Mechanisms of neurodevelopmental effects of parental exposure to commonly used general anesthetic agents Epidemiological studies and research in animal models demonstrate that parental germ cells are susceptible to reprogramming by environmental factors across the lifespan. General anesthetics (GAs) can be considered as highly active environmental factors. In our background study, we received the first experimental evidence that a frequently used GA, sevoflurane (SEVO), administered to young adult rats, induces 1) epigenetic reprogramming of the neuron-specific K+-2Cl- (Kcc2) Cl- exporter gene in germ cells of both exposed parents and in the hypothalamus and hippocampus of their male, but not female, offspring; 2) the hypothalamic and hippocampal Kcc2 expression impairment and behavioral deficiencies in these male offspring; and 3) long-term neurobehavioral abnormalities in exposed males (but not females). The plausibility of the epigenetic germ cell effects and, hence, intergenerational neurocognitive effects of GAs in humans is supported by findings of a recent clinical study that the DNA methylation status of 1,509 genes in the spermatozoa of male patients was persistently changed 1 week after bariatric surgery. The large number of young adults who require general anesthesia and a growing number of neurodevelopmental disorders of unknown etiology in unexposed children underscore the importance of investigating intergenerational effects of GAs. Based on our findings and extant literature and using a neuron-specific Kcc2 as a molecular biomarker, we developed the following hypotheses, which will be tested in three specific aims: 1: Determine whether the intergenerational effects of young adult anesthetic exposure are specific to SEVO or occur with other GABAergic anesthetics as well. Hypotheses: Propofol, an intravenous GA with a selective GABAAR-mediated action, but not ketamine, an intravenous GA that blocks the NMDA receptor/channel, will induce intergenerational effects qualitatively similar to those induced by SEVO. 2: Determine whether offspring are more susceptible to SEVO-induced neurobehavioral abnormalities than the exposed parents. Hypotheses: Parental germ cells and brain development in their offspring can be affected at levels/durations of SEVO exposures that are not sufficient to induce neurobehavioral abnormalities in parents. 3: Determine whether pretreatments with dexmedetomidine or formestane ameliorate the intergenerational effects of SEVO. Hypotheses: Formestane will alleviate SEVO- induced neurobehavioral abnormalities in both generations, while dexmedetomidine will alleviate neurobehavioral abnormalities in exposed parents only. The results of the proposed experiments, whose plausibility is supported by animal and human studies, will help to identify therapeutic strategies to improve general anesthesia safety in exposed parents and their future unexposed offspring and to form the foundation for clinical studies of intergenerational effects of GAs.
The epigenetic landscape of germ cells is highly dynamic and susceptible to reprogramming by environmental factors across the lifespan with the potential for life-changing effects on subsequent generations. This study is designed to elucidate the intergenerational neurobehavioral effects of highly active environmental factors: the commonly used general anesthetics sevoflurane, propofol, ketamine, and dexmedetomidine, which will be administered to young adult rats during their prime reproductive period. The results of the proposed experiments will help to identify therapeutic strategies to improve general anesthesia safety in exposed parents and their future unexposed offspring and to form the foundation for clinical studies of intergenerational effects of general anesthetics.
