{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T08:10:16Z","timestamp":1762071016207,"version":"build-2065373602"},"reference-count":126,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,23]],"date-time":"2022-10-23T00:00:00Z","timestamp":1666483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Introduction. Recent reports linking prenatal and community cannabis exposure to elevated uronephrological congenital anomaly (UCA) rates (UCAR\u2019s) raise the question of its European epidemiology given recent increases in community cannabinoid penetration there. Methods. UCAR data from Eurocat. Drug use data from European Monitoring Centre for Drugs and Drug Addiction. Income from World bank. Results. UCAR increased across Spain, Netherlands, Poland and France. UCAR\u2019s and cannabis resin THC increased simultaneously in France, Spain, Netherlands and Bulgaria. At bivariate analysis all UCA\u2019s were related to cannabis herb and resin THC concentrations. All UCAR\u2019s were bivariately related to cannabis metrics ordered by median minimum E-value (mEV) as hypospadias &gt; multicystic renal disease &gt; bilateral renal agenesis &gt; UCA\u2019s &gt; hydronephrosis &gt; posterior urethral valve &gt; bladder exstrophy\/epispadias. At inverse probability weighted multivariable analysis terms including cannabis were significant for the following series of anomalies: UCA\u2019s, multicystic renal disease, bilateral renal agenesis, hydronephrosis, congenital posterior urethral valves from P = 1.91 \u00d7 10\u22125, 2.61 \u00d7 10\u22128, 4.60 \u00d7 10\u221215, 4.60 \u00d7 10\u221215 and 2.66 \u00d7 10\u221210. At geospatial analysis the same series of UCA\u2019s were significantly related to cannabis from P = 7.84 \u00d7 10\u221215, 7.72 \u00d7 10\u22125, 0.0023, 6.95 \u00d7 10\u22125, and 8.82 \u00d7 10\u22125. 45\/51 (88.2%) of E-value estimates and 31\/51 (60.8%) of mEV\u2019s &gt;9. Conclusion. Analysis confirms a close relationship between cannabis metrics and all seven UCA\u2019s and fulfill formal criteria for quantitative causal inference. Given the exponential cannabinoid genotoxicity dose\u2013response relationship results provide a powerful stimulus to constrain community cannabinoid exposure including protection of the food chain to preserve the genome and epigenome of coming generations.<\/jats:p>","DOI":"10.3390\/ijerph192113769","type":"journal-article","created":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T02:31:03Z","timestamp":1666578663000},"page":"13769","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Epidemiological Patterns of Cannabis- and Substance- Related Congenital Uronephrological Anomalies in Europe: Geospatiotemporal and Causal Inferential Study"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3256-720X","authenticated-orcid":false,"given":"Albert","family":"Reece","sequence":"first","affiliation":[{"name":"Division of Psychiatry, University of Western Australia, Crawley, WA 6009, Australia"},{"name":"School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary","family":"Hulse","sequence":"additional","affiliation":[{"name":"Division of Psychiatry, University of Western Australia, Crawley, WA 6009, Australia"},{"name":"School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s13690-022-00811-8","article-title":"Geotemporospatial and Causal Inferential Epidemiological Overview and Survey of USA Cannabis, Cannabidiol and Cannabinoid Genotoxicity Expressed in Cancer Incidence 2003\u20132017: Part 1\u2013Continuous Bivariate Analysis","volume":"80","author":"Reece","year":"2022","journal-title":"Arch. Public Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s13690-022-00812-7","article-title":"Geotemporospatial and Causal Inferential Epidemiological Overview and Survey of USA Cannabis, Cannabidiol and Cannabinoid Genotoxicity Expressed in Cancer Incidence 2003\u20132017: Part 2\u2013Categorical Bivariate Analysis and Attributable Fractions","volume":"80","author":"Reece","year":"2022","journal-title":"Arch. Public Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s13690-022-00812-7","article-title":"Geotemporospatial and Causal Inferential Epidemiological Overview and Survey of USA Cannabis, Cannabidiol and Cannabinoid Genotoxicity Expressed in Cancer Incidence 2003\u20132017: Part 3\u2013Spatiotemporal, Multivariable and Causal Inferential Pathfinding and Exploratory Analyses of Prostate and