A Methyltransferase Inhibitor (Decitabine) Alleviates Intergenerational Effects of Paternal Neonatal Exposure to Anesthesia With Sevoflurane

Abstract

BACKGROUND:Neonatal exposure to sevoflurane induces neurobehavioral and neuroendocrine abnormalities in exposed male rats (generation F0) and neurobehavioral, but not neuroendocrine, abnormalities in their male, but not female, offspring (generation F1). These effects of sevoflurane are accompanied by a hypermethylated neuron-specific K + -2Cl − (Kcc2) Cl − exporter gene in the F0 spermatozoa and the F1 male hypothalamus, while the gene's expression is reduced in the F0 and F1 hypothalamus. We investigated whether inhibition of DNA methyltransferases (DNMTs) prior to paternal sevoflurane exposure could alleviate the anesthetic's F0 and F1 effects. METHODS:Sprague-Dawley male rats were anesthetized with 2.1% sevoflurane for 5 h on postnatal day (P) 5 and mated with control females on P90 to generate offspring. The nonselective DNMT inhibitor decitabine (0.5 mg/kg, intraperitoneally

Intergenerational Perioperative Neurocognitive Disorder

“…Studies in rodents not only support the ability of GAs, in particular those whose action involves the enhancement of GABA A R signaling, to induce stress-like responses but may also suggest mediating mechanisms of such effects. For example, sevoflurane, a volatile GA whose polyvalent action involves the enhancement of GABA A R activity, administered to neonatal or young adult rats caused an acute increase in corticosterone secretion immediately after anesthesia, as well as long-term neurobehavioral abnormalities and dysregulation of HPA axis functioning in the form of an exacerbated corticosterone responses to stress [ 57 , 58 , 59 , 125 , 126 , 127 , 128 ]. The findings in rats support the notion that GABAergic anesthetics act via specific molecular mechanisms to induce stress-like responses rather than the notion that GA-caused increases in GC levels are the result of a systemic stress response due to inadequately controlled physiological parameters during anesthesia.…”

“…Nevertheless, the persistent and heritable adverse effects of stress in specific circumstances, for instance, large groups of people affected by war or famine in relatively compact living areas within a defined period of time, have been extensively studied [ 36 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ]. The findings of such human studies—along with the findings of stress-like intergenerational effects of GAs in animal studies [ 57 , 58 , 59 ], which had the advantage of strictly controlled experiments—support the urgent need to elucidate the causes, mediating mechanisms, and biomarkers of PND in millions of patients and their potentially affected children.…”

“…The notion of heritable pathophysiological effects of parental exposure to persistent stress has evolved from being denied to being supported by numerous studies in animal models and humans [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ]. Emerging laboratory studies support the possibility that by acting via mechanisms involving aberrations in stress signaling and epigenomic regulations, GAs may induce neurobehavioral abnormalities not only in the exposed animals but also in their future unexposed offspring [ 56 , 57 , 58 , 59 , 60 ]. Remarkably, experimental findings show that GABAergic GAs may induce heritable effects when administered from the early postnatal period to at least young adulthood, thus covering nearly all age groups that typically procreate [ 57 , 58 , 59 ].…”

“…Emerging laboratory studies support the possibility that by acting via mechanisms involving aberrations in stress signaling and epigenomic regulations, GAs may induce neurobehavioral abnormalities not only in the exposed animals but also in their future unexposed offspring [ 56 , 57 , 58 , 59 , 60 ]. Remarkably, experimental findings show that GABAergic GAs may induce heritable effects when administered from the early postnatal period to at least young adulthood, thus covering nearly all age groups that typically procreate [ 57 , 58 , 59 ]. The large number of patients who require GA/surgery before or during their reproductive age, the even larger number of their future unexposed offspring whose health may be affected by parental PND, and a growing number of brain-related disorders of unknown etiology in unexposed individuals [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 61 , 62 ], in which parental experiences may be a predisposing factor, underscore the importance of investigating the heritability of PND.…”

Beyond Genes: Germline Disruption in the Etiology of Autism Spectrum Disorders

“…Studies by the same group found that expression of DNA methyltransferase 3a and 3b ( Dnmt3a and Dnmt3b , enzymes that catalyze the transfer of a methyl group to DNA) in the hypothalamus of F1 animals was increased by more than 40% compared to unexposed control males (Xu et al, 2020 ). When the animals were treated with Decitabine, a methyltransferase inhibitor, prior to sevoflurane exposure, the expression of Dnmt3a , Dnmt3b , and Kcc2 in the hypothalamus of F1 animals were similar as unexposed control animals and the animals exhibit normal behaviors.…”