fetal weight across pregnancy. STUDY DESIGN/METHODS:Cohort study of pregnant participants from 2016-2021 in New York City with urinary lipid, protein, and DNA oxidative stress biomarkers (<18, 18-25, >25 weeks) and estimated fetal weight from ultrasound fetal biometry with the HadlockIII formula (20, 30, 36 weeks). RESULT/RESULTS:percentile. Oxidative stress biomarkers of protein damage were associated with larger estimated fetal weight at 20 (3.4 [95% CI: 1.2, 5.7]) and 36 weeks (16.5 [95% CI: 5.2, 27.8]). CONCLUSION/CONCLUSIONS:These findings advance our understanding of different oxidative stress pathways and their potential role in fetal growth.

INTRODUCTION/BACKGROUND:Placental development, involving rapid vascularization, is regulated by concentration gradients of numerous growth factors and hormones. Placental growth factor (PlGF) promotes vasculogenesis and angiogenesis in the placenta, while soluble fms-like tyrosine kinase-1 (sFlt-1) inhibits these processes. An elevated ratio of sFlt-1/PlGF in maternal serum is predictive of preeclampsia. Exposure to two classes of ubiquitous endocrine-disrupting chemicals, bisphenols and phthalates, has also been previously linked to preeclampsia development. METHODS:We investigated the relation of urinary concentrations of bisphenols and phthalate metabolites, measured up to three times during pregnancy, with serum concentrations of sFlt-1, PlGF, and their ratio in the New York University Children's Health and Environment Study. Linear mixed models were used to analyze up to three measurements of PlGF and sFlt-1 adjusted for gestational age at the time of serum collection. RESULTS:We found that higher molar sum concentration of bisphenol A and bisphenol S was associated with lower sFlt-1 (-0.12, 95 % CI: -0.22, -0.03), higher PlGF (0.08, 95 % CI: -0.01, 0.18), and lower sFlt-1/PlGF ratio (-0.12, 95 % CI: -0.21, -0.02). Phthalic acid and metabolites of anti-androgenic and low molecular weight phthalates were similarly associated with higher PlGF and lower sFlt-1/PlGF, but only after 20 weeks of gestation. DISCUSSION/CONCLUSIONS:The unexpected relationship between prenatal bisphenol and phthalate exposure and lower sFlt-1/PlGF warrants further investigation. Our results suggest that the effect of these endocrine-disrupting chemicals on placental health may be more complicated than what is currently understood through these angiogenic biomarkers.

IMPORTANCE/UNASSIGNED:Chronic exposure to arsenic in drinking water has been associated with increased chronic disease mortality. However, there is limited evidence on associations between reduced exposure and mortality risk. OBJECTIVE/UNASSIGNED:To examine whether reductions in arsenic exposure, measured using urinary arsenic levels, are associated with lower mortality from chronic diseases, including cancer and cardiovascular disease (CVD). DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:A prospective cohort of 11 746 adults was enrolled between 2000 and 2002 in Araihazar, Bangladesh, with levels of well-water arsenic ranging from less than 1 µg/L to 864 µg/L (mean, 102 µg/L), exceeding the Bangladesh standard of 50 µg/L. Arsenic levels declined over time as a result of community mitigation. Mortality was tracked through 2022. Analyses included 10 977 participants with calculable changes in urinary arsenic levels. EXPOSURES/UNASSIGNED:Urinary arsenic levels were measured up to 5 times per participant through 2018. Participants were categorized based on changes in urinary arsenic levels. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Adjusted hazard ratios (aHRs) and 95% CIs for mortality from chronic diseases, including cancer and CVD. RESULTS/UNASSIGNED:Among 10 977 participants (57% female; mean age, 37.0 [SD, 10.1] years), mean urinary arsenic levels declined from 283 (SD, 314) to 132 (SD, 161) µg/g creatinine from 2000 to 2018. Each IQR decrease in urinary arsenic (197 µg/g creatinine) was associated with 22% lower chronic disease mortality (aHR, 0.78 [95% CI, 0.75-0.82]), 20% lower cancer mortality (aHR, 0.80 [95% CI, 0.73-0.87]), and 23% lower CVD mortality (aHR, 0.77 [95% CI, 0.73-0.81]). Time-varying Cox and restricted cubic spline analyses showed larger reductions were associated with lower mortality, while increases were linked to higher risk. Compared with participants with consistently high urinary arsenic levels (above the baseline median of 199 µg/g creatinine [n = 1757]), those whose levels declined below the median (n = 3757) had lower mortality from chronic diseases (aHR, 0.46 [95% CI, 0.39-0.53]), including cancer (aHR, 0.51 [95% CI, 0.35-0.73]) and CVD (aHR, 0.43 [95% CI, 0.34-0.53]), similar to those consistently below the median (n = 4959) (aHR, 0.43-0.49). Findings were similar in propensity score-matched analyses. CONCLUSIONS AND RELEVANCE/UNASSIGNED:These findings support an association between reduced arsenic exposure and improved health outcomes in populations exposed to contaminated drinking water.