Ovarian Cancers","volume":"80","author":"Reece","year":"2022","journal-title":"Arch. Public Health"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1186\/s12885-021-08598-7","article-title":"Cannabinoid exposure as a major driver of pediatric acute lymphoid Leukaemia rates across the USA: Combined geospatial, multiple imputation and causal inference study","volume":"21","author":"Reece","year":"2021","journal-title":"BMC Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1186\/s12885-021-07924-3","article-title":"A geospatiotemporal and causal inference epidemiological exploration of substance and cannabinoid exposure as drivers of rising US pediatric cancer rates","volume":"21","author":"Reece","year":"2021","journal-title":"BMC Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1186\/s12887-020-02431-z","article-title":"Contemporary epidemiology of rising atrial septal defect trends across USA 1991-2016: A combined ecological geospatiotemporal and causal inferential study","volume":"20","author":"Reece","year":"2020","journal-title":"BMC Pediatrics"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s12887-021-02996-3","article-title":"Geotemporospatial and causal inference epidemiological analysis of US survey and overview of cannabis, cannabidiol and cannabinoid genotoxicity in relation to congenital anomalies 2001\u20132015","volume":"22","author":"Reece","year":"2022","journal-title":"BMC Pediatrics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s40360-020-00450-1","article-title":"Broad Spectrum epidemiological contribution of cannabis and other substances to the teratological profile of northern New South Wales: Geospatial and causal inference analysis","volume":"21","author":"Reece","year":"2020","journal-title":"BMC Pharmacol. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s40360-021-00505-x","article-title":"Causal inference multiple imputation investigation of the impact of cannabinoids and other substances on ethnic differentials in US testicular cancer incidence","volume":"22","author":"Reece","year":"2021","journal-title":"BMC Pharmacol. Toxicol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1186\/s12889-020-09748-5","article-title":"Co-occurrence across time and space of drug- and cannabinoid- exposure and adverse mental health outcomes in the National Survey of Drug Use and Health: Combined geotemporospatial and causal inference analysis","volume":"20","author":"Reece","year":"2020","journal-title":"BMC Public Health"},{"key":"ref_11","unstructured":"Preedy, V., and Patel, V. (2022). Cannabis, Cannabinoids and Endocannabinoids. Volume 1, Elsevier. in press."},{"key":"ref_12","unstructured":"Preedy, V., and Patel, V. (2022). Cannabis, Cannabinoids and Endocannabinoids. Volume 1, Elsevier. in press."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1177\/0009922819861281","article-title":"Cannabis Teratology Explains Current Patterns of Coloradan Congenital Defects: The Contribution of Increased Cannabinoid Exposure to Rising Teratological Trends","volume":"58","author":"Reece","year":"2019","journal-title":"Clin. Pediatrics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.35248\/2572-0775.19.4.155","article-title":"Epidemiological Associations of Various Substances and Multiple Cannabinoids with Autism in USA","volume":"4","author":"Reece","year":"2019","journal-title":"Clin. Pediatrics Open Access"},{"key":"ref_15","first-page":"1","article-title":"Cannabinoid- and Substance- Relationships of European Congenital Anomaly Patterns: A Space-Time Panel Regression and Causal Inferential Study","volume":"8","author":"Reece","year":"2022","journal-title":"Environ. Epigenetics"},{"key":"ref_16","first-page":"1","article-title":"Geospatiotemporal and Causal Inference Study of Cannabis and Other Drugs as Risk Factors for Female Breast Cancer USA 2003-2017","volume":"2022","author":"Reece","year":"2022","journal-title":"Environ. Epigenetics"},{"key":"ref_17","first-page":"1","article-title":"Cannabis Consumption Patterns Explain the East-West Gradient in Canadian Neural Tube Defect Incidence: An Ecological Study","volume":"6","author":"Reece","year":"2019","journal-title":"Glob. Pediatrics Health"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e195","DOI":"10.1097\/ADM.0000000000000638","article-title":"Canadian Cannabis Consumption and Patterns of Congenital Anomalies: An Ecological Geospatial Analysis","volume":"14","author":"Reece","year":"2020","journal-title":"J. Addict. