Prenatal alcohol-induced sex differences in immune, metabolic and neurobehavioral outcomes in adult rats

Bake, Shameena; Pinson, Marisa R.; Pandey, Sivani; Chambers, Joanna P.; Mota, Roxanna; Fairchild, Ashlyn E.; Miranda, Rajesh C.; Sohrabji, Farida

doi:10.1016/j.bbi.2021.08.207

Cited by 24 publications

(35 citation statements)

References 102 publications

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“…Previous work has uncovered sex-specific effect of PAE in brain and other tissues (Weinberg et al, 2008;Terasaki et al, 2016;Loke et al, 2018;Bake et al, 2021). On a similar note, our previous study revealed that circRNAs are altered in a sex-specific manner in E18 prenatal brain following PAE (Paudel et al, 2020).…”

Section: Discussionsupporting

confidence: 72%

Prenatal alcohol exposure results in brain region- and sex-specific changes in circHomer1 expression in adult mouse brain

et al. 2023

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Circular RNAs (circRNAs) are a novel category of covalently-closed non-coding RNAs mainly derived from the back-splicing of exons or introns of protein-coding genes. In addition to their inherent high overall stability, circRNAs, have been shown to have strong functional effects on gene expression via a multitude of transcriptional and post-transcriptional mechanisms. Furthermore, circRNAs, appear to be particularly enriched in the brain and able to influence both prenatal development and postnatal brain function. However, little is known about the potential involvement of circRNAs in the long term influence of prenatal alcohol exposure (PAE) in the brain and their relevance for Fetal Alcohol Spectrum Disorders (FASD). Using circRNA-specific quantification, we have found that circHomer1, an activity-dependent circRNA derived from Homer protein homolog 1 (Homer1) and enriched in postnatal brain, is significantly down-regulated in the male frontal cortex and hippocampus of mice subjected to modest PAE. Our data further suggest that the expression of H19, an imprinted embryonic brain-enriched long non-coding RNA (lncRNA), is significantly up-regulated in the frontal cortex of male PAE mice. Furthermore, we show opposing changes in the developmental- and brain region specific- expression of circHomer1 and H19. Lastly, we show that knockdown of H19 results in robust increases in circHomer1 but not linear HOMER1 mRNA expression in human glioblastoma cell lines. Taken together, our work uncovers notable sex- and brain region-specific alterations in circRNA and lncRNA expression following PAE and introduces novel mechanistic insights with potential relevance to FASD.

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Section: Discussionsupporting

confidence: 72%

Prenatal alcohol exposure results in brain region- and sex-specific changes in circHomer1 expression in adult mouse brain

et al. 2023

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“…Similarly, limited preclinical studies have examined the effects of developmental ethanol exposure on plasma cytokines. A recent study reported no effects of prenatal alcohol exposure on cytokine levels in adult plasma, but did find altered cytokine profiles in other peripheral tissues (i.e., liver, spleen) [ 70 ]. Similarly, other preclinical studies have found limited effects of prenatal ethanol exposure on LPS-induced cytokine levels in adults [ 71 , 72 ].…”

Section: Discussionmentioning

confidence: 99%

Choline Supplementation Modifies the Effects of Developmental Alcohol Exposure on Immune Responses in Adult Rats

et al. 2022

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Prenatal alcohol exposure can disrupt the development of numerous systems, including the immune system. Indeed, alterations in cytokine levels may contribute to the neuropathological, behavioral, and cognitive problems, and other adverse outcomes observed in individuals with fetal alcohol spectrum disorders. Importantly, supplementation with the essential nutrient choline can improve performance in hippocampal-dependent behaviors; thus, the present study examined the effects of choline on plasma and hippocampal cytokines in adult rats exposed to ethanol in early development. From postnatal day (PD) 4–9 (third trimester equivalent), pups received ethanol (5.25 g/kg/day) or Sham intubations. Subjects were treated with choline chloride (100 mg/kg/day) or saline from PD10–30. On PD60, plasma and hippocampal tissue was collected before and after an immune challenge (lipopolysaccharide (LPS); 50 ug/kg). Prior to the immune challenge, ethanol-exposed subjects showed an overall increase in hippocampal pro-inflammatory cytokines, an effect mitigated by choline supplementation. In contrast, in the plasma, choline reduced LPS-related increases in pro-inflammatory markers, particularly in ethanol-exposed subjects. Thus, early choline supplementation may modify both brain and peripheral inflammation. These results suggest that early choline can mitigate some long-term effects of ethanol exposure on hippocampal inflammation, which may contribute to improved hippocampal function, and could also influence peripheral immune responses that may impact overall health.

