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Derivation and evaluation of putative adverse outcome pathways for the effects of cyclooxygenase inhibitors on reproductive processes in female fish
Citation:
Martinovic-Weigelt, D., A. Mehinto, G. Ankley, J. Berninger, Tim Collette, J. Davis, N. Denslow, E. Durhan, E. Eid, D. Ekman, K. Jensen, M. Kahl, C. LaLone, Q. Teng, AND Dan Villeneuve. Derivation and evaluation of putative adverse outcome pathways for the effects of cyclooxygenase inhibitors on reproductive processes in female fish. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 156(2):344-361, (2017).
Impact/Purpose:
Adverse outcome pathways are a conceptual framework intended to aid in making scientifically-credible linkages between measures of pathway perturbation, such as provided through high throughput in vitro testing batteries, and apical hazards considered relevant to risk assessment. The present study proposes several hypothesized AOPs linking inhibition of cyclooxygenase, a biochemical endpoint evaluated in EPA’s ToxCast program, with potential impacts on fish reproduction. Cyclooxygenase inhibitors include a wide range of human pharmaceuticals such as non-steroidal anti-inflammatory drugs which can be discharged to aquatic environments via wastewater streams. The present putative AOPs, immediately enhance the ability to interpret high throughput toxicology data in the context of potential ecological hazards. With adequate further development, these relationships can also support predictive approaches to assessing potential risks associated with exposure to compounds found to disrupt cyclooxygenase enzymes as critical biological targets.
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. High content (transcriptomic) empirical data and publicly available high throughput toxicity data (actor.epa.gov) were utilized to develop putative adverse outcome pathways (AOPs) for molecular initiating event (MIE) of COX inhibition. Effects of a waterborne, 96h exposure to indomethacin (IN; 100 µg/L), ibuprofen (IB; 200 µg/L) and celecoxib (CX; 20 µg/L) on liver metabolome and ovarian gene expression (using oligonucleotide microarrays) in sexually mature fathead minnows (n=8) 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.