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1080\/15287390600748799","article-title":"Risk of selected birth defects with prenatal illicit drug use, Hawaii, 1986\u20132002","volume":"70","author":"Forrester","year":"2007","journal-title":"J. Toxicol. Environ. Health"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100245","DOI":"10.1016\/j.lanepe.2021.100245","article-title":"Quadruple convergence\u2014Rising cannabis prevalence, intensity, concentration and use disorder treatment","volume":"10","author":"Reece","year":"2021","journal-title":"Lancet Reg. Health Eur."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Reece, A.S., and Hulse, G.K. (2022). Epidemiological Overview of Cannabis- and Substance- Carcinogenesis in Europe: A Lagged Causal Inferential Panel Regression Modelling and Marginal Effects Study, manuscript submitted.","DOI":"10.3390\/jox13030024"},{"key":"ref_22","unstructured":"Reece, A.S., and Hulse, G.K. (2020). Cannabis in Pregnancy\u2014Rejoinder, Exposition and Cautionary Tales. Psychiatr. Times, 37, Available online: https:\/\/www.psychiatrictimes.com\/view\/cannabis-pregnancy-rejoinder-exposition-cautionary-tales."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"13892","DOI":"10.1038\/s41598-021-93411-5","article-title":"Epidemiological Overview of Multidimensional Chromosomal and Genome Toxicity of Cannabis Exposure in Congenital Anomalies and Cancer Development","volume":"11","author":"Reece","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_24","first-page":"n3114","article-title":"Rapid Response: Cannabinoid Genotoxic Trifecta\u2014Cancerogenesis, Clinical Teratogenesis and Cellular Ageing","volume":"376","author":"Reece","year":"2022","journal-title":"Br. Med. J."},{"key":"ref_25","first-page":"n3114","article-title":"Limblessness: Cannabinoids Inhibit Key Embryonic Morphogens both Directly and Epigenomically","volume":"376","author":"Reece","year":"2022","journal-title":"Br. Med. J."},{"key":"ref_26","unstructured":"Reece, A.S., and Hulse, G.K. Epidemiology of Cannabis: Genotoxicity and Neurotoxicity, Epigenomics and Aging, Elsevier. in press."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Reece, A.S., and Hulse, G.K. (2022). European Epidemiological Patterns of Cannabis- and Substance- Related Congenital Body Wall Anomalies: Geospatiotemporal and Causal Inferential Study. Intern. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph19159027"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Reece, A.S., and Hulse, G.K. (2022). Cannabis- and Substance- Related Epidemiological Patterns of Chromosomal Congenital Anomalies in Europe: Geospatiotemporal and Causal Inferential Study. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph191811208"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Reece, A.S., and Hulse, G.K. (2022). State Trends of Cannabis Liberalization as a Causal Driver of Increasing Testicular Cancer Rates across the USA. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph191912759"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Reece, A.S., and Hulse, G.K. (2022). Epidemiology of \u03948THC-Related Carcinogenesis in USA: A Panel Regression and Causal Inferential Study. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph19137726"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"100480","DOI":"10.1016\/j.sste.2022.100480","article-title":"Epidemiological association of cannabinoid- and drug- exposures and sociodemographic factors with limb reduction defects across USA 1989\u20132016: A geotemporospatial study","volume":"41","author":"Reece","year":"2022","journal-title":"Spat. Spatio-Temporal Epidemiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"100227","DOI":"10.1016\/j.lanepe.2021.100227","article-title":"Public health monitoring of cannabis use in Europe: Prevalence of use, cannabis potency, and treatment rates","volume":"10","author":"Manthey","year":"2021","journal-title":"Lancet Reg. Health Eur."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Reece, A.S., and Hulse, G.K. (Mendeley Data, 2022). Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis, Mendeley Data, manuscript submitted.","DOI":"10.3390\/ijerph192416721"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e011891","DOI":"10.1136\/bmjopen-2016-011891","article-title":"Cannabis exposure as an interactive cardiovascular risk factor and accelerant of organismal ageing: A longitudinal study","volume":"6","author":"Reece","year":"2016","journal-title":"BMJ Open"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Reece, A.S., and Hulse, G.K. Extending the \u201cParacentral Dogma\u201d of biology with the metabolome: Implications for understanding genomic-glycomic-metabolic-epigenomic synchronization. Engineering, 2022. in press.","DOI":"10.1016\/j.eng.2022.07.011"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Reece, A.S., and Hulse, G.K. Cannabis, Cannabidiol, Cannabinoids and Multigenerational Policy. Engineering, 2022. in press.","DOI":"10.1016\/j.eng.2022.07.012"},{"key":"ref_37","first-page":"359","article-title":"Effects of Marijuana Inhalation on Spermatogenesis of the Rat","volume":"Volume 1","author":"Nahas","year":"1999","journal-title":"Marijuana in Medicine"},{"key":"ref_38","first-page":"347","article-title":"Effects of Cannabinoids on Spermatogensis in Mice","volume":"Volume 1","author":"Nahas","year":"1999","journal-title":"Marijuana and Medicine"},{"key":"ref_39","first-page":"25","article-title":"Effects of cannabis and natural cannabinoids on chromosomes and ova","volume":"44","author":"Morishima","year":"1984","journal-title":"NIDA Res. Monogr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1210\/jc.2004-1287","article-title":"Human sperm express cannabinoid receptor Cb1, the activation of which inhibits motility, acrosome reaction, and mitochondrial function","volume":"90","author":"Rossato","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1111\/j.1365-2826.2008.01680.x","article-title":"The cannabinoid system and male reproductive functions","volume":"20","author":"Rossato","year":"2008","journal-title":"J. Neuroendocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5017","DOI":"10.1210\/en.2010-0133","article-title":"Cannabinoid receptor 1 influences chromatin remodeling in mouse spermatids by affecting content of transition protein 2 mRNA and histone displacement","volume":"151","author":"Chioccarelli","year":"2010","journal-title":"Endocrinology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s00204-018-2322-9","article-title":"Low doses of widely consumed cannabinoids (cannabidiol and cannabidivarin) cause DNA damage and chromosomal aberrations in human-derived cells","volume":"93","author":"Russo","year":"2019","journal-title":"Arch. Toxicol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/S0002-9378(16)33653-5","article-title":"Chromosome breakage in users of marihuana","volume":"118","author":"Stenchever","year":"1974","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/234227a0","article-title":"Morphological and cytochemical effects of marijuana cigarette smoke on epithelioid cells of lung explants from mice","volume":"234","author":"Leuchtenberger","year":"1971","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1093\/genetics\/23.4.315","article-title":"The Production of Homozygous Deficient Tissues with Mutant Characteristics by Means of the Aberrant Mitotic Behavior of Ring-Shaped Chromosomes","volume":"23","author":"McClintock","year":"1938","journal-title":"Genetics"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3392","DOI":"10.1016\/j.celrep.2018.05.039","article-title":"Integrated Molecular Characterization of Testicular Germ Cell Tumors","volume":"23","author":"Shen","year":"2018","journal-title":"Cell Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/j.biopsych.2011.06.027","article-title":"Maternal cannabis use alters ventral striatal dopamine D2 gene regulation in the offspring","volume":"70","author":"DiNieri","year":"2011","journal-title":"Biol. Psychiatry"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1038\/npp.2013.352","article-title":"Parental THC exposure leads to compulsive heroin-seeking and altered striatal synaptic plasticity in the subsequent generation","volume":"39","author":"Szutorisz","year":"2014","journal-title":"Neuropsychopharmacology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2993","DOI":"10.1038\/npp.2015.155","article-title":"Genome-Wide DNA Methylation Profiling Reveals Epigenetic Changes in the Rat Nucleus Accumbens Associated with Cross-Generational Effects of Adolescent THC Exposure","volume":"40","author":"Watson","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.biopsych.2015.09.014","article-title":"Epigenetic Effects of Cannabis