Systems analysis of the liver transcriptome in adult male zebrafish exposed to the non-ionic surfactant nonylphenol

Abstract

Nonylphenol (NP) arises from the environmental degradation of nonylphenol ethoxylates. It is a ubiquitous environmental contaminant and has been detected at levels up to 167 nM in rivers in the United States. NP is an endocrine disruptor (ED) that can act as an agonist for estrogen receptors. The Adverse Outcome Pathway (AOP) framework defines an adverse outcome as the causal result of a series of molecular initiating events (MIEs) and key events (KEs) that lead to altered phenotypes. This study examined the liver transcriptome after a 21 day exposure to NP and 17β-estradiol (E2) by exploiting the zebrafish (Danio rerio) as a systems toxicology model. The goal of this study was to tease out non-estrogenic genomic signatures associated with NP exposure using DNA microarray and RNA sequencing. Our experimental design included E2 as a positive and potent estrogenic control in order to effectively compare and contrast the 2 compounds. This approach allowed us to identify hepatic transcriptomic perturbations that could serve as MIEs for adverse health outcomes in response to NP. Our results revealed that exposure to NP was associated with differential expression (DE) of genes associated with the development of steatosis, disruption of metabolism, altered immune response, and metabolism of reactive oxygen species, further highlighting NP as a chemical of emerging concern (CEC).

The mechanism of cytotoxicity of 4‐nonylphenol in a human hepatic cell line involves ER‐stress, apoptosis, and mitochondrial dysfunction

“…Finally, it has been demonstrated in zebrafish, through a transcriptomic approach, that 4-NP induced a perturbation in gene expression, compatible sponse and with a dysregulation of cell cycle. [38] In the present study, we have attempted to improve the knowledge of molecular mechanisms at the basis of 4-NP hepatotoxicity. Through the MTT viability assay, we found that the treatment with 4-NP for 24 h was cytotoxic for HepG2 cells, as it induced a reduction of more than 50% of viability at a concentration observed the highest increase of p53, a protein able to block the cell cycle in the presence of stressor compounds [39] and able to induce apoptosis when overexpressed.…”

“…Finally, it has been demonstrated in zebrafish, through a transcriptomic approach, that 4‐NP induced a perturbation in gene expression, compatible with the development of steatosis, with an altered immune response and with a dysregulation of cell cycle. [ 38 ]…”

“…[34,36] Yu et al [37] demonstrated that a subchronic exposure to 4-NP, combined with a high-sucrose/high-fat diet, in- sponse and with a dysregulation of cell cycle. [38] In the present study, we have attempted to improve the knowledge of molecular mechanisms at the basis of 4-NP hepatotoxicity. Through the MTT viability assay, we found that the treatment with 4-NP for 24 h was cytotoxic for HepG2 cells, as it induced a reduction of more than 50% of viability at a concentration of 100 μM.…”

Report of the Scientific Committee of the Spanish Agency for Food Safety and Nutrition (AESAN) on the available evidence in relation to the potential obesogenic activity of certain chemical compounds that may be present in foods

“…AESAN Scientific Committee: Available evidence in relation to the potential obesogenic activity of certain chemical compounds that may be present in foods mulation in hepatocytes, resulting in oxidative stress and alteration of the microbiota, among other demonstrated mechanisms (Chen et al, 2016) (Zhang et al, 2017(Zhang et al, , 2019b) (Jacobs et al, 2018) (Huff et al, 2019) (Buerger et al, 2019(Buerger et al, , 2020.…”

A systems biology approach reveals the endocrine disrupting potential of Aflatoxin B1.

“…To obtain enough differentially expressed genes suitable for systems-level analysis, a threshold qvalue of 0.4 of was applied. This q-value cut off was guided by the literature and previous articles on the study of estrogen receptor response (Irish et al 2016;Hardiman et al 2016;Dhamad et al 2016;Huff et al 2018Huff et al , 2019.…”