Effect of antipsychotics on mitochondrial bioenergetics of rat ovarian theca cells.
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 (6μM, 21μM, 35μM and 37μM 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 (1μM).


CONCLUSIONS
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.
Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Mansoura University, Egypt.
Ekramy
E
Elmorsy
Biochemistry Department, Faculty of Science, King Abdulaziz University (KAU), Jeddah, Saudi Arabia.
Ayat
A
Al-Ghafari
Clinical Pathology specialist, Ministry of Health, Egypt.
Amal Misbah
AM
Aggour
Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Mansoura University, Egypt.
Soaad Mohamed
SM
Mosad
Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Royal Derby Hospital, Uttoxeter Road, Derby DE22 3DT, UK.
Raheela
R
Khan
Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Royal Derby Hospital, Uttoxeter Road, Derby DE22 3DT, UK. Electronic address: Saad.amer@nottingham.ac.uk.
Saad
S
Amer
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013799:Theca Cells / Q000187:drug effects* / Q000378:metabolism
D014150:Antipsychotic Agents; D000255:Adenosine Triphosphate; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I
Antipsychotics; Mitochondrial bioenergetics; Ovarian cytotoxicity; Reproductive toxicity