Epigenetic alterations in cytochrome P450 oxidoreductase (Por) in sperm of rats exposed to tetrahydrocannabinol (THC)

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2020-12-01

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Abstract

As marijuana legalization is increasing, research regarding possible long-term risks for users and their offspring is needed. Little data exists on effects of paternal tetrahydrocannabinol (THC) exposure prior to reproduction. This study determined if chronic THC exposure alters sperm DNA methylation (DNAm) and if such effects are intergenerationally transmitted. Adult male rats underwent oral gavage with THC or vehicle control. Differentially methylated (DM) loci in motile sperm were identified using reduced representation bisulfite sequencing (RRBS). Another cohort was injected with vehicle or THC, and sperm DNAm was analyzed. Finally, THC-exposed and control adult male rats were mated with THC-naïve females. DNAm levels of target genes in brain tissues of the offspring were determined by pyrosequencing. RRBS identified 2,940 DM CpGs mapping to 627 genes. Significant hypermethylation was confirmed (p < 0.05) following oral THC administration for cytochrome P450 oxidoreductase (Por), involved in toxin processing and disorders of sexual development. Por hypermethylation was not observed after THC injection or in the subsequent generation. These results support that THC alters DNAm in sperm and that route of exposure can have differential effects. Although we did not observe evidence of intergenerational transmission of the DNAm change, larger studies are required to definitively exclude this possibility.

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10.1038/s41598-020-69204-7

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Acharya, KS, R Schrott, C Grenier, Z Huang, Z Holloway, A Hawkey, ED Levin, SK Murphy, et al. (2020). Epigenetic alterations in cytochrome P450 oxidoreductase (Por) in sperm of rats exposed to tetrahydrocannabinol (THC). Scientific Reports, 10(1). pp. 92A–92A. 10.1038/s41598-020-69204-7 Retrieved from https://hdl.handle.net/10161/29497.

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Scholars@Duke

Acharya

Kelly S Acharya

Assistant Professor of Obstetrics and Gynecology
Huang

Zhiqing Huang

Assistant Professor in Obstetrics and Gynecology

Dr. Huang is an Assistant Professor in the Department of Obstetrics and Gynecology, Division of Reproductive Sciences, at Duke University Medical Center. She obtained her MD at North China Coal Medical University in China and her PhD at the University of Heidelberg in Germany under the mentorship of Dr. Ralph Witzgall. She did her postdoctoral training with Dr. Jiemin Wong at Baylor College of Medicine, studying how histone methylation and chromatin modifications regulate androgen receptor transcription. 

Dr. Huang’s research includes the following:

•The factors in the tumor microenvironment contribute to ovarian cancer progress;
•New drug development for recurrent ovarian cancer treatment;
•The early DNA methylation profiles contribute to cancer development in late life;
•The special changes in the tumor microenvironment;
•Epigenetics and epigenomics.
*The impact of lipid metabolism in the tumor microenvironment in cancer progression and treatment.
*Impact of ferroptosis in endometriosis development. 

Dr. Huang has received an R03 funding titled “Role of Age-Related Changes in the Tumor Microenvironment on Ovarian Cancer Progression” from NIA at NIH for 2021-2023.
Dr. Huang received Charles B. Hammond's Research Fund from the Department of Obstetrics and Gynecology at Duke University in November 2022, for a project titled "Single Cell Spatial Transcriptomics in Highly Aggressive and Less Aggressive Ovarian Cancer".
Dr. Huang has received Duke Cancer Institute 2023 spring pilot study award for07012023-06302024, the project title is "Age Effects on Chemotherapy Targeting Cells Causing Ovarian Cancer Recurrence”.
Dr. Huang has received the American Cancer Society -Duke Cancer Institute (ASC-DCI) 2024 spring pilot study award for 07012024-06302025. The project title is "Early Establishment of Epigenetic Profiles that Increase Cancer Risk in Late Life”.
Dr. Huang received Charles B. Hammond's Research Fund from the Department of Obstetrics and Gynecology at Duke University in November 2023 for 01012024-12312024. The project's title is "Age Effects on Chemotherapy Targeting Cells Causing Ovarian Cancer Recurrence".

Levin

Edward Daniel Levin

Professor in Psychiatry and Behavioral Sciences

Dr. Levin is Chief of the Neurobehavioral Research Lab in the Psychiatry Department of Duke University Medical Center. His primary academic appointment is as Professor in the Department of Psychiatry and Behavioral Sciences. He also has secondary appointments in the Department Pharmacology and Cancer Biology, the Department of Psychological and Brain Sciences and the Nicholas School of the Environment at Duke. His primary research effort is to understand basic neural interactions underlying cognitive function and addiction and to apply this knowledge to better understand cognitive dysfunction and addiction disorders and to develop novel therapeutic treatments.

The three main research components of his laboratory are focused on the themes of the basic neurobiology of cognition and addiction, neurobehavioral toxicology and the development of novel therapeutic treatments for cognitive dysfunction and substance abuse. Currently, our principal research focus concerns nicotine. We have documented the basic effects of nicotine on learning memory and attention as well as nicotine self-administration. We are continuing with more mechanistic studies in rat models using selective lesions, local infusions and neurotransmitter interaction studies. We have found that nicotine improves memory performance not only in normal rats, but also in rats with lesions of hippocampal and basal forebrain connections. We are concentrating on alpha7 and alpha4beta2 nicotinic receptor subtypes in the hippocampus, amygdala , thalamus and frontal cortex and how they interact with dopamine D1 and D2 and glutamate NMDA systems with regard to memory and addiction. I am also conducting studies on human cognitive behavior. We have current studies to assess nicotine effects on attention, memory and mental processing speed in schizophrenia, Alzheimer's Disease and Attention Deficit Hyperactivity Disorder. In the area of neurobehavioral toxicology, I have continuing projects to characterize the adverse effects of prenatal and adolescent nicotine exposure. Our primary project in neurobehavioral toxicology focuses on the cognitive deficits caused by the marine toxins. The basic and applied aims of our research complement each other nicely. The findings concerning neural mechanisms underlying cognitive function help direct the behavioral toxicology and therapeutic development studies, while the applied studies provide important functional information concerning the importance of the basic mechanisms under investigation.

Murphy

Susan Kay Murphy

Associate Professor in Obstetrics and Gynecology

Dr. Murphy is a tenured Associate Professor in the Department of Obstetrics and Gynecology and serves as Chief of the Division of Reproductive Sciences. As a molecular biologist with training in human epigenetics, her research interests are largely centered around the role of epigenetic modifications in health and disease. 

Dr. Murphy has ongoing projects on gynecologic malignancies, including approaches to eradicate ovarian cancer cells that survive chemotherapy and later give rise to recurrent disease. Dr. Murphy is actively involved in many collaborative projects relating to the Developmental Origins of Health and Disease (DOHaD).

Her lab is currently working on preconception environmental exposures in males, particularly on the impact of cannabis on the sperm epigenome and the potential heritability of these effects. They are also studying the epigenetic and health effects of in utero exposures, with primary focus on children from the Newborn Epigenetics STudy (NEST), a pregnancy cohort she co-founded who were recruited from central North Carolina between 2005 and 2011. Dr. Murphy and her colleagues continue to follow NEST children to determine relationships between prenatal exposures and later health outcomes.


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