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Anandamide down-regulates placental transporter expression through CB2 receptor-mediated inhibition of cAMP synthesis.
Pharmacol Res. 2019 03; 141:331-342.PR

Abstract

The BCRP/ABCG2 efflux transporter is expressed on the membrane of placental syncytiotrophoblasts and protects the fetus from toxicant exposure. Syncytiotrophoblasts arise from the fusion of cytotrophoblasts, a process negatively regulated by the endocannabinoid, anandamide (AEA). It is unknown whether AEA can influence fetal concentrations of xenobiotics by modulating the expression of transporters in syncytiotrophoblasts. Here, we sought to characterize and identify the mechanism(s) responsible for AEA-mediated down-regulation of the BCRP transporter in human placental explants and BeWo trophoblasts. Treatment of human placental explants with AEA (1 μM, 24 h) reduced hCGα, syncytin-1, and BCRP mRNAs by ˜30%. Similarly, treatment of BeWo trophoblasts with AEA (0-10 μM, 3-24 h) coordinately down-regulated mRNAs for hCGβ, syncytin-2, and BCRP. In turn, AEA increased the sensitivity of trophoblasts to the cytotoxicity of mitoxantrone, a known BCRP substrate, and environmental and dietary contaminants including mycoestrogens and perfluorinated chemicals. AEA-treated trophoblasts also demonstrated reduced BCRP transport of the mycoestrogen zearalenone and the diabetes drug glyburide, labeled with BODIPY. The AEA-mediated reduction of BCRP mRNA was abrogated when placental cells were co-treated with AM630, a CB2 receptor inhibitor, or 8-Br-cAMP, a cAMP analog. AEA reduced intracellular cAMP levels in trophoblasts by 75% at 1 h, and completely inhibited forskolin-induced phosphorylation of the cAMP response element binding protein (CREB). AEA also decreased p-CREB binding to the BCRP promoter. Taken together, our data indicate that AEA down-regulates placental transporter expression and activity via CB2-cAMP signaling. This novel mechanism may explain the repression of placental BCRP expression observed during diseases of pregnancy.

Authors+Show Affiliations

Joint Graduate Program in Toxicology, Rutgers University, School of Graduate Studies, 170 Frelinghuysen Rd, Piscataway, NJ, 08854, USA. Electronic address: jtszilagyi@hotmail.com.Joint Graduate Program in Toxicology, Rutgers University, School of Graduate Studies, 170 Frelinghuysen Rd, Piscataway, NJ, 08854, USA. Electronic address: gabrieco@pharmacy.rutgers.edu.Department of Pharmacology and Toxicology, Rutgers University, 170 Frelinghuysen Rd, Piscataway, NJ, 08854, USA; Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, 08901, USA. Electronic address: lbjoseph@pharmacy.rutgers.edu.Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA. Electronic address: wangbi@rwjms.rutgers.edu.Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA. Electronic address: rosentj@rutgers.edu.Environmental and Occupational Health Sciences Institute, 170 Frelinghuysen Rd, Piscataway, NJ, 08854, USA; Department of Environmental and Occupational Health, School of Public Health, Rutgers University, 170 Frelinghuysen Rd, Piscataway, NJ, 08854, USA. Electronic address: jl1450@eohsi.rutgers.edu.Department of Pharmacology and Toxicology, Rutgers University, 170 Frelinghuysen Rd, Piscataway, NJ, 08854, USA; Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, 08901, USA; Department of Environmental and Occupational Health, School of Public Health, Rutgers University, 170 Frelinghuysen Rd, Piscataway, NJ, 08854, USA. Electronic address: aleksunes@eohsi.rutgers.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30610963

