二噁英对成骨肉瘤细胞增殖和胰岛素样生长因子2表达的影响

目的探讨环境类致癌因子二噁英(TCDD)对成骨肉瘤细胞增殖及胰岛素样生长因子2(IGF-2)mRNA和蛋白表达的影响。方法TCDD作用于人成骨肉瘤细胞SaOS-2细胞株24~48h。MTT法检测细胞增殖率;对硝基酚磷酸盐法测定细胞内碱性磷酸酶(ALP)活性;RT-PCR半定量分析细胞IGF-2 mRNA的表达;Western蛋白质印迹法测定细胞IGF-2和丝裂原激活蛋白激酶(MAPK)信号通路中p38 MAPK蛋白表达及其磷酸化水平。结果与对照组比较,TCDD 1,10和100nmol·L-1作用48h,使SaOS-2细胞内ALP活性分别增加38%,95%和142%。TCDD 1,10及100nmol·L-1作用24h后,SaOS-2细胞存活率分别增加21%,47%和56%,细胞内IGF-2 mRNA和IGF-2蛋白表达均增加。TCDD对SaOS-2细胞内p38 MAPK蛋白表达无明显影响,但明显降低其磷酸化水平。结论TCDD具有促进SaOS-2细胞增殖的作用。TCDD可能通过促进SaOS-2细胞内IGF-2的表达,并抑制MAPK信号通路中转录因子p38 MAPK活性而促进细胞增殖。     

四氯二苯对氧芑对胸腺细胞因子表达的影响

四氯二苯对氧芑对胸腺细胞因子表达的影响赖志伟（同济医科大学环境毒理学教研室，武汉４３００３０）四氯二苯对氧芑（２，３，７，８－ｔｅｔｒａｃｈｌｏｒｏｄｉｂｅｎｚｏ－ｐ－ｄｉｏｘｉｎ，ＴＣＤＤ）是一种具有广泛毒性作用的化合物，可引起胸腺萎缩并影响Ｔ细胞...     

胰岛素样生长因子-1对大鼠血管平滑肌细胞增殖及凋亡的影响

目的探讨在动脉粥样硬化过程中胰岛素样生长因子-1(IGF-1)对大鼠血管平滑肌细胞(VSMC)增殖及凋亡的影响。方法用脂多糖(LPS)诱导巨噬细胞RAW264.7制备炎症培养基(IM)。体外培养VSMC分为4组,给予IM、IM+IGF-1 60 ng/ml、IM+IGF-1 90 ng/ml、IM+IGF-1 120 ng/ml进行干预,然后分别用溴化噻唑蓝四氮唑(MTT)法和Annexin-异硫氰酸荧光素(FITC)/碘化丙啶(PI)流式细胞术对平滑肌细胞的细胞活力[用吸光度(A)值表示]及凋亡率进行检测。结果各组VSMC在不同干预下,用MTT法测得的A值分别是(0.26±0.06),(0.30±0.10),(0.62±0.09),(0.55±0.05)。IM+IGF-1 90 ng/ml组、IM+IGF-1 120 ng/ml组与IM组相比较差异有统计学意义(P<0.01)。不同干预条件下,各组VSMC凋亡率分别是(10.86±0.15)%,(9.64±0.65)%,(3.85±0.51)%,(4.82±0.08)%。干预后的3组与IM组相比较差异均有统计学意义(P<0.05)。结论在动脉粥样硬化发生发展过程中,IGF-1在促进VSMC增殖的同时抑制VSMC凋亡。     

