Abstract
Aims
Cytarabine (CYT), a prevalent anticancer drug for blood cancers, detrimentally affects male reproductive development and function. Alpha-lipoic acid (ALA), a universal antioxidant, offers defense against chemical-induced reproductive dysfunction. Our study sought to explore ALA's protective role against prenatal CYT-induced reproductive impairment in F1 male adult rats.
Main methods
Pregnant rats were divided into 5 groups and administered normal saline, ALA 200 mg/kg, CYT 12.5 mg/kg, CYT 25 mg/kg, and CYT 25 mg/kg + ALA 200 mg/ kg from gestational day 8 to 21. On postnatal day 73, F1 male rats were sacrificed, and general, oxidative, steroidogenic, spermatogenic, histological, and morphometrical parameters were evaluated.
Key findings
Prenatal CYT caused dose-dependent reductions in body weight, testis, and accessory gland weights; elevated oxidative stress; delayed puberty onset; sperm anomalies (decreased count, motility, viability, seminal fructose; increased morphological anomalies); impeded steroidogenesis (lower testosterone, follicle-stimulating hormone, luteinizing hormone, 3β-Hydroxysteroid dehydrogenase(HSD), 17β-HSD, and elevated cholesterol); and testicular histopathological and morphometric disturbances. Maternal supplementation of ALA was found to alleviate all the CYT-induced reproductive disruptions.
Significance
The present work accentuates the beneficial actions of ALA against CYT-induced impairment in reproductive development and functions by combating disruptions in oxidative balance, steroidogenesis, spermatogenesis, and testicular histological aberrations. However, future experimental and clinical studies are warranted to explore the molecular mechanisms involved in the ALA’s protection against prenatal CYT-induced testicular injury.
Graphical Abstract
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Data availability
All data and materials related to this study are available from the corresponding author on reasonable request.
References
(2015) Cancer Statistics - NCI.https://www.cancer.gov/about-cancer/understanding/statistics. Accessed 18 Aug 2023
Abbasi B, Molavi N, Tavalaee M et al (2020) Alpha-lipoic acid improves sperm motility in infertile men after varicocelectomy: a triple-blind randomized controlled trial. Reprod Biomed Online 41:1084–1091. https://doi.org/10.1016/j.rbmo.2020.08.013
AbdEl-Hamid ANM, Hodeeb YMI, El-Rewiny EM, Gaafar AM (2021) THE EFFECT OF ALPHA LIPOIC ACID ON IDIOPATHIC ASTHENOZOOSPERMIC PATIENTS. Al-Azhar Medical Journal 50:1497–1506. https://doi.org/10.21608/amj.2021.158490
Aitken RJ (2017) Reactive oxygen species as mediators of sperm capacitation and pathological damage. Mol Reprod Dev 84:1039–1052. https://doi.org/10.1002/mrd.22871
Akinola A, Oyeyemi A, Daramola O, Raji Y (2020) Effects of the methanol root extract of Carpolobia lutea on sperm indices, acrosome reaction, and sperm DNA integrity in cadmium-induced reproductive toxicity in male Wistar rats. JBRA assisted reproduction 24:454–465. https://doi.org/10.5935/1518-0557.20200036
Ali S, Jones GL, Culligan DJ et al (2015) Guidelines for the diagnosis and management of acute myeloid leukaemia in pregnancy. Br J Haematol 170:487–495. https://doi.org/10.1111/bjh.13554
Alison MR, Wright NA (1979) Differential lethal effects of both cytosine arabinoside and hydroxyurea on jejunal crypt cells and testosterone-stimulated accessory sex glands. Cell Tissue Kinet 12:477–491. https://doi.org/10.1111/j.1365-2184.1979.tb00170.x
