Bupropion promotes alterations in the spermatogenesis of mice and congenital malformations in the offspring
Eliane S. A. M. Sanches A B , Felipe Tsuzuki A , Fábio A. Joinhas A , Caio C. N. Martins A , Glaura S. A. Fernandes A and Maria J. S. Salles A C
+ Author Affiliations
- Author Affiliations
A Department of Biology, State University of Londrina (UEL), 86051-980, Londrina, Parana, Brazil.
B Department of General Pathology, State University of Londrina (UEL), 86051-980, Londrina, Parana, Brazil.
C Corresponding author. Email: salmjs00@gmail.com
Reproduction, Fertility and Development 30(12) 1751-1758 https://doi.org/10.1071/RD18007
Submitted: 7 January 2018 Accepted: 7 June 2018 Published: 5 July 2018
Abstract
Bupropion hydrochloride (BUP) has been associated with male sexual dysfunction. The aim of this study was to evaluate the effects of BUP on the reproductive function of male mice and to evaluate offspring development. The mice were distributed into BUP group (40 mg kg−1) and control group (saline). On Day 35 of treatment the males were placed to mate with females and then killed on Day 46 for evaluation of reproductive function. On Day 18 of pregnancy, pregnant females were killed for evaluation of congenital malformations in the offspring. The BUP group showed a decrease in the Johnsen score (Control, 9.354 ± 0.092; BUP, 7.615 ± 0.147), Sertoli (Control, 5.623 ± 0.184; BUP, 4.215 ± 0.097) and Leydig (Control, 11.430 ± 0.817; BUP, 7.531 ± 0.213) cell counts, testosterone levels (Control, 783.5 ± 154.2 ng dL−1; BUP, 201.4 ± 54.8 ng dL−1) and sperm production (Control, 2.852 ± 0.211; BUP, 1.988 ± 0.116) and increased morphological alterations of the sperm head (Control, 8.134%; BUP, 10.423%) and tail (Control, 4.96%; BUP, 16.211%). The congenital malformations observed in BUP-derived offspring were: kyphosis (Control, 0.00%; BUP, 5.26%), retroverted rear legs (Control, 14.43%; BUP, 53.68%), incomplete ossification of the supraoccipital and exoccipital (Control, 21.82%; BUP, 86.00%) and sternum (Control, 25.45%; BUP, 82.00%). BUP had toxic effects on testicular function and teratogenic potential.
Additional keywords: BUP, paternal toxicity, reproductive performance, teratogenesis.
References
Abdel-Hamid, I. A., and Saleh, el-S. (2011). Primary lifelong delayed ejaculation: characteristics and response to bupropion. J. Sex. Med. 8, 1772–1779.| Primary lifelong delayed ejaculation: characteristics and response to bupropion.Crossref | GoogleScholarGoogle Scholar |
Abdel-Hamid, I. A., Elsaied, M. A., and Mostafa, T. (2016). The drug treatment of delayed ejaculation. Transl. Androl. Urol. 5, 576–591.
| The drug treatment of delayed ejaculation.Crossref | GoogleScholarGoogle Scholar |
Adler, I. D. (2000). Spermatogenesis and mutagenicity of environmental hazards: extrapolation of genetic risk from mouse to man. Andrologia 32, 233–237.
| Spermatogenesis and mutagenicity of environmental hazards: extrapolation of genetic risk from mouse to man.Crossref | GoogleScholarGoogle Scholar |
Aitken, R. J., and Koppers, A. J. (2011). Apoptosis and DNA damage in human spermatozoa. Asian J. Androl. 13, 36–42.
| Apoptosis and DNA damage in human spermatozoa.Crossref | GoogleScholarGoogle Scholar |
Al-Habori, M., Al-Aghabari, A., Al-Mamay, M., and Baker, M. (2002). Toxicological evaluation of Catha edulis leaves: a long term feeding experiment in animals. J. Ethnopharmacol. 83, 209–217.
| Toxicological evaluation of Catha edulis leaves: a long term feeding experiment in animals.Crossref | GoogleScholarGoogle Scholar |
Amiaz, R., Pope, H. G., Mahne, T., Kelly, J. F., Brennan, B. P., Kanayama, G., Weiser, M., Hudson, J. I., and Seidman, S. N. (2011). Testosterone gel replacement improves sexual function in depressed men taking serotonergic antidepressants: a randomized, placebo-controlled clinical trial. J. Sex Marital Ther. 37, 243–254.
| Testosterone gel replacement improves sexual function in depressed men taking serotonergic antidepressants: a randomized, placebo-controlled clinical trial.Crossref | GoogleScholarGoogle Scholar |
Anderson, J. W., Greenway, F. L., Fujioka, K., Gadde, K. M., McKenney, J., and O’Neil, P. M. (2002). Bupropion Sr enhances weight loss: a 48-week double-blind, placebo-controlled trial. Obes. Res. 10, 633–641.
