There is a growing use of marijuana by individuals in their adolescent and prime childbearing years. Although no overt teratology is readily apparent from exposure to active cannabinoids, there is a paucity of information on the potential for more subtle, albeit deleterious, effects as a result of marijuana use. This is especially true for the high frequency user age group and for the female of childbearing age. The purpose of this study is to develop an animal model to address this information gap. Specifically, a pilot investigation to explore endocrinological aspects of the development of full, normal female reproductive competency after perinatal or neonatal exposure to delta9-tetrahydrocannabinol (THC) is proposed. Pregnant mothers will be subcutaneously injected with 2 mg delta9-THC/kg/day during days 9-17 of gestation. Alternatively, similar treatment groups of neonatal female rats will be exposed to THC through injections or beeswax pellet implants during day 1-10 of life. Controls will receive the oil vehicle or beeswax pellet alone. These exposure periods encompass critical developmental stages in the structural and/or functional aspects of reproductive differentiation. Prepubertal rats will then be used to evaluate the consequences of such exposure upon the hormonal sensitivity and functional competency of the uterus. This will be assessed by determining parallelism and magnitude of estradiol dose-response curves, quantitating the degree of estrogen- stimulated metabolsim of 14C-glucose, measuring the number of cellular binding sites for estrogen and assessing their temporal replenishment pattern after initial exposure to estradiol, and determining the degree of progesterone receptor induction by different doses of estradiol in the uterus of control and THC-treated 25 day old rats which have been ovariectomized for at last 72 hrs. Additionally, the decidual reaction in traumatized uterine horns of PMS-treated control and THC-exposed rats will be used as a model of the implantation process. Possible effects on the hypothalamic-pituitary-ovarian axis will also be ascertained by measuring cellular estrogen receptor sites in the anterior pituitary and hypothalamus, by determining the degree of ovarian compensatory hypertrophy two weeks after unilateral ovariectomy, and by hormonal induction of superovulation. Long-term goals of this research would be to direct efforts toward characterization of the underlying developmental """"""""organization"""""""" by THC for positive findings with particular reference to aspecs of molecular antagonism and prevention.
