Toxic equivalency factors of polychlorinated dibenzo-p-dioxins in an ovulation model: Validation of the toxic equivalency concept for one aspect of endocrine disruption

Polychlorinated dibenzo-p-dioxins (PCDDs) are structural analogues, which p roduce a similar spectrum of biological and toxicological responses in anim als, albeit with differential potencies. Very consistent structure-activity relationships have been found for acute toxicity and some biochemical effe cts among these compounds. For the current experiments, the gonadotropin-pr imed immature female rat model was used to study the effect of 2,3,7,8-tetr achlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCD D), 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) 2 4 h later to induce follicular maturation. Rats were decapitated at various times after PMSG, blood was collected, and ovarian weight was measured. Se rum concentrations of 17 beta-estradiol (E-2), progesterone (P-4), luteiniz ing hormone (LH), follicle stimulating hormone (FSH), and prolactin (PrL) w ere determined by radioimmunoassay. Ovulation was measured at 72 h after in jection of PMSG by counting ova flushed from oviducts. PCDDs dose dependent ly decreased the number of ova per ovary and reduced ovarian weight gain in duced by PMSG. The slopes of the dose-response curves generated by individu al PCDDs and/or their mixture were similar. PMSG-induced increase in serum E-2 was enhanced on the day of expected ovulation by PCDDs; in contrast, se rum P-4 and FSH were decreased at that same time point. PCDDs also altered the temporal pattern of serum E-2, FSH, and LH but not that of PrL. Histolo gically the effect of all three PCDDs consisted of ova trapped in preovulat ory 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 o f action on ovulation and the reproductive hormones, e.g., LH, FSH, P-4 and E-2. Furthermore, the dose responses of the individual congeners are paral lel to each other and also to that of their equipotent mixture, which repre sent a validation of the TEQ concept for one aspect of endocrine disruption , that is for inhibition of ovulation. (C) 1999 Academic Press.