| Bupropion Sr enhances weight loss: a 48-week double-blind, placebo-controlled trial.Crossref | GoogleScholarGoogle Scholar |
Barrow, M. V., and Taylor, W. J. (1969). A rapid method for detecting malformations in rat fetuses. J. Morphol. 127, 291–305.
| A rapid method for detecting malformations in rat fetuses.Crossref | GoogleScholarGoogle Scholar |
Beard, E., Shahab, L., Cummings, D. M., Michie, S., and West, R. (2016). New pharmacological agents to aid smoking cessation and tobacco harm reduction: what has been investigated, and what is in the pipeline? CNS Drugs 30, 951–983.
| New pharmacological agents to aid smoking cessation and tobacco harm reduction: what has been investigated, and what is in the pipeline?Crossref | GoogleScholarGoogle Scholar |
Billes, S. K., and Cowley, M. A. (2007). Inhibition of dopamine and norepinephrine reuptake produces additive effects on energy balance in lean and obese mice. Neuropsychopharmacology 32, 822–834.
| Inhibition of dopamine and norepinephrine reuptake produces additive effects on energy balance in lean and obese mice.Crossref | GoogleScholarGoogle Scholar |
Birkmayer, G., Nadlinger, K. F., and Hallstrom, S. (2004). On the safety of reduced nicotinamide adenine dinucleotide (NADH). J. Environ. Pathol. Toxicol. Oncol. 23, 179–194.
| On the safety of reduced nicotinamide adenine dinucleotide (NADH).Crossref | GoogleScholarGoogle Scholar |
Brambilla, G., Mottioli, F., and Marteli, A. (2009). Genotoxic and carcinogenic effects of antipsychotic and antidepressants. Toxicology 261, 77–88.
| Genotoxic and carcinogenic effects of antipsychotic and antidepressants.Crossref | GoogleScholarGoogle Scholar |
Calderon, I. M. P., Rudge, M. V. C., Brasil, M. A. M., and Henry, M. A. C. A. (1992). Modelo experimental em ratas para estudo do binômio diabete e gravidez. Acta Cir. Bras. 4, 136–144.
Cavariani, M. M., De Almeida Kiguti, L. R., De Lima Rosa, J., de Araújo Leite, G. A., Silva, P. V., Pupo, A. S., and De Grava Kempinas, W. (2015). Bupropion treatment increases epididymal contractility and impairs sperm quality with no effects on the epididymal sperm transit time of male rats. J. Appl. Toxicol. 35, 1007–1016.
| Bupropion treatment increases epididymal contractility and impairs sperm quality with no effects on the epididymal sperm transit time of male rats.Crossref | GoogleScholarGoogle Scholar |
Dirami, D., and Cooke, B. A. (1998). Effect of a dopamine agonist on luteinizing hormone receptors, cyclic AMP production and steroidogenesis in rat Leydig cells. Toxicol Appl Pharmacol. 150, 393–401.
de Kretser, D. M., Loveland, K. L., Meinhardt, A., Simorangkir, D., and Wreford, N. (1998). Spermatogenesis. Hum Reprod. 13, 1–8.
Dhir, A., and Kulkarni, S. K. (2007). Involvement of nitric oxide (NO) signaling pathway in the antidepressant action of bupropion, a dopamine reuptake inhibitor. Eur. J. Pharmacol. 568, 177–185.
| Involvement of nitric oxide (NO) signaling pathway in the antidepressant action of bupropion, a dopamine reuptake inhibitor.Crossref | GoogleScholarGoogle Scholar |
Dobrznka, M. M., Tyrkeil, E. J., and Pachocki, K. A. (2011). Developmental toxicity in mice following paternal exposure to Di-N-butyl-phthalate (DBP). Biomed. Environ. Sci. 24, 569–578.
Evgeni, E., Charalabopoilos, K., and Asimakopoulos, B. (2014). Human sperm DNA fragmentation and its correlation with conventional semen parameters. J. Reprod. Infertil. 15, 2–14.
