Effect of antipsychotics on mitochondrial bioenergetics of rat ovarian theca cells

Elmorsy, Ekramy; Al-Ghafari, Ayat; Aggour, Amal Misbah; Mosad, Soaad Mohamed; Khan, Raheela; Amer, Saad

Abstract

Background

Antipsychotics (APs) are widely prescribed drugs, which are well known to cause reproductive adverse effects through mechanisms yet to be determined. The purpose of this study was to investigate the effect of antipsychotics on mitochondrial bioenergetics of rat ovarian theca cells as a possible mechanism of reproductive toxicity.

Methods

Isolated rat theca interstitial cells (TICs) were treated with two typical (chlorpromazine [CPZ] and haloperidol [HAL]) and two atypical APs (risperidone [RIS] and clozapine [CLZ]). The effects of these APs on TICs bioenergetics (ATP content, mitochondrial complexes I and III activities, oxygen consumption rates (OCRs), mitochondrial membrane potential (MPP) and lactate production) and on steroidogenesis (androstenedione and progesterone synthesis) were investigated.

Results

All APs resulted in a concentration-dependent decrease in the ATP content of TICs. All APs at their estimated IC50s (6 μM, 21 μM, 35 μM and 37 μM for CPZ, HAL, CLZ and RIS respectively) significantly decreased TICs OCRs (p < 0.0001), MPP (p < 0.0001) and significantly (p = 0.0003) inhibited mitochondrial complex I activity. Only typical APs inhibited complex III (p = 0.005). Also, APs at IC50s increased TICs lactate production to varying degrees. All APs used at their IC50s significantly inhibited progesterone (p = 0.0022) and androstenedione (p = 0.0027) production. Only CPZ was found to inhibit these hormones at the low concentration (1 μM).

Conclusion

All four antipsychotics seem to inhibit mitochondrial bioenergetics and steroidogenesis in rat’s ovarian theca cells. These findings support the hypothesis that APs-induced reproductive toxicity may be through mechanisms involving mitochondrial insult>. Further research is required to establish the link between APs-induced mitochondrial dysfunction and disordered steroidogenesis.

Citation

Elmorsy, E., Al-Ghafari, A., Aggour, A. M., Mosad, S. M., Khan, R., & Amer, S. (2017). Effect of antipsychotics on mitochondrial bioenergetics of rat ovarian theca cells. Toxicology Letters, 272, https://doi.org/10.1016/j.toxlet.2017.03.018

• Journal Article Type: Article
• Acceptance Date: Mar 16, 2017
• Online Publication Date: Mar 18, 2017
• Publication Date: Apr 15, 2017
• Deposit Date: May 25, 2017
• Publicly Available Date: May 25, 2017
• Journal: Toxicology Letters
• Print ISSN: 0378-4274
• Electronic ISSN: 1879-3169
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 272
• DOI: https://doi.org/10.1016/j.toxlet.2017.03.018
• Keywords: Antipsychotics; Ovarian cytotoxicity; Mitochondrial bioenergetics; Reproductive toxicity
• Public URL: https://nottingham-repository.worktribe.com/output/856124
• Publisher URL: http://www.sciencedirect.com/science/article/pii/S0378427417301200
• Contract Date: May 25, 2017