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 during 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 evaluated 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 IC 50 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 pharmaceuticals 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.
ABSTRACT
An "endocrine disruptor" has been broadly defined as an exogenous chemical that interferes with the production, release, transportation, metabolism, binding, action, or the elimination of endogenous hormones, which are responsible for homeostasis, reproduction, development or behaviour. Diverse groups of chemicals such as pharmaceuticals, phytoestrogens, natural hormones, and synthetic chemicals such as pesticides, plasticizers, phthalates, parabens, polychlorinated/polybrominated biphenyls, bisphenols are shown to interfere with the endocrine system, and they have been defined as EDs in the last three decades. As for all chemicals, the biotransformation of EDs has a decisive role in their potential toxic effects. Humans are exposed to vast amounts of diverse chemicals throughout their lives. Fortunately, most of the chemicals are converted via biotransformation reactions catalyzed by the enzymes, into more hydrophilic metabolites, which are readily excreted in urine or bile. Biotransformation reactions resulting in less toxic metabolites are known as detoxification. However, some biotransformation reactions are called bioactivation, in which more toxic metabolites are formed. In the case of EDs, metabolites formed via bioactivation usually have a higher affinity for a hormone receptor or induce/inhibit an enzyme involved in the synthesis or catabolism of an endogenous hormone more dramatically compared to their parent compound. In the present review, the role of bioactivation in endocrine modulating effects of chemicals from all groups of EDs, namely endogenous estrogens, phytoestrogens, synthetic/industrial chemicals, and pharmaceuticals it can be were discussed.
