Abstract
The organic compound diethylhexyl phthalate (DEHP) represents a high production volume chemical found in cosmetics, personal care products, laundry detergents, and household items. DEHP, along with other phthalates causes endocrine disruption in males. Exposure to endocrine disrupting chemicals has been linked to the development of several adverse health outcomes with apical end points including Non-Alcoholic Fatty Liver Disease (NAFLD). This study examined the adult male zebrafish (Danio rerio) transcriptome after exposure to environmental levels of DEHP and 17α-ethinylestradiol (EE2) using both DNA microarray and RNA-sequencing technologies. Our results show that exposure to DEHP is associated with differentially expressed (DE) transcripts associated with the disruption of metabolic processes in the liver, including perturbation of five biological pathways: ‘FOXA2 and FOXA3 transcription factor networks’, ‘Metabolic pathways’, ‘metabolism of amino acids and derivatives’, ‘metabolism of lipids and lipoproteins’, and ‘fatty acid, triacylglycerol, and ketone body metabolism’. DE transcripts unique to DEHP exposure, not observed with EE2 (i.e. non-estrogenic effects) exhibited a signature related to the regulation of transcription and translation, and ruffle assembly and organization. Collectively our results indicate that exposure to low DEHP levels modulates the expression of liver genes related to fatty acid metabolism and the development of NAFLD.
Highlights
Two recent studies suggested that diethylhexyl phthalate (DEHP) may cause lipid accumulation and nonalcoholic fatty liver disease (NAFLD) by promoting PPARα and sterol regulator element-binding protein 1c (SREBP-1c) expression[17,18]
DEHP exposure enriched a number of carbohydrate metabolism processes, including chitin metabolic and chitin catabolic processes (q = 4.46E-05 and 8.91E-05 respectively), amino sugar catabolic process (q = 1.16E-04) and ion transport (q = 3.63E-02) (Table 1, DEHP Total and Fig. 1B)
We performed enrichment analysis using differentially expressed (DE) gene signatures that were unique for DEHP and observed significant enrichment in terms related to regulation of translational initiation (q = 1.65E-01), negative regulation of translation (q = 2.48E-01), ruffle organization (q = 1.93E-01) and ruffle assembly (q = 2.14E-01) (Table 1, DEHP Unique and Fig. 1D)
Summary
Two recent studies suggested that DEHP may cause lipid accumulation and nonalcoholic fatty liver disease (NAFLD) by promoting PPARα and sterol regulator element-binding protein 1c (SREBP-1c) expression[17,18]. We examined the effect of exposure to 5.8 nM of DEHP on the liver transcriptome, a concentration that is relevant to observed environmental levels[19]. To examine the effects of DEHP exposure on the adult male hepatic transcriptome, we exploited the zebrafish model (Danio rerio) and undertook a systems level analysis. We performed microarray and RNA sequencing analyses, and considered the data in the context of the recently described Adverse Outcomes Framework (AOF)[23] This approach defines an adverse outcome as the end result of a causal series of events punctuated by “key events” (KE), the results of a molecular initiating event (MIE), a molecular interaction between a chemical stressor and a target biomolecule that alters gene expression. This study is the first to use deep transcriptome profiling to explore the effects of exposure to DEHP on the zebrafish liver
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