Aly HAA, Alahdal AM, Nagy AA et al (2017) Lipoic acid and Calligonum comosumon attenuate aroclor 1260-induced testicular toxicity in adult rats. Environ Toxicol 32:1147–1157. https://doi.org/10.1002/tox.22310
Anto SK, Koyada N, Khan S, Jena G (2016) α-Lipoic acid attenuates transplacental nicotine-induced germ cell and oxidative DNA damage in adult mice. J Basic Clin Physiol Pharmacol 27:585–593. https://doi.org/10.1515/jbcpp-2015-0151
Asa E, Ahmadi R, Mahmoodi M, Mohammadniya A (2020) Supplementation of freezing media with alpha lipoic acid preserves the structural and functional characteristics of sperm against cryodamage in infertile men with asthenoteratozoospermia. Cryobiology 96:166–174. https://doi.org/10.1016/j.cryobiol.2020.07.001
Astiz M, Hurtado de Catalfo GE, García MN et al (2013) Pesticide-induced decrease in rat testicular steroidogenesis is differentially prevented by lipoate and tocopherol. Ecotoxicol Environ Saf 91:129–138. https://doi.org/10.1016/j.ecoenv.2013.01.022
Balci YI, Acer S, Yagci R et al (2017) N-acetylcysteine supplementation reduces oxidative stress for cytosine arabinoside in rat model. Int Ophthalmol 37:209–214. https://doi.org/10.1007/s10792-016-0259-7
Barbagallo F, Condorelli RA, Mongioì LM et al (2020) Effects of Bisphenols on Testicular Steroidogenesis. Front Endocrinol (lausanne) 11:373. https://doi.org/10.3389/fendo.2020.00373
Behnamifar A, Rahimi S, Karimi Torshizi MA et al (2021) Effects of dietary alpha-lipoic acid supplementation on the seminal parameters and fertility potential in aging broiler breeder roosters. Poult Sci 100:1221–1238. https://doi.org/10.1016/j.psj.2020.10.076
Bergmeyer H, M G, HE W (1983) Methods of enzymatic analysis, 3rd edn. Vol I-III Verlag Chemie, Deerfield Beach, FL. https://doi.org/10.1016/0307-4412(85)90136-0
Bilgin AO, Mammadov R, Suleyman B et al (2020) Effect of Rutin on Cytarabine-Associated Pulmonary Oedema and Oxidative Stress in Rats. An Acad Bras Cienc 92:e20190261. https://doi.org/10.1590/0001-3765202020190261
Canepa P, Dal Lago A, De Leo C et al (2018) Combined treatment with myo-inositol, alpha-lipoic acid, folic acid and vitamins significantly improves sperm parameters of sub-fertile men: a multi-centric study. Eur Rev Med Pharmacol Sci 22:7078–7085. https://doi.org/10.26355/eurrev_201810_16180
Cross CE (1995) Bloom and Fawcett: A Textbook of Histology. JAMA 274:352. https://doi.org/10.1001/jama.1995.03530040080050
Deore MS, S K, Saba N et al (2021) Alpha-lipoic acid protects co-exposure to lead and zinc oxide nanoparticles induced neuro, immuno and male reproductive toxicity in rats. Front Pharmacol 12:626238. https://doi.org/10.3389/fphar.2021.626238
Di Tucci C, Galati G, Mattei G et al (2021) The role of alpha lipoic acid in female and male infertility: a systematic review. Gynecol Endocrinol 37:497–505. https://doi.org/10.1080/09513590.2020.1843619
Dong L, Yang F, Li J et al (2022) Effect of oral alpha-lipoic acid (ALA) on sperm parameters: a systematic review and meta-analysis. Basic Clin Androl 32:23. https://doi.org/10.1186/s12610-022-00173-9
El-Beshbishy HA, Aly HAA, El-Shafey M (2013) Lipoic acid mitigates bisphenol A-induced testicular mitochondrial toxicity in rats. Toxicol Ind Health 29:875–887. https://doi.org/10.1177/0748233712446728