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“…Prenatal ethanol exposure (2 g/kg ethanol, twice daily, E10-E16) dramatically exacerbates the adult response to modest innate immune challenges (25 μg/kg lipopolysaccharide [LPS]), evidenced by exaggerated hippocampal gene expression of IL-1β and IL-6 in male rats but not female rats, relative to controls (Terasaki and Schwarz, 2016). Similar long-term alterations in the peripheral immune system in adulthood (approximately 4 months old rats) have been evidenced after gestational exposure to ethanol vapor across days 8-19, with adult males but not adult females exhibiting increased levels of circulating monocytes (Bake et al, 2021). Conversely, adult males exhibited decreased basal levels of peripherally circulating cytokines whereas adult females exhibited elevated peripheral levels of circulating cytokines.…”

Section: Perinatal Ethanol Acutely Disrupts the Proinflammatory-anti-...mentioning

confidence: 94%

Cholinergic and Neuroimmune Signaling Interact to Impact Adult Hippocampal Neurogenesis and Alcohol Pathology Across Development

2022

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Alcohol (ethanol) use and misuse is a costly societal issue that can affect an individual across the lifespan. Alcohol use and misuse typically initiates during adolescence and generally continues into adulthood. Not only is alcohol the most widely abused drug by adolescents, but it is also one of the most widely abused drugs in the world. In fact, high rates of maternal drinking make developmental ethanol exposure the most preventable cause of neurological deficits in the Western world. Preclinical studies have determined that one of the most consistent effects of ethanol is its disruption of hippocampal neurogenesis. However, the severity, persistence, and reversibility of ethanol’s effects on hippocampal neurogenesis are dependent on developmental stage of exposure and age at assessment. Complicating the neurodevelopmental effects of ethanol is the concurrent development and maturation of neuromodulatory systems which regulate neurogenesis, particularly the cholinergic system. Cholinergic signaling in the hippocampus directly regulates hippocampal neurogenesis through muscarinic and nicotinic receptor actions and indirectly regulates neurogenesis by providing anti-inflammatory regulatory control over the hippocampal environmental milieu. Therefore, this review aims to evaluate how shifting maturational patterns of the cholinergic system and its regulation of neuroimmune signaling impact ethanol’s effects on adult neurogenesis. For example, perinatal ethanol exposure decreases basal forebrain cholinergic neuron populations, resulting in long-term developmental disruptions to the hippocampus that persist into adulthood. Exaggerated neuroimmune responses and disruptions in adult hippocampal neurogenesis are evident after environmental, developmental, and pharmacological challenges, suggesting that perinatal ethanol exposure induces neurogenic deficits in adulthood that can be unmasked under conditions that strain neural and immune function. Similarly, adolescent ethanol exposure persistently decreases basal forebrain cholinergic neuron populations, increases hippocampal neuroimmune gene expression, and decreases hippocampal neurogenesis in adulthood. The effects of neither perinatal nor adolescent ethanol are mitigated by abstinence whereas adult ethanol exposure-induced reductions in hippocampal neurogenesis are restored following abstinence, suggesting that ethanol-induced alterations in neurogenesis and reversibility are dependent upon the developmental period. Thus, the focus of this review is an examination of how ethanol exposure across critical developmental periods disrupts maturation of cholinergic and neuroinflammatory systems to differentially affect hippocampal neurogenesis in adulthood.

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Prenatal alcohol-induced sex differences in immune, metabolic and neurobehavioral outcomes in adult rats

Cited by 24 publications

References 102 publications

Prenatal alcohol exposure results in brain region- and sex-specific changes in circHomer1 expression in adult mouse brain

Prenatal alcohol exposure results in brain region- and sex-specific changes in circHomer1 expression in adult mouse brain

Choline Supplementation Modifies the Effects of Developmental Alcohol Exposure on Immune Responses in Adult Rats

Cholinergic and Neuroimmune Signaling Interact to Impact Adult Hippocampal Neurogenesis and Alcohol Pathology Across Development

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