SAT-252 - Evidence that androgen and progesterone receptors are activated by ∆9-tetrahydrocannabinol (THC)

The developing brain is particularly sensitive to gonadal steroid hormones. The surge of steroid hormones from the fetal testis establishes the critical period of sexual differentiation, during which hormone-sensitive brain regions undergo morphological and functional changes to prepare individuals for sex-typical behaviors. The ability of steroid hormones to organize neural substrates depends on the activity of nuclear steroid receptors, which primarily act as transcription factors that bind to hormone response elements across the genome. In addition to these direct effects, we have shown that androgen receptor activity indirectly organizes the masculine phenotype of the medial amygdala by increasing endocannabinoid signaling, which promotes microglial phagocytosis of astrocytic progenitors (PMID:30827729). Importantly, exposure of female rat pups during this sensitive period to exogenous cannabinoids, such as 9-tetrahydrocannabinol (THC), induces a masculinized phenotype in their microglia, with associated behavioral changes. With recent changes in legalization and shifts in cultural perspectives regarding cannabis, there has been an increase in cannabis use during pregnancy. However, we have very limited information on how early-life exposure to cannabis can impact development, particularly the developing brain. Our recent work highlights a direct role of cannabis, primarily its psychoactive component THC, in disrupting steroid hormone-mediated brain development. We demonstrate in silico that THC can bind to the androgen (AR) and progesterone (PR) receptors with affinities comparable to those of testosterone and progesterone, respectively, thereby creating the potential to directly affect brain development through actions at these receptors. Similar in silico modeling shows no evidence of binding of the endogenous cannabinoids 2-AG and anandamide to the AR. In vitro binding kinetics of THC at the AR were evaluated using surface plasmon resonance and indicate a steady state Kd around 250nM for THC at the AR, which lies between that of DHT and androstenedione. A luciferase-based transactivation assay in N2A cells indicated transcriptional activity of AR bound to THC in a dose-dependent manner, with the highest dose resulting in similar luciferase expression as testosterone-bound AR. There is a profound sex difference in PR expression in the typically developing preoptic area, with higher levels in males than in females. Additionally, PR expression is sensitive to activation-dependent downregulation (PMID: 11509655). We observed that developmental THC exposure abolished the typical sex difference in PR expression, potentially due to agonism of the receptor by THC. These findings reveal a novel mechanism of THC action with potential impact of gestational cannabis exposure effects being mediated via steroid hormone receptors during neurodevelopment.

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