Effects of Moderate Prenatal Alcohol Exposure during Early Gestation in Rats on Inflammation across the Maternal-Fetal-Immune Interface and Later-Life Immune Function in the Offspring

Abstract

During early brain development, microglial activation can negatively impact long-term neuroimmune and cognitive outcomes. It is well-known that significant alcohol exposure during early gestation results in a number of cognitive deficits associated with fetal alcohol spectrum disorders (FASD). Additionally, microglia are activated following high levels of alcohol exposure in rodent models of FASD. We sought to examine whether moderate prenatal alcohol exposure (70 mg/dL blood alcohol concentration) activates microglia in the fetal rat brain, and whether moderate fetal alcohol exposure has long-term negative consequences for immune function and cognitive function in the rat. We also measured inflammation within the placenta and maternal serum following moderate alcohol exposure to determine whether either could be a source of cytokine production in the fetus. One week of moderate prenatal alcohol exposure produced a sex-specific increase in cytokines and chemokines within the fetal brain. Cytokines were also increased within the placenta, regardless of the sex of the fetus, and independent of the low levels of circulating cytokines within the maternal serum. Adult offspring exposed to alcohol prenatally had exaggerated cytokine production in the brain and periphery in response to lipopolysaccharide (25 μg/kg), as well as significant memory deficits precipitated by this low-level of inflammation. Thus the immune system, including microglia, may be a key link to understanding the etiology of fetal alcohol spectrum disorders and other unexplored cognitive or health risks associated with even low levels of fetal alcohol exposure.

Sex Differences in Early Postnatal Microglial Colonization of the Developing Rat Hippocampus Following a Single-Day Alcohol Exposure

“…Expression of the chemoattractant molecule CCL4 was consistently upregulated in AE females at both time points: on PD5, female AE pups had higher CCL4 expression compared to AE males, as well as had higher levels compared to both control females and AE males on PD8. Sex by treatment interactions in CCL family expression were also reported following prenatal alcohol exposure (Terasaki and Schwarz 2016), with female embryonic brain tissue showing an exaggerated CCL2, CCL5, and CCL9 response following alcohol exposure compared to controls and male alcohol-treated embryos. These results, combined with the increase in females reported in the current study, support that the CCL family is specifically activated in females following developmental alcohol exposure.…”

“…If sex-specific hormones can affect microglial function in response to physical insult, they may also be involved in driving sex-specific responses to developmental alcohol exposure. Prenatal AE can prime the immune system to an exaggerated response when given a “second-hit” immune challenge in adulthood (Terasaki and Schwarz 2016, 2017). Both LPS and acute alcohol exposure elicited an exaggerated production of cytokines and impaired performance on cognitive tasks.…”

Ifenprodil infusion in agranular insular cortex alters social behavior and vocalizations in rats exposed to moderate levels of ethanol during prenatal development

“…Nonetheless, unintended partial damage to AIC caused by cannula implantation may have contributed to altered social behaviors that masked some of the effects of gestational alcohol exposure. In addition, PAE rats may have altered recovery periods following surgery compared to SAC controls, which has the potential to cause functional deficits in implanted brain areas [79]. Future experiments examining social behaviors in cannulated rats will need to examine inflammatory cytokine expression in implanted brain areas to determine if PAE rats have an exaggerated immune response that could confound interpretation of experimental results.…”

Neuroimmune Interface in the Comorbidity between Alcohol Use Disorder and Major Depression

“…In adult rats prenatally exposed to ethanol, the corticosterone reservoir was depleted and the cytokine production upon immune challenge was exaggerated (46). The ensuing low-grade inflammation correlated with memory deficits, which implicated a microglial role in fetal alcohol spectrum disorders (47). Also, substantial neuroinflammation caused by traumatic brain injury induced escalation of drinking in ethanol-habituated animals (48).…”