Abstract
The incidence of depression among humans is growing worldwide, and so is the use of antidepressants. However, our fundamental understanding regarding the mechanisms by which these drugs function and their off-target effects against human sexuality remains poorly defined. The present study aimed to determine their differential toxicity on mouse spermatogenic cells and provide mechanistic data of cell-specific response to antidepressant and neuroleptic drug treatment. To directly test reprotoxicity, the spermatogenic cells (GC-1 spg and GC-2 spd cells) were incubated for 48 and 96 h with amitriptyline (hydrochloride) (AMI), escitalopram (ESC), fluoxetine (hydrochloride) (FLU), imipramine (hydrochloride) (IMI), mirtazapine (MIR), olanzapine (OLZ), reboxetine (mesylate) (REB), and venlafaxine (hydrochloride) (VEN), and several cellular and biochemical features were assessed. Obtained results reveal that all investigated substances showed considerable reprotoxic potency leading to micronuclei formation, which, in turn, resulted in upregulation of telomeric binding factor (TRF1/TRF2) protein expression. The TRF-based response was strictly dependent on p53/p21 signaling and was followed by irreversible G2/M cell cycle arrest and finally initiation of apoptotic cell death. In conclusion, our findings suggest that antidepressants promote a telomere-focused DNA damage response in germ cell lines, which broadens the established view of antidepressants’ and neuroleptic drugs’ toxicity and points to the need for further research in this topic with the use of in vivo models and human samples.
Highlights
According to the World Health Organization (WHO), depressive disorders are the greatest burden of disease in developed countries, affect millions of people, and are the leading cause of disability around the world [1]
The side effect of antidepressants and neuroleptic drugs may be related to the influence on ATP synthesis by oxidative phosphorylation inhibition in mitochondria and interaction with phospholipids in the inner mitochondrial membrane or with sulfhydryl groups present in the sperm cell membrane
High levels of oxidative stress can damage the DNA of reproductive cells in patients treated with antidepressants [34] and here, we observed a significant increase in cellular DNA fragmentation and micronuclei formation in all experimental sets
Summary
According to the World Health Organization (WHO), depressive disorders are the greatest burden of disease in developed countries, affect millions of people, and are the leading cause of disability around the world [1]. Depression itself is characterized by a comprehensive impact on all aspects of human life, and may have a recurrent and chronic nature and a synergistic exacerbation effect in the presence of other conditions [2]. Antidepressants are the first-line agents for the initial treatment of depressive disorders. They were first developed in the 1950s. There are several different generations and classes of antidepressants. Their mechanism of action is generally associated with the chemical imbalance correction of neurotransmitters in the human brain [3,4]. The recent data point to alternative mechanisms, such as interaction with tropomyosin receptor kinase B [5]
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