Pre-puberty cannabichromene exposure modulates reproductive function via alteration of spermatogenesis, steroidogenesis, and eNOS pathway metabolites
Authors: Taiwo OA, Dosumu OA, James AS, Ugwor EI, Ojo OA, Dedeke GA, Ademuyiwa O
Publication year: 2023
Journal: Toxicology Reports
Journal name in source: Toxicology reports
Journal acronym: Toxicol Rep
Volume: 10
First page : 690
Last page: 705
ISSN: 2214-7500
eISSN: 2214-7500
DOI: https://doi.org/10.1016/j.toxrep.2023.06.001
Abstract
BACKGROUND\nAIM\nMETHOD\nRESULTS\nCONCLUSION\nCannabis and cannabinoids affect almost every system of the body and exert systemic effects such as alterations in memory and cognitive functions, neurotransmission impediment, as well as obstruction of endocrine and reproductive system functions. Reproduction is a complicated phenomenon that integrates biological, psychological and behavioural aspects, hence susceptible to intracellular and extracellular modulations by numerous chemicals and toxicants like cannabis.\nThe effects of early-life exposure to cannabis on reproductive function biomarkers and genes were investigated in male and female Wistar rats in this study.\nAn initial computational analysis (molecular docking and induced fit docking) of some cannabinoids with reproductive enzymes; androgen and follicle stimulating hormone receptors was conducted. Overall, cannabichromene (CBC) had the best IFD scores and binding free energies for the two proteins studied and it interacted with notable amino acids within their active sites. Subsequently, forty (40) Wistar rats, 20 male and 20 female (24-28 days old, weighing 20-28 ± 2 g) were divided into two groups each and orally administered CBC for 21 days. Penile tissues, testes and ovaries, were collected for biochemical analysis (hormonal assays, enzyme activities, and metabolite concentrations), gene expressions, and histological evaluations.\nActivities of arginase and phosphodiesterase-5 in the penile tissue were significantly increased, while nitric oxide and calcium levels were significantly (p < 0.05) decreased in the CBC-exposed groups relative to the control group. Semen analysis showed significantly more abnormalities and decreased concentration of spermatozoa in the CBC-exposed group compared to the control. Activities of 17β-hydroxysteroid dehydrogenase and cholesterol level were decreased in both testes and ovaries of CBC-exposed groups. Furthermore, levels of testosterone, progesterone, luteinizing, and follicle-stimulating hormones were reduced in the serum of CBC rats. Moreover, relative expressions of androgen receptor and follicle-stimulating hormone receptor genes were significantly downregulated in the CBC-exposed groups. Histological evaluations revealed lesions, tubular necrosis, and cellular congestions in both the testes and ovaries.\nThis study suggests that pre-puberty exposure to cannabis modulates reproductive functions via cannabichromene inhibition of steroidogenesis, stimulation of erectile dysfunction (modulation of intermediates and enzymes of the endothelial nitric oxide synthase (eNOS) pathway in the penile tissue), and downregulation of the expressions of genes associated with reproduction.
BACKGROUND\nAIM\nMETHOD\nRESULTS\nCONCLUSION\nCannabis and cannabinoids affect almost every system of the body and exert systemic effects such as alterations in memory and cognitive functions, neurotransmission impediment, as well as obstruction of endocrine and reproductive system functions. Reproduction is a complicated phenomenon that integrates biological, psychological and behavioural aspects, hence susceptible to intracellular and extracellular modulations by numerous chemicals and toxicants like cannabis.\nThe effects of early-life exposure to cannabis on reproductive function biomarkers and genes were investigated in male and female Wistar rats in this study.\nAn initial computational analysis (molecular docking and induced fit docking) of some cannabinoids with reproductive enzymes; androgen and follicle stimulating hormone receptors was conducted. Overall, cannabichromene (CBC) had the best IFD scores and binding free energies for the two proteins studied and it interacted with notable amino acids within their active sites. Subsequently, forty (40) Wistar rats, 20 male and 20 female (24-28 days old, weighing 20-28 ± 2 g) were divided into two groups each and orally administered CBC for 21 days. Penile tissues, testes and ovaries, were collected for biochemical analysis (hormonal assays, enzyme activities, and metabolite concentrations), gene expressions, and histological evaluations.\nActivities of arginase and phosphodiesterase-5 in the penile tissue were significantly increased, while nitric oxide and calcium levels were significantly (p < 0.05) decreased in the CBC-exposed groups relative to the control group. Semen analysis showed significantly more abnormalities and decreased concentration of spermatozoa in the CBC-exposed group compared to the control. Activities of 17β-hydroxysteroid dehydrogenase and cholesterol level were decreased in both testes and ovaries of CBC-exposed groups. Furthermore, levels of testosterone, progesterone, luteinizing, and follicle-stimulating hormones were reduced in the serum of CBC rats. Moreover, relative expressions of androgen receptor and follicle-stimulating hormone receptor genes were significantly downregulated in the CBC-exposed groups. Histological evaluations revealed lesions, tubular necrosis, and cellular congestions in both the testes and ovaries.\nThis study suggests that pre-puberty exposure to cannabis modulates reproductive functions via cannabichromene inhibition of steroidogenesis, stimulation of erectile dysfunction (modulation of intermediates and enzymes of the endothelial nitric oxide synthase (eNOS) pathway in the penile tissue), and downregulation of the expressions of genes associated with reproduction.
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