Effects of polychlorinated dibenzofurans, biphenyls, and their mixture with dibenzo-p-dioxins on ovulation in the gonadotropin-primed immature rat: support for the toxic equivalency concept.
Previous studies have shown that 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), and their equipotent mixture block ovulation, reduce ovarian weight gain and alter preovulatory hormone levels in a similar manner. The objective of the current experiment was to investigate the effect of other structurally related compounds such as chlorinated furans and biphenyls on ovulation and related hormonal endpoints. The gonadotropin-primed immature female rat model was used to study the effect of 2,3,4,7, 8-pentachlorodibenzofuran (PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PeCB), and 2,2',5,5' tetrachlorobiphenyl (TCB) and their mixture with polychlorinated dibenzo-p-dioxins (PCDDs) on ovulation. Rats were dosed on Day 23 of age at 0900 h with individual congeners (PeCDF, PeCB, TCB) or a mixture of five compounds, which included TCDD, PeCDD, HxCDD, in addition to PeCDF and PeCB. Equine choronic gonadotropin (eCG; 5 IU) was injected 24 h later to induce follicular development. Blood and ovaries were harvested, and ovarian weights determined at various times after eCG. Serum concentrations of 17beta-estradiol (E(2)), progesterone (P(4)), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were determined by radioimmunoassay. At 72 h after injection of eCG, the number of ova shed was measured by irrigating the ova from oviducts. The slopes of the dose-responses for inhibition of ovulation generated by the individual PeCDF, PeCB, and/or their mixture with PCDDs were similar. PeCDF, PeCB, and the mixture increased serum concentrations of E(2) at 72 h after eCG injection, the day of expected ovulation; in contrast, serum P(4) and FSH were decreased at that same time point. Only the high doses of TCDD, PeCDF, and PeCB blocked LH and FSH surges at 58 h after eCG. The ovarian histology revealed that the effects of PeCDF, PeCB, and the mixture were very similar to those of PCDDs, consisting of ova in large preovulatory follicles and a lack of or reduced number of corpora lutea. Parallel dose-responses of the individual congeners (PeCDF and PeCB) and their equipotent mixture with PCDDs support the toxic equivalency (TEQ) concept for the blockage of ovulation. Thus, PCDDs, PCDFs, and PeCBs appear to block ovulation by the same or a very similar mechanism of action.
Gao
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X
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Terranova
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PF
Rozman
K K
KK
D000818:Animals; D001572:Benzofurans / Q000633:toxicity*; D000072338:Dibenzofurans, Polychlorinated; D004147:Dioxins / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000097:blood / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D010053:Ovary / Q000187:drug effects / Q000473:pathology; D010060:Ovulation / Q000187:drug effects*; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001572:Benzofurans; D000072338:Dibenzofurans, Polychlorinated; D004147:Dioxins; D004338:Drug Combinations; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D011078:Polychlorinated Biphenyls; C020887:dibenzo(1,4)dioxin