Heritable Effects of General Anesthesia

What is causing the staggering increase in autism prevalence? So far research has yielded few answers. In this recent letter to leaders at the NIH, research philanthropist Jill Escher, who focuses on germline (egg and sperm) perturbation, highlights the important question of adverse heritable effects of early life general anesthesia.

by Jill Escher

Let me start this missive by acknowledging that you probably receive a number of letters from community members opining about potential sources of the increasing prevalence of autism and related disorders. Now in my seventh year of funding pilot studies relating to autism, I have grown to share the research community’s skepticism toward the out-of-the-box ideas regarding causation, because, well, most of those ideas are just plain wrong.

However, I am writing today about a very particular concept that has leapt out at me as deserving serious attention at the NIH: the question of heritable, germline-borne effects of agents of general anesthesia.

My work as a funder of pilot studies in non-genetic inheritance began nearly seven years ago shortly after I discovered I had been very heavily and continuously exposed in utero to powerful synthetic steroid hormone drugs, prompting the idea that hormone signal disruption to my fetal primordial germ cells could have perturbed the epigenomic programming of my eggs, thus causing dysregulation of gene expression, seemingly limited to the prefrontal cortex, in my two children who have idiopathic nonverbal autism [Escher J, Bugs in the Program: can pregnancy drugs and smoking disturb molecular reprogramming of the fetal germline, increasing heritable risk for autism and neurodevelopmental disorders? Environ. Epigen. 2018;4:2].

To further develop hypotheses regarding non-genetic inheritance in neurodevelopmental disorders, I delved into the scientific literature regarding direct exposures to germline, engaged deeply with the scientific community, and interviewed autism families in an effort to detect patterns regarding parental fetal or early life exposures and adverse outcomes in their children.

A few years ago, I noticed a number of stray comments (as I was not asking about surgeries at all at first) that emerged as a strong pattern. Many of the parents made remarks about early exposure to surgery. These stories seemed to fall into three categories. [Here F2 = autistic child; F1= parent; F0 = gestating mother of F1 and grandmother of F2.]

(1) F0 gestational exposure. These are cases where the F0 grandmother of the F1 parent, male or female, had surgery during gestation with the F1. Reasons for the F0 surgeries during pregnancy included an appendectomy, surgery following an automobile accident, and surgery to correct a problem with the placenta. When an F1 parent had this prenatal exposure, he or she often had multiple F2 offspring, male and female, with autism. From a biological point of view this multiplex phenomenon would make sense because the early germ cells at this stage would likely be similarly exposed.

(2) F1 early childhood exposure. These are cases where the F1 parent, male or female, had surgery or a series of surgeries, in early life. Reasons for the F1 surgeries included tumor removal, hernia repair, surgeries to correct heart defects, and surgeries to correct birth defects such as clefts and club foot. When an F1 parent had this early life exposure, I saw he or she often had multiple F2 offspring, male and female, with autism. From a biological point of view this multiplex phenomenon might also make sense because the female oogonia are undergoing imprinting through the first year and are not yet mature, and the pre-meiotic male spermatogonial stem cells could also retain errors in their later-differentiated spermatocytes.

(3) F1 paternal pre-puberty/puberty exposure. These are cases where the F1 father had a series of surgeries around the time of puberty and beyond. In this category, two stories jump out. I have two male friends who suffered gunshot wounds in late childhood. Both underwent multiple surgeries in puberty and beyond to correct extensive damage. They each have one F2 son with extremely severe autism. Actually, the word autism does not do their phenotypes justice, as their conditions are catastrophic, involving profound intellectual disability and severe behaviors, including in one case continuous and extreme self-injurious behaviors. In both of these cases the father also has F2 children who are typically developing. From a biological point of view, this simplex phenomenon perhaps make sense because the germ cells were affected at a later stage of differentiation.

Of course these are all anecdotes, and alone prove nothing. But it is worth noting that in these cases, the families had no history of autism, and to my knowledge, the families and children had no risk factors for autism. As a rough control group, I noticed that where the F1 parent’s siblings did not have these sorts of surgical exposures, the F2s were typically developing. More important, though, is the fact that animal models of heritable effects of general anesthesia exposures demonstrate a biological plausibility.

