hiPSC-Based Model of Prenatal Exposure to Cannabinoids: Effect on Neuronal Differentiation

Miranda, Cláudia C.; Barata, Tiago; Vaz, Sandra H.; Ferreira, Carla; Quintas, Alexandre; Bekman, Evguenia

doi:10.3389/fnmol.2020.00119

Cited by 17 publications

(12 citation statements)

References 48 publications

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“…For example, in a recent study, human induced pluripotent stem cells (hiPSC) induced toward neuronal commitment, thus mimicking developing fetal neurons, were exposed to Δ9–THC and CBD for 37 days ( 86 ). At the clinically-relevant doses studied, CBD produced neurotoxic effects, while Δ9–THC promoted precocious neuronal and glial differentiation, and induced abnormal functioning of voltage-gated calcium channels.…”

Section: Neurodevelopmental Outcomes Of Prenatal Cannabinoid Exposurementioning

confidence: 99%

Prenatal Cannabinoid Exposure: Emerging Evidence of Physiological and Neuropsychiatric Abnormalities

2021

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Clinical reports of cannabis use prevalence during pregnancy vary widely from 3% to upwards of 35% in North America; this disparity likely owing to underestimates from self-reporting in many cases. The rise in cannabis use is mirrored by increasing global legalization and the overall perceptions of safety, even during pregnancy. These trends are further compounded by a lack of evidence-based policy and guidelines for prenatal cannabis use, which has led to inconsistent messaging by healthcare providers and medically licensed cannabis dispensaries regarding prenatal cannabis use for treatment of symptoms, such as nausea. Additionally, the use of cannabis to self-medicate depression and anxiety during pregnancy is a growing medical concern. This review aims to summarize recent findings of clinical and preclinical data on neonatal outcomes, as well as long-term physiological and neurodevelopmental outcomes of prenatal cannabis exposure. Although many of the outcomes under investigation have produced mixed results, we consider these data in light of the unique challenges facing cannabis research. In particular, the limited longitudinal clinical studies available have not previously accounted for the exponential increase in (-)-Δ9– tetrahydrocannabinol (Δ9–THC; the psychoactive compound in cannabis) concentrations found in cannabis over the past two decades. Polydrug use and the long-term effects of individual cannabis constituents [Δ9–THC vs. cannabidiol (CBD)] are also understudied, along with sex-dependent outcomes. Despite these limitations, prenatal cannabis exposure has been linked to low birth weight, and emerging evidence suggests that prenatal exposure to Δ9–THC, which crosses the placenta and impacts placental development, may have wide-ranging physiological and neurodevelopmental consequences. The long-term effects of these changes require more rigorous investigation, though early reports suggest Δ9–THC increases the risk of cognitive impairment and neuropsychiatric disease, including psychosis, depression, anxiety, and sleep disorders. In light of the current trends in the perception and use of cannabis during pregnancy, we emphasize the social and medical imperative for more rigorous investigation of the long-term effects of prenatal cannabis exposure.

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Section: Neurodevelopmental Outcomes Of Prenatal Cannabinoid Exposurementioning

confidence: 99%

Prenatal Cannabinoid Exposure: Emerging Evidence of Physiological and Neuropsychiatric Abnormalities

2021

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“…Little is known about the specific effects of CBD on the developing brain. In a study in which human induced pluripotent stem cells (hiPSC) were induced to differentiate into neuronal cells, thus mimicking developing fetal neurons, ∆ 9 -THC (10 µM) promoted precocious neuronal and glial differentiation, while CBD was neurotoxic at the same concentration [201]. In a recent study conducted in mice, adult F1 offspring that were perinatally exposed to CBD exhibited differentially methylated loci in the cerebral cortex and hippocampus, as well as sex-specific increases in anxiety and memory [202].…”

Section: Neurological Impactsmentioning

confidence: 99%

The Impact of Early Life Exposure to Cannabis: The Role of the Endocannabinoid System

Martínez-Peña

Perono

Gritis

et al. 2021

IJMS

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Cannabis use during pregnancy has continued to rise, particularly in developed countries, as a result of the trend towards legalization and lack of consistent, evidence-based knowledge on the matter. While there is conflicting data regarding whether cannabis use during pregnancy leads to adverse outcomes such as stillbirth, preterm birth, low birthweight, or increased admission to neonatal intensive care units, investigations into long-term effects on the offspring’s health are limited. Historically, studies have focused on the neurobehavioral effects of prenatal cannabis exposure on the offspring. The effects of cannabis on other physiological aspects of the developing fetus have received less attention. Importantly, our knowledge about cannabinoid signaling in the placenta is also limited. The endocannabinoid system (ECS) is present at early stages of development and represents a potential target for exogenous cannabinoids in utero. The ECS is expressed in a broad range of tissues and influences a spectrum of cellular functions. The aim of this review is to explore the current evidence surrounding the effects of prenatal exposure to cannabinoids and the role of the ECS in the placenta and the developing fetus.

