{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T14:52:00Z","timestamp":1788879120554,"version":"build-2803163510"},"reference-count":45,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,15]],"date-time":"2023-01-15T00:00:00Z","timestamp":1673740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UTHSC","award":["R01AA029270"],"award-info":[{"award-number":["R01AA029270"]}]},{"name":"UTHSC","award":["R01AA12307"],"award-info":[{"award-number":["R01AA12307"]}]},{"name":"UTHSC","award":["R01DK55532"],"award-info":[{"award-number":["R01DK55532"]}]},{"name":"NIH","award":["R01AA029270"],"award-info":[{"award-number":["R01AA029270"]}]},{"name":"NIH","award":["R01AA12307"],"award-info":[{"award-number":["R01AA12307"]}]},{"name":"NIH","award":["R01DK55532"],"award-info":[{"award-number":["R01DK55532"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Fetal alcohol spectrum disorders (FASDs) are associated with systemic inflammation and neurodevelopmental abnormalities. Several candidate genes were found to be associated with fetal alcohol exposure (FAE)-associated behaviors, but a sex-specific complete transcriptomic analysis was not performed at the adult stage. Recent studies have shown that they are regulated at the developmental stage. However, the sex-specific role of RNA in FAE offspring brain development and function has not been studied yet. Here, we carried out the first systematic RNA profiling by utilizing a high-throughput transcriptomic (RNA-seq) approach in response to FAE in the brain cortex of male and female offspring at adulthood (P60). Our RNA-seq data analysis suggests that the changes in RNA expression in response to FAE are marked sex-specific. We show that the genes Muc3a, Pttg1, Rec8, Clcnka, Capn11, and pnp2 exhibit significantly higher expression in the male offspring than in the female offspring at P60. FAE female mouse brain sequencing data also show an increased expression of Eno1, Tpm3, and Pcdhb2 compared to male offspring. We performed a pathway analysis using a commercial software package (Ingenuity Pathway Analysis). We found that the sex-specific top regulator genes (Rictor, Gaba, Fmri, Mlxipl) are highly associated with eIF2 (translation initiation), synaptogenesis (the formation of synapses between neurons in the nervous system), sirtuin (metabolic regulation), and estrogen receptor (involved in obesity, aging, and cancer) signaling. Taken together, our transcriptomic results demonstrate that FAE differentially alters RNA expression in the adult brain in a sex-specific manner.<\/jats:p>","DOI":"10.3390\/cells12020328","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T03:40:34Z","timestamp":1673840434000},"page":"328","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Sex-Specific Whole-Transcriptome Analysis in the Cerebral Cortex of FAE Offspring"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5718-9666","authenticated-orcid":false,"given":"Nitish K.","family":"Mishra","sequence":"first","affiliation":[{"name":"Department of Structural Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pulastya","family":"Shrinath","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radhakrishna","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2515-9766","authenticated-orcid":false,"given":"Pradeep K.","family":"Shukla","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,15]]},"reference":[{"key":"ref_1","unstructured":"Vorgias, D., and Bernstein, B. (2022). Fetal Alcohol Syndrome, StatPearls."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"695855","DOI":"10.3389\/fnhum.2021.695855","article-title":"Neurodevelopmental Trajectories Following Prenatal Alcohol Exposure","volume":"15","author":"Moore","year":"2021","journal-title":"Front. Hum. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1111\/acer.12183","article-title":"Low-dose thyroxine attenuates autism-associated adverse effects of fetal alcohol in male offspring\u2019s social behavior and hippocampal gene expression","volume":"37","author":"Ullmann","year":"2013","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.alcohol.2018.04.004","article-title":"Deletion of TLR-4 attenuates fetal alcohol exposure-induced gene expression and social interaction deficits","volume":"73","author":"Shukla","year":"2018","journal-title":"Alcohol"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e290","DOI":"10.1016\/S2214-109X(17)30021-9","article-title":"Estimation of national, regional, and global prevalence of alcohol use during pregnancy and fetal alcohol syndrome: A systematic review and meta-analysis","volume":"5","author":"Popova","year":"2017","journal-title":"Lancet Glob. Health"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1111\/dar.13425","article-title":"Why do women consume alcohol during pregnancy or while breastfeeding?","volume":"41","author":"Popova","year":"2022","journal-title":"Drug Alcohol Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e424","DOI":"10.1016\/S2468-2667(20)30159-6","article-title":"Fetal alcohol spectrum disorders: Preventing collateral damage from COVID-19","volume":"5","author":"Sher","year":"2020","journal-title":"Lancet Public Health"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/brainsci3010001","article-title":"Long-term consequences of developmental alcohol exposure on brain structure and function: Therapeutic benefits of physical activity","volume":"3","author":"Klintsova","year":"2012","journal-title":"Brain Sci."