Citation

Szilagyi, John T., et al. "Anandamide Down-regulates Placental Transporter Expression Through CB2 Receptor-mediated Inhibition of cAMP Synthesis." Pharmacological Research, vol. 141, 2019, pp. 331-342.
Szilagyi JT, Composto-Wahler GM, Joseph LB, et al. Anandamide down-regulates placental transporter expression through CB2 receptor-mediated inhibition of cAMP synthesis. Pharmacol Res. 2019;141:331-342.
Szilagyi, J. T., Composto-Wahler, G. M., Joseph, L. B., Wang, B., Rosen, T., Laskin, J. D., & Aleksunes, L. M. (2019). Anandamide down-regulates placental transporter expression through CB2 receptor-mediated inhibition of cAMP synthesis. Pharmacological Research, 141, 331-342. https://doi.org/10.1016/j.phrs.2019.01.002
Szilagyi JT, et al. Anandamide Down-regulates Placental Transporter Expression Through CB2 Receptor-mediated Inhibition of cAMP Synthesis. Pharmacol Res. 2019;141:331-342. PubMed PMID: 30610963.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anandamide down-regulates placental transporter expression through CB2 receptor-mediated inhibition of cAMP synthesis. AU - Szilagyi,John T, AU - Composto-Wahler,Gabriella M, AU - Joseph,Laurie B, AU - Wang,Bingbing, AU - Rosen,Todd, AU - Laskin,Jeffrey D, AU - Aleksunes,Lauren M, Y1 - 2019/01/02/ PY - 2018/10/08/received PY - 2019/01/01/revised PY - 2019/01/01/accepted PY - 2019/1/6/pubmed PY - 2019/8/24/medline PY - 2019/1/6/entrez KW - ABCG2 KW - Anandamide KW - BCRP KW - Endocannabinoid KW - Placenta KW - Transporter KW - cAMP SP - 331 EP - 342 JF - Pharmacological research JO - Pharmacol Res VL - 141 N2 - The BCRP/ABCG2 efflux transporter is expressed on the membrane of placental syncytiotrophoblasts and protects the fetus from toxicant exposure. Syncytiotrophoblasts arise from the fusion of cytotrophoblasts, a process negatively regulated by the endocannabinoid, anandamide (AEA). It is unknown whether AEA can influence fetal concentrations of xenobiotics by modulating the expression of transporters in syncytiotrophoblasts. Here, we sought to characterize and identify the mechanism(s) responsible for AEA-mediated down-regulation of the BCRP transporter in human placental explants and BeWo trophoblasts. Treatment of human placental explants with AEA (1 μM, 24 h) reduced hCGα, syncytin-1, and BCRP mRNAs by ˜30%. Similarly, treatment of BeWo trophoblasts with AEA (0-10 μM, 3-24 h) coordinately down-regulated mRNAs for hCGβ, syncytin-2, and BCRP. In turn, AEA increased the sensitivity of trophoblasts to the cytotoxicity of mitoxantrone, a known BCRP substrate, and environmental and dietary contaminants including mycoestrogens and perfluorinated chemicals. AEA-treated trophoblasts also demonstrated reduced BCRP transport of the mycoestrogen zearalenone and the diabetes drug glyburide, labeled with BODIPY. The AEA-mediated reduction of BCRP mRNA was abrogated when placental cells were co-treated with AM630, a CB2 receptor inhibitor, or 8-Br-cAMP, a cAMP analog. AEA reduced intracellular cAMP levels in trophoblasts by 75% at 1 h, and completely inhibited forskolin-induced phosphorylation of the cAMP response element binding protein (CREB). AEA also decreased p-CREB binding to the BCRP promoter. Taken together, our data indicate that AEA down-regulates placental transporter expression and activity via CB2-cAMP signaling. This novel mechanism may explain the repression of placental BCRP expression observed during diseases of pregnancy. SN - 1096-1186 UR - https://www.unboundmedicine.com/medline/citation/30610963/Anandamide_down_regulates_placental_transporter_expression_through_CB2_receptor_mediated_inhibition_of_cAMP_synthesis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1043-6618(18)31544-5 DB - PRIME DP - Unbound Medicine ER -