脐血中胰岛素、胰岛素样生长因子-Ⅰ及胰岛素样生长因子结合蛋白-2与胎儿生长发育的关系

目的探讨脐血中胰岛素、胰岛素样生长因子-Ⅰ(IGF-Ⅰ)及胰岛素样生长因子结合蛋白-2(IGFBP-2)的水平与胎儿生长发育的关系及意义。方法单胎足月正常妊娠(无产科并发症)孕妇及其新生儿各90例,根据出生体重将新生儿分为低体重儿(SGA)组、正常体重儿(AGA)组、巨大儿(LGA)组。胎儿娩出后即抽脐静脉血5ml,标本收集后用高效液相色谱法测定脐血中胰岛素、IGF-Ⅰ及IGFBP-2的水平。结果 SGA组脐带血清胰岛素、IGF-Ⅰ水平明显低于AGA、LGA组,AGA组脐血胰岛素、IGF-Ⅰ水平低于LGA组,差异均有统计学意义(P<0.01);SGA组脐血IGFBP-2水平明显高于AGA、LGA组,AGA组脐血IGFBP-2水平高于LGA组,差异均有统计学意义(P<0.01);脐血中IGF-Ⅰ与胰岛素水平呈正相关(r=0.462,P<0.05),而与IGFBP-2呈负相关(r=-0.451,P<0.05);脐血胰岛素、IGD-Ⅰ水平与新生儿出生体重呈正相关(r=0.511,0.562,P<0.05),而IGFBP-2与之呈负相关(r=-0.432,P<0.05)。结论脐血胰岛素、IGF-Ⅰ、IGFBP-2参与胎儿生长发育的病理、生理过程。     

二噁英对成骨肉瘤细胞中胰岛素样生长因子2基因表达的作用

目的 探讨环境类致癌因子对调控成骨肉瘤细胞中胰岛素样生长因子2(insulin-like growth factor 2,IGF-2)基因表达的作用机制.方法 应用环境类致癌因子二嗯英(TCDD)作用于人成骨肉瘤细胞(SaOS-2)细胞株;采用流式细胞仪检测TCDD对SaOS-2细胞凋亡的影响规律;采用实时定量PCR定量分析SaOS-2细胞中IGF-2 mRNA的表达;采用Western印迹杂交鉴定SAOS-2细胞中IGF-2和促分裂原活化蛋白激酶(MAPK)信号通路中的p38 MAPK蛋白质的表达及磷酸化水平的变化.结果 1×10-9mol/L、1×10-8molL、1×10-7mol/L剂量的TCDD对Saos-2细胞具有抗凋亡作用,在基因转录和翻译水平上增强SaOS-2细胞中IGF-2的表达;TCDD明显地降低了SaOS-2细胞内p38 MAPK磷酸化水平.结论 低生理浓度的TCDD可促进靶基因IGF-2的表达,并通过p38 MAPK信号转导通路,发挥拮抗成骨细胞凋亡的毒性作用.     

胰岛素样生长因子-1对小鼠胰岛细胞凋亡的保护作用

目的：探讨胰岛素样生长因子-1（IGF-1）对第三丁基过氧化氢（tBHP）诱导小鼠胰岛β细胞株MIN6凋亡的保护作用。方法：体外培养小鼠胰岛β细胞株MIN6,分为：对照组、tBHP（25μmol/L）组、IGF-1（100ng/mL）组和IGF-1＋tBHP组。丫啶橙-溴化乙锭（AO-EB）荧光染色法及原位末端标记法（TUNEL）镜下观测各实验组细胞凋亡情况,Griess法检测各实验组细胞内NO水平。结果：25μmol/LtB-HP作用1h可诱导MIN6细胞凋亡,并使细胞内NO含量明显增加。预先经过100ng/mLIGF-1作用24h后,tBHP诱导的MIN6细胞凋亡明显减少,同时细胞内NO含量亦显著降低。结论：IGF-1对tBHP诱导凋亡的小鼠胰岛β细胞株MIN6有一定的保护作用,其机制可能与IGF-1减少tBHP诱导的NO合成有关。     

胰岛素样生长因子2基因干扰对人膀胱癌细胞HTB-95637细胞周期和增殖的影响

目的:探讨胰岛素样生长因子2(insulinlike growth factor 2,IGF2)基因干扰对人膀胱癌细胞株HTB-95637细胞周期和增殖的影响。方法:以人膀胱癌细胞株HTB-95637为研究对象,针对其IGF2基因序列设计小干扰RNA(small interfering RNA,siRNA),筛选出能高效沉默目标基因的片段序列后,重组其短发夹状RNA(short hairpin RNA,shRNA)腺病毒表达载体,转染人膀胱癌细胞株HTB-95637,筛选出能稳定表达干扰质粒的细胞克隆。采用逆转录聚合酶链反应(RT-PCR)和免疫印迹法(Western blot)分别检测转染后IGF2的mRNA和蛋白表达水平,用四甲基偶氮唑蓝法(MTT法)检测细胞增殖能力,用PI单染流式细胞术分析细胞周期的改变。结果:RT-PCR和Western blot结果显示,shRNA对IGF2在基因和蛋白表达水平均有显著的下调作用。稳定转染IGF2-shRNA的人膀胱癌细胞株HTB-95637的生长速度明显减缓,处于细胞周期S期的细胞比例由42.0%±3.8%上升至70.2%±5.2%,而处于G2/M期的细胞比例由9.7%±2.4%下降为1.5%±1.6%。结论:靶向IGF2基因的shRNA可抑制膀胱癌细胞株HTB-95637细胞IGF2基因的表达,调控HTB-95637的细胞周期,抑制HTB-95637的细胞增殖,具有潜在的开发应用前景。     

