Behavioral Changes Across Generations

By Adriana Barbat

Dr. Anatoly Martynyuk
Anatoly Martynyuk, PhD

Clinical studies report learning disabilities, long-term memory impairment, and attention-deficit/hyperactivity disorders in those who had anesthesia early in life. The Martynyuk Lab in the UF Department of Anesthesiology has now demonstrated that exposure to anesthetics in early life may not affect just exposed animals, but even their offspring.

In a study, Anatoly Martynyuk, PhD, Professor of Anesthesiology and Neuroscience, and his team found that sevoflurane, the most frequently used anesthetic in pediatric patients, alters gene expression through epigenetic mechanisms, leading to intergenerational heritability of neurobehavioral abnormalities.

The study, titled “Role of epigenetic mechanisms in transmitting the effects of neonatal sevoflurane exposure to the next generation of male, but not female, rats” and published in the British Journal of Anaesthesia, found that abnormal DNA expression and profound behavioral deficits were passed on to offspring.

Experiments involved a single exposure of newborn rats to anesthesia. Interestingly, no matter whether sires only, dams only, or both parents were exposed to neonatal sevoflurane, the male offspring were affected, whereas the female offspring appeared to be relatively safe from the effects of anesthesia exposure.

The researchers found that these deficits in exposed parents and their male offspring were accompanied by reduced expression of the K+-2Cl- (Kcc2) Cl- exporter, which is essential for proper brain function. Findings suggest that impaired Kcc2 expression may be linked to increased DNA methylation of the Kcc2 gene in exposed parents’ germ cells and in the offspring’s brain. In other words, it appears parents exposed to anesthesia may pass on epigenetic marks that repress Kcc2 expression in their offspring. Impaired Kcc2 is linked to developmental neuropsychiatric disorders, including malepredominant conditions such as autism spectrum disorders and schizophrenia.

The team is currently conducting research to further understand mechanisms mediating intergenerational effects of early-in-life general anesthesia. With the rise of developmental psychiatric disorders, understanding how parental exposure to the most widely used pediatric anesthetic impacts offspring is of public health importance, Dr. Martynyuk said. The results of this work may help in the study of other psychiatric disorders involving Kcc2 dysregulation, he said.

This is an initial study in laboratory animals that deals with complex biological questions regarding how the effects of environmental factors — in this case, general anesthetic — in parents can be passed to their offspring. Additional studies are needed to understand if these findings are applicable to humans, Dr. Martynyuk said. For background information about sevoflurane’s effects on rats, see the article, “Subsequent maternal separation exacerbates neurobehavioral abnormalities in rats neonatally exposed to sevoflurane anesthesia.dna