RESUMO
The hormone estradiol affects the auditory system both by itself and by its interaction with neuroprotective factors. In this study, we examined the role of estrogen receptors (ERs) in response to auditory trauma. We found a ligand-dependent protective role for ERbeta in the auditory system by investigating mice deficient in ERalpha (ERKO mice), ERbeta (BERKO mice), and aromatase (ARKO mice). Basal auditory brainstem response (ABR) thresholds were similar in all animals. An acoustic trauma causing a temporary hearing loss raised ABR thresholds in male and female BERKO and ARKO mice compared with WT and ERKO mice. The ERalpha-selective agonist, propyl(1H) pyrazole-1,3,5-triyl-trisphenol (PPT), partially protected ARKO mice from trauma, while the ERbeta-selective agonist, 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN), protected WT and ARKO mice. Immunohistochemistry and western blotting confirmed the expression of ERbeta in cochlea of WT males and females. Levels of brain-derived neurotrophic factor (BDNF), a neuroprotective peptide that can be induced by estrogen, was lower in BERKO and ARKO mice compared with WT. DPN treatment increased BDNF expression in ARKO mice. These data indicate ERbeta-mediated neuroprotection involving BDNF in the auditory system of males and females.
Assuntos
Receptor beta de Estrogênio/metabolismo , Perda Auditiva Provocada por Ruído/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cóclea/metabolismo , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/deficiência , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/deficiência , Receptor beta de Estrogênio/genética , Feminino , Perda Auditiva Provocada por Ruído/tratamento farmacológico , Perda Auditiva Provocada por Ruído/genética , Perda Auditiva Provocada por Ruído/patologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Knockout , Nitrilas/uso terapêuticoRESUMO
Prenatal manipulations to the hypothalamic-pituitary-adrenal axis are shown to affect auditory responses to an acoustic challenge as well as behavior in adult life. To achieve these results, we examined the effect of prenatal dexamethasone (DEX) treatment in male and female adult rat offspring by assessing body and adrenal weight, anxiety using the elevated plus maze (EPM), and acoustic startle responses as well as the effects of acoustic challenge in the paraventricular nucleus (PVN). DEX male offspring had reduced adrenal gland weight in adult life and demonstrated anxiolytic-like behavior when tested on the EPM. The acoustic startle amplitude in naive DEX-treated male offspring was significantly higher compared with saline (SAL)-treated males and females and DEX-treated females. When challenged with either a glucocorticoid agonist or antagonist, the startle response of the SAL-treated males and females significantly increased or decreased in the presence of agonist and antagonist treatment, respectively, whereas DEX males and females were not affected. Acoustic challenge caused an increase in c-fos mRNA and glucocorticoid receptor nuclear translocation in the PVN of all groups. BDNF and TrkB mRNA increased in the PVN after acoustic challenge in the SAL-treated males and females but not in the DEX males or females. These findings exemplify the differential sensitivity of the developing nervous and endocrine systems to prenatal hormonal stress and demonstrate that prenatal DEX treatment elicits long-term behavioral alterations related to anxiety and auditory processing.
Assuntos
Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Dexametasona/toxicidade , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/genética , Regiões Promotoras Genéticas/genética , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Dexametasona/administração & dosagem , Éxons/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Glucocorticoides/toxicidade , Imuno-Histoquímica , Hibridização In Situ , Núcleo Hipotalâmico Paraventricular/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Proteínas Proto-Oncogênicas c-fos/genética , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/análiseRESUMO
Estrogens' effects on hearing are documented across species, but the responsible molecular mechanisms remain unknown. The presence of estrogen receptors (ER) throughout the auditory system offers a potential pathway of direct estrogenic effects on auditory function, but little is known about how each ER's expression is regulated by the overall hormonal status of the body. In the present study, we determined the effects of ovariectomy and chronic 17ß-estradiol treatment on mRNA and protein expression of ERα and ERß in peripheral (cochlea) and central (inferior colliculus) auditory structures of mice, as well as on auditory-related behavior using the acoustic startle response (ASR), prepulse inhibition (PPI), and habituation of the startle response. 17ß-Estradiol treatment down-regulated ERα but not ERß and increased PPI and latency of the ASR. Neither the magnitude nor the habituation of ASR was affected. Furthermore, ER's mRNA and protein expression in the inner ear were analyzed throughout the estrous cycle (proestrus, estrus, metestrus, and diestrus), revealing a negative correlation of circulating estrogens with ERα expression, whereas ERß was stable. Our findings show that ER not only are present in both the peripheral and central auditory system but also that circulating estrogen levels down-regulate ERα expression in the auditory system and affect PPI and the latency of ASR, suggesting a key role of ERα as a hormone-induced modulator of the auditory system and behavior.
Assuntos
Estradiol/farmacologia , Ciclo Estral/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Reflexo de Sobressalto/efeitos dos fármacos , Estimulação Acústica , Animais , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Camundongos , Ovariectomia , Receptores de Estrogênio/genéticaRESUMO
Recently significant progress was made in understanding the mechanisms by which the two estrogen receptors (alpha and beta) are involved in different pathways of estrogen action in a wide variance of tissues. Divergent responses of cells and tissues to estrogens or their ligands have been attributed to various isoforms and signaling pathways of estrogen receptors. Both subtypes of estrogen receptors have been identified in the cochlea and there are indications that they have neuroprotective effects but there is still limited information on the role and specific mechanisms of these two receptors in the auditory system. This review will examine the molecular and functional actions of the two estrogen receptor subtypes, the pivotal role they play in the auditory system and their therapeutic strategies for protecting against hearing loss.
Assuntos
Cóclea/fisiologia , Receptores de Estrogênio/fisiologia , Animais , Feminino , Audição/fisiologia , Perda Auditiva Provocada por Ruído/metabolismo , Humanos , Ligantes , Masculino , Modelos Animais , Modelos Biológicos , Neurotransmissores/fisiologia , Regiões Promotoras Genéticas , Estrutura Terciária de Proteína , Receptores de Estrogênio/agonistas , Receptores de Estrogênio/química , Receptores de Estrogênio/genética , Caracteres Sexuais , Transdução de SinaisRESUMO
HYPOTHESIS: Growth hormones have beneficial effects on increasing height in adults with Turner syndrome (TS) and may also affect auditory function. BACKGROUND: Turner syndrome is the most common sex-linked chromosomal abnormality in female conceptions. Epidermal growth factor and its receptor (EGFR) affect differentiation, proliferation, and migration of epithelial cells and function as survival factors. The expression of EGFR is found in the developing and juvenile inner ear of experimental animals but is absent in adults. METHODS: To determine whether EGFR plays a role in TS, its expression was analyzed in the cochlea of healthy fetus and fetus with TS and in healthy adults. RESULTS: In healthy fetuses, EGFR protein expression was localized to the inner and outer hair cells and the Reissner membrane. The fetuses with TS on the 13th gestational week (GW) showed a similar pattern of immunoreactivity as the normal 16th and 20th GW cochlea. By the 23rd GW, EGFR immunoreactivity was not detectable in the TS hair cells or the Reissner membrane, and less intensive staining was found in the surrounding fibrocytes of the spiral ganglion. CONCLUSION: This is the first demonstration of EGFR immunoreactivity in the human cochlea and illustrates how EGFR expression is altered during development in TS. These findings indicate the importance of growth hormone receptors for inner ear development in humans.