Molecular mechanisms of maternal cannabis and cigarette use on human neurodevelopment

Abstract

Prenatal development is highly sensitive to maternal drug use due to the vulnerability for disruption of the fetal brain with its ongoing neurodevelopment, resulting in lifelong consequences that can enhance risk for psychiatric disorders. Cannabis and cigarettes are the most commonly used illicit and licit substances, respectively, among pregnant women. Although the behavioral consequences of prenatal cannabis and cigarette exposure have been well-documented in epidemiological and clinical studies, only recently have investigations into the molecular mechanisms associated with the developmental impact of early drug exposure been addressed. This article reviews the literature relevant to long-term gene expression disturbances in the human fetal brain in relation to maternal cannabis and cigarette use. To provide translational insights, we discuss animal models in which protracted molecular consequences of prenatal cannabis and cigarette exposure can be better explored and which enable future evaluation of epigenetic pathways, such as DNA methylation and histone modification, that could potentially maintain abnormal gene regulation and related behavioral disturbances. Altogether, this information may help to address the current gaps of knowledge regarding the impact of early drug exposure that set in motion lifelong molecular disturbances that underlie vulnerability to psychiatric disorders.

Figure 1

Overview of developmental effects associated with prenatal cannabis and cigarette exposure in human subjects. Data compiled from two longitudinal studies Ottawa Prenatal Prospective Study and Maternal Health Practices and Childhood Development Project that followed offspring from mothers who used marijuana or cigarettes during pregnancy that are representative of other epidemiological studies. Maternal cannabis and cigarette use is clearly associated with neurobehavioral disturbances that persist into adulthood. Overall, in utero cannabis and cigarette exposure is characterized by impaired cognitive functioning, impulsivity, hyperactivity, and increased risk of developing an addiction disorder.

Figure 2. Mesolimbic dopamine D₂R gene is vulnerable to prenatal cannabis exposure

Prenatal cannabis affects dopamine D₂R gene expression in the nucleus accumbens of the human midgestational fetus exposed to cannabis in utero. The effects are mimicked in the prenatal THC animal model studied at postnatal day 2 (PND2; comparable to the midgestation human fetal period) and the early developmental disturbances on the Drd2 mRNA expression persist into adulthood (PND62) and are mediated by epigenetic modifications at the Drd2 promoter. Data modified from (Dinieri et al., 2011) 2meH3K9, di-methylation of lysine 9 on histone H3; 3meH3K4, tri-methylation of lysine 4 on histone H3; KB, kilobases; RNA Poly II, RNA Polymerase II; TSS, transcription start site. Values are expressed as mean ± SEM. *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001 vs control subjects. Black bars, THC exposed group; white bars, vehicle-exposed group; kb, kilobases; TSS, transcription start site.

Figure 3. A few possible epigenetic regulatory mechanisms that can be disrupted by maternal cannabis and nicotine u se, leading to persistent abnormal gene expression levels

Changes in DNA methylation at CpG islands, along with post-translational modification of histones, can create ‘repressive’ (transcriptionally silent) and ‘permissive’ (transcriptionally active) chromatin states. These states are dynamically regulated by the activities of DNA or histone modifying and chromatin remodeling enzymes and exposure to drugs during prenatal development is likely to disrupt the balance of repressive and permissive mechanisms. In silent chromatin, methylation of H3 lysine 9 (meK9) and lysine 27 (meK27) is known to be associated with the binding of repressor complexes (Rep) and this leads to chromatin condensation and decreased accessibility of the gene. In the permissive state, methylation of H3 lysine 4 (meK4) and acetylation (ac) is often associated with the binding of activator proteins (Act), generating increased accessibility for the recruitment of the RNA polymerase II transcription machinery (Pol II). Prenatal THC exposure was recently shown to enhance dimethylation of H3K9 of the dopamine D₂ R gene promoter in adult animals relevant to the THC-induced long-term impairment on gene expression (see Figure 3). MicroRNAs can regulate mRNA levels post-transciptionally and changes in the neuronal microRNA populations due to developmental drug exposure may lead to disturbances in protein function. TSS, transcription start site.