(L-466) Impact of maternal cannabis use on infant and fetal musculoskeletal development

Introduction:: Cannabis use is rapidly rising among individuals of reproductive age, but there remains a paucity of evidence on the safety and long-term patho-physiological effects of cannabis on reproductive biology. Limited existing studies suggest that prenatal cannabis exposure may lead to impaired fetal neurodevelopment; however, the effects on other tissues, including skeletal muscle, have not been explored. To address this research gap, we used a translational, rhesus macaque model to examine the impact of chronic maternal delta-9-tetrahydrocannabinol (THC, the main active component of cannabis) exposure on fetal and infant musculoskeletal development.

Materials and Methods:: The impact that THC has on musculoskeletal development was assessed in two cohorts: fetal (gestational day 155) and infant (180 days post-delivery). The fetal cohort included 10 adult female rhesus macaques that were divided into 2 groups, control (n=5) and THC-exposed (n=5). The infant cohort included 8 adult female rhesus macaques that were divided into 2 groups, control (n=4) and THC-exposed (n=4). For both fetal and infant cohorts, THC-exposed adult females received an oral dose of 2.5mg/7kg body weight/day of THC starting preconception and maintained throughout gestation. Both groups underwent time-mated breeding. The fetal cohort was delivered by cesarean delivery with fetal necropsy at gestational day 155. The infant cohort was delivered by natural birth at full term and underwent necropsy 180 days post-delivery. Skeletal muscle was collected at both fetal and infant necropsies. RNA was isolated from the skeletal muscle, validated for integrity, and evaluated for differential gene expression using the Nanostring nCounter neuroinflammatory panel comprised of ~700 genes. Samples that did not meet nCounter quality control metrics were excluded (n=1). Differential gene expression was analyzed using ROSALIND.

Results, Conclusions, and Discussions:: In the fetal cohort 13 differentially expressed (≥1.5-fold) genes were identified between the THC-exposed and control animals that are associated with angiogenesis and skeletal muscle development. Of particular interest, THC-exposure led to a 1.82-fold increase of vascular endothelial growth factor A (VEGFA). While VEGFA has been shown to promote skeletal muscle regeneration in aging, chronic upregulated expression has been associated with disturbed vessel morphology and cancer. Heme oxygenase-1 (HMOX1) was also upregulated by 2.6-fold in the THC-exposed group and has been shown to play a role in skeletal muscle aerobic capacity and shifts proportions of type IIa and type IIb muscle fibers. The infant cohort showed higher levels of differential gene expression, with 33 differentially expressed genes identified. Four of the differentially expressed genes, CCL2, CCR2, PTX3, and IGF1, are known to play a role in fibrosis and inflammation. CCL2 and CCR6, were upregulated by 14.86 and 2.56-fold respectively, and function together to drive the inflammatory response in skeletal muscle repair. Another gene, PTX3, was upregulated by 9.89-fold, and acts as an inflammatory mediator and has been shown to localize in fibrotic areas. Lastly, IGF-1, a key growth factor in skeletal muscle protein synthesis, anabolic, and catabolic pathways, was downregulated by 1.76-fold in the THC exposed group. Taken together, these findings suggest that prenatal THC exposure may adversely impact skeletal muscle development and promote inflammatory signaling in both prenatal and early postnatal development in non-human primates. THC exposure had a more pronounced effect on the infant cohort, indicating a lasting and progressive impact of prenatal THC exposure. Further studies are needed to understand the longer-term implications of these findings.


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