ERA4PHARM

"Environmental risk assessment of four pharmaceutical compounds employing genomic tools and the seabream, Sparus aurata."

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 Obiettivo del progetto (Objective)

'Human and veterinary pharmaceutical drugs are more and more consumed worldwide. Their detection in the environment and their bioactivity has now raised concern for potential adverse effects on non-target species. Notwithstanding recent attention for their environmental presence, there are significant research gaps for existing pharmaceuticals with regard to their potential ecological consequences. In this study, the four most abundantly used pharmaceuticals: Acetaminophen, Carbamazepine, Trimethoprim y Atenolol, will be examined for their long term effect on the genomic and proteomic expression of the gilthead seabream, Sparus aurata. These endpoints provide useful information on the xenobiotic-induced impairment resulting in the activation and silencing of specific genes by elucidating the underlying molecular mechanisms of higher level damage. Gene expression and protein products will be evaluated in liver and brain as target tissues by microarray and 2D differential gel electrophoresis (2D DIGE) techniques, and significantly up and down regulated proteins will be identified by liquid chromatography–tandem mass spectrometry (LC–MS–MS). These responses will be compared with the histopathological effects observed by histomorphological and histochemical techniques to link the toxic responses at different organizational levels. Together with already available toxicity data for this species and the chosen pharmaceutical compounds, we aim to elucidate toxicity mechanisms at molecular level that are linked with effects at higher organizational level. This will help to improve extrapolation techniques from laboratory tests to derive potential ecosystem effects. Also, the knowledge of molecular pathways and proteins involved in toxic processes forms the base for the development of specific biomarkers which will supply decision makers with information for the further monitoring of the effects of pharmaceuticals in the environment and the regulation of these compounds.'

Introduzione (Teaser)

Commonly prescribed pharmaceuticals are increasingly common in water bodies. Scientists studied the effects of this on gene and protein expression in a non-target fish species.

Descrizione progetto (Article)

Scientists initiated the EU-funded project ERA4PHARM to study three of the most widely used pharmaceuticals to evaluate their genetic effects and the molecular mechanisms of higher-level impairment.

Researchers investigated long-term effects of acetaminophen (APAP, an analgesic and antipyretic), carbamazepine (CBZ, an anti-convulsant and anti-depressant) and atenolol (AT, an anti-hypertensive) on one-year old gilthead seabream (Sparus aurata). They used changes in gene and protein expression in liver and brain as indicators of effects.

Exposure to all compounds at environmentally relevant concentrations produced changes in gene expression in the brain. The largest effect was seen after exposure to CBZ followed relatively closely by APAP, whereas minimal effects were produced on AT exposure. In addition, although some differences were shared, some were different, thus supporting potential biomarkers of exposure to specific drugs.

Automated gene enrichment analysis was performed to assign biological meaning to the changes in gene expression. CBZ exposure was associated with a number of altered functions, including glycosylation (addition of sugars to molecules such as proteins), RNA metabolic processes and DNA-dependent transcription. In addition, evidence supported activity as an endocrine disruptor. APAP changes were associated with epithelium development and morphogenesis, as well as with transcription and RNA metabolic processes. Further, a number of similarities were found between effects on seabream and those on rodents and humans, indicating a high degree of conservation of the genetic targets of these compounds.

ERA4PHARM contributed important information regarding the effects of widely used pharmaceuticals on gene and protein expression, and pointed to potential biomarkers of exposure to the various drugs. Studies also highlighted the possibility of using seabream as an animal model of human effects given highly conserved gene targets of the compounds. Data provided further the support of previous evidence suggesting that CBZ is an endocrine disruptor.

Taken together, ERA4PHARM results advanced limited existing knowledge regarding the effects of common pharmaceuticals that are often detected in water bodies, and should facilitate monitoring campaigns for greater safety in the future.