title: Exercise during pregnancy decreases doxorubicin-induced cardiotoxic effects on neonatal hearts.
abstract: Cancer treatment with Doxorubicin (DOX) is limited due its dose-dependent cardiotoxicity, mainly related to the oxidative stress production. In experimental models of DOX treatment exercise can be used as a beneficial adjuvant therapy. This work aimed to investigate the effects of exercise during pregnancy on DOX-induced cardiotoxicity in cardiomyocytes of progeny, examining the possible intergenerational cardioprotective effects of maternal exercise. For this purpose pregnant rats were divided in control and exercise groups and pre-treated during gestational days. Hearts of newborns were used to obtain a culture of cardiomyocytes to be treated with DOX for analyses of cell viability, apoptosis and necrosis; ROS production; DNA damage; SOD and CAT activities; and Sirt6 protein expression. The results showed that exercise during pregnancy induced an increase in the viability of neonatal cardiomyocytes and a decrease in DOX-induced apoptotic and necrotic death which were correlated to the decrease in ROS production and an increase in antioxidant defenses. Exercise also protected neonatal cardiomyocytes from DOX-induced DNA damage, demonstrating a reduction in the oxidative DNA breaks. Likewise, exercise induced an increase in expression of Sirt6 in neonatal cardiomyocytes. Therefore, these results demonstrate for the first time that exercise performed by mothers protects the neonatal heart against DOX-induced toxicity. Our data demonstrate the intergenerational effect of exercise in cardiomyocytes of progeny, where the modulation of oxidative stress through antioxidant enzymes, and DNA integrity via Sirt6, were induced due to exercise in mothers, increasing the resistance of the neonatal heart against DOX toxicity.
authors: Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil.
authors: Verônica B
authors: VB
authors: Brito
authors: Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil.
authors: Leopoldo V M
authors: LV
authors: Nascimento
authors: Laboratory of Physiology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil.
authors: Ramiro B
authors: RB
authors: Nunes
authors: Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil.
authors: Dinara J
authors: DJ
authors: Moura
authors: Laboratory of Physiology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil.
authors: Pedro Dal
authors: PD
authors: Lago
authors: Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil. Electronic address: jenifers@ufcspa.edu.br.
authors: Jenifer
authors: J
authors: Saffi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D066126:Cardiotoxicity / Q000209:etiology / Q000517:prevention & control*; D002374:Catalase / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010805:Physical Conditioning, Animal; D011247:Pregnancy; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D004317:Doxorubicin; D002374:Catalase; D013482:Superoxide Dismutase; D037761:Sirtuins; C560607:sirtuin 6, rat
keywords: Cardiomyocytes; DNA damage response; Doxorubicin; Exercise; Pregnancy; Sirt6