Exposure","volume":"79","author":"Szutorisz","year":"2016","journal-title":"Biol. Psychiatry"},{"key":"ref_52","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":"ref_53","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.biopsych.2021.09.017","article-title":"Prenatal \u0394(9)-Tetrahydrocannabinol Exposure in Males Leads to Motivational Disturbances Related to Striatal Epigenetic Dysregulation","volume":"92","author":"Ellis","year":"2021","journal-title":"Biol. Psychiatry"},{"key":"ref_54","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":"ref_55","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/eep\/dvab009","article-title":"Refraining from use diminishes cannabis-associated epigenetic changes in human sperm","volume":"7","author":"Schrott","year":"2021","journal-title":"Environ. Epigenetics"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/BF00372766","article-title":"delta-9-Tetrahydrocannabinol: Effect on macromolecular synthesis in human and other mammalian cells","volume":"35","author":"Blevins","year":"1976","journal-title":"Arch. Toxicol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1159\/000136610","article-title":"Action of delta 9-tetrahydrocannabinol on cell division and macromolecular synthesis in division-synchronized protozoa","volume":"14","author":"McClean","year":"1976","journal-title":"Pharmacology"},{"key":"ref_58","first-page":"1748","article-title":"Effects of cannabinoids on macromolecular synthesis and replication of cultured lymphocytes","volume":"36","author":"Nahas","year":"1977","journal-title":"Fed. Proc."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1016\/0006-2952(78)90553-1","article-title":"Influence of delta9-tetrahydrocannabinol on cell proliferation and macromolecular biosynthesis in human cells","volume":"27","author":"Mon","year":"1978","journal-title":"Biochem. Pharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/0006-2952(81)90282-3","article-title":"Influence of psychoactive and nonpsychoactive cannabinoids on cell proliferation and macromolecular biosynthesis in human cells","volume":"30","author":"Mon","year":"1981","journal-title":"Biochem. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/0006-2952(81)90282-3","article-title":"Influence of psychoactive and nonpsychoactive cannabinoids on chromatin structure and function in human cells","volume":"30","author":"Mon","year":"1981","journal-title":"Biochem. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"18707","DOI":"10.1074\/jbc.M113.545210","article-title":"Histone modifications are associated with Delta9-tetrahydrocannabinol-mediated alterations in antigen-specific T cell responses","volume":"289","author":"Yang","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"248","DOI":"10.4081\/aiua.2022.2.248","article-title":"The association of bladder cancer and Cannabis: A systematic review","volume":"94","author":"Mehrnoush","year":"2022","journal-title":"Arch. Ital. Urol. Androl."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1097\/JU.0000000000000248","article-title":"Cannabis and Male Fertility: A Systematic Review","volume":"202","author":"Payne","year":"2019","journal-title":"J. Urol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0304-3835(79)80088-9","article-title":"Mutagenic activity of marihuana smoke condensates","volume":"6","author":"Busch","year":"1979","journal-title":"Cancer Lett."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1159\/000137442","article-title":"Influence of cannabinoids on somatic cells in vivo","volume":"21","author":"Zimmerman","year":"1980","journal-title":"Pharmacology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/0091-3057(91)90372-9","article-title":"Influence of marihuana on cellular structures and biochemical activities","volume":"40","author":"Tahir","year":"1991","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0006-8993(98)00766-5","article-title":"Maternal exposure to delta9-tetrahydrocannabinol facilitates morphine self-administration behavior and changes regional binding to central mu opioid receptors in adult offspring female rats","volume":"807","author":"Vela","year":"1998","journal-title":"Brain Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.taap.2014.03.014","article-title":"Investigation of the in vitro toxicological properties of the synthetic cannabimimetic drug