Phenolic compounds may be harmful to the developing fetus, but many have not been studied in-depth for adverse childhood allergic and respiratory health effects. We hypothesized that higher levels of phenolic compounds in prenatal spot urine would be associated with greater odds of childhood atopic dermatitis, allergic rhinitis, and asthma, and that child sex may modify these associations. 3198 mother-child paired cases were enrolled from 16 cohorts in the U.S. ECHO consortium. Fifteen phenols (e.g. benzophenones, parabens, bisphenols, triclosans) were measured from mother's urine during pregnancy using a multi-class chemical panel. Childhood outcomes included parent-reported atopic dermatitis (1466 mother-child pairs) between ages 0-3 years, and allergic rhinitis (901 mother-child pairs) and asthma (1662 mother-child pairs) between ages 5-9 years. Prenatal parabens were associated with increased odds of atopic dermatitis (odds ratio (OR) 1.13, 95 % confidence intervals (CI) 1.02, 1.26). Benzophenones were associated with lower odds of asthma (OR 0.77, CI 0.66, 0.90). Compared to boys, girls demonstrated higher odds of parabens (1.21, CI 1.04, 1.42), benzophenones (1.18, CI 1.00, 1.38) and bisphenol S (1.21, CI 1.03, 1.43) being associated with atopic dermatitis, and of the benzophenones (1.46, CI 1.11, 1.93) being associated with allergic rhinitis. An association of benzophenones (0.66, CI 0.53, 0.83) with lower odds of asthma was stronger among boys. These findings suggest that prenatal paraben and other phenol exposures may adversely affect early-life allergic and respiratory outcomes, with sex-specific vulnerability. Novel, multi-modality approaches to reduce maternal phenol exposure during pregnancy are urgently needed to protect children's health.

Prior research links prenatal exposure to organophosphate (OP) pesticides to adverse health outcomes via molecular mechanisms, such as oxidative stress, neurotransmitter disruption, and mitochondrial dysfunction. This study investigates such mechanisms by assessing the relationships between prenatal OP pesticide exposure and targeted urinary maternal metabolomic profiles using data from the New York University Children's Health and Environment Study (NYU CHES) cohort (n = 890). Urine samples were collected at three time points during pregnancy (T

Environmental exposure-associated diseases, particularly in the context of rising air pollution and inhalant use, are an active area of research. Our group is dedicated to the study of exposure-related inflammation and its downstream adverse health effects. While many studies have focused on the impact of environmental exposures on respiratory sequelae, there is growing evidence of the involvement of other systems including gastrointestinal. This systematic review provides updates on the associations between inhalation exposures and the risk of upper gastrointestinal disease. Primary search identified N = 764 PubMed and N = 1,036 Web of Science studies, of which N = 111 met eligibility criteria. Our systematic review and meta-analysis showed significant associations between inhalational exposures (cigarette smoking, waterpipe smoking, and particulate matter) and upper gastrointestinal diseases. The pooled estimate of esophagitis was 1.32 (95% confidence interval [CI], 1.06-1.65; I²:86%), gastroesophageal reflux disease was 1.71 (1.14-2.55; I²:94%), peptic ulcer disease was 1.21 (1.03-1.43; I²:93%), esophageal cancer was 1.83 (1.54-2.18; I²:73%), and gastric cancer was 1.71 (1.39-2.10; I²:73%). However, the pooled estimate for Barrett's esophagus was 0.93 (0.65-1.34; I²:76%), indicating no significant association. Sensitivity analyses confirmed these findings. Risk of bias assessment showed most studies were of good quality. Our findings emphasize the impact of inhalational exposures on gastrointestinal disease risk, highlighting the need for further research to better understand this interaction and targeted public health interventions.