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Assessment of in vitro antiovulatory activities of nonsteroidal anti‐inflammatory drugs and comparison with in vivo reproductive toxicities of medaka (Oryzias latipes)

Yokota, Hirofumi, Eguchi, Sayaka, Hasegawa, Saki, Okada, Kana, Yamamoto, Fumiko, Sunagawa, Ayaka, Tanaka, Marie, Yamamoto, Rika, Nakano, Eiko
Environmental toxicology 2016 v.31 no.12 pp. 1710-1719
Oryzias latipes, anovulation, aspirin, diclofenac, eggs, fecundity, females, fish, gonadosomatic index, humans, inhibitory concentration 50, ketoprofen, models, mortality, prediction, reproductive toxicology, risk, salicylic acid, spawning
Nonsteroidal anti‐inflammatory drugs (NSAIDs) are widely used therapeutic agents; however, their pharmacological actions raise concerns about potential risks to the reproductive health of aquatic vertebrates. In the present study, a medaka ovulation assay was applied as an in vitro model to evaluate NSAID‐induced antiovulatory activity. We first tested five NSAIDs, including diclofenac sodium (DCF), ketoprofen (KP), salicylic acid (SA), mefenamic acid (MA), and acetylsalicylic acid (ASA) for their antiovulatory activities toward the follicles isolated from the ovaries of spawning females. Of all the chemicals tested, DCF had the highest antiovulatory activity, with the concentration that caused 50% inhibition (IC50) (101 µM). MA was the second most potent inhibitor following DCF, but KP, SA, or ASA had little inhibitory effect on the ovulation of the follicles. The in vitro antiovulatory activity of five NSAIDs showed good correlation with data published on the inhibitory activity on human COX‐2. Second, we selected DCF and SA as the most and least potent NSAIDs, respectively, and examined the effects on reproduction of intact fish in order to evaluate whether the ovulation assay was a reasonable predictor of potential reproductive effects in fish. Females exposed to DCF showed a concentration‐dependent decrease in the number of spawned eggs and an increment in the gonadosomatic index (GSI), possibly due to an anovulation in the females. In contrast, neither fecundity nor the GSI of females decreased at up to 20 mg/L of SA, at which acute lethality to medaka was induced. In conclusion, the medaka ovulation assay reflected the potency of NSAID‐induced antiovulatory activity and may thus serve as an in vitro model for the prediction of NSAID‐induced reproductive toxicity. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1710–1719, 2016.