Fernandes, G. S., Arena, A. C., Fernandez, C. D., Mercadante, A., Barbisan, L. F., and Kempinas, W. G. (2007). Reproductive effects in male rats exposed to diuron. Reprod. Toxicol. 23, 106–112.
| Reproductive effects in male rats exposed to diuron.Crossref | GoogleScholarGoogle Scholar |
Gadde, K. M., and Xiong, G. L. (2007). Bupropion for weight reduction. Expert Rev. Neurother. 7, 17–24.
| Bupropion for weight reduction.Crossref | GoogleScholarGoogle Scholar |
Gentile, S. (2005). The safety of newer antidepressants in pregnancy and breastfeeding. Drug Saf. 28, 137–152.
| The safety of newer antidepressants in pregnancy and breastfeeding.Crossref | GoogleScholarGoogle Scholar |
Gisslen, T., Nathan, B., Thompson, T., and Rao, R. (2011). Hyperinsulinism associated with gestational exposure to bupropion in a newborn infant. J. Pediatr. Endocrinol. Metab. 24, 819–822.
| Hyperinsulinism associated with gestational exposure to bupropion in a newborn infant.Crossref | GoogleScholarGoogle Scholar |
Griswold, M. D. (1998). The central role of Sertoli cells in spermatogenesis. Semin. Cell Dev. Biol. 9, 411–416.
| The central role of Sertoli cells in spermatogenesis.Crossref | GoogleScholarGoogle Scholar |
Janphet, S., Nudmamud-Thanoi, S., and Thanoi, S. (2017). Alteration of catecholamine concentrations in rat testis after methamphetamine exposure. Andrologia 49, .
| Alteration of catecholamine concentrations in rat testis after methamphetamine exposure.Crossref | GoogleScholarGoogle Scholar |
Johnsen, S. G. (1970). Testicular biopsy score count method for registration of spermatogenesis in human testes: normal values and results in 335 hypogonadal males. Hormones 1, 2–25.
Kankash, A., Shariati, M., and Khatamsaz, S. (2014). Effects of bupropion on physiology of reproduction in adult male rats. J. Appl. Environ. Biol. Sci 4, 106–110.
Karydis, S., Asimakopoulos, B., Papadopoulos, N., Vakalopoulos, I., Al-Hasani, S., and Nikolettos, N. (2005). ICSI outcome is not associated with the incidence of spermatozoa with abnormal chromatin condensation. In Vivo 19, 921–925.
Kravos, M. (2010). Bupropion-associated premature ejaculation. Pharmacopsychiatry 43, 156–157.
| Bupropion-associated premature ejaculation.Crossref | GoogleScholarGoogle Scholar |
Lewis, S. E., Agbaje, I., and Alvarez, J. (2008). Sperm DNA tests as useful adjuncts to semen analysis. Syst Biol Reprod Med 54, 111–125.
| Sperm DNA tests as useful adjuncts to semen analysis.Crossref | GoogleScholarGoogle Scholar |
Modell, J. G., Katholi, C. R., Modell, J. D., and DePalma, R. L. (1997). Comparative sexual side effects of bupropion, fluoxetine, paroxetine, and sertraline. Clin. Pharmacol. Ther. 61, 478–487.
| Comparative sexual side effects of bupropion, fluoxetine, paroxetine, and sertraline.Crossref | GoogleScholarGoogle Scholar |
Nam, B., Bae, S., Kim, S. M., Hong, J. S., and Han, D. H. (2017). Comparing the effects of bupropion and escitalopram on excessive internet game play in patients with major depressive disorder. Clin. Psychopharmacol. Neurosci. 15, 361–368.
| Comparing the effects of bupropion and escitalopram on excessive internet game play in patients with major depressive disorder.Crossref | GoogleScholarGoogle Scholar |
O’Hara, L., Mcinnes, K., Simitsidellis, I., Morgan, S., Atanassova, N., Slowikowska-Hilczer, J., Kula, K., Szarras-Czapnik, M., Milne, L., Mitchell, R. T., and Smith, L. B. (2015). Autocrine androgen action is essential for Leydig cell maturation and function, and protects against late-onset Leydig cell apoptosis in both mice and men. FASEB J. 29, 894–910.
| Autocrine androgen action is essential for Leydig cell maturation and function, and protects against late-onset Leydig cell apoptosis in both mice and men.Crossref | GoogleScholarGoogle Scholar |
Patel, K., Allen, S., Haque, M. N., Angelescu, I., Baumeister, D., and Tracy, D. K. (2016). Bupropion: a systematic review and meta-analysis of effectiveness as an antidepressant. Ther. Adv. Psychopharmacol. 6, 99–144.
| Bupropion: a systematic review and meta-analysis of effectiveness as an antidepressant.Crossref | GoogleScholarGoogle Scholar |
Poulton, A. S., Hibbert, E. J., Champion, B. L., and Nanan, R. K. H. (2016). Stimulants for the control of hedonic appetite. Front. Pharmacol. 7, 105.
| Stimulants for the control of hedonic appetite.Crossref | GoogleScholarGoogle Scholar |
Puchtler, H., Waldrop, F. S., Meloan, S. N., Terry, M. S., and Conner, H. M. (1970). Methacarn (methanol-carnoy) fixation: practical and theoretical considerations. Histochemie 21, 97–116.
