Evaluation of Endocrine Related Adverse Effects of Non-Endocrine Targeted Pharmaceuticals in Cellular Systems

Abstract

Background: Prenatal period is a critical developmental phase that is sensitive to hormonal disruption by natural and/or exogenous hormones. Some pharmaceuticals frequently prescribed and used safely during pregnancy are shown to interact with the developmental programming of fetus, resulting in endocrine-related adverse effects. Objective: In this research, we aimed to determine the endocrine disrupting potential of paracetamol, indomethacin, alpha-methyldopa and pantoprazole which are frequently prescribed pharmaceuticals dur-ing pregnancy. Methods: In vitro aromatase inhibitory, estrogen receptor (ER) agonist/antagonist (E-Screen assay) and hormone biosynthesis modulatory effects (H295R steroidogenesis assay) of the selected pharmaceuticals were evaluated. Furthermore, their effects on viability of MCF-7/BUS and H295R cells were also evalu-ated by MTT assay. Results: None of the pharmaceuticals affected H295R cell viability. Only indomethacin reduced MCF-7/BUS cell viability at 100μM and 300μM. Among the tested pharmaceuticals, only paracetamol and indomethacin showed aromatase inhibitory activity with IC50 values of 14.7 x 10-5 M and 57.6 x 10-5 M, respectively. Moreover, indomethacin displayed a biphasic ER agonist effect. ER antagonist effects of indomethacin and pantoprazole were confirmed by performing two stepped E-Screen assay. After the partial validation of the H295R steroidogenesis assay with forskolin and prochloraz, the effects of phar-maceuticals on synthesis of testosterone (T) and estradiol (E2) levels were tested. Alpha-methyldopa increased E2 at all tested concentrations and T at 1.48 and 4.4μM. Contrarily other tested pharmaceuticals did not affect steroidogenesis. Conclusion: Present data suggest that all tested pharmaceuticals may have potential endocrine disrupting effect, which should be considered when used in pregnancy.