CP-47,497-C8","volume":"277","author":"Koller","year":"2014","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.fct.2015.03.004","article-title":"Genotoxic properties of representatives of alkylindazoles and aminoalkyl-indoles which are consumed as synthetic cannabinoids","volume":"80","author":"Koller","year":"2015","journal-title":"Food Chem. Toxicol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"454","DOI":"10.3181\/00379727-140-36478","article-title":"Transformation of Fischer rat embryo cells by the combined action of murine leukemia virus and (-)-trans- 9 -tetrahydrocannabinol","volume":"140","author":"Price","year":"1972","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3265","DOI":"10.1007\/s00204-020-02821-3","article-title":"Following the adverse outcome pathway from micronucleus to cancer using H2B-eGFP transgenic healthy stem cells","volume":"94","author":"Pfannkuche","year":"2020","journal-title":"Arch. Toxicol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1139\/o92-162","article-title":"Cytoskeletal organization following cannabinoid treatment in undifferentiated and differentiated PC12 cells","volume":"70","author":"Tahir","year":"1992","journal-title":"Biochem. Cell Biol."},{"key":"ref_74","first-page":"L298","article-title":"Delta 9-tetrahydrocannabinol disrupts mitochondrial function and cell energetics","volume":"284","author":"Sarafian","year":"2003","journal-title":"Am. J. Physiol."},{"key":"ref_75","first-page":"L1202","article-title":"Inhaled marijuana smoke disrupts mitochondrial energetics in pulmonary epithelial cells in vivo","volume":"290","author":"Sarafian","year":"2006","journal-title":"Am. J. Physiol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"20739","DOI":"10.1074\/jbc.M700133200","article-title":"Identification and characterization of cannabinoids that induce cell death through mitochondrial permeability transition in Cannabis leaf cells","volume":"282","author":"Morimoto","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.toxlet.2014.09.002","article-title":"Cannabinoid-induced changes in respiration of brain mitochondria","volume":"231","author":"Fisar","year":"2014","journal-title":"Toxicol. Lett."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1007\/s12031-015-0545-2","article-title":"Cannabinoid-Induced Changes in the Activity of Electron Transport Chain Complexes of Brain Mitochondria","volume":"56","author":"Singh","year":"2015","journal-title":"J. Mol. Neurosci."},{"key":"ref_79","unstructured":"Gant, J. (2019). Daily Mail, Daily Mail."},{"key":"ref_80","unstructured":"Agence France-Presse in Paris (2018). The Guardian, The Guardian."},{"key":"ref_81","unstructured":"Willsher, K. (2018). Guardian, The Guardian."},{"key":"ref_82","unstructured":"(2022, September 18). Babies Born with Deformed Hands Spark Investigation in Germany. Available online: https:\/\/edition.cnn.com\/2019\/09\/16\/health\/hand-deformities-babies-gelsenkirchen-germany-intl-scli-grm\/index.html."},{"key":"ref_83","unstructured":"(2022, January 01). VACTERL Association. Available online: https:\/\/www.gosh.nhs.uk\/conditions-and-treatments\/conditions-we-treat\/vacterl-association-0\/."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Reece, A.S., and Hulse, G.K. (2022). Epidemiological Patterns of Cannabis- and Substance- Related General Congenital Anomalies Across Europe 2010\u20132019: Space-Time and Causal Inference Study, manuscript submitted.","DOI":"10.1093\/eep\/dvac015"},{"key":"ref_85","unstructured":"(2022, January 01). Eurocat Data: Prevalence Charts and Tables. Available online: https:\/\/eu-rd-platform.jrc.ec.europa.eu\/eurocat\/eurocat-data\/prevalence_en."},{"key":"ref_86","unstructured":"(2021, October 01). Global Health Observatory. Available online: https:\/\/www.who.int\/data\/gho\/data\/indicators\/indicator-details\/GHO\/total-(recorded-unrecorded)-alcohol-per-capita-(15-)-consumption."},{"key":"ref_87","unstructured":"European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) (2021, October 01). Statistical Bulletin 2021\u2014Prevalence of Drug Use. Available online: https:\/\/www.emcdda.europa.eu\/data\/stats2021\/gps_en."},{"key":"ref_88","unstructured":"The World Bank (2021, October 01). Crude Data: Adjusted Net National Income per Capita (Current US$). Available online: https:\/\/data.worldbank.org\/indicator\/NY.ADJ.NNTY.PC.CD."},{"key":"ref_89","unstructured":"(2021, October 01). R: A Language and Environment for Statistical Computing. Available online: https:\/\/cran.r-project.org\/."