脐血胰岛素样生长因子-1、-2含量与胎儿生长发育的关系

目的　探讨脐血胰岛素样生长因子 1、 2 (IGF 1、IGF 2 )含量与新生儿发育指数的关系。方法　 5 8例孕 37～ 4 2周的单胎新生儿 ,按出生体重与胎龄的关系分成三组 :小于胎龄儿(SGA)、适于胎龄儿 (AGA)、大于胎龄儿 (LGA) ,每例出生时抽取脐静脉血 3ml,用放射免疫分析法测定IGF 1、IGF 2的含量 ,同时记录出生体重、胎龄、身长、胎盘重量。结果　IGF 1的范围为 30～10 5ng/ml,在SGA、AGA、LGA的均值分别是 ( 4 0 4 5± 8 5 0 )ng/ml、( 5 3 96± 10 2 1)ng/ml、( 6 8 95± 14 0 8)ng/ml,LGA的值明显大于AGA的值 ,AGA的值大于SGA的值 (P均 <0 0 1)。IGF 2的范围为 2 6 4～ 5 2 0ng/ml,SGA、AGA、LGA的均值分别是 ( 35 2 2 7± 5 3 4 4 )ng/ml、( 381 4 6± 5 5 15 )ng/ml、( 4 35 95± 6 6 2 0 )ng/ml,LGA比AGA和SGA的值大 (P <0 0 5 ) ,AGA与SGA相比无显著性差异 (P >0 0 5 )。IGF 1与出生时的体重、体重指数 (PI)、胎盘重量 (PW )均呈正相关 (r分别为 0 6 6 6、0 5 33、0 5 4 3,P值均 <0 0 0 1)。IGF 2与出生体重、PI呈正相关 (r =0 4 0 6、P <0 0 1及r =0 372、P <0 0 1) ,与PW无相关性。多元回归分析显示与体重有关的应变量是PI、身长、IGF 1,无关的是PW、IGF 2、胎龄。结论　脐血I     

早产儿胰岛素样生长因子-1和胰岛素样生长因子结合蛋白-3早期检测的临床意义

目的:研究早产儿早期胰岛素样生长因子-1(IGF-1)和胰岛素样生长因子结合蛋白-3(IGFBP-3)水平,指导围产期临床孕产妇及早产儿合理营养干预。方法:对145例早产儿生后3天内进行IGF-1I、GFBP-3测定,将其按小于胎龄儿与适于胎龄儿、小早产儿(小于34周)与晚期早产儿(大于34周)、双胞胎大体重与小体重3种方式对比分组,分别比较IGF-1I、GFBP-3水平。结果:145例早产儿生后3天内监测IGF-1I、GFBP-3值显示适于胎龄儿组明显高于小于胎适龄儿组,大于34周组明显高于小于34周组,大体重组明显高于小体重组,组间比较有极显著性差异(P<0.01)。结论:应加强围生期孕产妇管理,避免早产和胎儿宫内发育迟缓发生,早产儿、小于胎龄儿生后应尽早给予合理营养支持。     

Wnt通路对胰岛素样生长因子-1抑制小鼠毛细胞凋亡的作用

目的探讨胰岛素样生长因子-1(IGF-1)抑制小鼠毛细胞凋亡作用的调控机制。方法体外培养新生小鼠耳蜗基底膜。在分别含有正常对照培养液(A组)、0.5 mmol/L庆大霉素(GM)(B组)、0.5 mmol/L GM+1 ng/mL IGF(C组)、0.5 mmol/L GM+1 ng/mL IGF+5μg/mL wif(D组)、0.5 mmol/L GM+1 ng/mL IGF+10μg/mLwif(E组)、0.5 mmol/L GM+1 ng/mL IGF+15μg/mL wif(F组)的成分中培养24 h后收集细胞及固定。应用TUNEL法观察各组耳蜗毛细胞的凋亡情况。应用Western blot及Real-time PCR法观察Caspase-3的表达情况。结果 B组耳蜗毛细胞经刺激后,细胞凋亡数量及Caspase-3 mRNA和蛋白表达较A组明显上升(P<0.01),C组耳蜗毛细胞经IGF刺激后,细胞凋亡数量及Caspase-3mRNA和蛋白表达较B组明显下降(P<0.01),应用Wnt阻断剂(wif)后D、E及F组细胞凋亡数量及Caspase-3 mRNA和蛋白表达较C组升高,其中F组升高显著(P<0.01)。结论 IGF可能通过激活Wnt通路抑制毛细胞凋亡。     

