TCDD TERATOGENICITY--MODULATION IN MIXTURES

TCDD 致畸性——混合物中的调节

• 批准号: 3918622
• 负责人: L S BIRNBAUM
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3918622
• 关键词: cleft palate; dioxins; embryo /fetus toxicology; environmental toxicology; halobiphenyl /halotriphenyl compound; hydronephrosis; laboratory mouse; polychlorodibenzofuran; pregnancy; retinoate; teratogens; toxicant interaction; toxicant screening; toxin metabolism

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) has been shown to be highly teratogenic in multiple species, causing cleft palate (CP) and hydronephrosis (HN) in the mouse at doses with no overt maternal or fetal toxicity. This response can be used as a method of determining whether compounds are dioxin-like or not. The interaction of several polychlorinated dibenzofurans (PCDFs) and certain polychlorinated biphenyls (PCBs) with TCDD are additive. However, the nonplanar PCB isomer, 2,4,5,2',4',5'- hexachlorobiphenyl (HCB), can antagonize the induction of CP by TCDD, only in a very narrow window - 8000-33000 times as much HCB as TCDD. We have not observed any inhibition of HN. In fact, HCB at 1000mg/kg may induce HN by itself. Treatment of pregnant mice with TCDD and retinoic acid (RA) causes an increase in the incidence of CP. However, RA does not affect the TCDD-induced incidence of HN, nor does TCDD alter the incidence of RA-induced limb bud abnormalities. RA interacts addictively with TCDD when treatment is on gestation day (gd) 10, however, the interaction is synergistic on gd 12. Hydrocortisone (HC) can also enhance the incidence of CP when given in combination with TCDD. Thus, TCDD can interact with endogenous-type growth factors to cause fetal abnormalities. TCDD is a developmental toxin in rats. The closely related compound, 2,3,4,7,8-pentachlorodibenzofuran, failed to cause HN in Fischer rats when administered on gd 8, 10, or 12 at doses as high as 300 mug/kg where extensive maternal and fetal toxicity and CP did occur. Whether this is related to maternal toxicity or is specific to TCDD remains to be determined.

TCDD（2,3,7,8-四氯二苯并-对二恶英）已被证明是