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Using transcriptomics data and Adverse Outcome Pathway networks to explore endocrine disrupting properties of Cadmium and PCB-126

ABSTRACT: Omics-technologies such as transcriptomics offer valuable insights into toxicity mechanisms. However, integrating this type of data into regulatory frameworks remains challenging due to uncertainties regarding toxicological relevance and links to adverse outcomes. Current assessments of endocrine disruptors (EDs) relevant for human health require substantial amounts of data and primarily rely on standardized animal studies. Identifying EDs is a high priority in the EU, and so are efforts to replace and reduce animal testing. Alternative methods to investigate EDs are needed, but there is also a lack of health risk assessment methodology that supports regulatory uptake of novel mechanistic information. This study aims to utilize Adverse Outcome Pathways (AOPs) to integrate transcriptomics data for identifying EDs, by establishing a link between molecular data and adverse outcomes. Cadmium (Cd) and 3,3',4,4',5-pentachlorobiphenyl (PCB126) were used as model compounds due to their observed effects on the endocrine system, but not yet being identified as EDs in the EU regulatory setting. Estrogen, androgen, thyroid and steroidogenesis (EATS)-related AOPs were extracted from AOPWiki to generate an AOP network. RNA sequencing (RNA-Seq) was conducted on zebrafish (Danio rerio) embryos exposed to Cd or PCB126 for 4 days. RNA-Seq data were then linked to the AOP network by connecting Gene Ontology biological process (GO BP) terms from the experimental data to key events in the network. Enrichment Maps in Cytoscape and the QIAGEN Ingenuity Pathway Analysis (IPA) software were also used to identify potential ED properties and support the assessment. Potentially EATS-related GO BP terms were identified for both compounds. A lack of accurate standardized terms in KEs of the AOP network hindered a data-driven mapping approach. Instead, manual mapping of GO BP terms onto the AOP network revealed more connections, underscoring the need for harmonizing AOP development for regulatory use. IPA results further supported potentially EATS-related effects of both compounds. Evidence from the Enrichment Maps revealed perturbations of several biological functions, which may be related to either EATS or non-EATS endocrine mechanisms. While AOP networks show promise in integrating RNA-Seq data, several challenges remain. Future research should focus on further developing this methodology to improve the use of mechanistic data in risk assessments. Standardizing AOP development to include accurate GO terms is crucial for enabling automatic integration of transcriptomics data through AOPs.

ORGANISM(S): Danio rerio

PROVIDER: GSE283372 | GEO | 2025/02/28

REPOSITORIES: GEO

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Project description:Adverse outcome pathways (AOP) contain summarizing sequences of key events (KE) relating toxicant exposures to specific adverse outcomes (AO) observed in exposed populations. Quantitative AOPs (qAOP) provide frameworks to assess AO risks based on KE quantification and the modeling of their relationships. This work aimed to develop the quantitative component of AOP 411 <Oxidative stress leading to decreased lung function>. To examine the pertinence of the resulting qAOP-based risk assessment approach, we applied it to predict the medium-term lung function evolution after switching from combustible cigarettes (CC) to heated tobacco products (HTP). We used publicly available data for oxidative stress (in vitro), ciliary beating frequency (in vitro), mucociliary clearance (human), and lung function (human). Following the course of smoking-related lung function decline (Fletcher and Peto, 1977, PMID 871704), we assumed a non-monotonic time evolution where the risk of the AO <decreased lung function> begins to decline after quitting smoking CC or switching to HTP use. Consequently, we designed our qAOP to evaluate the relative reduction (RR) of AO risk for HTP switching compared to the two scenarios of continuing or quitting CC consumption. We developed both data- and physiology-based KE relationship (KER) models. Despite sparse data with respect to dose- and time-response relationships, we successfully connected the measured KEs through in silico KER models. We then used the resulting qAOP to evaluate the exposure effects of switching from CC smoking to HTP use along AOP 411. This approach enabled in silico prediction of the AO RR for which in vivo data were not yet available. In summary, our qAOP provides a multiscale mechanistic approach to evaluate medium-term lung function evolution for the use case of switching from CC smoking to HTP use. The presented approach demonstrates how 21st Century Toxicology principles such as in vitro testing and in silico predictions can be integrated to achieve a meaningful risk assessment approach. It also represents a starting point for integrating additional AOP into an extended AOP network that includes other mechanisms leading to decreased lung function.

Project description:Cyclooxygenase (COX) inhibition is of concern in fish because COX inhibitors (e.g., ibuprofen) are ubiquitous in aquatic systems/fish tissues, and can disrupt synthesis of prostaglandins that modulate a variety of essential biological functions including reproduction. Transcriptomic data and publicly available high throughput toxicity data were utilized to develop putative adverse outcome pathways (AOPs) for molecular initiating event (MIE) of COX inhibition. Effects of a waterborne exposure to indomethacin (IN; 100 Âµg/L), ibuprofen (IB; 200 Âµg/L) and celecoxib (CX; 20 Âµg/L) on liver metabolome and ovarian gene expression (using oligonucleotide microarrays) in sexually mature fathead minnows were examined. Metabolomic profiles of IN, IB and CX were not significantly different from control or one another. Exposure to IB and CX resulted in differential expression of comparable numbers of genes (IB = 433, CX= 545). In contrast, 2558 genes were differentially expressed in IN-treated fish. Functional analyses (canonical pathway and gene set enrichment) indicated extensive effects of IN on prostaglandin synthesis pathway, oocyte meiosis and several other processes consistent with physiological roles of prostaglandins. Transcriptomic data was congruent with apical endpoint data - IN reduced plasma prostaglandin F2 alpha concentrations, and ovarian COX activity, whereas IB and CX did not. Putative AOPs pathways for COX inhibition (MIE) leading to reproductive failure (adverse outcome) via reduction of: 1) ovulation, 2) reproductive behaviors mediated by exogenous and endogenous prostaglandins, and 3) oocyte maturation were developed. Adult fathead minnow were exposed to either 100 Âµg/L indomethacin, 200 Âµg/L ibuprofen, 20 Âµg/L celecoxib or UV-treated Lake Superior (control) water for 96 hours. After exposure, microarray analyses were conducted using the female gonads (n=7-8 per treatment) and metabolomic analyses were conducted using the livers of all the exposed fish.

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Using transcriptomics data and Adverse Outcome Pathway networks to explore endocrine disrupting properties of Cadmium and PCB-126

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