Pregabalin alters reproductive performance in male mice and causes congenital anomalies in offspring
Viviane de Fátima Mestre
A B * , Caio Cezar Nantes Martins B , Lorrany Victor de Brito B , Aline Campos Zeffa A B , Camila Salvador Sestário A B and Maria José Sparça Salles B
A
B
Abstract
Pregabalin is an anticonvulsant drug with analgesic activity for the treatment of neuropathic pain.
To valuate the toxicity of pregabalin in reproductive parameters, spermatogenesis, and teratogenicity in the offspring of mice.
Twenty male mice were randomly distributed into two groups: PGB group and group C (n = 10 per group). The animals in the PGB group received, via gavage, 200 mg/kg of pregabalin diluted in distilled water daily, for a period of 45 days. Group C received distilled water under the same experimental design.
In the paternal parameters of the PGB group, there was a significant increase in the size of the testicles, morphological alterations in the spermatozoa, a decrease in the Johnsen score, an increase in the Leydig cells, and a decrease in the serum level of testosterone. In the intrauterine development parameters of females mated with males from the PGB group, a significant decrease in placental weight, weight and length of fetuses, and fetal viability rate was observed. There was a significant increase in the number of resorptions and post-implantation losses. The significant anomalies observed in the offspring were alteration in the size of the kidneys, absent metacarpals and phalanges, alteration in the sternum, and supernumerary thoracic vertebrae.
Results suggest that pregabalin had toxic effects on the reproductive function of male mice and teratogenic potential.
The findings of this study may provide new hypotheses, taking into account the risk–benefit ratio for male reproduction and offspring health.
Keywords: congenital malformations, infertility, pregabalin, pregnancy, reproductive performance, spermatogenesis, spermiogenesis, teratozoospermia.
References
Aitken RJ, Koppers AJ (2011) Apoptosis and DNA damage in human spermatozoa. Asian Journal of Andrology 13, 36-42.
| Crossref | Google Scholar | PubMed |
Alles SRA, Cain SM, Snutch TP (2020) Pregabalin as a pain therapeutic: beyond calcium channels. Frontiers in Cellular Neuroscience 14, 83.
| Crossref | Google Scholar | PubMed |
Barrow MV, Taylor WJ (1969) A rapid method for detecting malformations in rat fetuses. Journal of Morphology 127, 291-305.
| Crossref | Google Scholar | PubMed |
Bedi Y, Chang RC, Gibbs R, Clement TM, Golding MC (2019) Alterations in sperm-inherited noncoding RNAs associate with late-term fetal growth restriction induced by preconception paternal alcohol use. Reproductive Toxicology 87, 11-20.
| Crossref | Google Scholar | PubMed |
Ben Maamar M, Sadler-Riggleman I, Beck D, McBirney M, Nilsson E, Klukovich R, Xie Y, Tang C, Yan W, Skinner MK (2018) Alterations in sperm DNA methylation, non-coding RNA expression, and histone retention mediate vinclozolin-induced epigenetic transgenerational inheritance of disease. Environmental Epigenetics 4, dvy010.
| Crossref | Google Scholar |
Black E, Khor KE, Kennedy D, Chutatape A, Sharma S, Vancaillie T, Demirkol A (2019) Medication use and pain management in pregnancy: a critical review. Pain Practice 19, 875-899.
| Crossref | Google Scholar | PubMed |
Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P (2010) A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clinical Pharmacokinetics 49, 661-669.
| Crossref | Google Scholar | PubMed |
Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D (2006) Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. European Journal of Pain 10, 287.
| Crossref | Google Scholar | PubMed |
Calabrò RS, De Luca R, Pollicino P, Bramanti P (2013) Anorgasmia during pregabalin add-on therapy for partial seizures. Epileptic Disorders 15, 358-361.
| Crossref | Google Scholar | PubMed |
Casarini L, Crépieux P (2019) Molecular mechanisms of action of FSH. Frontiers in Endocrinology 10, 305.
| Crossref | Google Scholar |
Chen Q, Yan M, Cao Z, Li X, Zhang Y, Shi J, Feng G-H, Peng H, Zhang X, Zhang Y, Qian J, Duan E, Zhai Q, Zhou Q (2016) Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351, 397-400.