El-Beshbishy HA, Mariah RA, Al-Azhary NM et al (2014) Influence of lipoic acid on testicular toxicity induced by bi-n-butyl phthalate in rats. Food Chem Toxicol 71:26–32. https://doi.org/10.1016/j.fct.2014.05.024
Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77. https://doi.org/10.1016/0003-9861(59)90090-6
El-Maddawy ZK, Abd El Naby WSH (2018) Effects of ivermectin and its combination with alpha lipoic acid on expression of IGFBP-3 and HSPA1 genes and male rat fertility. Andrologia 50:e12891. https://doi.org/10.1111/and.12891
El-Maraghy SA, Nassar NN (2011) Modulatory effects of lipoic acid and selenium against cadmium-induced biochemical alterations in testicular steroidogenesis. J Biochem Mol Toxicol 25:15–25. https://doi.org/10.1002/jbt.20354
Erdem Guzel E, Kaya Tektemur N, Tektemur A (2021) Alpha-lipoic acid may ameliorate testicular damage by targeting dox-induced altered antioxidant parameters, mitofusin-2 and apoptotic gene expression. Andrologia 53:e13990. https://doi.org/10.1111/and.13990
Faruqi A, Tadi P (2023) Cytarabine. In: StatPearls. StatPearls Publishing, Treasure Island (FL). https://www.ncbi.nlm.nih.gov/books/NBK557680/
Gamidov SI, Ovchinnikov RI, Popova AY (2019) Double-blind, randomized placebo-controlled study of efficiency and safety of complex acetyl-L-carnitine, L-carnitine fumarate and alpha-lipoic acid (Spermactin Forte) for treatment of male infertility. Urologiia 4:62–68. https://doi.org/10.18565/urology.2019.4.61-68
Geller HM, Cheng KY, Goldsmith NK et al (2001) Oxidative stress mediates neuronal DNA damage and apoptosis in response to cytosine arabinoside. J Neurochem 78:265–275. https://doi.org/10.1046/j.1471-4159.2001.00395.x
Gomes MB, Negrato CA (2014) Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetol Metab Syndr 6:80. https://doi.org/10.1186/1758-5996-6-80
Goudarzi M, Haghi Karamallah M, Malayeri A et al (2020) Protective effect of alpha-lipoic acid on di-(2-ethylhexyl) phthalate-induced testicular toxicity in mice. Environ Sci Pollut Res Int 27:13670–13678. https://doi.org/10.1007/s11356-020-07817-1
Guarraci FA, Avendano L, Kelly M et al (2023) Chronic periadolescent leuprolide exposure affects the development of reproductive physiology and behavior of female and male rats differently, but both mature after treatment termination. Biol Sex Differ 14:1. https://doi.org/10.1186/s13293-022-00485-5
Güleş Ö, Eren Ü (2016) Protective role of alpha lipoic acid against polychlorobiphenyl (Aroclor 1254)-induced testicular toxicity in rats. Rom J Morphol Embryol 57:451–459
Habibi M, Abbasi B, FakhariZavareh Z et al (2022) Alpha-Lipoic Acid Ameliorates Sperm DNA Damage and Chromatin Integrity in Men with High DNA Damage: A Triple Blind Randomized Clinical Trial. Cell J 24:603–611. https://doi.org/10.22074/cellj.2022.8273
Habibi M, FakhariZavareh Z, Abbasi B et al (2023) Alpha-Lipoic Acid Supplementation for Male Partner of Couples with Recurrent Pregnancy Loss: A Post hoc analysis in Clinical Trial. Int J Fertil Steril 17:67–74. https://doi.org/10.22074/ijfs.2022.543027.1222
Haghighian HK, Haidari F, Mohammadi-Asl J, Dadfar M (2015) Randomized, triple-blind, placebo-controlled clinical trial examining the effects of alpha-lipoic acid supplement on the spermatogram and seminal oxidative stress in infertile men. Fertil Steril 104:318–324. https://doi.org/10.1016/j.fertnstert.2015.05.014
