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The validation case study of read-across based on IATA for hepatotoxicity of Naphthalene and its structurally similar analogs

ABSTRACT: Comparing biological similarity with in vitro test is expected to improve the reliability of read-across for systemic toxicity without animal test. However, because of few case studies, it was hindered to use of this concept for regulatory context. Thus, we compared biological similarity with in vitro test for structurally similar chemicals to demonstrate its validity for grouping chemicals and extract key considerations in read-across. In this study, we selected the hepatotoxicity of Naphthalene and its structurally similar analogs which have 90-day repeated dose toxicity data including 2,7-Naphthalenediol, 1,5-Naphthalenediol, and 1-Naphthol. To elucidate the potential mechanisms and compared them, we conducted in vitro microarray analysis with rat primary hepatocytes

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE156442 | GEO | 2021/12/31

REPOSITORIES: GEO

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Project description:Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the environment as components of fossil fuels and by-products of combustion. These multi-ring chemicals differentially activate the Aryl Hydrocarbon Receptor (AHR) in a structurally-dependent manner, and induce toxicity via both AHR-dependent and -independent mechanisms. PAH exposure is known to induce developmental malformations in zebrafish embryos, and recent studies have shown cardiac toxicity induced by compounds with low AHR affinity. Unraveling the potentially diverse molecular mechanisms of PAH toxicity is essential for understanding the hazard posed by complex PAH mixtures present in the environment. We analyzed transcriptional responses to PAH exposure in zebrafish embryos exposed to benz(a)anthracene (BAA), dibenzothiophene (DBT) and pyrene (PYR) at a concentration that induces developmental malformations by 120 hours post-fertilization (hpf). Whole genome microarray analysis of mRNA expression at 24 and 48 hpf identified genes that were differentially regulated over time and in response to the three PAH structures. PAH body burden was analyzed at these time points using GC-MS, and demonstrated differences in PAH uptake into the embryos. This was important for discerning dose-related differences from those that represented unique molecular mechanisms. While BAA misregulated the smallest number of transcripts, it caused strong induction of cyp1a and other genes known to be downstream of the AHR, which were not induced by the other two PAHs. Analysis of functional roles of misregulated genes and their predicted regulatory transcription factors also distinguished the BAA response from regulatory networks disrupted by DBT and PYR exposure. These results indicate that systems approaches can be used to classify the toxicity of PAHs based on the networks perturbed following exposure and may provide a path for unraveling the toxicity of complex PAH mixtures. Gene expression was measured in zebrafish embryos after exposure to PAHs. Embryos were batch-exposed in groups of 40 to 25 μM BAA, 25 μM DBT, 25 μM PYR or 1% DMSO vehicle control starting at 6 hpf and collected at 24 or 48 hpf. Four independent biological replicates were prepared for each treatment. The reference was a pool of zebrafish embryos exposed to DMSO control until 24 and 48 hpf.

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The validation case study of read-across based on IATA for hepatotoxicity of Naphthalene and its structurally similar analogs

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