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“…This result is important, as it addresses and contributes to a major point of contention within the literature. Notably, while there is consensus that prenatal cannabinoid exposure likely alters human neuron development [ 148 ] and function [ 149 ] in a manner that likely induces protracted risk to behavioral alterations [ 150 , 151 ], there is conflicting data regarding the specificity of cannabinoid use/abuse/stimulation/modeling upon cell death. For example, synthetic cannabinoids (the accessibility and abuse of which have become a major public health concern [ 148 ]) have been shown to elicit cytotoxic effects via the CB 1 receptor in mouse forebrain cultures [ 152 ].…”

Section: Discussionmentioning

confidence: 99%

Neurodevelopmental signatures of narcotic and neuropsychiatric risk factors in 3D human-derived forebrain organoids

et al. 2021

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It is widely accepted that narcotic use during pregnancy and specific environmental factors (e.g., maternal immune activation and chronic stress) may increase risk of neuropsychiatric illness in offspring. However, little progress has been made in defining human-specific in utero neurodevelopmental pathology due to ethical and technical challenges associated with accessing human prenatal brain tissue. Here we utilized human induced pluripotent stem cells (hiPSCs) to generate reproducible organoids that recapitulate dorsal forebrain development including early corticogenesis. We systemically exposed organoid samples to chemically defined “enviromimetic” compounds to examine the developmental effects of various narcotic and neuropsychiatric-related risk factors within tissue of human origin. In tandem experiments conducted in parallel, we modeled exposure to opiates (μ-opioid agonist endomorphin), cannabinoids (WIN 55,212-2), alcohol (ethanol), smoking (nicotine), chronic stress (human cortisol), and maternal immune activation (human Interleukin-17a; IL17a). Human-derived dorsal forebrain organoids were consequently analyzed via an array of unbiased and high-throughput analytical approaches, including state-of-the-art TMT-16plex liquid chromatography/mass-spectrometry (LC/MS) proteomics, hybrid MS metabolomics, and flow cytometry panels to determine cell-cycle dynamics and rates of cell death. This pipeline subsequently revealed both common and unique proteome, reactome, and metabolome alterations as a consequence of enviromimetic modeling of narcotic use and neuropsychiatric-related risk factors in tissue of human origin. However, of our 6 treatment groups, human-derived organoids treated with the cannabinoid agonist WIN 55,212-2 exhibited the least convergence of all groups. Single-cell analysis revealed that WIN 55,212-2 increased DNA fragmentation, an indicator of apoptosis, in human-derived dorsal forebrain organoids. We subsequently confirmed induction of DNA damage and apoptosis by WIN 55,212-2 within 3D human-derived dorsal forebrain organoids. Lastly, in a BrdU pulse-chase neocortical neurogenesis paradigm, we identified that WIN 55,212-2 was the only enviromimetic treatment to disrupt newborn neuron numbers within human-derived dorsal forebrain organoids. Cumulatively this study serves as both a resource and foundation from which human 3D biologics can be used to resolve the non-genomic effects of neuropsychiatric risk factors under controlled laboratory conditions. While synthetic cannabinoids can differ from naturally occurring compounds in their effects, our data nonetheless suggests that exposure to WIN 55,212-2 elicits neurotoxicity within human-derived developing forebrain tissue. These human-derived data therefore support the long-standing belief that maternal use of cannabinoids may require caution so to avoid any potential neurodevelopmental effects upon developing offspring in utero.

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hiPSC-Based Model of Prenatal Exposure to Cannabinoids: Effect on Neuronal Differentiation

Cited by 17 publications

References 48 publications

Prenatal Cannabinoid Exposure: Emerging Evidence of Physiological and Neuropsychiatric Abnormalities

Prenatal Cannabinoid Exposure: Emerging Evidence of Physiological and Neuropsychiatric Abnormalities

The Impact of Early Life Exposure to Cannabis: The Role of the Endocannabinoid System

Neurodevelopmental signatures of narcotic and neuropsychiatric risk factors in 3D human-derived forebrain organoids

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