Haidari F, Mohammadi-Asl J, Kavianpour M et al (2021) Effect of lipoic acid supplementation on gene expression and activity of glutathione S-transferase enzyme in infertile men. Hum Fertil (camb) 24:276–283. https://doi.org/10.1080/14647273.2019.1639221
Hamada A, Kawaguchi T, Nakano M (2002) Clinical pharmacokinetics of cytarabine formulations. Clin Pharmacokinet 41:705–718. https://doi.org/10.2165/00003088-200241100-00002
Han S, Xiu M, Li S et al (2023) Exposure to cytarabine causes side effects on adult development and physiology and induces intestinal damage via apoptosis in Drosophila. Biomed Pharmacother 159:114265. https://doi.org/10.1016/j.biopha.2023.114265
Hepner A, Negrini D, Hase EA et al (2019) Cancer During Pregnancy: The Oncologist Overview. World J Oncol 10:28–34. https://doi.org/10.14740/wjon1177
Hudson MM (2010) Reproductive outcomes for survivors of childhood cancer. Obstet Gynecol 116:1171–1183. https://doi.org/10.1097/AOG.0b013e3181f87c4b
Huleihel M, Khaleel B, Kapilushnik J, Lunenfeld E (2022) P-081 Effect of chemotherapy (cytarabine) and acute myeloid leukemia on the development of spermatogenesis, spermatogonial microenvironment and inflammatory factors at the adult age of immature-treated mice. Hum Reprod 37(deac107):077. https://doi.org/10.1093/humrep/deac107.077
Hussain T, Kandeel M, Metwally E et al (2023) Unraveling the harmful effect of oxidative stress on male fertility: A mechanistic insight. Front Endocrinol (lausanne) 14:1070692. https://doi.org/10.3389/fendo.2023.1070692
Ibrahim NA, Al-Shmgani HS, Ibrahim R (2017) Cytarabine Induced Reproductive Histopathological Changes in Albino Male Mice. Al-Nahrain University / Journal of Biotechnology Research Center 11:6–12. https://doi.org/10.24126/jobrc.2017.11.1.489
Ibrahim Fouad G, Mousa MR (2021) The protective potential of alpha lipoic acid on amiodarone-induced pulmonary fibrosis and hepatic injury in rats. Mol Cell Biochem 476:3433–3448. https://doi.org/10.1007/s11010-021-04173-7
Iuliano S, Greco F, Seminara G et al (2023) Positive effects of dietary supplementation with nutraceuticals on male subclinical hypogonadism: a pilot study. Minerva Endocrinol (Torino) 48:274–281. https://doi.org/10.23736/S2724-6507.23.04024-1
Jana K, Dutta A, Chakraborty P et al (2014) Alpha-lipoic acid and N-acetylcysteine protects intensive swimming exercise-mediated germ-cell depletion, pro-oxidant generation, and alteration of steroidogenesis in rat testis. Mol Reprod Dev 81:833–850. https://doi.org/10.1002/mrd.22354
Javitt MC (2023) Cancer in pregnancy: overview and epidemiology. Abdom Radiol (NY) 48:1559–1563. https://doi.org/10.1007/s00261-022-03633-y
Kabel AM, Salama SA, Alghorabi AA, Estfanous RS (2020) Amelioration of cyclosporine-induced testicular toxicity by carvedilol and/or alpha-lipoic acid: Role of TGF-β1, the proinflammatory cytokines, Nrf2/HO-1 pathway and apoptosis. Clin Exp Pharmacol Physiol 47:1169–1181. https://doi.org/10.1111/1440-1681.13281
Karvonen MJ, Malm M (1955) Colorimetric determination of fructose with indol. Scand J Clin Lab Invest 7:305–307. https://doi.org/10.3109/00365515509134669
Khaleel B, Lunenfeld E, Kapelushnik J, Huleihel M (2022) Effect of Chemotherapy Cytarabine and Acute Myeloid Leukemia on the Development of Spermatogenesis at the Adult Age of Immature Treated Mice. Int J Mol Sci 23:4013. https://doi.org/10.3390/ijms23074013
Koga T, Ishida T, Takeda T et al (2012) Restoration of dioxin-induced damage to fetal steroidogenesis and gonadotropin formation by maternal co-treatment with α-lipoic acid. PLoS ONE 7:e40322. https://doi.org/10.1371/journal.pone.0040322