Liver-specific decrease in Tff3 gene expression in infant mice perinatally exposed to 2,3,7,8-tetrabromodibenzofuran or 2,3,7,8-tetrachlorodibenzo-p-dioxin

Polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/DFs) are byproducts of brominated flame retardants and can cause adverse health effects. Although exposure to polychlorinated (PC) DD/DFs induces toxic effects, including liver injury and neurobehavioral disorder, little is known about toxicities associated with PBDD/DF exposure. Thus, we examined effects of perinatal exposure to brominated congener on the infant mouse. Gene expression in several organs, such as the liver and brain, was analyzed in mouse offspring born to dams administered 2,3,7,8-tetrabromodibenzofuran (TBDF; 9 or 45 μg/kg body weight) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 3 μg/kg body weight) on gestational day 12.5. An increase in liver size was observed in TBDF- or TCDD-exposed offspring in infancy. Gene microarray analysis revealed that 163 and 36 genes were markedly upregulated and downregulated, respectively, in the liver of TBDF-exposed mice compared with those in vehicle-treated mice on postnatal day (PND) 5. Significant increases in Cyp1a1, Cyp1a2, Fmo3, and Pnliprp1 and decreases in Tff3, Ocstamp, Kcnk16, and Lgals2 mRNA levels in TBDF-exposed offspring on PNDs 5 and 12 were confirmed by quantitative PCR. In particular, a significant reduction in Tff3 mRNA in the liver, but not in the brain, small intestine, colon, and kidney, was observed in offspring perinatally exposed to TBDF or TCDD. Ultrasonic calls of TBDF- or TCDD-exposed offspring on PNDs 3–5 were impaired. Taken together, perinatal exposure to polyhalogenated dioxin/furan congeners disrupts gene expression patterns in the liver and ultrasonic calling during infancy. These results suggest that liver injury may contribute to neurobehavioral disorder.     

骨化三醇体外诱导人肝癌细胞IGFBP-3的表达及细胞凋亡的实验研究

目的:探讨骨化三醇[2β-(3一hydro-)-calcitriol]对人肝癌细胞HepG2增殖和凋亡的影响及其作用机制。方法:应用MTT比色法观察骨化三醇对HepG2的生长抑制作用,以荧光显微镜和流式细胞仪观察HepGz的凋亡,RT-PCR检测骨化三醇处理前后HepG2细胞中胰岛素样生长因子受体结合蛋白-3(IGFBP- 3)mRNA表达水平的变化。结果:骨化三醇显著抑制HepG2细胞的体外增殖,并诱导细胞凋亡。不同浓度的骨化三醇(10-8,10-7,10-6,10-5mol·L-1)作用HepG2 48 h细胞凋亡率分别达(27.3±s 2．3)％,(33±6)％,(35±5)％,(48±7)％,明显高于对照组(8±4)％(P<0．05)。RT-PCR结果显示骨化三醇处理HepG2 24 h后IGFBP-3 mRNA表达水平明显升高。结论:骨化三醇体外显著抑制HepG2增殖并促进其凋亡,其作用机制可能与通过激活细胞内IGFBP-3 mRNA的表达有关。     

Effects of epidermal growth factor receptor deficiency and 2,3,7,8-tetrachlorodibenzo-p-dioxin on fetal development in mice

Dioxins are persistent environmental contaminants that cause multiple disorders in laboratory animals, including teratogenesis. In mice, the most important teratogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are hydronephrosis and cleft palate. Aryl hydrocarbon receptor (AHR) mediates most of the TCDD-induced effects, but modulation of these effects by other factors such as epidermal growth factor receptor (EGFR) has been propounded. TCDD changes the expression of both EGF and its receptor EGFR, which may be one step in the pathway leading to cleft palate and hydronephrosis. In the present study, the importance of EGFR in TCDD-induced teratogenicity was evaluated. Heterozygous EGFR^+/−-mice were mated and pregnant females exposed to 1.5–106.0 μg/kg TCDD on gestation day (GD) 10 and killed on GD 18. The fetuses were studied for cleft palate, hydronephrosis, and open eyes. There was no marked difference among the three genotypes in sensitivity to cleft palate or hydronephrosis, but in EGFR^−/−-mice frequency of the open eye malformation decreased dose-dependently. In conclusion, EGFR signaling is not required for TCDD-induced cleft palate or hydronephrosis but TCDD appears to counteract the effect of EGFR deficiency on eye opening.     

