Placental and immune cell DNA methylation reference panel for bulk tissue cell composition estimation in epidemiological studies.

To distinguish DNA methylation (DNAm) from cell proportion changes in whole placental villous tissue research, we developed a robust cell type-specific DNAm reference to estimate cell composition. We collated new and existing cell type DNAm profiles quantified via Illumina EPIC or 450k microarrays. To estimate cell composition, we deconvoluted whole placental samples ( = 36) with robust partial correlation based on the top 30 hyper- and hypomethylated sites identified per cell type.

Body dissatisfaction widens the racial disparities of Benzophenone-3, a chemical biomarker of personal care and consumer product usage.

Background: Body dissatisfaction can drive individuals to use personal care products, exposing themselves to Benzophenone-3 (BP3). Yet, no study has examined the link between body dissatisfaction and elevated chemical exposures.

Objectives: Our study examines how body dissatisfaction impacts the racial differences in BP3 exposures.

Applying cell painting in non-tumorigenic breast cells to understand impacts of common chemical exposures.

The general population is exposed to many chemicals which have putative, but incompletely understood, links to breast cancer. Cell Painting is a high-content imaging-based in vitro assay that allows for unbiased measurements of concentration-dependent effects of chemical exposures on cellular morphology. We used Cell Painting to measure effects of 16 human exposure relevant chemicals, along with 21 small molecules with known mechanisms of action, in non-tumorigenic mammary epithelial cells, the MCF10A cell line.

Exposome-wide association study of cognition among older adults in the National Health and Nutrition Examination Survey.

Cognitive impairment among older adults is a growing public health challenge and environmental chemicals may be modifiable risk factors. A wide array of chemicals has not yet been tested for association with cognition in an environment-wide association framework. In the US National Health and Nutrition Examination Survey (NHANES) 1999-2000 and 2011-2014 cross-sectional cycles, cognition was assessed using the Digit Symbol Substitution Test (DSST, scores 0-117) among participants aged 60 years and older.

Random survival forest for predicting the combined effects of multiple physiological risk factors on all-cause mortality.

Understanding the combined effects of risk factors on all-cause mortality is crucial for implementing effective risk stratification and designing targeted interventions, but such combined effects are understudied. We aim to use survival-tree based machine learning models as more flexible nonparametric techniques to examine the combined effects of multiple physiological risk factors on mortality. More specifically, we (1) study the combined effects between multiple physiological factors and all-cause mortality, (2) identify the five most influential factors and visualize their combined influence on all-cause mortality, and (3) compare the mortality cut-offs with the current clinical thresholds.

Investigating phenotypic plasticity due to toxicants with exposure disparities in primary human breast cells .

Introduction: Breast cancer is the second most diagnosed cancer, as well as the primary cause of cancer death in women worldwide. Of the different breast cancer subtypes, triple-negative breast cancer (TNBC) is particularly aggressive and is associated with poor prognosis. Black women are two to three times more likely to be diagnosed with TNBCs than white women.

Placental and Immune Cell DNA Methylation Reference Panel for Bulk Tissue Cell Composition Estimation in Epidemiological Studies.

To distinguish DNA methylation (DNAm) from cell proportion changes in whole placental tissue research, we developed a robust cell type-specific DNAm reference to estimate cell composition. We collated newly collected and existing cell type DNAm profiles quantified via Illumina EPIC or 450k microarrays. To estimate cell composition, we deconvoluted whole placental samples (n=36) with robust partial correlation based on the top 50 hyper- and hypomethylated sites per cell type.

Applying Cell Painting in Non-Tumorigenic Breast Cells to Understand Impacts of Common Chemical Exposures.

There are a substantial number of chemicals to which individuals in the general population are exposed which have putative, but still poorly understood, links to breast cancer. Cell Painting is a high-content imaging-based assay that allows for rapid and unbiased measurements of the concentration-dependent effects of chemical exposures on cellular morphology. We optimized the Cell Painting assay and measured the effect of exposure to 16 human exposure relevant chemicals, along with 21 small molecules with known mechanisms of action, for 48 hours in non-tumorigenic mammary epithelial cells, the MCF10A cell line.

