Effects of the Chemotherapeutic Agents for Non‐Hodgkin Lymphoma, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP), on the Male Rat Reproductive System and Progeny Outcome

Abstract

Chemotherapy of non-Hodgkin lymphoma (NHL) with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is associated with significant gonadal damage. Our goal was to determine the impact of CHOP chemotherapy on the male reproductive system, fertility, and progeny outcome in the rat model. Adult male Sprague-Dawley rats received saline or CHOP, 4 cycles of 3 weeks each, at doses analogous to 1/36, 2/36, or 16 the human dose; males were mated to evaluate effects on progeny outcome. Reproductive organ weights were significantly decreased in the 16 CHOP-exposed group. The spermatozoal contents of the testes and epididymides were decreased in 16 CHOP-treated males; the 1/36 and 2/36 doses also affected testicular sperm contents. Seminiferous tubule diameters were decreased by 20% in 16 CHOP-treated males. Damage ranged from the presence of small vacuoles in the epithelium to tubules deprived of spermatocytes and spermatids and was accompanied by an increased incidence of germ cell apoptosis. The acridine orange assay revealed a significant increase in sperm with abnormal DNA integrity profiles in the 16 CHOP group. Despite effects on germ cell number and quality, CHOP-exposed rats remained fertile. However, a 50% decrease in live fetuses was observed in litters sired by 16 CHOPtreated males due to a significant increase in both pre-implantation and postimplantation losses; postimplantation loss was also elevated among litters sired by 2/36 CHOP-treated males. Thus, CHOP treatment affected both the quantity and quality of male germ cells; conceptal loss is a sensitive measure of the integrity of the male genome.

Effect of chemotherapy exposure prior to pregnancy on fetal brain tissue and the potential protective role of quercetin

“…Numerous reports suggest that MDA expression is enhanced by lipid peroxidation resulting from oxidative stress (Sun et al 1988;Singh et al2003;Shen et al 2008;Staedler et al 2011), while SOD activity is known to suppress lipid peroxidation (Vaisheva et al 2007). Despite elevated SOD activity in the CYC-and DOXexposed fetal brain tissues, increased MDA expression is a clear indicator of ongoing lipid peroxidation.…”

“…Alkylating agents are particularly gonadotoxic, producing adducts and cross-links in DNA that may result in prolonged azoospermia (Vaisheva et al 2007). At moderate doses, recovery of normospermic conditions may occur within 1-3 years; however, increased exposure can result in extended or permanent azoospermia (Claeson et al 2000;Cheng et al 2002;Doganay et al 2006;Ciftci et al 2013;Delbes et al 2010).…”

Toxic Effect of Cyclophosphamide on Sperm Morphology, Testicular Histology and Blood Oxidant‐Antioxidant Balance, and Protective Roles of Lycopene and Ellagic Acid

“…An other mechanism for CP toxicity on sperm morphology may also be peroxidation of polyunsaturated fatty acids in plasma membranes of spermatozoa by free radicals. Cyclophosphamide causes histopathological reduction in size and number of the seminiferous tubules, degeneration and vacuolation in spermatogonia, spermatocytes and less number of germ cells, irregular seminiferous tubules, reduced seminiferous epithelial layers, significant maturation arrest, perivascular fibrosis and hyalinization of intertubular tissue [4, [28][29][30][31]. Necrosis, degeneration, desquamation, disorganization and reduction in germinal cells, atrophy in tubules, vacuolization in Sertoli cells, multi-nucleated giant cell formation, interstitial oedema and congestion, reduced diameters of seminiferous tubules, GCLT and Johnsen's Testicular Score were observed in histological structure of CP-treated rats in the present study.…”

Comparative Mitochondrial Proteomic Analysis of Raji Cells Exposed to Adriamycin

“…Although the mitochondrial proteins and their functional processes have been widely studied (9)(10)(11), little is known about mitochondrial proteome alterations of various cells or fractions after exposure to various conditions. Furthermore, although the effects of ADR on NHL have been investigated (12,13), most studies have focused only on evaluating single-protein changes and none on the total cellular proteome or the mitochondrial proteome. We selected Raji cells for study because Raji cells can serve as a model for human lymphomas with mutant p53 and increased BCL2 expression, which are commonly present in patients with NHL and are considered a source of chemotherapy failure in patients whose disease is chemoresistant (14).…”