Coupling Genome-wide Transcriptomics and Developmental Toxicity Profiles in Zebrafish to Characterize Polycyclic Aromatic Hydrocarbon (PAH) Hazard

Abstract

Polycyclic Aromatic Hydrocarbons (PAHs) are diverse environmental pollutants associated with adverse human health effects. Many studies focus on the carcinogenic effects of a limited number of PAHs and there is an increasing need to understand mechanisms of developmental toxicity of more varied yet environmentally relevant PAHs. A previous study characterized the developmental toxicity of 123 PAHs in zebrafish. Based on phenotypic responses ranging from complete inactivity to acute mortality, we classified these PAHs into eight bins, selected 16 representative PAHs, and exposed developing zebrafish to the concentration of each PAH that induced 80% phenotypic effect. We conducted RNA sequencing at 48 h post fertilization to identify gene expression changes as a result of PAH exposure. Using the Context Likelihood of Relatedness algorithm, we inferred a network that links the PAHs based on coordinated gene responses to PAH exposure. The 16 PAHs formed two broad clusters: Cluster A was transcriptionally more similar to the controls, while Cluster B consisted of PAHs that were generally more developmentally toxic, significantly elevated cyp1a transcript levels, and induced Ahr2-dependent Cyp1a protein expression in the skin confirmed by gene-silencing studies. We found that cyp1a transcript levels were associated with transcriptomic response, but not with PAH developmental toxicity. While all cluster B PAHs predominantly activated Ahr2, they also each enriched unique pathways like ion transport signaling, which likely points to differing molecular events between the PAHs downstream of Ahr2. Thus, using a systems biology approach, we have begun to evaluate, classify, and define mechanisms of PAH toxicity.

Sustainable Synthesis of Bright Green Fluorescent Nitrogen‐Doped Carbon Quantum Dots from Alkali Lignin

“…[25] However,m ost organic molecules are stille xpensive and pose challenges to the natural environmenta nd humanh ealth:f or instance, polycyclic aromatic hydrocarbons are strong carcinogens, and thus searching for low-cost and environmentally friendly molecule precursors could boost their abundant applications. [28,29] In accordance with the precepts of sustainability,e fforts have been made to utilize sustainable biomass precursors or their extractives, such as Mangifera indica, [30] starch, [31] citric acid, [32] soy milk, [33] sucrose, [28] and others. Unfortunately,f ew biomass wastes can produce highquality CQDs.T herefore, there is an urgent need to develop Sustainable, inexpensive, and environmentally friendly biomass waste can be exploitedf or large-scale production of carbon nanomaterials.…”

Diesel exhaust exposure alters the expression of networks implicated in neurodegeneration in zebrafish brains

“…These findings are consistent with a similar study conducted by Shankar and co-workers who tested the effects of different groups of environmental polycyclic aromatic hydrocarbons (PAHs) on the development of embryos and further evaluated the impact of each treatment regimen on the transcriptome profile. On the whole body of 48 h post-fertilization (hpf) embryos, they showed that the upregulation of Cyp1a at both transcription and protein levels to be an early reliable biomarker of xenobiotic AHR activation and downstream transcriptomic changes (Shankar et al 2019).…”

Environmental mechanisms of orofacial clefts

“…The AHR also responds to endogenous ligands including tryptophan derivatives, tetrapyrroles, and arachidonic acid metabolites. The AHR exhibits a structure–activity relationship (SAR) with its ligands (P. Shankar et al, 2019). While dioxins and PCBs are known to induce OFCs (Courtney & Moore, 1971; Watanabe & Sugahara, 1981), the endogenous ligand 2‐(1′H‐indole‐3′‐carbonyl)‐thiazole‐4‐carboxylic acid methyl ester (ITE) does not appear to affect orofacial development (Henry, Bemis, Henry, Kende, & Gasiewicz, 2006).…”

“…As an example, little is known of the full range of possible AHR ligands that could contribute to OFCs, as well as their relative potencies for inducing cleft palate. For example, in toxicity assays using the embryonic zebrafish, the screening of over a hundred AHR ligands revealed varying teratological effects based on chemical structure, ranging from craniofacial malformations to appendage duplication (Reynolds et al, 2020; Shankar, Dasgupta, Hahn, & Tanguay, 2020; P. Shankar et al, 2019). Characterizing these hazards will be important for evaluating environmental risks for craniofacial defects mediated by AHR signaling.…”