The reproductive system is unique among the bodily systems in the complexity of the mechanisms that control it. Many classes of psychoactive drugs can disrupt aspects of these controlling mechanisms and alter reproductive function. Research on the reproductive effects of drugs has numerous methodologic and interpretive problems, and several important questions remain unanswered (Reviewed by Smith & Asch, 1987). One of the most controversial issues in the research of marihuana on reproduction has been whether this drug is estrogenic or not. In the adult uterus, a large spectrum of estrogenic responses is elicited by a variety of steroidal and non-steroidal compounds. The type(s) of response(s) and the cell-types involved are dependent upon the nature of the compound and the hormonal environment the uterus is exposed to. In this respect, progesterone remarkably alters estrogenic responses in the uterus in a cell type- specific manner. Therefore, sensitive and defined systems are essential to determine the estrogenicity of marihuana, and the problem necessitates a concerted effort from various angles. The diverse but combined expertise of the investigators present a unique opportunity to fulfill this purpose.
Our specific aims are to: 1) determine the stage specific effects of delta-9-tetrahydrocannabinol (THC) on preimplantation embryo development, implantation and decidualization; 2) determine if the effects of THC are on the embryo, the uterus or both; 3) determine whether THC functions as an estrogen or an estrogen antagonist in inducing implantation in delayed implanting mice; 4) determine whether the effects of THC follow phasic estrogenic responses in the ovariectomized uterus and are modulated by progesterone; 5) determine whether THC discordantly alters the gene expression (as an estrogen) induces gene expression in the ovariectomized uterus in a cell type-specific manner that is altered by progesterone pretreatment. To determine stage and site specific effects of THC during early pregnancy, the blue dye method, embryo manipulation, culture and transfer will be employed. To determine estrogenicity of THC, the model of delayed implantation, assessment of Phase I (125I-BSA uptake) and Phase II (3H-thymidine incorporation) estrogenic responses and studies of gene expression in the uterus will be used. Expression of c-myc and IGF-I genes will be determined by detection of mRNAs by northern blot hybridization and their cell type-specific expression by in situ hybridization. Immunocytochemistry will be used to localize cell type-specific accumulation of c-myc and IGF-I proteins. The results obtained from the proposed study will not only establish whether THC elicits any estrogenic effects and interferes with early pregnancy, but will also show for the first time whether THC has any effect on gene expression in the uterus. Because in most cases pregnancy failure occurs during the peri-implantation period, the proposed experiments on the effects of THC during early pregnancy will provide important information as to the cause (embryo, uterus or both?) of pregnancy failure following exposure to the drug.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA006668-03
Application #
3213355
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1990-07-01
Project End
1995-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Kansas
Department
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Leishman, Emma; Manchanda, Meera; Thelen, Rachel et al. (2018) Cannabidiol's Upregulation of N-acyl Ethanolamines in the Central Nervous System Requires N-acyl Phosphatidyl Ethanolamine-Specific Phospholipase D. Cannabis Cannabinoid Res 3:228-241
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Yuan, Jia; Deng, Wenbo; Cha, Jeeyeon et al. (2018) Tridimensional visualization reveals direct communication between the embryo and glands critical for implantation. Nat Commun 9:603
Leishman, Emma; Kunkler, Phillip E; Manchanda, Meera et al. (2017) Environmental Toxin Acrolein Alters Levels of Endogenous Lipids, Including TRP Agonists: A Potential Mechanism for Headache Driven by TRPA1 Activation. Neurobiol Pain 1:28-36
Ho, Jacqueline M; Bergeon Burns, Christine M; Rendon, Nikki M et al. (2017) Lipid signaling and fat storage in the dark-eyed junco. Gen Comp Endocrinol 247:166-173
Rowley, Shane; Sun, Xiaofei; Lima, Isabel V et al. (2017) Cannabinoid receptor 1/2 double-knockout mice develop epilepsy. Epilepsia 58:e162-e166
Lanekoff, Ingela; Cha, Jeeyeon; Kyle, Jennifer E et al. (2016) Trp53 deficient mice predisposed to preterm birth display region-specific lipid alterations at the embryo implantation site. Sci Rep 6:33023
McAllister, Stacy L; Giourgas, Barbra K; Faircloth, Elizabeth K et al. (2016) Prostaglandin levels, vaginal innervation, and cyst innervation as peripheral contributors to endometriosis-associated vaginal hyperalgesia in rodents. Mol Cell Endocrinol 437:120-129
Bradshaw, Heather B; Leishman, Emma (2016) Levels of bioactive lipids in cooking oils: olive oil is the richest source of oleoyl serine. J Basic Clin Physiol Pharmacol 27:247-52
Yuan, Jia; Cha, Jeeyeon; Deng, Wenbo et al. (2016) Planar cell polarity signaling in the uterus directs appropriate positioning of the crypt for embryo implantation. Proc Natl Acad Sci U S A 113:E8079-E8088

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