Chronic exposure to delta-9-tetrahydrocannabinol impacts testicular volume and male reproductive health in rhesus macaques

Hedges, Jason C.; Hanna, Carol; Bash, Jasper; Boniface, Emily R.; Burch, Fernanda C.; Mahalingaiah, Shruthi; Roberts, Victoria H. J.; Terrobias, Juanito Jose D.; Mishler, Emily; Jensen, Jared V.; Easley, Charles A.; Lo, Jamie O.

doi:10.1016/j.fertnstert.2021.12.028

Cited by 15 publications

(11 citation statements)

References 44 publications

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“…This study was notable for a significant decrease in fetal testicular weight associated with maternal cannabis consumption. Although this finding was in a small sample, it is consistent with our published findings of a significant impact of chronic cannabis use on adult male testicular atrophy 25 . This is likely in part due to the presence of CB1 and CB2 receptors in both fetal and adult testes, suggesting that cannabis exposure can adversely affect male reproductive health, even in utero.…”

Section: Discussionsupporting

confidence: 93%

“…This study used indoor-housed rhesus macaques (n = 10) maintained on a standard chow diet (TestDiet, St. Louis, Missouri). Cookies containing THC (THC edible) were made using research-grade THC obtained directly from the National Institute of Drug Abuse (NIDA) 24,25 .…”

Section: Methodsmentioning

confidence: 99%

“…To address key gaps in the evidence and overcome the limitations of previous human studies, we built upon our novel non-human primate (NHP) model of chronic cannabis exposure via edible THC consumption 24,25 . Edibles are the second most common mode of cannabis delivery 26 , especially in non-daily pregnant users 27 , and are often recommended by dispensaries to pregnant individuals for nausea 28 .…”

mentioning

confidence: 99%

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Chronic prenatal delta-9-tetrahydrocannabinol exposure adversely impacts placental function and development in a rhesus macaque model

Roberts

Schabel

Boniface

et al. 2022

Sci Rep

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Cannabis use in pregnancy is associated with adverse perinatal outcomes, which are likely mediated by the placenta. However, the underlying mechanisms and specific vasoactive effects of cannabis on the placenta are unknown. Our objective was to determine the impact of chronic prenatal delta-tetrahydrocannabinol (THC, main psychoactive component of cannabis) exposure on placental function and development in a rhesus macaque model using advanced imaging. Animals were divided into two groups, control (CON, n = 5) and THC-exposed (THC, n = 5). THC-exposed animals received a THC edible daily pre-conception and throughout pregnancy. Animals underwent serial ultrasound and MRI at gestational days 85 (G85), G110, G135 and G155 (full term is ~ G168). Animals underwent cesarean delivery and placental collection at G155 for histologic and RNA-Seq analysis. THC-exposed pregnancies had significantly decreased amniotic fluid volume (p < 0.001), placental perfusion (p < 0.05), and fetal oxygen availability (p < 0.05), all indicators of placental insufficiency. Placental histological analysis demonstrated evidence of ischemic injury with microinfarctions present in THC-exposed animals only. Bulk RNA-seq demonstrated that THC alters the placental transcriptome and pathway analysis suggests dysregulated vasculature development and angiogenesis pathways. The longer-term consequences of these adverse placental findings are unknown, but they suggest that use of THC during pregnancy may deleteriously impact offspring development.

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Section: Discussionsupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Chronic prenatal delta-9-tetrahydrocannabinol exposure adversely impacts placental function and development in a rhesus macaque model

Roberts

Schabel

Boniface

et al. 2022

Sci Rep

Self Cite

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“…Animals were slowly titrated up to 2.5 mg/7 kg/day of THC using published weight-based medical cannabis acclimation recommendations [72] approximately 4 months prior to undergoing time-mated breeding as previously published [40]. We previously established [40,41] that NHP peak THC levels are within the expected reported contemporary dosing range (e.g., 5-8 ng/mL) in humans 3 h following a similar oral THC dose [84,85]. Each THC-exposed pregnant animal (n = 5) continued to consume a daily THC edible of 2.5 mg/7 kg/day throughout pregnancy.…”

