PMID- 26708672 OWN - NLM STAT- MEDLINE DCOM- 20171222 LR - 20181113 IS - 1872-9738 (Electronic) IS - 0892-0362 (Print) IS - 0892-0362 (Linking) VI - 58 DP - 2016 Nov-Dec TI - Dose-dependent teratogenicity of the synthetic cannabinoid CP-55,940 in mice. PG - 15-22 LID - S0892-0362(15)30053-2 [pii] LID - 10.1016/j.ntt.2015.12.004 [doi] AB - Potent synthetic cannabinoids (SCBs) are illegally distributed drugs of abuse that are frequently consumed in spite of their adverse consequences. This study was designed to determine if the toxicity observed in adults also extends to the prenatal period by examining the developmental toxicity/teratogenicity of one of these SCBs, CP-55,940, in a mammalian model. First, immunohistochemistry was employed for cannabinoid receptor 1 (CB1) localization within gestational day (GD) 8 mouse embryos; this receptor was identified in the cranial neural plate, suggesting that the endogenous cannabinoid system may be involved in normal development. Based on this information and on previous avian teratogenicity studies, the current investigation focused on cannabinoid exposure during neurulation. The treatment paradigm involved acute i.p. administration of vehicle, 0.0625, 0.125, 0.25, 0.5, 1.0, or 2.0mg/kg CP-55,940 to time-mated C57Bl/6J mice on their 8th day of pregnancy (n>10 litters per treatment group). On GD 17, litters were harvested and examined for numbers of live, dead, or resorbed fetuses, as well as for fetal weight, length, and gross morphological abnormalities. No effect on litter size, fetal weight, or crown rump length was seen at any of the CP-55,940 dosages tested. Major malformations involving the craniofacies and/or eyes were noted in all drug-treated groups. Selected fetuses with craniofacial malformations were histologically sectioned and stained, allowing investigation of brain anomalies. Observed craniofacial, ocular, and brain abnormalities in drug-treated fetuses included lateral and median facial clefts, cleft palate, microphthalmia, iridial coloboma, anophthalmia, exencephaly, holoprosencephaly, and cortical dysplasia. With the most commonly observed defects involving the eyes, the incidence and severity of readily identifiable ocular malformations were utilized as a basis for dose-response analyses. Ocular malformation ratings revealed dose-dependent CP-55,940 teratogenicity within the full range of dosages tested. While examination of additional critical periods and in depth mechanistic studies is warranted, the results of this investigation clearly show the dose-dependent teratogenicity of this SCB. CI - Copyright (c) 2015 Elsevier Inc. All rights reserved. FAU - Gilbert, Marcoita T AU - Gilbert MT AD - Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, NC 27599-7178, United States. FAU - Sulik, Kathleen K AU - Sulik KK AD - Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, NC 27599-7178, United States; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599-7255, United States; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599-7545, United States. FAU - Fish, Eric W AU - Fish EW AD - Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, NC 27599-7178, United States. FAU - Baker, Lorinda K AU - Baker LK AD - Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, NC 27599-7178, United States. FAU - Dehart, Deborah B AU - Dehart DB AD - Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, NC 27599-7178, United States. FAU - Parnell, Scott E AU - Parnell SE AD - Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, NC 27599-7178, United States; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599-7255, United States; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599-7545, United States. Electronic address: sparnell@med.unc.edu. LA - eng GR - K99 AA018697/AA/NIAAA NIH HHS/United States GR - P60 AA011605/AA/NIAAA NIH HHS/United States GR - R00 AA018697/AA/NIAAA NIH HHS/United States GR - U01 AA021651/AA/NIAAA NIH HHS/United States PT - Journal Article DEP - 20151218 PL - United States TA - Neurotoxicol Teratol JT - Neurotoxicology and teratology JID - 8709538 RN - 0 (Cyclohexanols) RN - 0 (Receptor, Cannabinoid, CB1) RN - 0 (Teratogens) RN - 83003-12-7 (3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol) SB - IM MH - Abnormalities, Drug-Induced/*embryology MH - Animals MH - Brain/*drug effects/*embryology/*pathology MH - Cyclohexanols/administration & dosage/*toxicity MH - Dose-Response Relationship, Drug MH - Female MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Neurulation/drug effects MH - Pregnancy MH - Prenatal Exposure Delayed Effects/*pathology MH - Receptor, Cannabinoid, CB1/metabolism MH - Teratogens PMC - PMC4912947 MID - NIHMS748198 OTO - NOTNLM OT - C57BL/6J mice OT - CP-55,940 OT - Neurulation OT - Synthetic cannabinoid OT - Teratogen EDAT- 2015/12/29 06:00 MHDA- 2017/12/23 06:00 PMCR- 2017/11/01 CRDT- 2015/12/29 06:00 PHST- 2015/08/14 00:00 [received] PHST- 2015/12/15 00:00 [revised] PHST- 2015/12/16 00:00 [accepted] PHST- 2015/12/29 06:00 [pubmed] PHST- 2017/12/23 06:00 [medline] PHST- 2015/12/29 06:00 [entrez] PHST- 2017/11/01 00:00 [pmc-release] AID - S0892-0362(15)30053-2 [pii] AID - 10.1016/j.ntt.2015.12.004 [doi] PST - ppublish SO - Neurotoxicol Teratol. 2016 Nov-Dec;58:15-22. doi: 10.1016/j.ntt.2015.12.004. Epub 2015 Dec 18.