Kono Y (1978) Generation of superoxide radical during autoxidation of hydroxylamine and an assay for superoxide dismutase. Arch Biochem Biophys 186:189–195. https://doi.org/10.1016/0003-9861(78)90479-4
Lebda M, Gad S, Gaafar H (2014) Effects of lipoic Acid on acrylamide induced testicular damage. Mater Sociomed 26:208–212. https://doi.org/10.5455/msm.2014.26.208-212
Lemez P, Urbánek V (2005) Chemotherapy for acute myeloid leukemias with cytosine arabinoside, daunorubicin, etoposide, and mitoxantrone may cause permanent oligoasthenozoospermia or amenorrhea in middle-aged patients. Neoplasma 52:398–401
Li D-W, Wang Y-D, Zhou S-Y, Sun W-P (2016) α-lipoic acid exerts neuroprotective effects on neuronal cells by upregulating the expression of PCNA via the P53 pathway in neurodegenerative conditions. Mol Med Rep 14:4360–4366. https://doi.org/10.3892/mmr.2016.5754
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Magina KN, Pregartner G, Zebisch A et al (2017) Cytarabine dose in the consolidation treatment of AML: a systematic review and meta-analysis. Blood 130:946–948. https://doi.org/10.1182/blood-2017-04-777722
Medrano JV, Hervás D, Vilanova-Pérez T et al (2021) Histologic Analysis of Testes from Prepubertal Patients Treated with Chemotherapy Associates Impaired Germ Cell Counts with Cumulative Doses of Cyclophosphamide, Ifosfamide, Cytarabine, and Asparaginase. Reprod Sci 28:603–613. https://doi.org/10.1007/s43032-020-00357-6
Michailov Y, Lunenfeld E, Kapilushnik J et al (2019) Acute Myeloid Leukemia Affects Mouse Sperm Parameters, Spontaneous Acrosome Reaction, and Fertility Capacity. Int J Mol Sci 20:219. https://doi.org/10.3390/ijms20010219
Michailov Y, AbuMadighem A, Lunenfeld E et al (2021) Granulocyte Colony-Stimulating Factor Restored Impaired Spermatogenesis and Fertility in an AML-Chemotherapy Mice Model. Int J Mol Sci 22:11157. https://doi.org/10.3390/ijms222011157
Miller W, Auchus R (2011) The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev 32:81–151. https://doi.org/10.1210/er.2010-0013
Milojkovic D, Apperley JF (2014) How I treat leukemia during pregnancy. Blood 123:974–984. https://doi.org/10.1182/blood-2013-08-283580
Mitkov MD, Aleksandrova IY, Orbetzova MM (2013) Effect of transdermal testosterone or alpha-lipoic acid on erectile dysfunction and quality of life in patients with type 2 diabetes mellitus. Folia Med (plovdiv) 55:55–63. https://doi.org/10.2478/folmed-2013-0006
Mohasseb M, S E, Ma Y, N H (2011) Testicular oxidative damage and role of combined antioxidant supplementation in experimental diabetic rats. J Physiol Biochem 67:185–94. https://doi.org/10.1007/s13105-010-0062-2
Motawi TMK, Sadik NAH, Refaat A (2010) Cytoprotective effects of DL-alpha-lipoic acid or squalene on cyclophosphamide-induced oxidative injury: an experimental study on rat myocardium, testicles and urinary bladder. Food Chem Toxicol 48:2326–2336. https://doi.org/10.1016/j.fct.2010.05.067
Naderi N, Darmishonnejad Z, Tavalaee M, Nasr-Esfahani MH (2023) The effect of alpha-lipoic acid on sperm functions in rodent models for male infertility: A systematic review. Life Sci 323:121383. https://doi.org/10.1016/j.lfs.2023.121383
Najafi M, Cheki M, Amini P et al (2019) Evaluating the protective effect of resveratrol, Q10, and alpha-lipoic acid on radiation-induced mice spermatogenesis injury: A histopathological study. Int J Reprod Biomed 17:907–914. https://doi.org/10.18502/ijrm.v17i12.5791