| Methacarn (methanol-carnoy) fixation: practical and theoretical considerations.Crossref | GoogleScholarGoogle Scholar |
Richardson, J. L., Stephens, S., Yates, L. M., Diav-Citrin, O., Arnon, J., Beghin, D., Kayser, A., Kennedy, D., Cupitt, D., Te Winkel, B., Peltonen, M., Kaplan, Y. C., and Thomas, S. H. (2017). Pregnancy outcomes after maternal varenicline use; analysis of surveillance data collected by the European Network of Teratology Information Services. Reprod. Toxicol. 67, 26–34.
| Pregnancy outcomes after maternal varenicline use; analysis of surveillance data collected by the European Network of Teratology Information Services.Crossref | GoogleScholarGoogle Scholar |
Robb, G. W., Amann, R. P., and Killian, G. J. (1978). Daily sperm production and epididymal sperm reserves of pubertal and adult rats. J. Reprod. Fertil. 54, 103–107.
| Daily sperm production and epididymal sperm reserves of pubertal and adult rats.Crossref | GoogleScholarGoogle Scholar |
Roopan, S., and Larsen, E. (2017). Use of antidepressants in patients with depression and comorbid diabetes mellitus: a systematic review. Acta Neuropsychiatr. 29, 127–139.
| Use of antidepressants in patients with depression and comorbid diabetes mellitus: a systematic review.Crossref | GoogleScholarGoogle Scholar |
Roshdy, H. M., and Fyiad, A. A. (2010). Cytogenetic and biochemical effects of anti-depression drug (Wellbutrin) on male mice. New York Sci. 3, 121–126.
Serretti, A., and Chiesa, A. (2009). Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis. J. Clin. Psychopharmacol. 29, 259–266.
| Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis.Crossref | GoogleScholarGoogle Scholar |
Sharpe, R. M. (1994). Regulation of spermatogenesis. In ‘The Physiology of Reproduction’. (Eds E. Knobil and J. D. Neil.) pp. 1363–1434. (Raven Press: New York.)
Staples, R. E., and Schnell, V. L. (1964). Refinements in rapid clearing technic in the KOH-alizarin red S method for fetal bone. Stain Technol. 39, 61–63.
Stassinos, G. L., and Klein-Schwartz, W. (2016). Bupropion “abuse” reported to US Poison Centers. J. Addict. Med. 10, 357–362.
| Bupropion “abuse” reported to US Poison Centers.Crossref | GoogleScholarGoogle Scholar |
Taylor, P. (1986). Skeletal examination. In ‘Practical Teratology’. pp. 77–100. (Academic Press: New York.)
Urra, J. A., Villaroel-Espónola, F., Covarrubias, A. A., Rodríguez-Gil, J. E., Ramírez-Reveco, A., and Concha, I. I. (2014). Presence and function of dopamine transporter (DAT) in stallion sperm: dopamine modulates sperm motility and acrosomal integrity. PLoS One 9, e112834.
| Presence and function of dopamine transporter (DAT) in stallion sperm: dopamine modulates sperm motility and acrosomal integrity.Crossref | GoogleScholarGoogle Scholar |
Van Assche, V. E., Bonduelle, M., Tournaye, H., Joris, H., Verheyen, G., Devroey, P., Van Steirteghem, A., and Liebaers, I. (1996). Cytogenetics of infertile men. Hum. Reprod. 11, 1–26.
| Cytogenetics of infertile men.Crossref | GoogleScholarGoogle Scholar |
Walker, W. H., and Cheng, J. (2005). FSH and testosterone signaling in Sertoli cells. Reproduction 130, 15–28.
Wilson, J. G. (1965). Methods for administering agents and detecting malformations in experimental animals. In ‘Teratology: Principles and Techniques’. (Eds J Warkany, JG Wilson.) pp. 262–277. (University of Chicago Press: Chicago, IL, USA.)
Wilson, M. D. (2014). A study of male reproductive form and function in a rat model. Asian Pac. J. Reprod. 3, 258–262.
| A study of male reproductive form and function in a rat model.Crossref | GoogleScholarGoogle Scholar |
Wyrobek, A. J., and Bruce, W. R. (1975). Chemical induction of sperm abnormalities in mice. Proc. Natl Acad. Sci USA 72, 4425–4429.
Wyrobek, A. J., Gordon, L. A., Burkhart, J. G., Francis, M. W., Kapp, R. W., Letz, G., Malling, H. V., Topham, J. C., and Whorton, M. D. (1983). An evaluation of the mouse sperm morphology test and other sperm tests in non-human mammals: a report of the US Environmental Protection Agency Gene-Tox Program. Mutat Res. 115, 1–72.
