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Polycyclic aromatic hydrocarbons (PAHs) are a class of organic compounds frequently detected in the environment with widely varying toxicities. Many PAHs activate the aryl hydrocarbon receptor (AHR), inducing the expression of a battery of genes, including xenobiotic metabolizing enzymes like cytochrome P450s (CYPs); however, not all PAHs act via this mechanism. We screened several parent and substituted PAHs in in vitro AHR activation assays to classify their unique activity. Retene (1-methyl-7-isopropylphenanthrene) displays Ahr2-dependent teratogenicity in zebrafish, but did not activate human AHR or zebrafish Ahr2, suggesting a retene metabolite activates Ahr2 in zebrafish to induce developmental toxicity. To investigate the role of metabolism in retene toxicity, studies were performed to determine the functional role of cyp1a , cyp1b1 , and the microbiome in retene toxicity, identify the zebrafish window of susceptibility, and measure retene uptake, loss, and metabolite formation in vivo. Cyp1a-null fish were generated using CRISPR-Cas9. Cyp1a-null fish showed increased sensitivity to retene toxicity, whereas Cyp1b1-null fish were less susceptible, and microbiome elimination had no significant effect. Zebrafish required exposure to retene between 24 and 48 hours post fertilization (hpf) to exhibit toxicity. After static exposure, retene concentrations in zebrafish embryos increased until 24 hpf, peaked between 24 and 36 hpf, and decreased rapidly thereafter. We detected retene metabolites at 36 and 48 hpf, indicating metabolic onset preceding toxicity. This study highlights the value of combining molecular and systems biology approaches with mechanistic and predictive toxicology to interrogate the role of biotransformation in AHR-dependent toxicity. [ABSTRACT FROM AUTHOR]

Per- and polyfluoroalkyl substances (PFAS) are a widespread and persistent class of contaminants posing significant environmental and human health concerns. Comprehensive understanding of the modes of action underlying toxicity among structurally diverse PFAS is mostly lacking. To address this need, we recently reported on our application of developing zebrafish to evaluate a large library of PFAS for developmental toxicity. In the present study, we prioritized 15 bioactive PFAS that induced significant morphological effects and performed RNAsequencing to characterize early transcriptional responses at a single timepoint (48 h post fertilization) after early developmental exposures (8 h post fertilization). Internal concentrations of 5 of the 15 PFAS were measured from pooled whole fish samples across multiple timepoints between 24-120 h post fertilization, and additional temporal transcriptomics at several timepoints (48-96 h post fertilization) were conducted for Nafion byproduct 2. A broad range of differentially expressed gene counts were identified across the PFAS exposures. Most PFAS that elicited robust transcriptomic changes affected biological processes of the brain and nervous system development. While PFAS disrupted unique processes, we also found that similarities in some functional head groups of PFAS were associated with the disruption in expression of similar gene sets. Body burdens after early developmental exposures to select sulfonic acid PFAS, including Nafion byproduct 2, increased from the 24-96 h post fertilization sampling timepoints and were greater than those of sulfonamide PFAS of similar chain lengths. In parallel, the Nafion byproduct 2-induced transcriptional responses increased between 48 and 96 h post fertilization. PFAS characteristics based on toxicity, transcriptomic effects, and modes of action will contribute to further prioritization of PFAS structures for testing and informed hazard assessment. [ABSTRACT FROM AUTHOR]

Report-back of research results (RBRR) is becoming standard practice for environmental health research studies. RBRR is thought to increase environmental health literacy (EHL), although standardized measurements are limited. For this study, we developed a report back document on exposure to air pollutants, Polycyclic Aromatic Hydrocarbons, during pregnancy through community engaged research and evaluated whether the report increased EHL. We used focus groups and surveys to gather feedback on the report document from an initial group of study participants (Group 1, n = 22) and then sent the revised report to a larger number of participants (Group 2, n = 168). We conducted focus groups among participants in Group 1 and discussed their suggested changes to the report and how those changes could be implemented. Participants in focus groups demonstrated multiple levels of EHL. While participant engagement critically informed report development, a survey comparing feedback from Group 1 (initial report) and Group 2 (revised report) did not show a significant difference in the ease of reading the report or knowledge gained about air pollutants. We acknowledge that our approach was limited by a lack of EHL tools that assess knowledge and behavior change, and a reliance on quantitative methodologies. Future approaches that merge qualitative and quantitative methodologies to evaluate RBRR and methodologies for assessing RBRR materials and subsequent changes in knowledge, attitudes, and behavior, may be necessary. [ABSTRACT FROM AUTHOR]

