title: Females uniquely vulnerable to alcohol-induced neurotoxicity show altered glucocorticoid signaling.
abstract: Women are more sensitive to the harmful effects of alcohol (EtOH) abuse than men, yet the underlying mechanisms remain poorly understood. Previous gene expression analysis of the medial prefrontal cortex (mPFC) following a chronic intoxication paradigm using continuous 72 h vapor inhalation found that females, but not males, exhibit an inflammatory response at peak withdrawal that is associated with cell damage. Given that glucocorticoids can function as anti-inflammatories, are known to increase with EtOH exposure, and influence neurotoxicity, we hypothesized that males and females may exhibit an altered corticosterone (CORT) response following chronic intoxication. Analysis of serum CORT levels revealed the expected increase during withdrawal with no difference between males and females, while control males but not females exhibited higher CORT concentrations than naive animals. Glucocorticoid signaling characterized using focused qPCR arrays identified a sexually dimorphic response in the mPFC during withdrawal, particularly among astrocyte-enriched genes. These genes include aquaporin-1 (Aqp1), sphingosine kinase 1 (Sphk1) and connective tissue growth factor (Ctgf); genes associated with inflammatory signaling, and tissue damage and repair. Bioinformatic analysis also revealed activation of inflammatory signaling and cell death pathways in females. Confirmation studies showed that female mice exhibited significant neuronal degeneration within the anterior cingulate cortex (ACC). By contrast, EtOH exposure lead to a significant reduction in cell death in males. Thus, distinct glucocorticoid signaling pathways are associated with sexually dimorphic neurotoxicity, suggesting one mechanism by which EtOH-exposed females are particularly vulnerable to the damaging effects of alcohol in the CNS.
authors.affiliation: VA Portland Health Care System, Portland, OR 97239, USA; Department of Psychiatry, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: wilhelmc@ohsu.edu.
authors.forename: Clare J
authors.initials: CJ
authors.lastname: Wilhelm
authors.affiliation: VA Portland Health Care System, Portland, OR 97239, USA; Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Joel G
authors.initials: JG
authors.lastname: Hashimoto
authors.affiliation: VA Portland Health Care System, Portland, OR 97239, USA.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Roberts
authors.affiliation: VA Portland Health Care System, Portland, OR 97239, USA.
authors.forename: Shelley H
authors.initials: SH
authors.lastname: Bloom
authors.affiliation: VA Portland Health Care System, Portland, OR 97239, USA.
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Beard
authors.affiliation: VA Portland Health Care System, Portland, OR 97239, USA; Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Wiren
mesh_terms: D000437:Alcoholism / Q000097:blood / Q000235:genetics* / Q000473:pathology; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D015870:Gene Expression; D005938:Glucocorticoids / Q000235:genetics*; D006179:Gyrus Cinguli / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000473:pathology; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013375:Substance Withdrawal Syndrome / Q000097:blood / Q000235:genetics* / Q000473:pathology
chemical_list: D005938:Glucocorticoids; D000431:Ethanol; D003345:Corticosterone
keywords: Alcohol; Astrocyte; Glucocorticoid signaling; Neurodegeneration; Neurotoxicity