Metabolic consequences of gestational cannabinoid exposure

Up to 20% of pregnant women ages 18–24 consume cannabis during pregnancy. Moreover, clinical studies indicate that cannabis consumption during pregnancy leads to fetal growth restriction (FGR), which is associated with an increased risk of obesity, type II diabetes (T2D), and cardiovascular disease in the offspring. This is of great concern considering that the concentration of D9- tetrahydrocannabinol (D9-THC), a major psychoactive component of cannabis, has doubled over the last decade and can readily cross the placenta and enter fetal circulation, with the potential to negatively impact fetal development via the endocannabinoid (eCB) system. Cannabis exposure in utero could also lead to FGR via placental insufficiency. In this review, we aim to examine current pre-clinical and clinical findings on the direct effects of exposure to cannabis and its constituents on fetal development as well as indirect effects, namely placental insufficiency, on postnatal metabolic diseases

Exposure to Δ9-tetrahydrocannabinol during rat pregnancy leads to impaired cardiac dysfunction in postnatal life

Background: Cannabis use in pregnancy leads to fetal growth restriction (FGR), but the long-term effects on cardiac function in the offspring are unknown, despite the fact that fetal growth deficits are associated with an increased risk of developing postnatal cardiovascular disease. We hypothesize that maternal exposure to Δ9-tetrahydrocannabinol (Δ9-THC) during pregnancy will impair fetal development, leading to cardiac dysfunction in the offspring. Methods: Pregnant Wistar rats were randomly selected and administered 3 mg/kg of Δ9-THC or saline as a vehicle daily via intraperitoneal injection from gestational days 6 to 22, followed by echocardiogram analysis of cardiac function on offspring at postnatal days 1 and 21. Heart tissue was harvested from the offspring at 3 weeks for molecular analysis of cardiac remodelling. Results: Exposure to Δ9-THC during pregnancy led to FGR with a significant decrease in heart-to-body weight ratios at birth. By 3 weeks, pups exhibited catch-up growth associated with significantly greater left ventricle anterior wall thickness with a decrease in cardiac output. Moreover, these Δ9-THC-exposed offsprings exhibited increased expression of collagen I and III, decreased matrix metallopeptidase-2 expression, and increased inactivation of glycogen synthase kinase-3β, all associated with cardiac remodelling. Conclusions: Collectively, these data suggest that Δ9-THC-exposed FGR offspring undergo postnatal catch-up growth concomitant with cardiac remodelling and impaired cardiac function early in life. Impact: To date, the long-term effects of perinatal Δ9-THC (the main psychoactive component) exposure on the cardiac function in the offspring remain unknown.We demonstrated, for the first time, that exposure to Δ9-THC alone during rat pregnancy results in significantly smaller hearts relative to body weight.These Δ9-THC-exposed offsprings exhibited postnatal catch-up growth concomitant with cardiac remodelling and impaired cardiac function.Given the increased popularity of cannabis use in pregnancy along with rising Δ9-THC concentrations, this study, for the first time, identifies the risk of perinatal Δ9-THC exposure on early postnatal cardiovascular health

In utero exposure to Δ9‐tetrahydrocannabinol leads to postnatal catch‐up growth and dysmetabolism in the adult rat liver

The rates of gestational cannabis use have increased despite limited evidence for its safety in fetal life. Recent animal studies demonstrate that prenatal exposure to Δ9‐tetrahydrocannabinol (Δ9‐THC, the psychoactive component of cannabis) promotes intrauterine growth restriction (IUGR), culminating in postnatal metabolic deficits. Given IUGR is associated with impaired hepatic function, we hypothesized that Δ9‐THC offspring would exhibit hepatic dyslipidemia. Pregnant Wistar rat dams received daily injections of vehicular control or 3 mg/kg Δ9‐THC i.p. from embry-onic day (E) 6.5 through E22. Exposure to Δ9‐THC decreased the liver to body weight ratio at birth, followed by catch‐up growth by three weeks of age. At six months, Δ9‐THC‐exposed male offspring exhibited increased visceral adiposity and higher hepatic triglycerides. This was instigated by augmented expression of enzymes involved in triglyceride synthesis (ACCα, SCD, FABP1, and DGAT2) at three weeks. Furthermore, the expression of hepatic DGAT1/DGAT2 was sustained at six months, concomitant with mitochondrial dysfunction (i.e., elevated p66shc) and oxidative stress. Interest-ingly, decreases in miR‐203a‐3p and miR‐29a/b/c, both implicated in dyslipidemia, were also observed in these Δ9‐THC‐exposed offspring. Collectively, these findings indicate that prenatal Δ9‐ THC exposure results in long‐term dyslipidemia associated with enhanced hepatic lipogenesis. This is attributed by mitochondrial dysfunction and epigenetic mechanisms

