Toxic effect of antidepressants on male reproductive system cells: evaluation of possible fertility reduction mechanism.

Abstract

Depression is acknowledged as a major public health problem. Pharmacological treatment may cause adverse drug reactions and sexual side effects. At the same time, the knowledge of the molecular mechanisms associated with antidepressant-mediated toxicity to reproductive cells is fragmentary. The aim of this study was the multilevel evaluation of the potential toxicity of several antidepressants or antipsychotic drugs (amitriptyline, 10 μM; escitalopram, 30 μM; fluoxetine, 5 μM; imipramine, 20 μM; mirtazapine, 150 μM; olanzapine, 40 μM; reboxetine, 30 μM; venlafaxine, 250 μM) on the cells of the spermatogenesis pathway. Effects of various drugs were monitored by several methods including mitochondrial activity MTT test, fluorescent staining, real-time PCR, morphology analysis, immunofluorescence, and Western blots. Obtained results suggest the concentration- and the time-dependent cytotoxic effect. The molecular mechanism of cytotoxic effect is mediated by disturbances in the redox balance (increased production of reactive oxygen species and reactive nitrogen species), failure of enzymatic and non-enzymatic cell protection mechanisms (glutathione system, nuclear factor-κB and fibroblast growth factor 2-mediated pathways), and impairment of mitochondrial functions. In addition, we provide for the first time, to our knowledge, evidence that antidepressant treatment may contribute to spindle apparatus assembly defects and organelle distribution during cell division in vitro (alterations in the levels of small C terminal domain phosphatase-1 and -3, NuMa, and calnexin protein levels). This study sheds new light on the pathomechanisms of antidepressants action and their associated toxicity towards the reproductive system, emerging issues linked with animal or human reproductive health, and treatment of mood disorders.