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Gen Comp Endocrinol ; 189: 33-42, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23631900


The presence of a robust estrogen (E2) response system throughout heart and blood vessel tissues of vertebrates, including humans, has led to the speculation that this ubiquitous hormone may play a prominent role in the health and maintenance of the adult cardiovascular system (CVS). We previously established an embryonic zebrafish model called 'listless', which results from the inhibition of E2 synthesis by treatment with aromatase enzyme inhibitors (AI). These fish have outward symptoms similar to the human condition of congestive heart failure and tamponade. E2 replacement therapy (1) reduced the severity of cardiac sac abnormalities, (2) protected heart function, (3) prevented reduction in heart size, and (4) reduced blood vessel deterioration. Nitric oxide may be a critical downstream mediator of these events. We also demonstrate that removal of fluid around the heart increases survival of AI-treated fish. These results strongly indicate the importance of E2 in the developing CVS of the zebrafish and offer a potential model for the study of its role in CVS development, maintenance, and disease conditions.

Inibidores da Aromatase/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Estrogênios/farmacologia , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Animais , Sistema Cardiovascular/metabolismo , Coração/efeitos dos fármacos , Coração/embriologia , Óxido Nítrico/metabolismo
Brain Res ; 1222: 118-28, 2008 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-18586226


The brain is a steroidogenic organ and is thus dependent on estrogen for many aspects of its development and maintenance in both males and females. The purpose of this study was to develop a model to investigate the effect of estrogen on zebrafish sensory-motor (S-M) maturation through mechanisms found in the central nervous (CNS) and peripheral nervous (PNS) systems. In these experiments the aromatase inhibitor (AI), 4-hydroxy androstenedione (4-OH-A), which blocks estrogen synthesis, was used to diminish estrogen's effects on zebrafish CNS and PNS development. During these various treatments the zebrafish were analyzed for neurological deficits, including tactile response, swimming movements, vestibular behavior, pectoral fin and eye movements. Over a three to five day time period (48-168 h post fertilization), in response to AI treatment, none of these S-M behaviors were developmentally expressed creating a "listless" or non-responding condition. Furthermore, when the AI was removed from the treatment medium the S-M behaviors were fully expressed over a two to three day time period. Most importantly, when estrogen was added at the same time as the AI in a co-treatment paradigm, normal developmental appearance of S-M behaviors was rescued in all neurological parameters measured. Furthermore, the addition of estrogen alone after AI washout accelerated the recovery of the tactile response during the first 24 h of treatment. Treatment of developing zebrafish with the selective estrogen receptor blocker ICI 182,780 mimicked the deficit in S-M behaviors caused by AI treatment. This deficit was overcome by low concentrations of estrogen in a co-treatment paradigm with high ICI levels indicating the possibility of a non-genomic mechanism for estrogen's actions on the developmental expression of these S-M behaviors. Eventually, AI exposed fish died of cardiac arrest 4 to 5 days after the start of treatment; however, AI/estrogen co-treatment allowed for 90-100% survival and the maintenance of normal heart rates during this time period. In conclusion, these studies have demonstrated that the presence of estrogen in the early developing zebrafish embryo is necessary for the proper developmental expression of critical nervous system S-M behaviors necessary for survival, as well as the health of the cardiovascular system. These studies also establish a unique "listless" model for further analysis of estrogen's role in the development of brain, brainstem, and spinal cord circuitry related to the maturation of these behavioral and cardiovascular phenomena.

Comportamento Animal/fisiologia , Desenvolvimento Embrionário/fisiologia , Estrogênios/fisiologia , Atividade Motora/fisiologia , Fatores Etários , Androstenodiona/análogos & derivados , Androstenodiona/farmacologia , Animais , Inibidores da Aromatase/farmacologia , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Embrião não Mamífero , Desenvolvimento Embrionário/efeitos dos fármacos , Estradiol/análogos & derivados , Estradiol/farmacologia , Antagonistas de Estrogênios/farmacologia , Estrogênios/farmacologia , Fulvestranto , Frequência Cardíaca/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Atividade Motora/efeitos dos fármacos , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/crescimento & desenvolvimento , Estimulação Física/métodos , Natação/fisiologia , Vestíbulo do Labirinto/efeitos dos fármacos , Vestíbulo do Labirinto/fisiologia , Peixe-Zebra