{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T04:52:45Z","timestamp":1778129565005,"version":"3.51.4"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T00:00:00Z","timestamp":1632960000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000925","name":"The John Templeton Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["ES010356"],"award-info":[{"award-number":["ES010356"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["ES022831"],"award-info":[{"award-number":["ES022831"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The legalization and increasing availability of cannabis products raises concerns about the impact on offspring of users, and little has appeared on the potential contribution of paternal use. We administered cannabis extract to male rats prior to mating, with two different 28-day exposures, one where there was a 56-day interval between the end of exposure and mating (\u201cEarly Cannabis\u201d), and one just prior to mating (\u201cLate Cannabis\u201d); the extract delivered 4\u2009mg\/kg\/day of the main psychoactive component, \u03949-tetrahydrocannabinol. We then assessed the impact on dopamine (DA) systems in the offspring from the onset of adolescence (postnatal day 30) through middle age (postnatal day 150), measuring the levels of DA and its primary metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) in various brain regions. Paternal cannabis with either regimen elicited a profound and persistent deficit in DA utilization (DOPAC\/DA ratio) in the offspring, indicative of subnormal presynaptic activity. However, the two regimens differed in the underlying mechanism, with Early Cannabis reducing DOPAC whereas Late Cannabis increased DA and elicited a smaller reduction in DOPAC. Effects were restricted to male offspring. The effects of cannabis were not reproduced by equivalent exposure to its \u03949-tetrahydrocannabinol, nor did we see the effects with perinatal exposure to tobacco smoke or some of its fetotoxic contributors (benzo[a]pyrene without or with nicotine). Our studies provide some of the first evidence for adverse effects of paternal cannabis administration on neurodevelopment in the offspring, and reinforce the important consequences of paternal drug use in the preconception period.<\/jats:p>","DOI":"10.1093\/toxsci\/kfab117","type":"journal-article","created":{"date-parts":[[2021,9,24]],"date-time":"2021-09-24T03:44:00Z","timestamp":1632455040000},"page":"252-264","source":"Crossref","is-referenced-by-count":11,"title":["Paternal Cannabis Exposure Prior to Mating, but Not \u03949-Tetrahydrocannabinol, Elicits Deficits in Dopaminergic Synaptic Activity in the Offspring"],"prefix":"10.1093","volume":"184","author":[{"given":"Theodore A","family":"Slotkin","sequence":"first","affiliation":[{"name":"Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5060-9602","authenticated-orcid":false,"given":"Edward D","family":"Levin","sequence":"additional","affiliation":[{"name":"Department of Psychiatry & Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederic J","family":"Seidler","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,9,30]]},"reference":[{"key":"2021120108290511300_kfab117-B1","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S0163-1047(80)90469-0","article-title":"Prenatal exposure to cannabis: A critical review of effects on growth, development, and behavior","volume":"29","author":"Abel","year":"1980","journal-title":"Behav. Neural Biol"},{"key":"2021120108290511300_kfab117-B2","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3390\/ijms21010025","article-title":"Cannabinoid receptors signaling in the development, epigenetics, and tumours of male germ cells","volume":"21","author":"Barchi","year":"2020","journal-title":"Intl. J. Mol. Sci"},{"key":"2021120108290511300_kfab117-B3","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.neuro.2007.05.005","article-title":"Down-regulation of early ionotrophic glutamate receptor subunit developmental expression as a mechanism for observed plasticity deficits following gestational exposure to benzo(a)pyrene","volume":"28","author":"Brown","year":"2007","journal-title":"Neurotoxicology"},{"key":"2021120108290511300_kfab117-B4","doi-asserted-by":"crossref","first-page":"3022","DOI":"10.1242\/dev.146571","article-title":"The nature and dynamics of spermatogonial stem cells","volume":"144","author":"de