| Crossref | Google Scholar | PubMed |
Conine CC, Sun F, Song L, Rivera-Pérez JA, Rando OJ (2018) Small RNAs gained during epididymal transit of sperm are essential for embryonic development in mice. Developmental Cell 46, 470-480.e3.
| Crossref | Google Scholar |
Crofford LJ, Rowbotham MC, Mease PJ, Russell IJ, Dworkin RH, Corbin AE, Young JP, Jr., LaMoreaux LK, Martin SA, Sharma U, Pregabalin 1008-105 Study Group (2005) Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis & Rheumatism 52, 1264-1273.
| Crossref | Google Scholar | PubMed |
Daoud AS, Bataineh H, Otoom S, Abdul-Zahra E (2004) The effect of Vigabatrin, Lamotrigine and Gabapentin on the fertility, weights, sex hormones and biochemical profiles of male rats. Neuro Endocrinology Letters 25, 178-183.
| Google Scholar | PubMed |
Davanzo R, Dal Bo S, Bua J, Copertino M, Zanelli E, Matarazzo L (2013) Antiepileptic drugs and breastfeeding. Italian Journal of Pediatrics 39, 50.
| Crossref | Google Scholar |
De Gendt K, Swinnen JV, Saunders PTK, Schoonjans L, Dewerchin M, Devos A, Tan K, Atanassova N, Claessens F, Lécureuil C, Heyns W, Carmeliet P, Guillou F, Sharpe RM, Verhoeven G (2004) A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis. Proceedings of the National Academy of Sciences of the United States of America 101, 1327-1332.
| Crossref | Google Scholar | PubMed |
Derry S, Bell RF, Straube S, Wiffen PJ, Aldington D, Moore RA (2019) Pregabalin for neuropathic pain in adults. Cochrane Database of Systematic Reviews 1, CD007076.
| Crossref | Google Scholar |
Di Guilmi MN, Urbano FJ, Inchauspe CG, Uchitel OD (2011) Pregabalin modulation of neurotransmitter release is mediated by change in intrinsic activation/inactivation properties of Cav2.1 calcium channels. The Journal of Pharmacology and Experimental Therapeutics 336, 973-982.
| Crossref | Google Scholar | PubMed |
Ding J, Shang X, Zhang Z, Jing H, Shao J, Fei Q, Rayburn ER, Li H (2017) FDA-approved medications that impair human spermatogenesis. Oncotarget 8, 10714-10725.
| Crossref | Google Scholar | PubMed |
Etemad L, Mohammad A, Mohammadpour AH, Vahdati Mashhadi N, Moallem SA (2013) Teratogenic effects of pregabalin in mice. Iranian Journal of Basic Medical Sciences 16, 1065-1070.
| Google Scholar | PubMed |
Evoy KE, Morrison MD, Saklad SR (2017) Abuse and misuse of pregabalin and gabapentin. Drugs 77, 403-426.
| Crossref | Google Scholar | PubMed |
Gòdia M, Swanson G, Krawetz SA (2018) A history of why fathers’ RNA matters. Biology of Reproduction 99, 147-159.
| Crossref | Google Scholar | PubMed |
Goins A, Patel K, Alles SRA (2021) The gabapentinoid drugs and their abuse potential. Pharmacology & Therapeutics 227, 107926.
| Crossref | Google Scholar | PubMed |
Hai Y, Hou J, Liu Y, Liu Y, Yang H, Li Z, He Z (2014) The roles and regulation of Sertoli cells in fate determinations of spermatogonial stem cells and spermatogenesis. Seminars in Cell & Developmental Biology 29, 66-75.
| Crossref | Google Scholar | PubMed |
Haider SG (2004) Cell biology of Leydig cells in the testis. International Review of Cytology 233, 181-241.
| Crossref | Google Scholar | PubMed |
Häuser W, Fitzcharles M-A (2018) Facts and myths pertaining to fibromyalgia. Dialogues in Clinical Neuroscience 20, 53-62.
| Crossref | Google Scholar | PubMed |
Heinonen S, Taipale P, Saarikoski S (2001) Weights of placentae from small-for-gestational age infants revisited. Placenta 22, 399-404.
| Crossref | Google Scholar | PubMed |
Hennemann-Krause L, Sredni S (2016) Systemic drug therapy for neuropathic pain. Revista Dor 17(Suppl 1), S91-S94.