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.21105\/joss.01686","article-title":"Welcome to the Tidyverse","volume":"4","author":"Wickham","year":"2019","journal-title":"J. Open Source Softw."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"439","DOI":"10.32614\/RJ-2018-009","article-title":"Simple Features for R: Standardized Support for Spatial Vector Data","volume":"10","author":"Pebesma","year":"2018","journal-title":"R J."},{"key":"ref_92","unstructured":"(2021, October 01). Viridis: Default Color Maps from \u2018matplotlib\u2019. Available online: https:\/\/CRAN.R-project.org\/package=viridis."},{"key":"ref_93","unstructured":"(2021, October 01). Colorplaner: Ggplot2 Extension to Visualize Two Variables Per Color Aesthetic Through Colorspace Projection. Available online: https:\/\/github.com\/wmurphyrd\/colorplaner."},{"key":"ref_94","first-page":"1","article-title":"Linear and Nonlinear Mixed Effects Models","volume":"3","author":"Pinheiro","year":"2020","journal-title":"R Package Version"},{"key":"ref_95","unstructured":"(2021, October 01). Broom.Mixed: Tidying Methods for Mixed Models. Available online: http:\/\/github.com\/bbolker\/broom.mixed."},{"key":"ref_96","unstructured":"(2021, October 01). Broom: Convert Statistical Objects into Tidy Tibbles. Available online: https:\/\/CRAN.R-project.org\/package=broom."},{"key":"ref_97","unstructured":"Leeper, T.J. (2021). Margins: Marginal Effects for Model Objects, Central R Archive Network. R package version 0.3.26."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v077.i01","article-title":"ranger: A Fast Implementation of Random Forests for High Dimensional Data in C++ and R","volume":"77","author":"Wright","year":"2017","journal-title":"J. Stat. Softw."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"343","DOI":"10.32614\/RJ-2020-013","article-title":"Variable Importance Plots\u2014An Introduction to the vip Package","volume":"12","author":"Greenwell","year":"2021","journal-title":"R J."},{"key":"ref_100","unstructured":"(2021, October 01). Package \u2018plm\u2019. Available online: https:\/\/cran.r-project.org\/web\/packages\/plm\/plm.pdf."},{"key":"ref_101","unstructured":"Bivand, R., Anselin, L., Berke, O., Bernat, A., Carvalho, M., Chun, Y., Dormann, C., Dray, S., Halbersma, R., and Lewis-Koh, N. (2007). The spdep Package, CRAN (Central R-Archive Network)."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v047.i01","article-title":"splm: Spatial Panel Data Models in R","volume":"47","author":"Millo","year":"2012","journal-title":"J. Stat. Softw."},{"key":"ref_103","unstructured":"Millo, G., and Piras, G. (2018). Package \u2018splm\u2019, CRAN (Central R-Archive Network). Available online: https:\/\/cran.r-project.org\/web\/packages\/splm\/splm.pdf."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Croissant, Y., and Millo, G. (2019). Panel Data Econometrics with R, John Wiley and Sons.","DOI":"10.1002\/9781119504641"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v043.i13","article-title":"ipw: An R Package for Inverse Probability Weighting","volume":"43","author":"Wal","year":"2011","journal-title":"J. Stat. Softw."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"268","DOI":"10.7326\/M16-2607","article-title":"Sensitivity Analysis in Observational Research: Introducing the E-Value","volume":"167","author":"VanderWeele","year":"2017","journal-title":"Ann. Intern. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"e51","DOI":"10.1097\/EDE.0000000000001238","article-title":"E-values and incidence density sampling","volume":"31","author":"VanderWeele","year":"2020","journal-title":"Epidemiology"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1093\/ije\/dyaa094","article-title":"Commentary: Developing best-practice guidelines for the reporting of E-values","volume":"49","author":"VanderWeele","year":"2020","journal-title":"Int. J. Epidemiol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1515\/jci-2018-0007","article-title":"Technical Considerations in the Use of the E-Value","volume":"7","author":"VanderWeele","year":"2019","journal-title":"J. Causal Inference"},{"key":"ref_110","unstructured":"Pearl, J., and Mackaenzie, D. (2019). The Book of Why. The New Science of Cause and Effect, Basic Books."},{"key":"ref_111","unstructured":"(2021, October 01). Package \u2018EValue\u2019. Available online: https:\/\/cran.r-project.org\/web\/packages\/EValue\/EValue.pdf."