Rooij","year":"2017","journal-title":"Development"},{"key":"2021120108290511300_kfab117-B5","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.1152\/jappl.2001.90.5.1968","article-title":"Threshold levels of maternal nicotine impairing protective responses of newborn rats to intermittent hypoxia","volume":"90","author":"Fewell","year":"2001","journal-title":"J. Appl. Physiol"},{"key":"2021120108290511300_kfab117-B6","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1038\/s41593-019-0512-2","article-title":"Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone","volume":"22","author":"Frau","year":"2019","journal-title":"Nat. Neurosci"},{"key":"2021120108290511300_kfab117-B7","doi-asserted-by":"crossref","first-page":"97S","DOI":"10.1002\/j.1552-4604.2002.tb06009.x","article-title":"Adolescents prenatally exposed to marijuana: Examination of facets of complex behaviors and comparisons with the influence of in utero cigarettes","volume":"42","author":"Fried","year":"2002","journal-title":"J. Clin. Pharmacol"},{"key":"2021120108290511300_kfab117-B8","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1007\/BF02244012","article-title":"Antianxiety effect of cannabidiol in the elevated plus-maze","volume":"100","author":"Guimar\u00e3es","year":"1990","journal-title":"Psychopharmacology"},{"key":"2021120108290511300_kfab117-B9","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.ntt.2010.05.001","article-title":"Sexually dimorphic alterations in locomotion and reversal learning after adolescent tetrahydrocannabinol exposure in the rat","volume":"32","author":"Harte","year":"2010","journal-title":"Neurotoxicol. Teratol"},{"key":"2021120108290511300_kfab117-B10","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1016\/j.euroneuro.2017.10.037","article-title":"Pharmacokinetic and behavioural profile of THC, CBD, and THC+CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of conversion in vivo of CBD to THC","volume":"27","author":"Hlo\u017eek","year":"2017","journal-title":"Eur. Neuropsychopharmacol"},{"key":"2021120108290511300_kfab117-B11","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.neuro.2020.01.009","article-title":"Paternal factors in neurodevelopmental toxicology: THC exposure of male rats causes long-lasting neurobehavioral effects in their offspring","volume":"78","author":"Holloway","year":"2020","journal-title":"Neurotoxicology"},{"key":"2021120108290511300_kfab117-B12","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.neuro.2020.10.007","article-title":"Paternal cannabis extract exposure in rats: Preconception timing effects on neurodevelopmental behavior in offspring","volume":"81","author":"Holloway","year":"2020","journal-title":"Neurotoxicology"},{"key":"2021120108290511300_kfab117-B13","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1002\/cbdv.200790152","article-title":"Human cannabinoid pharmacokinetics","volume":"4","author":"Huestis","year":"2007","journal-title":"Chem. Biodivers"},{"key":"2021120108290511300_kfab117-B14","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.pnpbp.2013.09.014","article-title":"Prenatal cannabis exposure and infant outcomes: Overview of studies","volume":"52","author":"Huizink","year":"2014","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiat"},{"key":"2021120108290511300_kfab117-B15","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.1007\/s00213-015-3942-x","article-title":"Persistent effects of chronic \u03949-THC exposure on motor impulsivity in rats","volume":"232","author":"Irimia","year":"2015","journal-title":"Psychopharmacology"},{"key":"2021120108290511300_kfab117-B16","doi-asserted-by":"crossref","first-page":"20","DOI":"10.2174\/1876528900902010020","article-title":"The role of the Y chromosome in brain function","volume":"2","author":"Kopsida","year":"2009","journal-title":"Open Neuroendocrinol. J"},{"key":"2021120108290511300_kfab117-B17","doi-asserted-by":"crossref","first-page":"16577","DOI":"10.1073\/pnas.1900406116","article-title":"Sex-specific neuroprotection by inhibition of the Y-chromosome gene, SRY, in experimental Parkinson\u2019s disease","volume":"116","author":"Lee","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U.S.A"},{"key":"2021120108290511300_kfab117-B18","doi-asserted-by":"crossref","first-page":"106806","DOI":"10.1016\/j.ntt.2019.04.003","article-title":"Paternal THC exposure in rats causes long-lasting neurobehavioral effects in the