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Sperm DNA methylation alterations from cannabis extract exposure are evident in offspring

BACKGROUND: Cannabis legalization is expanding and men are the predominant users. We have limited knowledge about how cannabis impacts sperm and whether the effects are heritable. RESULTS: Whole genome bisulfite sequencing (WGBS) data were generated for sperm of rats exposed to: (1) cannabis extract...

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Autores principales: Schrott, Rose, Modliszewski, Jennifer L., Hawkey, Andrew B., Grenier, Carole, Holloway, Zade, Evans, Janequia, Pippen, Erica, Corcoran, David L., Levin, Edward D., Murphy, Susan K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9463823/
https://www.ncbi.nlm.nih.gov/pubmed/36085240
http://dx.doi.org/10.1186/s13072-022-00466-3
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author Schrott, Rose
Modliszewski, Jennifer L.
Hawkey, Andrew B.
Grenier, Carole
Holloway, Zade
Evans, Janequia
Pippen, Erica
Corcoran, David L.
Levin, Edward D.
Murphy, Susan K.
author_facet Schrott, Rose
Modliszewski, Jennifer L.
Hawkey, Andrew B.
Grenier, Carole
Holloway, Zade
Evans, Janequia
Pippen, Erica
Corcoran, David L.
Levin, Edward D.
Murphy, Susan K.
author_sort Schrott, Rose
collection PubMed
description BACKGROUND: Cannabis legalization is expanding and men are the predominant users. We have limited knowledge about how cannabis impacts sperm and whether the effects are heritable. RESULTS: Whole genome bisulfite sequencing (WGBS) data were generated for sperm of rats exposed to: (1) cannabis extract (CE) for 28 days, then 56 days of vehicle only (~ one spermatogenic cycle); (2) vehicle for 56 days, then 28 days of CE; or (3) vehicle only. Males were then mated with drug-naïve females to produce F1 offspring from which heart, brain, and sperm tissues underwent analyses. There were 3321 nominally significant differentially methylated CpGs in F0 sperm identified via WGBS with select methylation changes validated via bisulfite pyrosequencing. Significant methylation changes validated in F0 sperm of the exposed males at the gene 2-Phosphoxylose Phosphatase 1 (Pxylp1) were also detectable in their F1 sperm but not in controls. Changes validated in exposed F0 sperm at Metastasis Suppressor 1-Like Protein (Mtss1l) were also present in F1 hippocampal and nucleus accumbens (NAc) of the exposed group compared to controls. For Mtss1l, a significant sex-specific relationship between DNA methylation and gene expression was demonstrated in the F1 NAc. Phenotypically, rats born to CSE-exposed fathers exhibited significant cardiomegaly relative to those born to control fathers. CONCLUSIONS: This is the first characterization of the effect of cannabis exposure on the entirety of the rat sperm methylome. We identified CE-associated methylation changes across the sperm methylome, some of which persisted despite a “washout” period. Select methylation changes validated via bisulfite pyrosequencing, and genes associated with methylation changes were involved in early developmental processes. Preconception CE exposure is associated with detectable changes in offspring DNA methylation that are functionally related to changes in gene expression and cardiomegaly. These results support that paternal preconception exposure to cannabis can influence offspring outcomes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13072-022-00466-3.
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spelling pubmed-94638232022-09-11 Sperm DNA methylation alterations from cannabis extract exposure are evident in offspring Schrott, Rose Modliszewski, Jennifer L. Hawkey, Andrew B. Grenier, Carole Holloway, Zade Evans, Janequia Pippen, Erica Corcoran, David L. Levin, Edward D. Murphy, Susan K. Epigenetics Chromatin Research BACKGROUND: Cannabis legalization is expanding and men are the predominant users. We have limited knowledge about how cannabis impacts sperm and whether the effects are heritable. RESULTS: Whole genome bisulfite sequencing (WGBS) data were generated for sperm of rats exposed to: (1) cannabis extract (CE) for 28 days, then 56 days of vehicle only (~ one spermatogenic cycle); (2) vehicle for 56 days, then 28 days of CE; or (3) vehicle only. Males were then mated with drug-naïve females to produce F1 offspring from which heart, brain, and sperm tissues underwent analyses. There were 3321 nominally significant differentially methylated CpGs in F0 sperm identified via WGBS with select methylation changes validated via bisulfite pyrosequencing. Significant methylation changes validated in F0 sperm of the exposed males at the gene 2-Phosphoxylose Phosphatase 1 (Pxylp1) were also detectable in their F1 sperm but not in controls. Changes validated in exposed F0 sperm at Metastasis Suppressor 1-Like Protein (Mtss1l) were also present in F1 hippocampal and nucleus accumbens (NAc) of the exposed group compared to controls. For Mtss1l, a significant sex-specific relationship between DNA methylation and gene expression was demonstrated in the F1 NAc. Phenotypically, rats born to CSE-exposed fathers exhibited significant cardiomegaly relative to those born to control fathers. CONCLUSIONS: This is the first characterization of the effect of cannabis exposure on the entirety of the rat sperm methylome. We identified CE-associated methylation changes across the sperm methylome, some of which persisted despite a “washout” period. Select methylation changes validated via bisulfite pyrosequencing, and genes associated with methylation changes were involved in early developmental processes. Preconception CE exposure is associated with detectable changes in offspring DNA methylation that are functionally related to changes in gene expression and cardiomegaly. These results support that paternal preconception exposure to cannabis can influence offspring outcomes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13072-022-00466-3. BioMed Central 2022-09-10 /pmc/articles/PMC9463823/ /pubmed/36085240 http://dx.doi.org/10.1186/s13072-022-00466-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Schrott, Rose
Modliszewski, Jennifer L.
Hawkey, Andrew B.
Grenier, Carole
Holloway, Zade
Evans, Janequia
Pippen, Erica
Corcoran, David L.
Levin, Edward D.
Murphy, Susan K.
Sperm DNA methylation alterations from cannabis extract exposure are evident in offspring
title Sperm DNA methylation alterations from cannabis extract exposure are evident in offspring
title_full Sperm DNA methylation alterations from cannabis extract exposure are evident in offspring
title_fullStr Sperm DNA methylation alterations from cannabis extract exposure are evident in offspring
title_full_unstemmed Sperm DNA methylation alterations from cannabis extract exposure are evident in offspring
title_short Sperm DNA methylation alterations from cannabis extract exposure are evident in offspring
title_sort sperm dna methylation alterations from cannabis extract exposure are evident in offspring
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9463823/
https://www.ncbi.nlm.nih.gov/pubmed/36085240
http://dx.doi.org/10.1186/s13072-022-00466-3
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