Animal models demonstrate biological plausibility

While there is surprisingly little literature on heritable effects of general anesthesia—considering that many of the agents commonly used in the 1950s through today are known to be genotoxic and epigenetically disruptive—the three mammal studies published on the question all point in the same direction. Most recently, neonatal exposure to the widely used general anesthetic agent sevoflurane (sub-clinical doses, in this case) affected the brains and behavior of the next generation of male rats through epigenetic modification of gene expression, while F1 females were at diminished risk [Ju LS, et al., Role of epigenetic mechanisms in transmitting the effects of neonatal sevoflurane exposure to the next generation of male, but not female, rats. Brit. J Anesth. 2018;121:2,406-416]. The implications of this finding could be significant. To quote an accompanying editorial, ““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.” [Vutskits L, et al. A poisoned chalice: the heritage of parental anaesthesia exposure. Brit. J Anesth. 2018;121;2,337-339.]

The two earlier studies to observe offspring impairment are from the 1980s, well before epigenomic or chromatin mechanisms were under consideration. Learning retardation was seen in F2 mouse offspring of F1 parents exposed to general anesthesia in utero—in other words, mental impairment in the grandpups of the exposed gestating dams [Chalon J, et al. Exposure to halothane and enflurane affects learning function of murine progeny. Anesth. Analg.1981;60:794–7]. This phenomenon was also seen with the sires were exposed in adulthood. The general anesthetic agent enflurane administered to male mice was found to adversely affected learning function of their offspring [Tang CK, et al. Exposure of sires to enflurane affects learning function of murine progeny. Obstet. Anesth. Dig. 1985;5:2,67].

When I attended the Environmental Mutagenesis and Genomics Society meeting in September of this year, several scientists, agreeing about the need for a research program regarding these questions, suggested I contact the NIEHS NTP {National Toxicology Project]. When I attended the Cold Spring Harbor Laboratories meeting on Germ Cells in October of this year, several of the scientists also saw the value of these questions, and recommended that I suggest a research program to the NICHD. However, with regard to the FDA’s National Center for Toxicological Research, my discussions with Robert Heflich of the NCTR were not promising, as his department appeared to be neither interested in germ cells nor epigenomic disruptions.

Accordingly, I write NIH leaders to ask, what will it take to create a research program specifically devoted to these questions of non-genetic inheritance caused by germ cell exposure to agents of general anesthesia in use from the 1950s to today? While I do plan to submit a nomination to the NIEHS NTP on this topic, I feel that that, while possibly a useful avenue, that is alone insufficient to address the great breadth and weight of these questions.

Since the 1980s, the United States has experienced a staggering surge in the prevalence of idiopathic neurodevelopmental disorders we tend to label as autism. We know for certain these serious mental disabilities are highly heritable. We also know with reasonable certainty they are not highly genetic in any classic sense [“Genetic factors do not fully account for the relatively high heritability of neurodevelopmental conditions, suggesting that non-genetic heritable factors contribute to their etiology.” Martinez et al., Thyroid hormone influences brain gene expression programs and behaviors in later generations by altering germ line epigenetic information, Mol. Psych. 2018.] In light of that and the foregoing it makes sense to shift some attention to routes of non-genetic inheritance. While I believe that a great many ancestral germline exposures should concern us (my principal focus remains pregnancy drugs), I cannot help but see the germline effects of general anesthesia issue as an unexplored question of dramatic importance for public health that alone should be addressed without delay.

One response to “Heritable Effects of General Anesthesia

  1. Thanks for sharing your ideas in this missive.You express clearly your opinion and your findings on the adverse heritable effects of early life general anesthesia exposure.This heritable nature of a effect cause by an environmental agent had to be study.I think F-2 carry with F-0, F-1(maternal), F-1(paternal) adverse heritable effects but also in my opinion with all the adverse effects of his own interaction with high frequency ultrasound waves eduring pregnancy examination.Ultrasound could be one of the environmental factor in this equation.Almost all fetuses(some embryos) are exposed to high frequency ultrasound imaging during pregnancy this is a share factor.
    FDA guidance clearly state:
    “Although ultrasound imaging is generally safe when use prudently by appropriately trained health providers ultrasound has the potential to produce biological effect on the body.” FDA 2018-05-02.
    Generally safe? Use prudently? By appropriated trained health providers? Potential biological effect on the body?This is not a medical or scientific language too many uncertainties.

    Ultrasound is to powerful for the fetus brain, autism could be it most severe outcome ID the other result.
    Any condition or disorder that require extensive ultrasound examination during pregnancy can increase the ASD risk factor.

    Like

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