胰岛素样生长因子-1对氯化钴诱导的PC12细胞凋亡的抑制作用

目的 探讨胰岛素样生长因子-1（IGF-1）对氯化钴（CoCl2）诱导的肾上腺嗜铬细胞瘤 PC12细胞凋亡的作 用及机制。方法 取对数生长期的 PC12细胞,分别以 10、20、40、80 μmol/L的 CoCl2溶液和 100、200、400 μg/L的 IGF- 1溶液处理细胞,CCK-8法检测细胞活力,得出 CoCl2和 IGF-1最佳干预浓度。根据选定的实验条件,应用 CoCl2处理 PC12细胞建立 HIE细胞模型,实验分为对照组、CoCl2处理组、IGF-1+CoCl2处理组。分组处理 24 h后采用 CCK-8法 检测细胞存活率;TUNEL染色检测细胞凋亡情况;Western blot检测各组细胞 Bax、Bcl-2及 Caspase-3的蛋白的表达 水平。最后在上述实验的基础上,设 CoCl2处理组、CoCl2+IGF-1处理组、HIF-1α抑制剂 2-甲氧雌二醇（2-MeOE2）+ CoCl 2组和 CoCl2+2-MeOE2+IGF-1组,Western blot观察 IGF-1、2-MeOE2及两者共用对 PC12细胞 HIF-1α及 Bax的表 达水平的影响。结果 CCK-8检测结果显示,40 μmol/L CoCl2和 200 μg/L IGF-1为最佳干预浓度。利用以上浓度分 组干预细胞 24 h后,与 CoCl2组相比,IGF-1+CoCl2处理组细胞存活率明显提升,TUNEL阳性细胞数和细胞比例降低, 同时抗凋亡蛋白 Bcl-2表达上调,促凋亡蛋白 Bax、Caspase-3,HIF-1α表达下调,差异均有统计学意义（均P＜0.05）。 应用 2-MeOE2对细胞进行预处理后,CoCl2+2-MeOE2组与 2-MeOE2+IFG-1组 HIF-1α和 Bax蛋白表达差异无统计 学意义,但均较 CoCl2+IGF-1组明显下调（P＜0.01）。结论 IGF-1可抑制 CoCl2诱导的 PC12细胞凋亡,其保护作用 可能与 HIF-1α表达下调有关。     

格列吡嗪控释片对2型糖尿病病人血清胰岛素样生长因子的影响

目的 :探讨格列吡嗪控释片对 2型糖尿病病人血糖、胰岛素及胰岛素样生长因子Ⅰ ,Ⅱ (IGF Ⅰ ,Ⅱ )的影响。方法 :糖尿病组初次诊断的 2型糖尿病病人 6 8例 ,对照组健康体检者 4 3例。糖尿病组予格列吡嗪控释片 5～ 10mg ,每日 1次 ,早餐前服用 ,疗程 4wk。观察治疗前后空腹血糖 (FBG)、糖化血红蛋白 (HbA1c)、空腹胰岛素 (FINS)、IGF Ⅰ和IGF Ⅱ的情况。结果 :与对照组比 ,糖尿病组治疗前FINS ,IGF Ⅰ ,IGF Ⅱ水平较低 ,FBG和HbA1c水平较高 (均P <0 .0 1)。治疗后 ,FBG和HbA1c下降 ,FINS ,IGF Ⅰ ,IGF Ⅱ升高 (P <0 .0 1)。结论 :每日服用 1次格列吡嗪控释片可以改善 2型糖尿病病人的糖代谢及血清IGF Ⅰ和IGF Ⅱ的水平。     

