Cannabidiol Inhibited Reproductive Ability of Zebrafish (Danio Rerio) with Gender-Dependent Manner

<title>Abstract</title> Cannabidiol (CBD), a medically active component of hemp, is a popular ingredient in healthcare and personal-care products. The increasing demand for CBD and the legalization of hemp growth may promote chronic exposure of non-target organisms and animals to CBD. In the present study, the reproductive toxicity of CBD was investigated using zebrafish as a model organism. With CBD treatment, parent female zebrafish spawned less with higher natural mortality and malformation rates, showed a decreased gonadosomatic index with an increased percentage of pre-mature oocytes and sperm and had an increased hepatosomatic index. The value of estrogen/testosterone (E2/T) decreased in female zebrafish and increased in male zebrafish. Vitellogenin content was decreased in both female and male zebrafish. Reproductive-related genes were downregulated in the zebrafish brain and liver, whereas <italic>esr-α</italic>, <italic>esr-β</italic>, and <italic>ar</italic> were downregulated in ovaries and upregulated in testicles. Sex hormone synthesis genes were downregulated in ovaries and upregulated in testicles, except for <italic>cyp11a</italic>, in contrast to the other genes. Apoptosis-related genes were upregulated in the zebrafish brain, gonad, and liver. These results show that CBD might damage the hypothalamus-pituitary-gonad-liver axis function by inducing an apoptotic response, further inhibiting zebrafish reproductive ability in a sex-dependent manner.