TCDD TERATOGENICITY--MODULATION IN MIXTURES

TCDD（2，3，7，8-四氯二苯并对二恶英）已被证明是 在多个物种中高度致畸，导致腭裂（CP） 和肾积水（HN）的小鼠在剂量没有明显的 母体或胎儿毒性。 这种反应可以作为一种方法 来判断化合物是否是二恶英类的。 的 几种多氯二苯并呋喃（PCDFs）与 某些多氯联苯与四氯二苯并对二恶英是相加的。 然而，非平面PCB异构体2，4，5，2'，4'，5'- 六氯联苯（HCB），可拮抗CP的诱导 TCDD，仅在非常窄的窗口内-是HCB的8000 - 33000倍 作为TCDD。 我们没有观察到HN的任何抑制。 事实上，六氯苯 1000mg/kg可单独诱发HN。 妊娠小鼠的处理 与TCDD和视黄酸（RA）一起使用会导致 CP的发病率。 然而，RA不影响TCDD诱导的 HN的发病率，TCDD也不改变RA诱导的 肢芽异常 RA与TCDD相互作用成瘾， 在妊娠第10天（GD）给药，然而， 对GD 12有协同作用。 氢化可的松（HC）也可以增强 与TCDD联合给药时CP发生率。 TCDD 可以与内源性生长因子相互作用， 异常 TCDD是一种发育毒素。 密切 相关化合物2，3，4，7，8-五氯二苯并呋喃未能 在gd 8、10或12给药时， 剂量高达300微克/公斤， 毒性和CP发生。 这是否与母性有关 毒性或特异性TCDD仍有待确定。

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.