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. 2022 Dec 8;17(12):e0271217.
doi: 10.1371/journal.pone.0271217. eCollection 2022.

Paroxetine treatment in an animal model of depression improves sperm quality

Reyhane Aghajani  1   2 , Marziyeh Tavalaee  1   2 , Niloofar Sadeghi  2 , Mazdak Razi  3 , Parviz Gharagozloo  4 , Maryam Arbabian  2 , Joël R Drevet  5 , Mohammad Hossein Nasr-Esfahani  1   2
Affiliations

Paroxetine treatment in an animal model of depression improves sperm quality

Reyhane Aghajani et al. PLoS One. .

Expression of concern in

Abstract

Depression in mammals is known to be associated with poor reproductive capacity. In males, it has been associated with decreased efficiency of spermatogenesis as well as the production of spermatozoa of reduced structural and functional integrity. Although antidepressants are effective in correcting depressive states, there is controversy regarding their effectiveness in restoring male reproductive function. Here, using an animal model of depression induced by a forced swim test, we confirmed that depression is accompanied by impaired male reproductive function. We further show that administration of a conventional antidepressant of the serotonin reuptake inhibitor class (paroxetine) impairs male reproductive performance in terms of sperm production and quality when administered to healthy animals. Intriguingly, when paroxetine is administered to "depressed" animals, it resulted in a complete restoration of the animal's ability to produce sperm that appears to be as capable of meeting the parameters evaluated here as those of control animals. The one-carbon cycle (1CC) is one of the most important metabolic cycles that include the methionine and folate cycles and plays a major role in DNA synthesis, amino acids, and also the production of antioxidants. Our results show that depression affects the main components of this cycle and paroxetine on healthy mice increases homocysteine levels, decreases glycine and vitamin B12, while in depressed mice, it increases folate levels and decreases vitamin B12. Thus, paroxetine exerts negative impacts on male reproductive function when administered to healthy animals and it well correlate with the altered sperm parameters and functions of depressed animals, and its mechanism remains to be explored.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Flowchart of study design in animal model.
Fig 2
Fig 2. Histological illustration of mouse testicular tissues.
Top panels: Comparison of testis sections between groups [A: Control, B: Saline (sham), C: Paroxetine (7 mg/kg), D: Stress (FST), E: Stress + Paroxetine (7 mg/kg)] at two different magnifications (100μm: Upper photographs; 400μm: Lower photographs). Bottom bar graphs: Comparison of testicular morphometric parameters including percentages of Johnsen score (left), the tubular differentiation index = TDI (middle), and spermatogenic index = SPI (right) between groups. Bars with different superscript letters are significantly different (p<0.05). Par=paroxetine.
Fig 3
Fig 3. Immunohistochemical staining of CASPASE-3 in testes cross-sections.
Comparison of mean percentage of Caspase-3 -positive cells in germ cells (spermatogonia, spermatocytes, spermatids, Leydig, and Sertoli cells) within groups. The values with different superscript letters in each row are significantly different (p≤0.05).
Fig 4
Fig 4. Immunohistochemical staining of TUNEL positive cells in testes cross-sections.
Comparison of mean percentage of TUNEL-positive cells (spermatogonia, spermatocytes, spermatids, Leydig, and Sertoli cells) within groups. The values with different superscript letters in each row are significantly different (p≤0.05).
Fig 5
Fig 5. Comparison of mouse sperm parameters in the different groups (N=6 for each group).
A: Concentration (in million /ml). B: Motile spermatozoa (in %). C: Spermatozoa with abnormal morphology (in %). D: Spermatozoa showing lipid peroxidation (in %). E: Spermatozoa having immature sperm chromatin (in %). F: Spermatozoa showing protamine deficiency (in %). G: Spermatozoa showing DNA damage (in %). Bars with different superscript letters are significantly different (p<0.05). Par = paroxetine.
Fig 6
Fig 6. Comparison of serum follicle-stimulating hormone (FSH) and Luteinizing hormone (LH) levels in mouse serum between groups (N=3 for each group).
Bars with different superscript letters are significantly different (p<0.05). Par = paroxetine.
Fig 7
Fig 7. Evaluation of one-carbon cycle indicators between mouse groups (N=3 for each group).
Bars with different superscript letters are significantly different (p<0.05).
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