| Crossref | Google Scholar |
Hitiris N, Barrett JA, Brodie MJ (2006) Erectile dysfunction associated with pregabalin add-on treatment in patients with partial seizures: five case reports. Epilepsy & Behavior 8, 418-421.
| Crossref | Google Scholar | PubMed |
Huhtaniemi I (2015) A short evolutionary history of FSH-stimulated spermatogenesis. Hormones 14, 468-478.
| Crossref | Google Scholar | PubMed |
Johnsen SG (1970) Testicular biopsy score count – a method for registration of spermatogenesis in human testes: normal values and results in 335 hypogonadal males. Hormones 1, 2-25.
| Crossref | Google Scholar | PubMed |
Karancı Y (2020) Priapism associated with pregabalin. The American Journal of Emergency Medicine 38, 852.e1-852.e2.
| Crossref | Google Scholar | PubMed |
Klastrup LK, Bak ST, Nielsen AL (2019) The influence of paternal diet on sncRNA-mediated epigenetic inheritance. Molecular Genetics and Genomics 294, 1-11.
| Crossref | Google Scholar | PubMed |
Kleshchev M, Osadchuk A, Osadchuk L (2021) Impaired semen quality, an increase of sperm morphological defects and DNA fragmentation associated with environmental pollution in urban population of young men from Western Siberia, Russia. PLoS ONE 16, e0258900.
| Crossref | Google Scholar | PubMed |
Legoff L, D’Cruz SC, Tevosian S, Primig M, Smagulova F (2019) Transgenerational inheritance of environmentally induced epigenetic alterations during mammalian development. Cells 8, 1559.
| Crossref | Google Scholar | PubMed |
Li R, Li H, Rao K, Liu K, Zhang Y, Liu X, Wang T, Wang S, Liu Z, Liu J (2019) Curcumin ameliorates atrophy of seminal vesicle via reduction of oxidative stress in castrated mice. PeerJ 7, e7192.
| Crossref | Google Scholar | PubMed |
Lyrica® (2020) Annex I: summary of product characteristics, Pfizer. Available at https://www.ema.europa.eu/en/documents/product-information/pregabalin-sandoz-gmbh-epar-product-information_en.pdf
Mathieson S, Lin C-WC, Underwood M, Eldabe S (2020) Pregabalin and gabapentin for pain. The BMJ 369, m1315.
| Crossref | Google Scholar | PubMed |
Morse DC, Henck JW, Bailey SA (2016) Developmental toxicity studies with pregabalin in rats: significance of alterations in skull bone morphology. Birth Defects Research Part B: Developmental and Reproductive Toxicology 107, 94-107.
| Crossref | Google Scholar | PubMed |
Ni F-D, Hao S-L, Yang W-X (2020) Molecular insights into hormone regulation via signaling pathways in Sertoli cells: with discussion on infertility and testicular tumor. Gene 753, 144812.
| Crossref | Google Scholar | PubMed |
Ohta H, Oka H, Usui C, Ohkura M, Suzuki M, Nishioka K (2012) A randomized, double-blind, multicenter, placebo-controlled phase III trial to evaluate the efficacy and safety of pregabalin in Japanese patients with fibromyalgia. Arthritis Research & Therapy 14, R217.
| Crossref | Google Scholar | PubMed |
O’Shaughnessy PJ, Verhoeven G, De Gendt K, Monteiro A, Abel MH (2010) Direct action through the sertoli cells is essential for androgen stimulation of spermatogenesis. Endocrinology 151, 2343-2348.
| Crossref | Google Scholar | PubMed |
Osuntokun OS, Olayiwola G, Oladele A, Ola I, AyokaAbiodun O (2017) Chronic administration of gabapentin and a gabapentin-carbamazepine combination reversibly suppress testicular function in male Wistar rats (Rattus norvegicus). Pathophysiology 24, 63-69.
| Crossref | Google Scholar | PubMed |
Patorno E, Bateman BT, Huybrechts KF, MacDonald SC, Cohen JM, Desai RJ, Panchaud A, Mogun H, Pennell PB, Hernandez-Diaz S (2017) Pregabalin use early in pregnancy and the risk of major congenital malformations. Neurology 88, 2020-2025.
| Crossref | Google Scholar | PubMed |
Pauer L, Winkelmann A, Arsenault P, Jespersen A, Whelan L, Atkinson G, Leon T, Zeiher B (2011) An international, randomized, double-blind, placebo-controlled, phase III trial of pregabalin monotherapy in treatment of patients with fibromyalgia. The Journal of Rheumatology 38, 2643-2652.
