Toxic Equivalency Factors of Polychlorinated Dibenzo-p-dioxins in an Ovulation Model: Validation of the Toxic Equivalency Concept for One Aspect of Endocrine Disruption

Abstract

Polychlorinated dibenzo-p-dioxins (PCDDs) are structural analogues, which produce a similar spectrum of biological and toxicological responses in animals, albeit with differential potencies. Very consistent structure–activity relationships have been found for acute toxicity and some biochemical effects among these compounds. For the current experiments, the gonadotropin-primed immature female rat model was used to study the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), and 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (HxCDD) on ovulation. Single doses of different PCDDs and their mixture were given orally to 23-day-old rats. Gonadotropin from pregnant mare's serum (PMSG) was injected (5 IU) 24 h later to induce follicular maturation. Rats were decapitated at various times after PMSG, blood was collected, and ovarian weight was measured. Serum concentrations of 17β-estradiol (E2), progesterone (P4), luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin (PrL) were determined by radioimmunoassay. Ovulation was measured at 72 h after injection of PMSG by counting ova flushed from oviducts. PCDDs dose dependently decreased the number of ova per ovary and reduced ovarian weight gain induced by PMSG. The slopes of the dose–response curves generated by individual PCDDs and/or their mixture were similar. PMSG-induced increase in serum E2 was enhanced on the day of expected ovulation by PCDDs; in contrast, serum P4 and FSH were decreased at that same time point. PCDDs also altered the temporal pattern of serum E2, FSH, and LH but not that of PrL. Histologically the effect of all three PCDDs consisted of ova trapped in preovulatory follicles and a lack of or reduced number of corpora lutea. The results indicate that the PCDDs, tested in the present model, have the same mode of action on ovulation and the reproductive hormones, e.g., LH, FSH, P4 and E2. Furthermore, the dose responses of the individual congeners are parallel to each other and also to that of their equipotent mixture, which represent a validation of the TEQ concept for one aspect of endocrine disruption, that is for inhibition of ovulation.