Namoju R, Chilaka NK (2021) Alpha-lipoic acid ameliorates cytarabine-induced developmental anomalies in rat fetus. Hum Exp Toxicol 40:851–868. https://doi.org/10.1177/0960327120975114
Namoju R, Chilaka NK (2022) Maternal supplementation of α-lipoic acid attenuates prenatal cytarabine exposure-induced oxidative stress, steroidogenesis suppression and testicular damage in F1 male rat fetus. Beni-Suef University Journal of Basic and Applied Sciences 11:60. https://doi.org/10.1186/s43088-022-00240-0
Namoju RC, Khan S, Patel RS et al (2014) Pre-pubertal exposure of cytarabine-induced testicular atrophy, impaired spermatogenesis and germ cell DNA damage in SD rats. Toxicol Mech Methods 24:703–712. https://doi.org/10.3109/15376516.2014.970679
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358. https://doi.org/10.1016/0003-2697(79)90738-3
Ojo OO, Omolola O, Tosin OB (2019) Quercetin controlled Cytarabine-induced testicular damage in Swiss albino mice 1. Int J Adv Res Biol Sci 6:1–13. https://doi.org/10.22192/ijarbs.2019.06.05.001
Omu AE (2013) Sperm parameters: paradigmatic index of good health and longevity. Med Princ Pract 22(Suppl 1):30–42. https://doi.org/10.1159/000354208
Othman AI, El-Missiry MA, Koriem KM, El-Sayed AA (2012) Alfa-lipoic acid protects testosterone secretion pathway and sperm quality against 4-tert-octylphenol induced reproductive toxicity. Ecotoxicol Environ Saf 81:76–83. https://doi.org/10.1016/j.ecoenv.2012.04.018
Pınar N, Çakırca G, Özgür T, Kaplan M (2018) The protective effects of alpha lipoic acid on methotrexate induced testis injury in rats. Biomed Pharmacother 97:1486–1492. https://doi.org/10.1016/j.biopha.2017.11.078
Prahalathan C, Selvakumar E, Varalakshmi P (2006) Lipoic acid modulates adriamycin-induced testicular toxicity. Reprod Toxicol 21:54–59. https://doi.org/10.1016/j.reprotox.2005.07.002
Prathima P, Venkaiah K, Pavani R et al (2017) α-lipoic acid inhibits oxidative stress in testis and attenuates testicular toxicity in rats exposed to carbimazole during embryonic period. Toxicol Rep 4:373–381. https://doi.org/10.1016/j.toxrep.2017.06.009
Prathima P, Venkaiah K, Daveedu T et al (2020) α-lipoic acid protects testis and epididymis against linuron-induced oxidative toxicity in adult rats. Toxicol Res 36:343–357. https://doi.org/10.1007/s43188-019-00036-y
Prathima P, Pavani R, Sukeerthi S, Sainath SB (2018) α-Lipoic acid inhibits testicular and epididymal oxidative damage and improves fertility efficacy in arsenic-intoxicated rats. J Biochem Mol Toxicol 32:e22016. https://doi.org/10.1002/jbt.22016
Raaia MF, Atyeah AA, Elkhiat YI, Elenany HG (2012) Treatment of idiopathic asthenozoospermia, either isolated or oligoasthenozoospermia, with α-lipoic acid: a placebo-controlled, double-blind study. Human Andrology 2:94. https://doi.org/10.1097/01.XHA.0000419798.52349.2e
Ramaswamy S, Weinbauer GF (2014) Endocrine control of spermatogenesis: Role of FSH and LH/ testosterone. Spermatogenesis 4:e996025. https://doi.org/10.1080/21565562.2014.996025
Rotruck JT, Pope AL, Ganther HE et al (1973) Selenium: biochemical role as a component of glutathione peroxidase. Science 179:588–590. https://doi.org/10.1126/science.179.4073.588
Said RS, Mohamed HA, Kassem DH (2020) Alpha-lipoic acid effectively attenuates ionizing radiation-mediated testicular dysfunction in rats: Crosstalk of NF-ĸB, TGF-β, and PPAR-ϒ pathways. Toxicology 442:152536. https://doi.org/10.1016/j.tox.2020.152536
