Unknown,Transcriptomics,Genomics,Proteomics

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Derivation and Evaluation of Putative Adverse Outcome Pathways for the Effects of Cyclooxygenase Inhibitors on Reproductive Processes in Fish

ABSTRACT: 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.

ORGANISM(S): Pimephales promelas

SUBMITTER: Alvine Mehinto

PROVIDER: E-GEOD-72976 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Propranolol is a beta-adrenergic receptor antagonist (Î²-blocker) that has been detected in United States wastewater effluents at concentrations ranging from 0.026 to 1.90 Âµg/l. In mammals, there is evidence that Î²-blockers can cause sexual dysfunction, and alter serotonergic pathways which may impact reproductive behavior but little is known about the effects on fish behavior. The present study tested the effects of propranolol on fecundity and on reproductive behavior of the fathead minnow, Pimephales promelas, a fish that exhibits male parental care. Sexually mature fathead minnows were housed at a ratio of one male and two females per tank and exposed to nominal concentrations of 0, 0.1, 1, 10 Âµg/l for 21 days. Measured concentrations (Â±SD) of propranolol were 0.05Â±0.02, 0.88Â±0.34 and 4.11Â±1.19 Âµg/l. There were no statistically significant differences in fecundity, fertilization rate, hatchability and time to hatch. Propranolol exposure was not associated with a change in nest rubbing behavior, time spent in the nest or approaching the females. There was a significant difference in the number of visits to the nest with males receiving low and medium propranolol treatments. The microarray analysis showed that there were 335 genes up-regulated and 400 genes down-regulated in the brain after exposure to the highest dose of propranolol. Among those genes, myoglobin and calsequestrin transcripts (fold change=10.84 and 5.49, respectively) were highly up-regulated. Ontological analyses indicated changes in genes involved in calcium ion transport, transcription, proteolysis and apoptosis/anti-apoptosis. The results showed that exposure to propranolol at concentrations as high as 4.11 Âµg/l did not significantly impact reproductive behavior or spawning abilities of fathead minnow but did alter the regulation of genes within the brain of fish. Effects of propanolol exposure were investigated in the brain of adult male fathead minnow exposed to 10 Âµg/L of propanolol or a solvent control solution (0.01% ethanol). For each treatment, the brain of four different fish were analyzed.

Project description:Pharmacological inhibition of cyclooxygenase-2 (COX-2) is being explored as a chemotherapeutic option because COX-2 protein expression is often elevated in many cancers. Cancer cells treated with COX-2 inhibitors, such as the selective COX-2 inhibitor celecoxib, show growth inhibition and the induction of apoptosis, through alterations in inflammatory processes, angiogenesis, cell adhesion and transforming growth factor-Î² signaling. This study was conducted to determine if the same processes are relevant to celecoxibâs effects on human colorectal adenocarcinomas treated in vivo. A cohort of 23 patients with primary colorectal adenocarcinomas was randomized to receive a 7-day course of celecoxib (400 mg b.i.d.) or no drug prior to surgical resection. Gene expression profiling was performed on resected adenocarcinomas from patients with and without celecoxib pre-treatment. Using fold change (>1.5) and p-value (<0.05) cut-offs, 190 genes were differentially expressed between adenocarcinomas from patients receiving celecoxib and those that did not. Of the differentially expressed genes, multiple genes involved in cellular lipid and glutathione metabolism showed decreased expression levels in celecoxib pre-treated samples; changes associated with diminished cellular proliferation. Other observed gene expression changes consistent with reduced proliferation include: altered expression of genes involved in cell adhesion (including collagen, laminin, von Willebrand factor and tenascin C), increased expression of inflammatory modulators (including inerleukin-6, S100 calcium binding protein A8, and several chemokines) and decreased expression of the pro-angiogenic gene, angiogenin. Celecoxib pre-treatment for 7 days in vivo is associated with alterations in colorectal adenocarcinoma gene expression which are suggestive of diminished cellular proliferation. Experiment Overall Design: Patients undergoing surgical resection of histologically proven primary colorectal adenocarcinomas were consented for participation in the study. The patients enrolled in this study were randomized to receive either 400 mg celecoxib two times per day (n=11) or no COX-2 inhibitor (n=12) for 7 days prior to surgical resection. Total RNA (5 ug) from each sample was converted to double stranded cDNA using a dT-T7 promoter primer. The double stranded cDNA was then used as a template to synthesize biotinylated RNA, which was fragmented and hybridized to the Affymetrix HG_U95av2 microarray chip using Affymetrixâs labeling and hybridization protocol. Experiment Overall Design: The array data was imported into GeneSpring GX 7.3 using the GC-RMA file preprocessor. The data was normalized by: (1) setting all expression measurements <0.01 to 0.01, (2) a per chip normalization to the 50th percentile, and (3) a per gene normalization to the median value across all chips.

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Derivation and Evaluation of Putative Adverse Outcome Pathways for the Effects of Cyclooxygenase Inhibitors on Reproductive Processes in Fish

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