title: Initial genetic dissection of serum neuroactive steroids following chronic intermittent ethanol across BXD mouse strains.
abstract: Neuroactive steroids modulate alcohol's impact on brain function and behavior. Ethanol exposure alters neuroactive steroid levels in rats, humans, and some mouse strains. We conducted an exploratory analysis of the neuroactive steroids (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP), (3α,5α)-3,21-dihydroxypregnan-20-one (3α,5α-THDOC), and pregnenolone across 126-158 individuals and 19 fully inbred strains belonging to the BXD family, which were subjected to air exposure, or chronic intermittent ethanol (CIE) exposure. Neuroactive steroids were measured by gas chromatography-mass spectrometry in serum following five cycles of CIE or air exposure (CTL). Pregnenolone levels in CTLs range from 272 to 578 pg/mL (strain variation of 2.1 fold with p = 0.049 for strain main effect), with heritability of 0.20 ± 0.006 (SEM), whereas in CIE cases values range from 304 to 919 pg/mL (3.0-fold variation, p = 0.007), with heritability of 0.23 ± 0.005. 3α,5α-THP levels in CTLs range from 375 to 1055 pg/mL (2.8-fold variation, p = 0.0007), with heritability of 0.28 ± 0.01; in CIE cases they range from 460 to 1022 pg/mL (2.2-fold variation, p = 0.004), with heritability of 0.23 ± 0.005. 3α,5α-THDOC levels in CTLs range from 94 to 448 pg/mL (4.8-fold variation, p = 0.002), with heritability of 0.30 ± 0.01, whereas levels in CIE cases do not differ significantly. However, global averages across all BXD strains do not differ between CTL and CIE for any of the steroids. 3α,5α-THDOC levels were lower in females than males in both groups (CTL -53%, CIE -55%, p < 0.001). Suggestive quantitative trait loci are identified for pregnenolone and 3α,5α-THP levels. Genetic variation in 3α,5α-THP was not correlated with two-bottle choice ethanol consumption in CTL or CIE-exposed animals. However, individual variation in 3α,5α-THP correlated negatively with ethanol consumption in both groups. Moreover, strain variation in neuroactive steroid levels correlated with numerous behavioral phenotypes of anxiety sensitivity accessed in GeneNetwork, consistent with evidence that neuroactive steroids modulate anxiety-like behavior.
authors.affiliation: Neuroscience Institute, National Research Council of Italy (CNR), Cagliari, Italy. Electronic address: patrizia.porcu@in.cnr.it.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Porcu
authors.affiliation: Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Todd K
authors.initials: TK
authors.lastname: O'Buckley
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA; Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Marcelo F
authors.initials: MF
authors.lastname: Lopez
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA; Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC, USA; Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA; Department of Veterans Affairs Ralph H. Johnson Medical Center, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Becker
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA; Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA; VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Miles
authors.affiliation: Department of Genetics, Genomics and Informatics, The University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
authors.affiliation: Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Electronic address: morrow@med.unc.edu.
authors.forename: A Leslie
authors.initials: AL
authors.lastname: Morrow
mesh_terms: D006907:17-alpha-Hydroxypregnenolone / Q000097:blood; D000818:Animals; D015415:Biomarkers / Q000097:blood; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000502:physiology; D014644:Genetic Variation / Q000187:drug effects / Q000502:physiology; D019570:Inhalation Exposure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018377:Neurotransmitter Agents / Q000097:blood / Q000235:genetics; D011284:Pregnenolone / Q000097:blood* / Q000235:genetics*; D013045:Species Specificity; D013256:Steroids / Q000097:blood
chemical_list: D015415:Biomarkers; D018377:Neurotransmitter Agents; D013256:Steroids; D006907:17-alpha-Hydroxypregnenolone; D000431:Ethanol; D011284:Pregnenolone
keywords: 3α,5α-THP (allopregnanolone); BXD recombinant inbred strains; Ethanol dependence; Neuroactive steroids