},{"key":"ref_112","first-page":"295","article-title":"The Environment and Disease: Association or Causation?","volume":"58","author":"Hill","year":"1965","journal-title":"Proc. R Soc. Med."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1","DOI":"10.35248\/2572-0775.19.4.154","article-title":"Effect of Cannabis Legalization on US Autism Incidence and Medium Term Projections","volume":"4","author":"Reece","year":"2019","journal-title":"Clin. Pediatrics Open Access"},{"key":"ref_114","first-page":"k3357","article-title":"Rapid Response: Known Cannabis Teratogenicity Needs to be Carefully Considered","volume":"362","author":"Reece","year":"2018","journal-title":"BMJ"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1080\/15592294.2019.1633868","article-title":"Impacts of cannabinoid epigenetics on human development: Reflections on Murphy et al. \u2018cannabinoid exposure and altered DNA methylation in rat and human sperm\u2019 epigenetics","volume":"14","author":"Reece","year":"2019","journal-title":"Epigenetics"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"16057","DOI":"10.1038\/s41598-019-52336-w","article-title":"Cannabinoids exacerbate alcohol teratogenesis by a CB1-hedgehog interaction","volume":"9","author":"Fish","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"23892","DOI":"10.1074\/jbc.M700678200","article-title":"The CB1 cannabinoid receptor mediates excitotoxicity-induced neural progenitor proliferation and neurogenesis","volume":"282","author":"Aguado","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1083\/jcb.200210164","article-title":"The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response","volume":"160","author":"Williams","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.plipres.2012.08.001","article-title":"Manipulating molecular switches in brown adipocytes and their precursors: A therapeutic potential","volume":"52","author":"Birerdinc","year":"2013","journal-title":"Prog. Lipid Res."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.2741\/3786","article-title":"Brown fat biology and thermogenesis","volume":"16","author":"Richard","year":"2011","journal-title":"Front. Biosci."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1016\/j.cellsig.2013.07.025","article-title":"Orexin receptors: Multi-functional therapeutic targets for sleeping disorders, eating disorders, drug addiction, cancers and other physiological disorders","volume":"25","author":"Xu","year":"2013","journal-title":"Cell. Signal."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"3596","DOI":"10.1210\/EN.2015-1315","article-title":"Lipid Abundance in Zebrafish Embryos Is Regulated by Complementary Actions of the Endocannabinoid System and Retinoic Acid Pathway","volume":"156","author":"Fraher","year":"2015","journal-title":"Endocrinology"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"219","DOI":"10.24869\/psyd.2019.219","article-title":"Genetic susceptibility to posttraumatic stress disorder: Analyses of the oxytocin receptor, retinoic acid receptor-related orphan receptor A and cannabinoid receptor 1 genes","volume":"31","author":"Agani","year":"2019","journal-title":"Psychiatr. Danub."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1111\/j.1440-1746.2011.07007.x","article-title":"Retinoic acids and hepatic stellate cells in liver disease","volume":"27","author":"Lee","year":"2012","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.stem.2021.11.001","article-title":"Genome-wide screening in human kidney organoids identifies developmental and disease-related aspects of nephrogenesis","volume":"29","author":"Ungricht","year":"2022","journal-title":"Cell Stem Cell"},{"key":"ref_126","unstructured":"Carlson, B.M. (2019). Human Embryology and Developmental Biology, Elsevier."}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/19\/21\/13769\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:01:11Z","timestamp":1760144471000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/19\/21\/13769"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,23]]},"references-count":126,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijerph192113769"],"URL":"https:\/\/doi.org\/10.3390\/ijerph192113769","relation":{},"ISSN":["1660-4601"],"issn-type":[{"type":"electronic","value":"1660-4601"}],"subject":[],"published":{"date-parts":[[2022,10,23]]}}}