Sex-Specific Deflection of Age-Related DNA Methylation and Gene Expression in Mouse Heart by Perinatal Toxicant Exposures.

Background: Global and site-specific changes in DNA methylation and gene expression are associated with cardiovascular aging and disease, but how toxicant exposures during early development influence the normal trajectory of these age-related molecular changes, and whether there are sex differences, has not yet been investigated.

Objectives: We used an established mouse model of developmental exposures to investigate the effects of perinatal exposure to either lead (Pb) or diethylhexyl phthalate (DEHP), two ubiquitous environmental contaminants strongly associated with CVD, on age-related cardiac DNA methylation and gene expression.

Methods: Dams were randomly assigned to receive human physiologically relevant levels of Pb (32 ppm in water), DEHP (25 mg/kg chow), or control water and chow.

Environmental chemical-wide associations with immune biomarkers in US adults: A cross-sectional analysis.

Environmental chemical exposures influence immune system functions, and humans are exposed to a wide range of chemicals, termed the chemical "exposome". A comprehensive, discovery analysis of the associations of multiple chemical families with immune biomarkers is needed. In this study, we tested the associations between environmental chemical concentrations and immune biomarkers.

High-Throughput Transcriptomics of Nontumorigenic Breast Cells Exposed to Environmentally Relevant Chemicals.

Background: There is a suite of chemicals, including metals, pesticides, and personal care product compounds, which are commonly detected at high levels in US Center for Disease Control's National Health and Nutrition Examination Survey (NHANES) chemical biomarker screens. Whether these chemicals influence development of breast cancer is not well understood.

Objectives: The objectives were to perform an unbiased concentration-dependent assessment of these chemicals, to quantify differences in cancer-specific genes and pathways, to describe if these differences occur at human population-relevant concentrations, and to specifically test for differences in markers of stemness and cellular plasticity.

Gene Target Prediction of Environmental Chemicals Using Coupled Matrix-Matrix Completion.

Human exposure to toxic chemicals presents a huge health burden. Key to understanding chemical toxicity is knowledge of the molecular target(s) of the chemicals. Because a comprehensive safety assessment for all chemicals is infeasible due to limited resources, a robust computational method for discovering targets of environmental exposures is a promising direction for public health research.

Longitudinal Position and Cancer Risk in the United States Revisited.

Unlabelled: The debate over daylight saving time (DST) has surged, with interests in the effects of sunlight exposure on health. Prior studies simulated DST and standard time conditions by analyzing different locations within time zones and neighboring areas across time zone borders. We analyzed cancer incidence rates from various longitudinal positions within time zones and at time zone borders in the contiguous United States.

Glucose-6-phosphate dehydrogenase deficiency accelerates pancreatic acinar-to-ductal metaplasia.

Activating mutations in extensively reprogram cellular metabolism to support the continuous growth, proliferation, and survival of pancreatic tumors. Targeting these metabolic dependencies are promising approaches for the treatment of established tumors. However, metabolic reprogramming is required early during tumorigenesis to provide transformed cells selective advantage towards malignancy.

Non-Toxicological Role of Aryl Hydrocarbon Receptor in Obesity-Associated Multiple Myeloma Cell Growth and Survival.

Obesity is not only a risk factor for multiple myeloma (MM) incidence, but it is also associated with an increased risk of progression from myeloma precursors-monoclonal gammopathy of undetermined significance-and smoldering myeloma. Adipocytes in the bone marrow (BMAs) microenvironment have been shown to facilitate MM cell growth via secreted factors, but the nature of these secreted factors and their mechanism of action have not been fully elucidated. The elevated expression of aryl hydrocarbon receptor (AhR) is associated with a variety of different cancers, including MM; however, the role of AhR activity in obesity-associated MM cell growth and survival has not been explored.

Effects of Developmental Lead and Phthalate Exposures on DNA Methylation in Adult Mouse Blood, Brain, and Liver Identifies Tissue- and Sex-Specific Changes with Implications for Genomic Imprinting.

Background: Maternal exposure to environmental chemicals can cause adverse health effects in offspring. Mounting evidence supports that these effects are influenced, at least in part, by epigenetic modifications.