Lect2 deficiency is characterised by altered cytokine levels and promotion of intestinal tumourigenesis

Leukocyte cell-derived chemotaxin 2 (Lect2) is a chemokine-like chemotactic factor that has been identified as a downstream target of the Wnt signalling pathway. Whilst the primary function of Lect2 is thought to be in modulating the inflammatory process, it has recently been implicated as a potential inhibitor of the Wnt pathway. Deregulation of the Wnt pathway, often due to loss of the negative regulator APC, is found in ~80% of colorectal cancer (CRC). Here we have used the ApcMin/+Lect2−/− mouse model to characterise the role of Lect2 in Wnt-driven intestinal tumourigenesis. Histopathological, immunohistochemical, PCR and flow cytometry analysis were employed to identify the role of Lect2 in the intestine. The ApcMin/+Lect2−/− mice had a reduced mean survival and a significantly increased number of adenomas in the small intestine with increased severity. Analysis of Lect2 loss indicated it had no effect on the Wnt pathway in the intestine but significant differences were observed in circulating inflammatory markers, CD4+ T cells, and T cell lineage-specification factors. In summary, in the murine intestine loss of Lect2 promotes the initiation and progression of Wnt-driven colorectal cancer. This protection is performed independently of the Wnt signalling pathway and is associated with an altered inflammatory environment during Wnt-driven tumorigenesis

Maternal exposure to Δ9-tetrahydrocannabinol impairs female offspring glucose homeostasis and endocrine pancreatic development in the rat.

Recent reports indicate that 7% of pregnant mothers in North America use cannabis. This is concerning given that in utero exposure to Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive component in cannabis, causes fetal growth restriction and may alter replication and survival of pancreatic β-cells in the offspring. Accordingly, we hypothesized that maternal exposure to Δ9-THC during pregnancy would impair postnatal glucometabolic health of offspring. To test this hypothesis, pregnant Wistar rats were treated with daily intraperitoneal injections of either 3 mg/kg Δ9-THC or vehicle from gestational day 6 to birth. Offspring were subsequently challenged with glucose and insulin at 5 months of age to assess glucose tolerance and peripheral muscle insulin sensitivity. Female offspring exposed to Δ9-THC in utero were glucose intolerant, associated with blunted insulin response in muscle and increased serum insulin concentration 15 min after glucose challenge. Additionally, pancreata from male and female offspring were harvested at postnatal day 21 and 5 months of age for assessment of endocrine pancreas morphometry by immunostaining. This analysis revealed that gestational exposure to Δ9-THC reduced the density of islets in female, but not male, offspring at postnatal day 21 and 5 months, culminating in reduced β-cell mass at 5 months. These results demonstrate that fetal exposure to Δ9-THC causes female-specific impairments in glucose homeostasis, raising concern regarding the metabolic health of offspring, particularly females, exposed to cannabis in utero

