RESUMO
Bisphenol A (BPA) is a ubiquitous environmental chemical that has been linked to behavioral differences in children and shown to impact critical neurodevelopmental processes in animal models. Though data is emerging, we still have an incomplete picture of how BPA disrupts neurodevelopment; in particular, how its impacts may vary across different genetic backgrounds. Given the genetic tractability of Drosophila melanogaster, they present a valuable model to address this question. Fruit flies are increasingly being used for assessment of neurotoxicants because of their relatively simple brain structure and variety of measurable behaviors. Here we investigated the neurodevelopmental impacts of BPA across two genetic strains of Drosophila-w1118 (control) and the Fragile X Syndrome (FXS) model-by examining both behavioral and neuronal phenotypes. We show that BPA induces hyperactivity in larvae, increases repetitive grooming behavior in adults, reduces courtship behavior, impairs axon guidance in the mushroom body, and disrupts neural stem cell development in the w1118 genetic strain. Remarkably, for every behavioral and neuronal phenotype examined, the impact of BPA in FXS flies was either insignificant or contrasted with the phenotypes observed in the w1118 strain. This data indicates that the neurodevelopmental impacts of BPA can vary widely depending on genetic background and suggests BPA may elicit a gene-environment interaction with Drosophila fragile X mental retardation 1 (dFmr1)-the ortholog of human FMR1, which causes Fragile X Syndrome and is associated with autism spectrum disorder.
Assuntos
Compostos Benzidrílicos/toxicidade , Drosophila melanogaster/efeitos dos fármacos , Sistema Nervoso/efeitos dos fármacos , Fenóis/toxicidade , Animais , Corte , Modelos Animais de Doenças , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Feminino , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/veterinária , Asseio Animal/efeitos dos fármacos , Larva/efeitos dos fármacos , Larva/fisiologia , Locomoção/efeitos dos fármacos , Masculino , Sistema Nervoso/crescimento & desenvolvimentoRESUMO
Lack of the FMR1 gene product causes fragile X syndrome, the commonest inherited cause of mental impairment. We know little of the roles that fragile X related (FXR) gene family members (FMR1, FXR2 and FXR1) play during embryonic development. Although all are expressed in the brain and testis, FXR1 is the principal member found in striated and cardiac muscle. The Fxr1 knockout mice display a striated muscle phenotype but it is not known why they die shortly after birth; however, a cardiac cause is possible. The zebrafish is an ideal model to investigate the role of fxr1 during development of the heart. We have carried out morpholino knockdown of fxr1 and have demonstrated abnormalities of striated muscle development and abnormal development of the zebrafish heart, including failure of looping and snapping of the atrium from its venous pole. In addition, we have measured cardiac function using high-speed video microscopy and demonstrated a significant reduction in cardiac function. This cardiac phenotype has not been previously described and suggests that fxr1 is essential for normal cardiac form and function.
Assuntos
Doenças dos Peixes/genética , Proteína do X Frágil da Deficiência Intelectual/genética , Distrofia Muscular Animal/genética , Peixe-Zebra/genética , Regiões 5' não Traduzidas/genética , Animais , Sequência de Bases , Causas de Morte , Desenvolvimento Embrionário , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/veterinária , Coração/fisiopatologia , Hibridização In Situ , Camundongos , Músculo Esquelético/patologia , Músculo Esquelético/fisiologia , Miocárdio/metabolismo , Biossíntese de Proteínas , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Peixe-Zebra/embriologia , Peixe-Zebra/crescimento & desenvolvimentoRESUMO
In search of an animal model for the human fragile X syndrome, the chromosomes of Holstein cows were examined. This breed was chosen because of previous studies on the baldy calf syndrome. An achromatic gap was observed at a specific site on the X chromosome closer to the centromere than that identified in humans. This unstained gap was found in 3%-4% of cells of the following four animals: an affected calf, her sister, their mother, and an unrelated Holstein cow. The bovine fragile X may not be analogous to the human fragile X but its location may be important as a genetic marker in linkage studies involving the loci for hypoxanthine phosphoribosyltransferase (HPRT) and glucose-6-phosphate dehydrogenase (G-6-PD).