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Preparation and Characterization of Lipophilic Doxorubicin Pro-drug Micelles
Published on: August 2, 2016
Doxorubicin affects testicular lipids with long-chain (C18-C22) and very long-chain (C24-C32) polyunsaturated fatty
Samanta R Zanetti1, Eduardo N Maldonado, Marta I Aveldaño
1Instituto de Investigaciones Bioquímicas de Bahía Blanca, Consejo Nacional de investigaciones Científicas y Técnicas y Universidad Nacional del Sur, La Carrindanga km. 7, 8000 Bahía Blanca, Argentina.
Abstract:
Doxorubicin disrupts spermatogenesis by causing apoptosis of spermatogonia and primary spermatocytes. The aim of this study was to examine the effect of this agent on adult rat testicular lipids and their fatty acids. A single dose (7.5 mg/kg) and a multidose regime (3 mg/kg once a week for 4 weeks) were evaluated. Both treatments resulted in the gradual loss of spermatogenic cells and determined a marked reduction in testicular size and weight 9 weeks after their start. Germ cell loss was accompanied by a decrease in phospholipids, including glycerophospholipids and sphingomyelin. Concomitantly, glycerophospholipids lost selectively their major polyunsaturated fatty acid (PUFA), 22:5n-6, and sphingomyelin lost its major very long-chain PUFA (VLCPUFA), 28:4n-6 and 30:5n-6. The molecular species from which the lost polyenes originated were thus a trait of germ cells. A transient peak of 16:0-ceramide was observed 48 h after the single dose. In both doxorubicin regimes, sphingomyelin and ceramide with reduced amounts of VLCPUFA after about 4 weeks and with no VLCPUFA after 9 weeks resulted. By contrast, triglycerides and especially cholesterol esters (CE) tended to accumulate in the testes undergoing germ cell death, probably in the surviving Sertoli cells, their fatty acid patterns suggesting that initially, these lipids retained part of the PUFA coming from, or no longer used for, the synthesis of germ cell glycerophospholipids. As the latter decreased, CE accumulated massively 9 weeks after starting doxorubicin treatment, 20:4n-6 becoming their major PUFA. Part of these CEs may derive from surviving steroidogenic cells.
Insights
Doxorubicin chemotherapy significantly alters testicular lipids and fatty acids in adult rats, impacting germ cell development and lipid composition. This study reveals chemotherapy-induced changes in phospholipids, sphingomyelin, and accumulating cholesterol esters in testes.
Area of Science:
- Reproductive Biology
- Toxicology
- Biochemistry
Background:
- Doxorubicin is a potent chemotherapy agent known to induce apoptosis in germ cells, disrupting spermatogenesis.
- The precise impact of doxorubicin on testicular lipid metabolism and fatty acid profiles remains incompletely understood.
Purpose of the Study:
- To investigate the effects of single and multiple doxorubicin doses on adult rat testicular lipids and their fatty acid composition.
- To identify specific lipid classes and fatty acids affected by doxorubicin-induced testicular toxicity.
Main Methods:
- Adult rats were administered single or multiple doses of doxorubicin.
- Testicular size, weight, and lipid profiles, including phospholipids, sphingomyelin, triglycerides, and cholesterol esters, were analyzed over 9 weeks.
- Fatty acid composition of these lipids was determined using gas chromatography.
Main Results:
- Doxorubicin treatment led to significant testicular atrophy and germ cell loss.
- Phospholipids and sphingomyelin decreased, with selective loss of specific polyunsaturated fatty acids (PUFAs) and very long-chain PUFAs (VLC-PUFAs) associated with germ cells.
- Triglycerides and cholesterol esters accumulated, particularly in Sertoli and possibly steroidogenic cells, with altered fatty acid profiles, including increased 20:4n-6.
Conclusions:
- Doxorubicin significantly alters testicular lipid metabolism, with germ cell loss correlating to specific PUFA and VLC-PUFA depletion in phospholipids and sphingomyelin.
- Accumulation of cholesterol esters in surviving somatic cells suggests a shift in testicular lipid handling following chemotherapy.
- These findings highlight the complex biochemical changes in the testis induced by doxorubicin, impacting both germ and somatic cell lipid profiles.