Section: Experimental Designmentioning

confidence: 99%

Prenatal delta-9-tetrahydrocannabinol exposure is associated with changes in rhesus macaque DNA methylation enriched for autism genes

et al. 2023

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Background With the growing availability of cannabis and the popularization of additional routes of cannabis use beyond smoking, including edibles, the prevalence of cannabis use in pregnancy is rapidly increasing. However, the potential effects of prenatal cannabis use on fetal developmental programming remain unknown. Results We designed this study to determine whether the use of edible cannabis during pregnancy is deleterious to the fetal and placental epigenome. Pregnant rhesus macaques consumed a daily edible containing either delta-9-tetrahydrocannabinol (THC) (2.5 mg/7 kg/day) or placebo. DNA methylation was measured in 5 tissues collected at cesarean delivery (placenta, lung, cerebellum, prefrontal cortex, and right ventricle of the heart) using the Illumina MethylationEPIC platform and filtering for probes previously validated in rhesus macaque. In utero exposure to THC was associated with differential methylation at 581 CpGs, with 573 (98%) identified in placenta. Loci differentially methylated with THC were enriched for candidate autism spectrum disorder (ASD) genes from the Simons Foundation Autism Research Initiative (SFARI) database in all tissues. The placenta demonstrated greatest SFARI gene enrichment, including genes differentially methylated in placentas from a prospective ASD study. Conclusions Overall, our findings reveal that prenatal THC exposure alters placental and fetal DNA methylation at genes involved in neurobehavioral development that may influence longer-term offspring outcomes. The data from this study add to the limited existing literature to help guide patient counseling and public health polices focused on prenatal cannabis use in the future.

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“…This hypothesis is supported by research conducted on rhesus macaques, where chronic exposure to THC resulted in notable testicular atrophy in a dose-dependent manner, accompanied by elevated serum gonadotropin levels and diminished serum sex steroids. These findings indicate a potential occurrence of primary testicular failure (Hedges et al, 2022). Cannabis use can also reduce sperm count and motility, which can lead to infertility in some males (Gunder et al, 2015;Du Plessis et al, 2015).…”

Section: Sex Differences In Health and Quality Of Lifementioning

confidence: 95%

Sex Differences in Cannabis Use and Effects

Omar,

Shirazi

2023

J Stud Res

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Cannabis, the most widely used illicit substance globally, has seen a significant increase in usage, driven by the growth of the cannabis industry and evolving public opinion on potential risks. Understanding the differential effects of cannabis on males and females is becoming increasingly significant. This paper aims to investigate the sex differences in cannabis use, including patterns, motivations, and physiological responses, and their impact on health and well-being. Usage patterns exhibit variations between genders, with men using cannabis more frequently, in larger quantities, and starting at a younger age. Conversely, women tend to experience a "telescoping effect," progressing more rapidly from initial use to dependence. Sex differences are observed in the effects of cannabis, including increased heart rate and heightened sensitivity in women, and long-term consequences like Cannabis Use Disorder (CUD) and cognitive impairment in men. Cannabis use has also been linked to negative effects on reproductive health in women, as well as sexual function and testosterone levels in men. Mental health concerns are also prevalent, with women at a higher risk of developing dependence and experiencing severe withdrawal symptoms. Conversely, heavy cannabis use may exacerbate anxiety and depression in men. Further research is imperative to inform the general population and the healthcare industry, enabling informed decision-making regarding the potential benefits and risks of cannabis use. This knowledge will facilitate the development of gender-specific prevention and treatment strategies for cannabis use disorders, promoting the overall well-being of individuals.

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Chronic exposure to delta-9-tetrahydrocannabinol impacts testicular volume and male reproductive health in rhesus macaques

Cited by 15 publications

References 44 publications

Chronic prenatal delta-9-tetrahydrocannabinol exposure adversely impacts placental function and development in a rhesus macaque model

Chronic prenatal delta-9-tetrahydrocannabinol exposure adversely impacts placental function and development in a rhesus macaque model

Prenatal delta-9-tetrahydrocannabinol exposure is associated with changes in rhesus macaque DNA methylation enriched for autism genes

Sex Differences in Cannabis Use and Effects

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