offspring","volume":"74","author":"Levin","year":"2019","journal-title":"Neurotoxicol. Teratol"},{"key":"2021120108290511300_kfab117-B19","doi-asserted-by":"crossref","first-page":"10","DOI":"10.3389\/fphar.2014.00010","article-title":"Effects of cannabinoid drugs on the deficit of prepulse inhibition of startle in an animal model of schizophrenia: The SHR strain","volume":"5","author":"Levin","year":"2014","journal-title":"Front. Pharmacol"},{"key":"2021120108290511300_kfab117-B20","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1093\/toxsci\/kfv212","article-title":"Revealing behavioral learning deficit phenotypes subsequent to in utero exposure to benzo(a)pyrene","volume":"149","author":"McCallister","year":"2016","journal-title":"Toxicol. Sci"},{"key":"2021120108290511300_kfab117-B21","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1016\/j.neuro.2008.07.008","article-title":"Prenatal exposure to benzo(a)pyrene impairs later-life cortical neuronal function","volume":"29","author":"McCallister","year":"2008","journal-title":"Neurotoxicology"},{"key":"2021120108290511300_kfab117-B22","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1080\/15592294.2018.1554521","article-title":"Cannabinoid exposure and altered DNA methylation in rat and human sperm","volume":"13","author":"Murphy","year":"2018","journal-title":"Epigenetics"},{"key":"2021120108290511300_kfab117-B23","doi-asserted-by":"crossref","first-page":"624275","DOI":"10.3389\/fpsyt.2020.624275","article-title":"Prenatal cannabinoid exposure: Emerging evidence of physiological and neuropsychiatric abnormalities","volume":"11","author":"Nashed","year":"2021","journal-title":"Front. Psychiat"},{"key":"2021120108290511300_kfab117-B24","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1016\/j.addbeh.2006.12.024","article-title":"Secondhand smoke and nicotine exposure: A brief review","volume":"32","author":"Okoli","year":"2007","journal-title":"Addict. Behav"},{"key":"2021120108290511300_kfab117-B25","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.ntt.2010.10.006","article-title":"Silver exposure in developing zebrafish produces persistent synaptic and behavioral changes","volume":"33","author":"Powers","year":"2011","journal-title":"Neurotoxicol. Teratol"},{"key":"2021120108290511300_kfab117-B26","first-page":"1297","article-title":"Adolescent cannabinoid exposure induces a persistent sub-cortical hyper-dopaminergic state and associated molecular adaptations in the prefrontal cortex","volume":"27","author":"Renard","year":"2017","journal-title":"Cereb. Cortex"},{"key":"2021120108290511300_kfab117-B27","doi-asserted-by":"crossref","first-page":"11420","DOI":"10.1038\/s41598-017-11645-8","article-title":"Adolescent THC exposure causes enduring prefrontal cortical isruption of GABAergic inhibition and dysregulation of sub-cortical dopamine function","volume":"7","author":"Renard","year":"2017","journal-title":"Sci. Rep."},{"key":"2021120108290511300_kfab117-B28","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.brainresbull.2021.05.026","article-title":"Paternal and\/or maternal preconception-induced neurobehavioral teratogenicity in animal and human models","volume":"174","author":"Rimawi","year":"2021","journal-title":"Brain Res. Bull"},{"key":"2021120108290511300_kfab117-B29","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1002\/hipo.20554","article-title":"Changes in hippocampal morphology and neuroplasticity induced by adolescent THC treatment are associated with cognitive impairment in adulthood","volume":"19","author":"Rubino","year":"2009","journal-title":"Hippocampus"},{"key":"2021120108290511300_kfab117-B30","doi-asserted-by":"crossref","first-page":"e20181889","DOI":"10.1542\/peds.2018-1889","article-title":"Marijuana use during pregnancy and breastfeeding: Implications for neonatal and childhood outcomes","volume":"142","author":"Ryan","year":"2018","journal-title":"Pediatrics"},{"key":"2021120108290511300_kfab117-B31","first-page":"1","article-title":"Cannabis use is associated with potentially heritable widespread changes in autism candidate gene DLGAP2 DNA methylation in sperm","volume":"15","author":"Schrott","year":"2019","journal-title":"Epigenetics"},{"key":"2021120108290511300_kfab117-B32","first-page":"1","article-title":"Refraining from use diminishes cannabis-associated epigenetic changes in human sperm","author":"Schrott","year":"2021","journal-title":"Environ. Epigenet"},{"key":"2021120108290511300_kfab117-B33","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.taap.2003.06.001","article-title":"Cholinergic