Resources: Reviews, studies, and presentations

Reviews and commentaries

Vutskits L, Sall JW, Jevtovic-Todorovic V. A poisoned chalice: the heritage of parental anaesthesia exposure. Br J Anesth 2018;121:337–9. (“Hence, we are faced with a real possibility that general anaesthetics are not innocuous agents that ‘only put children to sleep’ but rather formidable modulators of chromatin remodeling and function…. The current study extends previous reports of sex differences by showing that anaesthetic exposure itself can alter expression of chloride channels in certain brain regions and that this effect is heritable from exposed male parents to unexposed offspring.”) 

Martynyuk et al. Neuroendocrine, epigenetic, and intergenerational effects of general anesthetics. World J Psychiatr 2020; 10(5): 81-94.  https://www.wjgnet.com/2220-3206/full/v10/i5/81.htm

Escher J and Ford LD. General anesthesia, germ cells and the missing heritability of autism: an urgent need for research. Environ Epigenetics 2020;6:1,dvaa007.

Studies

Intergenerational inheritance in rodent models

Chalon J, Tang CK, Ramanathan S, Eisner M, Katz R, Turndorf H. Exposure to halothane and enflurane affects learning function of murine progeny. Anesth Analg 1981;60:794–7.
In a mouse model, learning retardation was seen in offspring of murine parents exposed to GA in utero—in other words, mental impairment in the grandpups of the exposed gestating dams.

Tang CK, Chalon J, Markham JR, Ramanathan S, Turndorf H. Exposure of sires to enflurane affects learning function of murine progeny. Obstet Anesth Dig 1985;5:67.
In a mouse model, the general anesthetic agent enflurane administered to male mice was found to adversely affected learning function of their offspring.

Ju LS, Yang JJ, Morey TE, Gravenstein N, Seubert CN, Resnick JL, Zhang JQ, Martynyuk AE. Role of epigenetic mechanisms in transmitting the effects of neonatal sevoflurane exposure to the next generation of male, but not female, rats. Br J Anesth 2018;121:406–16.
In a rat model, neonatal exposure to the widely used general anesthetic agent sevoflurane can affect the brains and behavior of the next generation of males through epigenetic modification of Kcc2 expression, while F1 females are at diminished risk.

Ju LS, Yang JJ, Xu N, Li J, Morey TE, Gravenstein N, Seubert CN, Setlow B, Martynyuk AE. Intergenerational effects of sevoflurane in young adult rats. Anesthesiol 2019;131:1092–109.
Adult sevoflurane exposure affects brain development in male offspring by epigenetically reprograming both parental germ cells, while it induces neuroendocrine and behavioral abnormalities only in exposed males. Sex steroids may be required for mediation of the adverse effects of adult sevoflurane in exposed males.

Chastain-Potts SE, Tesic V, Tat QL, Cabrera OH, Quillinan N, Jevtovic-Todorovic V. 2019. Sevoflurane exposure results in sex-specific transgenerational upregulation of target IEGs in the subiculum. Mol Neurobiol 2020;57:11–22.
Neonatal female rats exposed to 6h of the general anesthesia gas sevoflurane had offspring whose brains exhibited epigenetic abnormalities, including reduced DNA methylation, an effect linked to functional decline in learning and memory. An upregulation of Arc and JunB mRNA expression, 71.6% and 74.0%, was seen in the male offspring. Also hypomethylation and modifications to IEGs crucial to synaptic plasticity were observed. The results suggest sevoflurane causes epigenetic modifications in the early rat oocytes.

Xu et al. A Methyltransferase Inhibitor (Decitabine) Alleviates Intergenerational Effects of Paternal Neonatal Exposure to Anesthesia With Sevoflurane. Anesth Analg 2020; doi: 10.1213/ANE.0000000000005097

Presentations