Amphibole: A major carrier of helium isotopes in crustal rocks

The first evidence for a specific role of amphiboles in He isotope balance of crustal rocks was presented in early contributions by Gerling et al. (1971, 1976). Since then it was shown that 4He and 3He concentrations in amphiboles generally exceed those in the host rock samples. Recently amphibole was considered as an important carrier of noble gases and other volatiles components in the course of their subduction into the mantle. This paper presents new data on the balance and mobility of noble gas isotopes and major gas constituents in amphibole separates in order to understand sources and evolution of volatile components of 2666 Ma old alkaline granites from Ponoy massif (Kola Peninsula), which underwent metamorphism 1802 Ma ago.In the amphiboles 3He, 4He and 40Ar* were dominantly produced in situ due to radioactive decay of the parent isotopes and associated nuclear reactions. A small fraction of He (≈ 3% of the total) is liberated by crushing and shows 3He/4He ratio indistinguishable from that found by total extraction. The fraction of trapped 40Ar* amounts to ≈ 40%; both these fractions presumably occupy fluid inclusions and show rather low 4He/40Ar* ≈ 0.1, a factor of ≈ 150 below the production ratio (calculated assuming no loss / gain of the species has happened since the time of metamorphism).3He has been better preserved in amphiboles compared with 4He: the retention parameter (measured amount of He / totally produced amount) for 3He (≈ 0.4) exceeds that for 4He (≈ 0.15).He extraction by fast and slow linear heating of amphiboles resulted in different release patterns. The fast heating (within 12 to 40 °C min− 1) revealed a superposition of two peaks. When heating with slower heating rate (below 8 °C min− 1) was applied, the high-temperature peak disappeared (the “disappearing site”). Extractions of He atoms from grain and powder samples at different heating rates have shown that: (1) the “disappearing site” is revealed by the fast heating analyses of different amphibole samples but not only those from the Ponoy massif; (2) amount of He liberated from the “disappearing site” is variable and generally much less than the total amount of He in the sample; (3) analysis of the powder produced in the crushing experiments never reveals the “disappearing site”; the temperature of He release from the powder is lower than that from the mm grain size sample by ≈ 50 °C. Possible explanations of the nature of the “disappearing site” are discussed. However, independently on nature of this effect, repeated gas extractions by heating at different rates would give additional information about structure and its transformation during heating of amphiboles.The simplest explanation of the observed abundances of noble gas isotopes in the amphibole separates from Ponoy granites suggests local production, redistribution and partial loss of noble gases during evolution of the massif

Physical restraint in residential child care : the experiences of young people and residential workers

There have long been concerns about the use of physical restraint in residential care. This paper presents the findings of a qualitative study which explores the experiences of children, young people and residential workers about physical restraint. The research identifies the dilemmas and ambiguities for both staff and young people, and participants discuss the situations where they feel physical restraint is appropriate as well as their concerns about unjustified or painful restraints. They describe the negative emotions involved in restraint but also those situations where, through positive relationships and trust, restraint can help young people through unsafe situations

Prenatal Exposure to Delta-9-tetrahydrocannabinol (THC) Alters the Expression of miR-122-5p and Its Target Igf1r in the Adult Rat Ovary

As cannabis use during pregnancy increases, it is important to understand its effects on the developing fetus. Particularly, the long-term effects of its psychoactive component, delta-9-tetrahydrocannabinol (THC), on the offspring’s reproductive health are not fully understood. This study examined the impact of gestational THC exposure on the miRNA profile in adult rat ovaries and the possible consequences on ovarian health. Prenatal THC exposure resulted in the differential expression of 12 out of 420 evaluated miRNAs. From the differentially expressed miRNAs, miR-122-5p, which is highly conserved among species, was the only upregulated target and had the greatest fold change. The upregulation of miR-122-5p and the downregulation of its target insulin-like growth factor 1 receptor (Igf1r) were confirmed by RT-qPCR. Prenatally THC-exposed ovaries had decreased IGF-1R-positive follicular cells and increased follicular apoptosis. Furthermore, THC decreased Igf1r expression in ovarian explants and granulosa cells after 48 h. As decreased IGF-1R has been associated with diminished ovarian health and fertility, we propose that these THC-induced changes may partially explain the altered ovarian follicle dynamics observed in THC-exposed offspring. Taken together, our data suggests that prenatal THC exposure may impact key pathways in the developing ovary, which could lead to subfertility or premature reproductive senescence