Effects of Cohabitation on Neurodevelopmental Outcomes in Rats Discordant for Neonatal Exposure to Sevoflurane.

ABSTRACT

Background: Having a sibling with autism spectrum disorder is a risk factor for autism spectrum disorder. We used a rat model in which the general anesthetic sevoflurane (SEVO) induces autism spectrum disorder-like neurodevelopmental abnormalities to test whether they can be transmitted via cohabitation. Methods: Male rat pups from several litters were mixed and randomized to 3 new litter types SEVO-exposed (SEVO), SEVO-unexposed (control), and equal numbers of SEVO-exposed and SEVO-unexposed (MIXED). After weaning, rats in experiment 1 were housed with littermates in SEVO, control, and MIXED (MIXED-exposed and MIXED-unexposed) pairs. In experiment 2, MIXED-exposed and MIXED-unexposed rats were paired with an unfamiliar naïve cagemate. Corticosterone levels, gene expression, central inflammatory markers (experiment 1), and behavior and corticosterone levels (experiment 2) were assessed in adulthood. Results: In experiment 1, compared with control rats, SEVO rats exhibited abnormalities in the hypothalamic-pituitary-adrenal axis, inflammatory markers, oxytocin, arginine vasopressin, and DNA methylation systems. Almost all these measures in MIXED-exposed and MIXED-unexposed rats were statistically indistinguishable from and similar to those in SEVO or control rats, with most measures in MIXED rats being similar to those in SEVO rats. Experiment 2 showed that pairing with unfamiliar, naïve rats after weaning caused MIXED-unexposed and MIXED-exposed rats' behavior to be no different from that of control and SEVO rats, respectively; however, the 2 groups of MIXED rats also did not differ from each other. Conclusions: These findings suggest that neurodevelopmental abnormalities can be transmitted to otherwise healthy individuals through interactions during cohabitation; however, subsequent pairing with unfamiliar, naïve cohabitants may weaken this interaction effect.

This study was driven by the results of human studies that found poorer neurocognitive performance than expected in both twins, even though only one of the twins had early-life exposure to general anesthesia. We evaluated whether rats housed together in the same cage but discordant for neonatal exposure to the general anesthetic sevoflurane share similar neurodevelopmental abnormalities in adulthood. The gene expression, neuroendocrine, neuroinflammatory marker, and behavioral measurements revealed that cohoused neonatally sevoflurane-exposed and sevoflurane-unexposed cagemates exhibited similar deficiencies. These findings suggest that in studies of anesthesia-induced neurodevelopmental abnormalities in particular, and neurocognitive development in general, interactions between cohabitants should be considered as a factor that may influence outcomes.