Salehi B, Berkay Yılmaz Y, Antika G et al (2019) Insights on the Use of α-Lipoic Acid for Therapeutic Purposes. Biomolecules 9:E356. https://doi.org/10.3390/biom9080356
Sèdes L, L T, S M et al (2018) Cholesterol: A Gatekeeper of Male Fertility? Front Endocrinol 9:369. https://doi.org/10.3389/fendo.2018.00369
Selvakumar E, Prahalathan C, Mythili Y, Varalakshmi P (2004) Protective effect of DL-alpha-lipoic acid in cyclophosphamide induced oxidative injury in rat testis. Reprod Toxicol 19:163–167. https://doi.org/10.1016/j.reprotox.2004.06.015
Selvakumar E, Prahalathan C, Mythili Y, Varalakshmi P (2005) Mitigation of oxidative stress in cyclophosphamide-challenged hepatic tissue by DL-alpha-lipoic acid. Mol Cell Biochem 272:179–185. https://doi.org/10.1007/s11010-005-7322-4
Sharpe RM (2020) Androgens and the masculinization programming window: human-rodent differences. Biochem Soc Trans 48:1725–1735. https://doi.org/10.1042/BST20200200
Shaygannia E, Ghandehari-Alavijeh R, Tavalaee M, Nasr-Esfahani MH (2020) The Protective Effects of Alpha Lipoic Acid on Human Sperm Function During Freezing-Thawing. Cryo Letters 41:344–350
Sinha AK (1972) Colorimetric assay of catalase. Anal Biochem 47:389–394. https://doi.org/10.1016/0003-2697(72)90132-7
Sönmez M, Türk G, Yüce A (2005) The effect of ascorbic acid supplementation on sperm quality, lipid peroxidation and testosterone levels of male Wistar rats. Theriogenology 63:2063–2072. https://doi.org/10.1016/j.theriogenology.2004.10.003
Stentoft J (1990) The toxicity of cytarabine. Drug Saf 5:7–27. https://doi.org/10.2165/00002018-199005010-00003
Stocco D, X W, Y J, Pr M (2005) Multiple signaling pathways regulating steroidogenesis and steroidogenic acute regulatory protein expression: more complicated than we thought. Mol Endocrinol (Baltimore, Md) 19:2647-59. https://doi.org/10.1210/me.2004-0532
Takalani NB, Monaneng EM, Mohlala K et al (2023) Role of oxidative stress in male infertility. Reprod Fertil 4:e230024. https://doi.org/10.1530/RAF-23-0024
Takeda T, Matsuo Y, Nishida K et al (2017) α-Lipoic acid potentially targets AMP-activated protein kinase and energy production in the fetal brain to ameliorate dioxin-produced attenuation in fetal steroidogenesis. J Toxicol Sci 42:13–23. https://doi.org/10.2131/jts.42.13
Tohamy HG, Lebda MA, Sadek KM et al (2022) Biochemical, molecular and cytological impacts of alpha-lipoic acid and Ginkgo biloba in ameliorating testicular dysfunctions induced by silver nanoparticles in rats. Environ Sci Pollut Res Int 29:38198–38211. https://doi.org/10.1007/s11356-021-18441-y
Wang P, Yang Z, Shan M et al (2021) Maternal and Fetal Outcomes of Acute Leukemia in Pregnancy: A Retrospective Study of 52 Patients. Front Oncol 11:803994. https://doi.org/10.3389/fonc.2021.803994
Xiong Y, Yin Q, Li J, He S (2020) Oxidative Stress and Endoplasmic Reticulum Stress Are Involved in the Protective Effect of Alpha Lipoic Acid Against Heat Damage in Chicken Testes. Animals (basel) 10:384. https://doi.org/10.3390/ani10030384
Yamauchi H, Katayama K, Ueno M et al (2004) Involvement of p53 in 1-beta-D-arabinofuranosylcytosine-induced trophoblastic cell apoptosis and impaired proliferation in rat placenta. Biol Reprod 70:1762–1767. https://doi.org/10.1095/biolreprod.103.026252