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Luan, Y., Cos\u00edn-Tom\u00e1s, M., Leclerc, D., Malysheva, O.V., Caudill, M.A., and Rozen, R. (2022). Moderate Folic Acid Supplementation in Pregnant Mice Results in Altered Sex-Specific Gene Expression in Brain of Young Mice and Embryos. Nutrients, 14.","DOI":"10.3390\/nu14051051"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1111\/acer.14928","article-title":"Brain volume and magnetic susceptibility differences in children and adolescents with prenatal alcohol exposure","volume":"46","author":"Nakhid","year":"2022","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2318","DOI":"10.1002\/hbm.22772","article-title":"Volume changes and brain-behavior relationships in white matter and subcortical gray matter in children with prenatal alcohol exposure","volume":"36","author":"Gautam","year":"2015","journal-title":"Hum. Brain Mapp."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.4161\/15548627.2014.981916","article-title":"Autophagy and ethanol neurotoxicity","volume":"10","author":"Luo","year":"2014","journal-title":"Autophagy"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"497","DOI":"10.4103\/1673-5374.314294","article-title":"Oligodendrocyte pathology in fetal alcohol spectrum disorders","volume":"17","author":"Darbinian","year":"2022","journal-title":"Neural Regen. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.phrs.2018.11.030","article-title":"Role of MCP-1 and CCR2 in alcohol neurotoxicity","volume":"139","author":"Zhang","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Al-Shaer, A.E., Flentke, G.R., Berres, M.E., Garic, A., and Smith, S.M. (2019). Exon level machine learning analyses elucidate novel candidate miRNA targets in an avian model of fetal alcohol spectrum disorder. PLoS Comput. Biol., 15.","DOI":"10.1371\/journal.pcbi.1006937"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wall\u00e9n, E., Auvinen, P., and Kaminen-Ahola, N. (2021). The Effects of Early Prenatal Alcohol Exposure on Epigenome and Embryonic Development. Genes, 12.","DOI":"10.3390\/genes12071095"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s11689-020-09316-3","article-title":"Hippocampal transcriptome analysis following maternal separation implicates altered RNA processing in a mouse model of fetal alcohol spectrum disorder","volume":"12","author":"Alberry","year":"2020","journal-title":"J. Neurodev. Disord."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1111\/acer.13090","article-title":"Modeling Fetal Alcohol Spectrum Disorder: Validating an Ex Vivo Primary Hippocampal Cell Culture System","volume":"40","author":"Ferreira","year":"2016","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Morozova, T.V., Shankar, V., MacPherson, R.A., Mackay, T.F.C., and Anholt, R.R.H. (2022). Modulation of the Drosophila transcriptome by developmental exposure to alcohol. BMC Genom., 23.","DOI":"10.1186\/s12864-022-08559-9"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1093\/bioinformatics\/btw354","article-title":"MultiQC: Summarize analysis results for multiple tools and samples in a single report","volume":"32","author":"Ewels","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Li, B., and Dewey, C.N. (2011). RSEM: Accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinform., 12.","DOI":"10.1186\/1471-2105-12-323"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"R29","DOI":"10.1186\/gb-2014-15-2-r29","article-title":"Voom: Precision weights unlock linear model analysis tools for RNA-seq read counts","volume":"15","author":"Law","year":"2014","journal-title":"Genome Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","first-page":"100141","article-title":"clusterProfiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1111\/acer.14846","article-title":"Prenatal alcohol exposure contributes to negative pregnancy outcomes by altering fetal vascular dynamics and the placental transcriptome","volume":"46","author":"Pinson","year":"2022","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"285","DOI":"10.3389\/fgene.2014.00285","article-title":"Epigenetic regulation of the neural transcriptome and alcohol interference during development","volume":"5","author":"Resendiz","year":"2014","journal-title":"Front. