Intergenerational Effects of Sevoflurane in Young Adult Rats.

Abstract

WHAT WE ALREADY KNOW ABOUT THIS TOPIC\nExposure to environmental stressors and endocrine disruptors can induce multigenerational effects resulting in neurobehavioral and other abnormalities in the offspringEarly-life anesthesia exposure in rodents alters neurocognitive function in their offspring, but whether exposure of adult animals affects offspring has not been previously reported WHAT THIS ARTICLE TELLS US THAT IS NEW: Repeated exposures of adult rats to sevoflurane (2.1%, three times, 3 h on every second day) induce neurobehavioral abnormalities in the exposed males and in male but not female progenyThe neurobehavioral abnormalities in male offspring are accompanied by increased methylation and decreased expression of the potassium ion-chloride ion cotransporter Kcc2 gene that regulates neuronal chloride homeostasis, and, thereby, the functional modalities of γ-aminobutyric acid type A receptor-mediated neurotransmissionSevoflurane exposure also induces hypermethylation of the Kcc2 gene in both male and female parental germ cellsThese observations suggest that epigenetic reprograming of parental germ cells is involved in transmitting the adverse effects of sevoflurane exposure of adult rats to their male progeny BACKGROUND:: Sevoflurane administered to neonatal rats induces neurobehavioral abnormalities and epigenetic reprogramming of their germ cells; the latter can pass adverse effects of sevoflurane to future offspring. As germ cells are susceptible to reprogramming by environmental factors across the lifespan, the authors hypothesized that sevoflurane administered to adult rats could induce neurobehavioral abnormalities in future offspring, but not in the exposed rats themselves.\n\n\nMETHODS\nSprague-Dawley rats were anesthetized with 2.1% sevoflurane for 3 h every other day between postnatal days 56 and 60. Twenty-five days later, exposed rats and nonexposed controls were mated to produce offspring.\n\n\nRESULTS\nAdult male but not female offspring of exposed parents of either sex exhibited deficiencies in elevated plus maze (mean ± SD, offspring of both exposed parents vs. offspring of control parents, 35 ± 12 vs. 15 ± 15 s, P < 0.001) and prepulse inhibition of acoustic startle (offspring of both exposed parents vs. offspring of control parents, 46.504 ± 13.448 vs. 25.838 ± 22.866%, P = 0.009), and increased methylation and reduced expression of the potassium ion-chloride ion cotransporter KCC2 gene (Kcc2) in the hypothalamus. Kcc2 was also hypermethylated in sperm and ovary of the exposed rats. Surprisingly, exposed male rats also exhibited long-term abnormalities in functioning of the hypothalamic-pituitary-gonadal and -adrenal axes, reduced expression of hypothalamic and hippocampal Kcc2, and deficiencies in elevated plus maze (sevoflurane vs. control, 40 ± 24 vs. 25 ± 12 s, P = 0.038) and prepulse inhibition of startle (sevoflurane vs. control, 39.905 ± 21.507 vs. 29.193 ± 24.263%, P < 0.050).\n\n\nCONCLUSIONS\nAdult 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.