To understand how chemical exposure can impact health, researchers need tools that capture the complexities of personal chemical exposure. In practice, fine particulate matter (PM2.5) air quality index (AQI) data from outdoor stationary monitors and Hazard Mapping System (HMS) smoke density data from satellites are often used as proxies for personal chemical exposure, but do not capture total chemical exposure. Silicone wristbands can quantify more individualized exposure data than stationary air monitors or smoke satellites. However, it is not understood how these proxy measurements compare to chemical data measured from wristbands. In this study, participants wore daily wristbands, carried a phone that recorded locations, and answered daily questionnaires for a 7‐day period in multiple seasons. We gathered publicly available daily PM2.5 AQI data and HMS data. We analyzed wristbands for 94 organic chemicals, including 53 polycyclic aromatic hydrocarbons. Wristband chemical detections and concentrations, behavioral variables (e.g., time spent indoors), and environmental conditions (e.g., PM2.5 AQI) significantly differed between seasons. Machine learning models were fit to predict personal chemical exposure using PM2.5 AQI only, HMS only, and a multivariate feature set including PM2.5 AQI, HMS, and other environmental and behavioral information. On average, the multivariate models increased predictive accuracy by approximately 70% compared to either the AQI model or the HMS model for all chemicals modeled. This study provides evidence that PM2.5 AQI data alone or HMS data alone is insufficient to explain personal chemical exposures. Our results identify additional key predictors of personal chemical exposure. Plain Language Summary: Tools are needed to determine how chemical exposures may affect people's health. It is not understood how air quality data from stationary air monitors and smoke density data from satellites align with personal chemical exposure data from silicone wristbands; we present the first study to evaluate this. In this study, people wore wristbands, carried phones to track their locations, and answered questions for a week in different seasons. We also collected fine particulate matter data from outdoor monitors and satellites and tested the wristbands for 94 different chemicals. The results showed that the wristband data, along with other information like where people spent time and the air quality, varied between seasons. We used machine learning models to predict personal chemical exposure using only the data from monitors or satellites, and then using a mix of data from both, along with additional data about the environment and people's behaviors. Models that used a mix of data were much better at predicting exposure compared to using just one type of data. This study tells us that using fine particulate data from monitors or satellites is not enough to understand personal chemical exposure. Key Points: Explaining personal chemical exposures required more than fine particulate matter air quality index (AQI) or hazard mapping system dataModels with variables in addition to fine particulate matter AQI increased predictive accuracy of exposureHeavy wildfire smoke was measured during the study [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AHR) is required for vertebrate development and is also activated by exogenous chemicals, including polycyclic aromatic hydrocarbons (PAHs) and 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD). AHR activation is well-understood, but roles of downstream molecular signaling events are largely unknown. From previous transcriptomics in 48 h postfertilization (hpf) zebrafish exposed to several PAHs and TCDD, we found wfikkn1 was highly coexpressed with cyp1a (marker for AHR activation). Thus, we hypothesized wfikkn1 's role in AHR signaling, and showed that wfikkn1 expression was Ahr2 (zebrafish ortholog of human AHR)-dependent in developing zebrafish exposed to TCDD. To functionally characterize wfikkn1 , we made a CRISPR-Cas9 mutant line with a 16-bp deletion in wfikkn1 's exon, and exposed wildtype and mutants to dimethyl sulfoxide or TCDD. 48-hpf mRNA sequencing revealed over 700 genes that were differentially expressed (p  <  .05, log2FC > 1) between each pair of treatment combinations, suggesting an important role for wfikkn1 in altering both the 48-hpf transcriptome and TCDD-induced expression changes. Mass spectrometry-based proteomics of 48-hpf wildtype and mutants revealed 325 significant differentially expressed proteins. Functional enrichment demonstrated wfikkn1 was involved in skeletal muscle development and played a role in neurological pathways after TCDD exposure. Mutant zebrafish appeared morphologically normal but had significant behavior deficiencies at all life stages, and absence of Wfikkn1 did not significantly alter TCDD-induced behavior effects at all life stages. In conclusion, wfikkn1 did not appear to be significantly involved in TCDD's overt toxicity but is likely a necessary functional member of the AHR signaling cascade. [ABSTRACT FROM AUTHOR]