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1111\/j.1530-0277.2010.01373.x","article-title":"Candidate placental biomarkers for intrauterine alcohol exposure","volume":"35","author":"Shukla","year":"2011","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2523","DOI":"10.7150\/ijbs.59430","article-title":"MUC3A promotes non-small cell lung cancer progression via activating the NFkappaB pathway and attenuates radiosensitivity","volume":"17","author":"Sun","year":"2021","journal-title":"Int. J. Biol. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Breugelmans, T., Arras, W., Boen, L.E., Borms, E., Kamperdijk, L., De Man, J., van de Vijver, E., van Gils, A., de Winter, B.Y., and Moes, N. (2022). Aberrant Mucin Expression Profiles Associate With Pediatric Inflammatory Bowel Disease Presentation and Activity. Inflamm. Bowel Dis., print.","DOI":"10.1093\/ibd\/izac217"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"566734","DOI":"10.3389\/fgene.2020.566734","article-title":"Pituitary Tumor Transforming Gene 1 Orchestrates Gene Regulatory Variation in Mouse Ventral Midbrain During Aging","volume":"11","author":"Gui","year":"2020","journal-title":"Front. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1101\/gad.348052.120","article-title":"Meikin synergizes with shugoshin to protect cohesin Rec8 during meiosis I","volume":"35","author":"Ma","year":"2021","journal-title":"Genes Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1136\/jmg.2007.052944","article-title":"Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness","volume":"45","author":"Nozu","year":"2008","journal-title":"J. Med. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"bvac079","DOI":"10.1210\/jendso\/bvac079","article-title":"The Bartter-Gitelman Spectrum: 50-Year Follow-up With Revision of Diagnosis After Whole-Genome Sequencing","volume":"6","author":"Stevenson","year":"2022","journal-title":"J. Endocr. Soc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1006\/geno.1999.5859","article-title":"CAPN11: A calpain with high mRNA levels in testis and located on chromosome 6","volume":"59","author":"Dear","year":"1999","journal-title":"Genomics"},{"key":"ref_37","first-page":"5053","article-title":"The gene regulatory network in different brain regions of neuropathic pain mouse models","volume":"24","author":"Li","year":"2020","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1002\/ajmg.a.62759","article-title":"A genome-wide association study of obstructive heart defects among participants in the National Birth Defects Prevention Study","volume":"188","author":"Rashkin","year":"2022","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/ng0696-183","article-title":"Bartter\u2019s syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2","volume":"13","author":"Simon","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s12519-012-0333-9","article-title":"Understanding Bartter syndrome and Gitelman syndrome","volume":"8","author":"Fremont","year":"2012","journal-title":"World J. Pediatr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1080\/15257770.2011.630852","article-title":"Purine nucleoside phosphorylase deficiency: A mutation update","volume":"30","author":"Walker","year":"2011","journal-title":"Nucleosides Nucleotides Nucleic Acids"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/1476-4598-13-65","article-title":"Alpha-enolase as a potential cancer prognostic marker promotes cell growth, migration, and invasion in glioma","volume":"13","author":"Song","year":"2014","journal-title":"Mol. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"284","DOI":"10.4161\/bioa.1.6.19336","article-title":"TPM3 and TPM4 gene products segregate to the postsynaptic region of central nervous system synapses","volume":"1","author":"Guven","year":"2011","journal-title":"Bioarchitecture"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"753537","DOI":"10.3389\/fnmol.2021.753537","article-title":"Altering Cell-Cell Interaction in Prenatal Alcohol Exposure Models: Insight on Cell-Adhesion Molecules During Brain Development","volume":"14","author":"Licheri","year":"2021","journal-title":"Front. Mol. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/S0092-8674(00)80789-8","article-title":"A striking organization of a large family of human neural cadherin-like cell adhesion genes","volume":"97","author":"Wu","year":"1999","journal-title":"Cell"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/2\/328\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:06:31Z","timestamp":1760119591000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/2\/328"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,15]]},"references-count":45,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["cells12020328"],"URL":"https:\/\/doi.org\/10.3390\/cells12020328","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,15]]}}}