| Crossref | Google Scholar | PubMed |
Pegg D, Bleavins M, Herman J, Wojcinski Z, Graziano M, Henck J, Criswell KA, Anderson T, Duddy S (2012) Hemangiosarcoma in mice administered pregabalin: analysis of genotoxicity, tumor incidence, and tumor genetics. Toxicological Sciences 128, 9-21.
| Crossref | Google Scholar | PubMed |
Ray JA, Kushnir MM, Meikle AW, Sindt JE, Strathmann FG (2017) An exploratory study Evaluating the impact of opioid and non-opioid pain medications on serum/plasma free testosterone and free estradiol concentrations. Drug Testing and Analysis 9, 1555-1560.
| Crossref | Google Scholar | PubMed |
Rayburn ER, Gao L, Ding J, Ding H, Shao J, Li H (2018) FDA-approved drugs that are spermatotoxic in animals and the utility of animal testing for human risk prediction. Journal of Assisted Reproduction and Genetics 35, 191-212.
| Crossref | Google Scholar | PubMed |
Recchia K, Jorge AS, Pessôa LVdF, Botigelli RC, Zugaib VC, de Souza AF, Martins DdS, Ambrósio CE, Bressan FF, Pieri NCG (2021) Actions and roles of FSH in germinative cells. International Journal of Molecular Sciences 22, 10110.
| Crossref | Google Scholar | PubMed |
Robinson L, Gallos ID, Conner SJ, Rajkhowa M, Miller D, Lewis S, Kirkman-Brown J, Coomarasamy A (2012) The effect of sperm DNA fragmentation on miscarriage rates: a systematic review and meta-analysis. Human Reproduction 27, 2908-2917.
| Crossref | Google Scholar | PubMed |
Rompala GR, Mounier A, Wolfe CM, Lin Q, Lefterov I, Homanics GE (2018) Heavy chronic intermittent ethanol exposure alters small noncoding RNAs in mouse sperm and epididymosomes. Frontiers in Genetics 9, 32.
| Crossref | Google Scholar | PubMed |
Salem Hareedy M, Mohamed Tawfik K, Badary DM, Ahmed Mahmoud W, Mohamed Mohamed EE (2020) Pregabalin administration and withdrawal affect testicular structure and functions in rats. Andrologia 52, e13808.
| Crossref | Google Scholar | PubMed |
Schuster A, Skinner MK, Yan W (2016) Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs. Environmental Epigenetics 2, dvw001.
| Crossref | Google Scholar |
Semet M, Paci M, Saïas-Magnan J, Metzler-Guillemain C, Boissier R, Lejeune H, Perrin J (2017) The impact of drugs on male fertility: a review. Andrology 5, 640-663.
| Crossref | Google Scholar | PubMed |
Shah W, Khan R, Shah B, Khan A, Dil S, Liu W, Wen J, Jiang X (2021) The molecular mechanism of sex hormones on sertoli cell development and proliferation. Frontiers in Endocrinology 12, 648141.
| Crossref | Google Scholar | PubMed |
Shneker BF, McAuley JW (2005) Pregabalin: a new neuromodulator with broad therapeutic indications. Annals of Pharmacotherapy 39, 2029-2037.
| Crossref | Google Scholar | PubMed |
Shokry DA, El Nabrawy N, Yassa HD, Gaber SS, Batiha GE-S, Welson NN (2020) Pregabalin induced reproductive toxicity and body weight changes by affecting caspase3 and leptin expression: protective role of wheat germ oil. Life Sciences 260, 118344.
| Crossref | Google Scholar | PubMed |
Sikka SC, Chen C, Almas M, Dula E, Knapp LE, Hellstrom WJG (2015) Pregabalin does not affect sperm production in healthy volunteers: a randomized, double-blind, placebo-controlled, noninferiority study. Pain Practice 15, 150-158.
| Crossref | Google Scholar | PubMed |
Siklenka K, Erkek S, Godmann M, Lambrot R, McGraw S, Lafleur C, Cohen T, Xia J, Suderman M, Hallett M, Trasler J, Peters AHFM, Kimmins S (2015) Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science 350, aab2006.
