RESUMO
Human epidemiological studies reveal that dietary and environmental alterations influence the health of the offspring and that the effect is not limited to the F1 or F2 generations. Non-Mendelian transgenerational inheritance of traits in response to environmental stimuli has been confirmed in non-mammalian organisms including plants and worms and are shown to be epigenetically mediated. However, transgenerational inheritance beyond the F2 generation remains controversial in mammals. Our lab previously discovered that the treatment of rodents (rats and mice) with folic acid significantly enhances the regeneration of injured axons following spinal cord injury in vivo and in vitro, and the effect is mediated by DNA methylation. The potential heritability of DNA methylation prompted us to investigate the following question: Is the enhanced axonal regeneration phenotype inherited transgenerationally without exposure to folic acid supplementation in the intervening generations? In the present review, we condense our findings showing that a beneficial trait (i.e., enhanced axonal regeneration after spinal cord injury) and accompanying molecular alterations (i.e., DNA methylation), triggered by an environmental exposure (i.e., folic acid supplementation) to F0 animals only, are inherited transgenerationally and beyond the F3 generation.
RESUMO
Folate supplementation in F0 mating rodents increases regeneration of injured spinal axons in vivo in 4 or more generations of progeny (F1-F4) in the absence of interval folate administration to the progeny. Transmission of the enhanced regeneration phenotype to untreated progeny parallels axonal growth in neuron culture after in vivo folate administration to the F0 ancestors alone, in correlation with differential patterns of genomic DNA methylation and RNA transcription in treated lineages. Enhanced axonal regeneration phenotypes are observed with diverse folate preparations and routes of administration, in outbred and inbred rodent strains, and in two rodent genera comprising rats and mice, and are reversed in F4-F5 progeny by pretreatment with DNA demethylating agents prior to phenotyping. Uniform transmission of the enhanced regeneration phenotype to progeny together with differential patterns of DNA methylation and RNA expression is consistent with a non-Mendelian mechanism. The capacity of an essential nutritional co-factor to induce a beneficial transgenerational phenotype in untreated offspring carries broad implications for the diagnosis, prevention, and treatment of inborn and acquired disorders.
Assuntos
Ácido Fólico/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Neurônios/fisiologia , Administração Oral , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Azacitidina/farmacologia , Metilação de DNA/genética , Feminino , Ácido Fólico/administração & dosagem , Genoma , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Injeções Intraperitoneais , Masculino , Neurônios/efeitos dos fármacos , Fenótipo , Ratos Sprague-Dawley , Transcrição Gênica/efeitos dos fármacosRESUMO
Folic acid supplementation has proved to be extremely effective in reducing the occurrence of neural tube defects (NTDs) and other congenital abnormalities in humans, suggesting that folic acid can modulate key mechanisms for growth and differentiation in the central nervous system (CNS). To prevent NTDs, however, supplemental folate must be provided early in gestation. This suggests that the ability of folic acid to activate growth and differentiation mechanisms may be confined to the early embryonic period. Here, we show that folic acid can enhance growth and repair mechanisms even in the adult CNS. Using lesion models of CNS injury, we found that intraperitoneal treatment of adult rats with folic acid significantly improves the regrowth of sensory spinal axons into a grafted segment of peripheral nerve in vivo. Regrowth of retinal ganglion cell (RGC) axons into a similar graft also was enhanced, although to a smaller extent than spinal axons. Furthermore, folic acid supplementation enhances neurological recovery from a spinal cord contusion injury, showing its potential clinical impact. The results show that the effects of folic acid supplementation on CNS growth processes are not restricted to the embryonic period, but can also be effective for enhancing growth, repair, and recovery in the injured adult CNS.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Suplementos Nutricionais , Ácido Fólico/uso terapêutico , Traumatismos do Nervo Óptico/tratamento farmacológico , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Contagem de Células , Sistema Nervoso Central/citologia , Sistema Nervoso Central/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ácido Fólico/farmacologia , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Masculino , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/fisiologia , Estatísticas não Paramétricas , Fatores de TempoRESUMO
Regeneration in the central nervous system (CNS) is prohibitive. This is likely due to an interplay of cellular (gene expression, growth factors) and environmental (inhibition by CNS myelin) factors. Calcium supports various intracellular functions, and multiple in vitro studies have shown a role of calcium in axonal growth. In this study, we examine the role of a calcium agonist, S(-)-Bay K 8644, in promoting or impeding CNS growth in vivo, in an effort to understand further the relationship between the voltage-gated L type calcium channel and regeneration. Using a well-established rat spinal cord model of regeneration, we have injected various doses of S(-)-Bay K 8644 (30-240 M) around the injured spinal cord. Our results demonstrate that S(-)-Bay K 8644 enhances regeneration in a dose-dependent fashion. In addition, at very specific concentrations, the same agonist has no effect on or even inhibits regeneration. We conclude that spinal regeneration is highly dependent on intracellular calcium concentration. Furthermore, depending on the dose used, the effect of calcium agonist supplementation on spinal regeneration can be supportive or inhibitory.