-Tetrahydrocannabinol Targeting Estrogen Receptor Signaling: The Possible Mechanism of Action Coupled with Endocrine Disruption

cancer effects (anti-proliferative and anti-migration effects).1–11) 9-THC’s biological activities, its recognized endocrine-disrupting effects, including anti-estrogenic activity, have been the subjects of previous investigations. It has been reported that chronic oral administration of marijuana resin is able to reduce fertility in female rats.12,13) 9-THC on reproductive behavior has been suspected for at least 40 years14) 9-THC modulates the estrous cycle and inhibits ovulation, and in males, 9-THC attenuates the mobility of mouse sperm.15) 9-THC inhibitory effect on ovulation is also suggested in the case of the human female.12) 9-THC disrupts the normal ovulatory cycle in both animals and humans. Estrogen receptors (ERs) are hormone (17 -estradiol, E2)dependent transcription factors existing in two forms: ER and ER . ER and ER have both unique and overlapping physiological roles in mediating estrogen signaling. The two forms of ERs have been known to be involved in the regulation of ovarian maturation/function and breast development.16–21) Because of the similarity in structure between 9-THC and E2 (i.e., phenol moiety), it was initially thought 9-THC abrogation of E2/ER signaling was attributed to the competitive inhibition of each of these toward ER via the common moiety22); however, this early hypothesis that 9-THC could directly bind to the estrogen receptor has now been “abandoned” by research groups, including us.10,23–25) 9-THC has no inhibitory activity on the CYP19A1 enzyme, also known as aromatase, which catalyzes the conversion of testosterone (an androgen) to E2 (an estrogen).26) Thus, no one can answer the question of 9-THC disrupts estrogen signaling as an anti-estrogen, possibly leading to the disruption of ovarian function and 9-THC is used as both a drug of abuse (marijuana) and as a preventive therapeutic for pain and nausea in cancer patients undergoing chemotherapy in 9-THC; dronabinol), it is important to investigate the mechanistic 9-THC’s E2 signaling disruption. In this study, we 9-THC-mediated disruption of E2/ER signaling through ER , as revealed by our