| Crossref | Google Scholar |
Singh KP, Gupta K (2018) Teratogenic effects of third-generation antiepileptic drug, pregabalin: an in vivo study. Current Drug Safety 13, 113-121.
| Crossref | Google Scholar | PubMed |
Svechnikov K, Landreh L, Weisser J, Izzo G, Colón E, Svechnikova I, Söder O (2010) Origin, development and regulation of human Leydig cells. Hormone Research in Paediatrics 73, 93-101.
| Crossref | Google Scholar | PubMed |
Taha SHN, Zaghloul HS, Ali AAER, Rashed LA, Sabry RM, Gaballah IF (2020) Molecular and hormonal changes caused by long-term use of high dose pregabalin on testicular tissue: the role of p38 MAPK, oxidative stress and apoptosis. Molecular Biology Reports 47, 8523-8533.
| Crossref | Google Scholar | PubMed |
Torjesen I (2019) Pregabalin and gabapentin: what impact will reclassification have on doctors and patients? The BMJ 364, l1107.
| Crossref | Google Scholar | PubMed |
Tripathi R, Mishra DP, Shaha C (2009) Male germ cell development: turning on the apoptotic pathways. Journal of Reproductive Immunology 83, 31-35.
| Crossref | Google Scholar | PubMed |
Urquhart L (2018) Top drugs and companies by sales in 2017. Nature Reviews Drug Discovery 17, 232.
| Crossref | Google Scholar | PubMed |
Van Assche E, Bonduelle M, Tournaye H, Joris H, Verheyen G, Devroey P, Van Steirteghem A, Liebaers I (1996) Cytogenetics of infertile men. Human Reproduction 11, 1-26.
| Crossref | Google Scholar | PubMed |
Vasco GC, Gil Villa AM, Piedrahita Ochoa C, Cardona Maya W, Cadavid Jaramillo A (2008) Influencia de la impronta genómica masculina en la reproducción [Influence of the male genomic imprinting on the reproduction]. Actas Urológicas Españolas 32, 1004-1012.
| Crossref | Google Scholar | PubMed |
Welsh M, Saunders PTK, Atanassova N, Sharpe RM, Smith LB (2009) Androgen action via testicular peritubular myoid cells is essential for male fertility. The FASEB Journal 23, 4218-4230.
| Crossref | Google Scholar | PubMed |
Willems A, Roesl C, Mitchell RT, Milne L, Jeffery N, Smith S, Verhoeven G, Brown P, Smith LB (2015) Sertoli cell androgen receptor signalling in adulthood is essential for post-meiotic germ cell development. Molecular Reproduction and Development 82, 626-627.
| Crossref | Google Scholar | PubMed |
Winterfeld U, Merlob P, Baud D, Rousson V, Panchaud A, Rothuizen LE, Bernard N, Vial T, Yates LM, Pistelli A, Ellfolk M, Eleftheriou G, de Vries LC, Jonville-Bera A-P, Kadioglu M, Biollaz J, Buclin T (2016) Pregnancy outcome following maternal exposure to pregabalin may call for concern. Neurology 86, 2251-2257.
| Crossref | Google Scholar | PubMed |
Wyrobek AJ, Gordon LA, Burkhart JG, Francis MW, Kapp RW, Jr., Letz G, Malling HV, Topham JC, Whorton MD (1983) An evaluation of the mouse sperm morphology test and other sperm tests in nonhuman mammals: a report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation Research/Reviews in Genetic Toxicology 115, 1-72.
| Crossref | Google Scholar | PubMed |
Yang M, Qian C, Liu Y (2015) Suboptimal treatment of diabetic peripheral neuropathic pain in the United States. Pain Medicine 16, 2075-2083.
| Crossref | Google Scholar | PubMed |
Zheng X, Li Z, Wang G, Wang H, Zhou Y, Zhao X, Cheng CY, Qiao Y, Sun F (2021) Sperm epigenetic alterations contribute to inter- and transgenerational effects of paternal exposure to long-term psychological stress via evading offspring embryonic reprogramming. Cell Discovery 7, 101.
| Crossref | Google Scholar | PubMed |
Zhou R, Wu J, Liu B, Jiang Y, Chen W, Li J, He Q, He Z (2019) The roles and mechanisms of Leydig cells and myoid cells in regulating spermatogenesis. Cellular and Molecular Life Sciences 76, 2681-2695.
| Crossref | Google Scholar | PubMed |