抑制生长因子受体连接蛋白-2表达对乳癌细胞生长的影响

目的进一步验证生长因子受体连接蛋白-2(Grb2)的表达在乳癌发展中的作用。方法应用脂质体转染技术将Grb2小干扰RNA(siRNA)转染至乳癌细胞SKBr3中,台盼蓝计数法测定存活细胞数,TUNEL技术和AnnexinⅤ/PI染色分析转染后细胞的凋亡,免疫细胞化学技术分析转染后细胞Grb2的表达。Western蛋白质印迹法测定Grb2、细胞外信号调节激酶(p42/44ERK)、磷酸化p42/44ERK(P-p42/44ERK)、原癌基因蛋白质c-akt(Akt)、磷酸化Akt(P-Akt)和STAT5转录因子表达的改变。流式细胞术检测细胞活化的半胱氨酸天冬氨酸蛋白酶(caspase)3的表达。结果台盼蓝计数法结果显示,转染Grb2siRNA可有效抑制SKBr3的生长。TUNEL实验显示,Grb2siRNA转染SKBr3细胞后,随着时间延长,凋亡细胞明显增加。AnnexinⅤ/PI测定结果亦提示,Grb2的抑制可明显诱导SKBr3细胞凋亡。转染48h后,SKBr3的活化caspase3表达水平由0.99%升至17.43%。免疫组化染色表明,Grb2siRNA转染细胞后,SKBr3细胞Grb2表达明显下降,由转染24h后的下降至转染72h后的+～-。Western蛋白质印迹分析证实,Grb2的抑制可导致SKBr3细胞P-p42/44ERK,P-Akt以及STAT5表达明显下降。P-p42ERK与p42ERK的相对吸光度值之比由未转染的(60±17)%下降至转染24h后的(38±13)%,及转染48h后的(21±8)%;P-p44ERK与p44ERK的相对吸光度值之比,由未转染时(104±16)%,分别下降至(49±13)%及(30±10)%;P-Akt与Akt的相对吸光度值之比由未转染的(40±6)%下降至(32±10)%和(15±4)%。与未转染组相比,转染24及48h后STAT5相对吸光度值分别下降为(64±6)%和(52±14)%。结论抑制Grb2的表达可抑制乳癌细胞生长并诱导细胞凋亡。     

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on behavior of monkeys in peer groups.

Adult female rhesus monkeys were fed diets containing 0, 5, or 25 ppt 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for approximately 4 years. They were bred to unexposed males during TCDD exposure (Experiment 1) and again after TCDD exposure ended (Experiment 2). Offspring from both experiments were weaned at 4 months and socialized for 1.5 h/day in groups of four monkeys each beginning at approximately 8 months of age. Each social group contained both control and TCDD-exposed monkeys. In Experiment 2, the offspring were later placed in new social groups containing only monkeys from the same TCDD exposure condition. The TCDD-exposed offspring born concurrent with maternal TCDD exposure (Experiment 1) initiated more rough-tumble play, retreated less during play bouts, and were less often displaced from preferred positions in the playroom. They also engaged in more self-directed behaviors. The behavior of offspring born after maternal TCDD exposure ended (Experiment 2) was not altered when they were socialized with control monkeys. However, some behavioral changes did emerge when they were placed in social groups containing only TCDD-exposed monkeys.     

Issues in risk assessment for developmental effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds.

Recent risk assessments for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds have focused on adverse effects observed in rodent offspring exposed while in utero during critical gestational periods as among the most sensitive adverse effects attributable to TCDD exposure. In addition, these risk assessments have converged on the use of body concentration (or "body burden") of TCDD as a dose metric superior to administered dose for cross-species comparisons and risk assessments, due to the interspecies differences in elimination kinetics and substantial persistence of these compounds. The detailed, although incomplete, data that are available on maternal-fetal distribution of TCDD and related compounds illustrate differences in distribution among these compounds that impact assessments on a body-burden basis. These data also demonstrate differences in distribution after subchronic or chronic administration compared to acute administration. Some data are now also available addressing inconsistencies that may arise from the use of TCDD toxic equivalency factors (TEFs), which were derived on an administered-dose basis, in evaluating responses to mixtures of dioxins on a body-burden basis in the context of chronic exposure situations. Finally, the use of body burden as a dose metric does not account for or eliminate the substantial differences in sensitivity to dioxin observed across species or between different strains of the same species and, thus, does not eliminate the need to consider the relative sensitivity of humans compared to laboratory animal models in risk assessments. Additional research areas that may increase the foundation for interspecies extrapolations are discussed.