Objective: We examined tissue- and sex-specific changes in DNA methylation (DNAm) associated with human-relevant lead (Pb) and di(2-ethylhexyl) phthalate (DEHP) exposure during perinatal development in cerebral cortex, blood, and liver.

Exploratory profiles of phenols, parabens, and per- and poly-fluoroalkyl substances among NHANES study participants in association with previous cancer diagnoses.

Background: Some hormonally active cancers have low survival rates, but a large proportion of their incidence remains unexplained. Endocrine disrupting chemicals may affect hormone pathways in the pathology of these cancers.

Objective: To evaluate cross-sectional associations between per- and polyfluoroalkyl substances (PFAS), phenols, and parabens and self-reported previous cancer diagnoses in the National Health and Nutrition Examination Survey (NHANES).

Integrating NHANES and toxicity forecaster data to compare pesticide exposure and bioactivity by farmwork history and US citizenship.

Background: Farmworkers in the United States, especially migrant workers, face unique barriers to healthcare and have documented disparities in health outcomes. Exposure to pesticides, especially those persistent in the environment, may contribute to these health disparities.

Objective: Quantify differences in pesticide exposure bioactivity by farmworker category and US citizenship status.

Spatiotemporal protein dynamics during early organogenesis in mouse conceptuses treated with valproic acid.

Valproic acid (VPA) is an anti-epileptic medication that increases the risk of neural tube defect (NTD) outcomes in infants exposed during gestation. Previous studies into VPA's mechanism of action have focused on alterations in gene expression and metabolism but have failed to consider how exposure changes the abundance of critical developmental proteins over time. This study evaluates the effects of VPA on protein abundance in the developmentally distinct tissues of the mouse visceral yolk sac (VYS) and embryo proper (EMB) using mouse whole embryo culture.

Developmental exposures to common environmental contaminants, DEHP and lead, alter adult brain and blood hydroxymethylation in mice.

The developing epigenome changes rapidly, potentially making it more sensitive to toxicant exposures. DNA modifications, including methylation and hydroxymethylation, are important parts of the epigenome that may be affected by environmental exposures. However, most studies do not differentiate between these two DNA modifications, possibly masking significant effects.

Trichloroethylene Metabolite -(1,2-Dichlorovinyl)-l-cysteine Stimulates Changes in Energy Metabolites and Amino Acids in the BeWo Human Placental Trophoblast Model during Syncytialization.

Syncytialization, the fusion of cytotrophoblasts into an epithelial barrier that constitutes the maternal-fetal interface, is a crucial event of placentation. This process is characterized by distinct changes to amino acid and energy metabolism. A metabolite of the industrial solvent trichloroethylene (TCE), -(1,2-dichlorovinyl)-l-cysteine (DCVC), modifies energy metabolism and amino acid abundance in HTR-8/SVneo extravillous trophoblasts.

Placental cell type deconvolution reveals that cell proportions drive preeclampsia gene expression differences.

The placenta mediates adverse pregnancy outcomes, including preeclampsia, which is characterized by gestational hypertension and proteinuria. Placental cell type heterogeneity in preeclampsia is not well-understood and limits mechanistic interpretation of bulk gene expression measures. We generated single-cell RNA-sequencing samples for integration with existing data to create the largest deconvolution reference of 19 fetal and 8 maternal cell types from placental villous tissue (n = 9 biological replicates) at term (n = 40,494 cells).

Harmonized US National Health and Nutrition Examination Survey 1988-2018 for high throughput exposome-health discovery.

The National Health and Nutrition Examination Survey (NHANES) provides data on the health and environmental exposure of the non-institutionalized US population. Such data have considerable potential to understand how the environment and behaviors impact human health. These data are also currently leveraged to answer public health questions such as prevalence of disease.

Integrating NHANES and Toxicity Forecaster Data to Compare Pesticide Exposure and Bioactivity by Farmwork History and US Citizenship.

Introduction: Farmworkers in the United States, especially migrant workers, face unique barriers to healthcare and have documented disparities in health outcomes. Exposure to pesticides, especially those persistent in the environment, may contribute to these health disparities.

Methods: We queried the National Health and Nutrition Examination Study (NHANES) from 1999-2014 for pesticide exposure biomarker concentrations among farmworkers and non-farmworkers by citizenship status.