title: Reproductive hormone levels and differential mitochondria-related oxidative gene expression as potential mechanisms for gender differences in cardiosensitivity to Doxorubicin in tumor-bearing spontaneously hypertensive rats.
abstract: OBJECTIVE
  Chemotherapy with doxorubicin (Dox) causes dose-limiting cardiotoxicity. We investigated the role that gender has on cardiosensitivity to Dox treatment by evaluating reproductive hormone levels in male, castrated male (c-male), female and ovariectomized female (o-female) adult spontaneously hypertensive rats (SHRs) and expression of mitochondria-related genes in male and female adult SHRs.
  
  
  METHODS
  SST-2 breast tumor-bearing SHRs were treated with saline, Dox, dexrazoxane (Drz) or both Dox and Drz and monitored for 14 days. Tumor size was used to monitor anticancer activity. Heart weight, cardiac lesion score and serum levels of cardiac troponin T (cTnT) were used to determine cardiotoxicity. Serum estradiol (E2) and testosterone were evaluated using electrochemiluminescence immunoassays. Expression of mitochondria-related genes was profiled in heart by MitoChip array analyses.
  
  
  RESULTS
  Dox significantly reduced tumor volume (±Drz) and increased heart weight in all genders (13-30% vs. control). Higher heart lesion scores were observed in reproductively normal animals (male 2.9, female 2.2) than in hormone-deficient animals (c-male 1.7, o-female 1.9). Lesion score and cTnT inversely correlated with hormone levels. Reduced levels of both sex hormones were observed after Dox treatment. Gene expression analyses of Dox-treated hearts showed significant differential expression of oxidative stress genes in male hearts and apoptotic genes in both male and female hearts.
  
  
  CONCLUSIONS
  Our results demonstrate that adult tumor-bearing male SHRs are more cardiosensitive to Dox than female or hormone-deficient animals. We provide evidence to suggest that reproductive hormones negatively regulate or are inhibited by Dox-induced cardiotoxicity and the selective cytotoxic mechanism likely functions through the greater activation of oxidative stress and apoptosis in male SHRs.
authors.affiliation: Laboratory of Chemistry, Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave/Bldg 52/72 Rm 2212, Silver Spring, MD, 20993, USA.
authors.forename: Yanira
authors.initials: Y
authors.lastname: Gonzalez
authors.forename: Kaytee L
authors.initials: KL
authors.lastname: Pokrzywinski
authors.forename: Elliot T
authors.initials: ET
authors.lastname: Rosen
authors.forename: Steven
authors.initials: S
authors.lastname: Mog
authors.forename: Baikuntha
authors.initials: B
authors.lastname: Aryal
authors.forename: Leena M
authors.initials: LM
authors.lastname: Chehab
authors.forename: Vikrant
authors.initials: V
authors.lastname: Vijay
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Moland
authors.forename: Varsha G
authors.initials: VG
authors.lastname: Desai
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Dickey
authors.forename: V Ashutosh
authors.initials: VA
authors.lastname: Rao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004317:Doxorubicin / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D012739:Gonadal Steroid Hormones / Q000378:metabolism*; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism*; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D023421:Models, Animal; D018384:Oxidative Stress / Q000235:genetics; D051381:Rats; D011918:Rats, Inbred SHR; D012737:Sex Factors
chemical_list: D012739:Gonadal Steroid Hormones; D004317:Doxorubicin