@article{truong_rericha_thunga_marvel_wallis_simonich_field_cao_reif_tanguay_2022, title={Systematic developmental toxicity assessment of a structurally diverse library of PFAS in zebrafish}, volume={431}, ISSN={["1873-3336"]}, url={http://dx.doi.org/10.1016/j.jhazmat.2022.128615}, DOI={10.1016/j.jhazmat.2022.128615}, abstractNote={Per- and polyfluoroalkyl substances (PFAS) are a class of widely used chemicals with limited human health effects data relative to the diversity of structures manufactured. To help fill this data gap, an extensive in vivo developmental toxicity screen was performed on 139 PFAS provided by the US EPA. Dechorionated embryonic zebrafish were exposed to 10 nominal water concentrations of PFAS (0.015-100 µM) from 6 to 120 h post-fertilization (hpf). The embryos were assayed for embryonic photomotor response (EPR), larval photomotor response (LPR), and 13 morphological endpoints. A total of 49 PFAS (35%) were bioactive in one or more assays (11 altered EPR, 25 altered LPR, and 31 altered morphology). Perfluorooctanesulfonamide (FOSA) was the only structure that was bioactive in all 3 assays, while Perfluorodecanoic acid (PFDA) was the most potent teratogen. Low PFAS volatility was associated with developmental toxicity (p < 0.01), but no association was detected between bioactivity and five other physicochemical parameters. The bioactive PFAS were enriched for 6 supergroup chemotypes. The results illustrate the power of a multi-dimensional in vivo platform to assess the developmental (neuro)toxicity of diverse PFAS and in the acceleration of PFAS safety research.}, journal={JOURNAL OF HAZARDOUS MATERIALS}, publisher={Elsevier BV}, author={Truong, Lisa and Rericha, Yvonne and Thunga, Preethi and Marvel, Skylar and Wallis, Dylan and Simonich, Michael T. and Field, Jennifer A. and Cao, Dunping and Reif, David M. and Tanguay, Robyn L.}, year={2022}, month={Jun} }
 @article{shankar_garcia_ladu_sullivan_dunham_goodale_waters_stanisheuski_maier_thunga_et al._2022, title={The Ahr2-Dependent wfikkn1 Gene Influences Zebrafish Transcriptome, Proteome, and Behavior}, volume={4}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfac037}, abstractNote={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.}, journal={TOXICOLOGICAL SCIENCES}, author={Shankar, Prarthana and Garcia, Gloria R. and LaDu, Jane K. and Sullivan, Christopher M. and Dunham, Cheryl L. and Goodale, Britton C. and Waters, Katrina M. and Stanisheuski, Stanislau and Maier, Claudia S. and Thunga, Preethi and et al.}, year={2022}, month={Apr} }
 @article{thunga_truong_rericha_du_morshead_tanguay_reif_2022, title={Utilizing a Population-Genetic Framework to Test for Gene-Environment Interactions between Zebrafish Behavior and Chemical Exposure}, volume={10}, ISSN={["2305-6304"]}, url={https://doi.org/10.3390/toxics10120769}, DOI={10.3390/toxics10120769}, abstractNote={Individuals within genetically diverse populations display broad susceptibility differences upon chemical exposures. Understanding the role of gene-environment interactions (GxE) in differential susceptibility to an expanding exposome is key to protecting public health. However, a chemical’s potential to elicit GxE is often not considered during risk assessment. Previously, we’ve leveraged high-throughput zebrafish (Danio rerio) morphology screening data to reveal patterns of potential GxE effects. Here, using a population genetics framework, we apportioned variation in larval behavior and gene expression in three different PFHxA environments via mixed-effect modeling to assess significance of GxE term. We estimated the intraclass correlation (ICC) between full siblings from different families using one-way random-effects model. We found a significant GxE effect upon PFHxA exposure in larval behavior, and the ICC of behavioral responses in the PFHxA exposed population at the lower concentration was 43.7%, while that of the control population was 14.6%. Considering global gene expression data, a total of 3746 genes showed statistically significant GxE. By showing evidence that heritable genetics are directly affecting gene expression and behavioral susceptibility of individuals to PFHxA exposure, we demonstrate how standing genetic variation in a heterogeneous population such as ours can be leveraged to test for potential GxE.}, number={12}, journal={TOXICS}, author={Thunga, Preethi and Truong, Lisa and Rericha, Yvonne and Du, Jane La and Morshead, Mackenzie and Tanguay, Robyn L. and Reif, David M.}, year={2022}, month={Dec} }
 @article{thunga_truong_tanguay_reif_2021, title={Concurrent Evaluation of Mortality and Behavioral Responses: A Fast and Efficient Testing Approach for High-Throughput Chemical Hazard Identification}, volume={3}, url={http://dx.doi.org/10.3389/ftox.2021.670496}, DOI={10.3389/ftox.2021.670496}, abstractNote={The continual introduction of new chemicals into the market necessitates fast, efficient testing strategies for evaluating their toxicity. Ideally, these high-throughput screening (HTS) methods should capture the entirety of biological complexity while minimizing reliance on expensive resources that are required to assess diverse phenotypic endpoints. In recent years, the zebrafish ( Danio rerio ) has become a preferred vertebrate model to conduct rapid in vivo toxicity tests. Previously, using HTS data on 1060 chemicals tested as part of the ToxCast program, we showed that early, 24 h post-fertilization (hpf), behavioral responses of zebrafish embryos are predictive of later, 120 h post-fertilization, adverse developmental endpoints—indicating that embryonic behavior is a useful endpoint related to observable morphological effects. Here, our goal was to assess the contributions (i.e., information gain) from multiple phenotypic data streams and propose a framework for efficient identification of chemical hazards. We systematically swept through analysis parameters for data on 24 hpf behavior, 120 hpf behavior, and 120 hpf morphology to optimize settings for each of these assays. We evaluated the concordance of data from behavioral assays with that from morphology. We found that combining information from behavioral and mortality assessments captures early signals of potential chemical hazards, obviating the need to evaluate a comprehensive suite of morphological endpoints in initial screens for toxicity. We have demonstrated that such a screening strategy is useful for detecting compounds that elicit adverse morphological responses, in addition to identifying hazardous compounds that do not disrupt the underlying morphology. The application of this design for rapid preliminary toxicity screening will accelerate chemical testing and aid in prioritizing chemicals for risk assessment.}, journal={Frontiers in Toxicology}, publisher={Frontiers Media SA}, author={Thunga, Preethi and Truong, Lisa and Tanguay, Robyn L. and Reif, David M.}, year={2021}, month={Jun} }