systems in brain development and disruption by neurotoxicants: Nicotine, environmental tobacco smoke, organophosphates","volume":"198","author":"Slotkin","year":"2004","journal-title":"Toxicol. Appl. Pharmacol"},{"key":"2021120108290511300_kfab117-B34","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0006-8993(00)02767-0","article-title":"Cellular determinants of reduced adaptability of the aging brain: Neurotransmitter utilization and cell signaling responses after MDMA lesions","volume":"879","author":"Slotkin","year":"2000","journal-title":"Brain Res"},{"key":"2021120108290511300_kfab117-B35","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1093\/toxsci\/kfv123","article-title":"Developmental neurotoxicity of tobacco smoke directed toward cholinergic and serotonergic systems: More than just nicotine","volume":"147","author":"Slotkin","year":"2015","journal-title":"Toxicol. Sci"},{"key":"2021120108290511300_kfab117-B36","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1093\/toxsci\/kfy241","article-title":"The developmental neurotoxicity of tobacco smoke can be mimicked by a combination of nicotine and benzo[a]pyrene: Effects on cholinergic and serotonergic systems","volume":"167","author":"Slotkin","year":"2019","journal-title":"Toxicol. Sci"},{"key":"2021120108290511300_kfab117-B37","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1093\/toxsci\/kfaa004","article-title":"Paternal \u03949-tetrahydrocannabinol exposure prior to mating elicits deficits in cholinergic synaptic function in the offspring","volume":"174","author":"Slotkin","year":"2020","journal-title":"Toxicol. Sci"},{"key":"2021120108290511300_kfab117-B38","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1093\/toxsci\/kfw180","article-title":"Is there a critical period for the developmental neurotoxicity of low-level tobacco smoke exposure?","volume":"155","author":"Slotkin","year":"2017","journal-title":"Toxicol. Sci"},{"key":"2021120108290511300_kfab117-B39","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.neubiorev.2017.05.011","article-title":"High times for cannabis: Epigenetic imprint and its legacy on brain and behavior","volume":"85","author":"Szutorisz","year":"2018","journal-title":"Neurosci. Biobehav. Rev"},{"key":"2021120108290511300_kfab117-B40","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0006-8993(00)02208-3","article-title":"An animal model of adolescent nicotine exposure: Effects on gene expression and macromolecular constituents in rat brain regions","volume":"867","author":"Trauth","year":"2000","journal-title":"Brain Res"},{"key":"2021120108290511300_kfab117-B41","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.ejphar.2008.01.058","article-title":"Cannabis and the developing brain: Insights from behavior","volume":"585","author":"Trezza","year":"2008","journal-title":"Eur. J. Pharmacol"},{"key":"2021120108290511300_kfab117-B42","doi-asserted-by":"crossref","first-page":"5407","DOI":"10.1038\/s41467-018-07862-y","article-title":"Dissection of genetic variation and evidence for pleiotropy in male pattern baldness","volume":"9","author":"Yap","year":"2018","journal-title":"Nat. Commun"},{"key":"2021120108290511300_kfab117-B43","doi-asserted-by":"crossref","first-page":"259","DOI":"10.3389\/fphar.2017.00259","article-title":"Inverted U-shaped dose-response curve of the anxiolytic effect of cannabidiol during public speaking in real life","volume":"8","author":"Zuardi","year":"2017","journal-title":"Front. Pharmacol"}],"container-title":["Toxicological Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/toxsci\/advance-article-pdf\/doi\/10.1093\/toxsci\/kfab117\/40874144\/kfab117.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/184\/2\/252\/41325277\/kfab117.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/184\/2\/252\/41325277\/kfab117.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T13:05:17Z","timestamp":1638363917000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/toxsci\/article\/184\/2\/252\/6378255"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,30]]},"references-count":43,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,9,30]]},"published-print":{"date-parts":[[2021,11,24]]}},"URL":"https:\/\/doi.org\/10.1093\/toxsci\/kfab117","relation":{},"ISSN":["1096-6080","1096-0929"],"issn-type":[{"value":"1096-6080","type":"print"},{"value":"1096-0929","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,12,1]]},"published":{"date-parts":[[2021,9,30]]}}}