Yardimci A, Akkoc RF, Tektemur A et al (2020) Chronic Maternal Tobacco Smoke Exposure and/or Alpha-Lipoic Acid Treatment Causes Long-Term Deterioration of Testis and Sexual Behavior in Adult Male Rats. J Sex Med 17:1835–1847. https://doi.org/10.1016/j.jsxm.2020.07.002
Ye N, Lv Z, Dai H et al (2021) Dietary alpha-lipoic acid supplementation improves spermatogenesis and semen quality via antioxidant and anti-apoptotic effects in aged breeder roosters. Theriogenology 159:20–27. https://doi.org/10.1016/j.theriogenology.2020.10.017
Yuan M, Sano H, Nishino T et al (2023) α-Lipoic acid eliminates dioxin-induced offspring sexual immaturity by improving abnormalities in folic acid metabolism. Biochem Pharmacol 210:115490. https://doi.org/10.1016/j.bcp.2023.115490
Yumura Y, Takeshima T, Komeya M et al (2022) Fertility and sexual dysfunction in young male cancer survivors. Reprod Med Biol 21:e12481. https://doi.org/10.1002/rmb2.12481
Zaletel LZ, Bratanic N, Jereb B (2004) Gonadal function in patients treated for leukemia in childhood. Leuk Lymphoma 45:1797–1802. https://doi.org/10.1080/1042819042000219458
Zhang Q-F, Wang S, Zhang H et al (2022) Effects of alpha-lipoic acid on sperm quality in patients with varicocele-related male infertility: study protocol for a randomized controlled clinical trial. Trials 23:1002. https://doi.org/10.1186/s13063-022-06951-0
Zhang Z, Wen R, Zhang W et al (2023) Efficacy and mechanism of lipoic acid in the treatment of reproductive injury caused by perfluorooctanoic acid. Exp Ther Med 25:116. https://doi.org/10.3892/etm.2023.11815
Zlatkis A, Zak B, Boyle AJ (1953) A new method for the direct determination of serum cholesterol. J Lab Clin Med 41:486–492
Acknowledgements
We would like to acknowledge Bhaskar Medical College, Hyderabad, and Bhaskar Pharmacy College, Hyderabad for providing facilities and Vivo Bio Tech Ltd, Pregnapur, Telangana for the support in technological aspects.
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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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RN and NKC involved in conceiving the concept and designing the study; analysing and interpretation of data; reviewing and editing of manuscript; approval of the manuscript. RN contributed for literature search, carried out the experiment, wrote the manuscript. NKC supervised the study. Both the authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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Institutional Animal Ethics Committee (IAEC) has approved the protocol (Approval Number: MLRIP/IAEC/2018/02).
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Highlights
• Prenatal cytarabine reduced body weight and testes weight in F1 male rats.
• It increased oxidative stress and delayed the onset of puberty.
• It reduced 3β-HSD, 17β-HSD, testosterone, FSH, and LH levels.
• It caused anomalies in sperm and testicular histology.
• Alpha-lipoic acid mitigated prenatal cytarabine-induced reproductive lesions.
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Chilaka, K.N., Namoju, R. Maternal supplementation of alpha-lipoic acid ameliorates prenatal cytarabine-induced mutilation in reproductive development and function in F1 male adult rats. Naunyn-Schmiedeberg's Arch Pharmacol 397, 4035–4053 (2024). https://doi.org/10.1007/s00210-023-02852-4
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DOI: https://doi.org/10.1007/s00210-023-02852-4