EFFECTS OF INVIVO-ADMINISTERED 2,3,7,8-TETRACHLORODIBENZO-PARA-DIOXIN ON RECEPTOR-BINDING OF EPIDERMAL GROWTH-FACTOR IN THE HEPATIC PLASMA-MEMBRANE OF RAT, GUINEA-PIG, MOUSE, AND HAMSTER
EFFECTS OF INVIVO-ADMINISTERED 2,3,7,8-TETRACHLORODIBENZO-PARA-DIOXIN ON RECEPTOR-BINDING OF EPIDERMAL GROWTH-FACTOR IN THE HEPATIC PLASMA-MEMBRANE OF RAT, GUINEA-PIG, MOUSE, AND HAMSTER
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DOI：
10.1073/pnas.81.23.7407
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发表时间：
1984-01-01
期刊：
影响因子：
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通讯作者：
MATSUMURA, F
中科院分区：
文献类型：
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作者：
MADHUKAR, BV;BREWSTER, DW;MATSUMURA, F
本文研究了2，3，7，8-四氯二苯并-对-二恶英（TCDD）对大鼠肝细胞膜表皮生长因子（EGF）受体活性的影响。TCDD在毒性早期（第2天）和在非常低的剂量（1 μ g/kd，单次腹膜内，大鼠）。这种减少似乎是由于受体数量的下降。在经TCDD治疗的大鼠中，EGF结合水平下降与体重减轻之间存在良好的相关性。EGF结合的减少发生在相对低剂量的豚鼠（一种非常敏感的物种）和高剂量的仓鼠（一种耐受物种）。在3种小鼠品系中，TCDD（115 μ g/kg，单次i. p.）在敏感菌株（C57 BL/6 J和CBA/J）中EGF结合减少98%，但在耐受菌株（AKR/J）中仅减少50%。为了将上述生物化学变化与体内效应联系起来，对新生小鼠进行了出生后给药（通过母乳）。最突出的毒性表现是早期睁眼和门牙萌出，体重增加减少和毛发生长迟缓。所有这些症状都归因于EGF的作用。TCDD也刺激大鼠肝细胞膜EGF受体的磷酸化。在第1天观察到这种磷酸化作用，并持续到试验结束（第10天）。长期以来，人们已经认识到，引起EGF受体数量减少的试剂（例如，佛波醇酯）引发体内细胞反应，其类似于暴露于过量的生长因子所引起的反应。因此，有人提出一种假说，认为TCDD的某些EGF样效应，如肝脏脂肪浸润和胃上皮细胞和表皮细胞的增生性增殖，都是由于其对EGF受体的作用。
The effect on in vivo-administered 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on epidermal growth factor (EGF) receptor activity of the rat hepatic plasma membrane was studied. TCDD causes a significant reduction in EGF binding at an early stage of toxicity (day 2) and at very low doses (1 .mu.g/kd, single i.p., rat). This reduction appears to be due to a decline in the number of receptors. There is a good correlation between levels of decline in EGF binding and loss of body weight among TCDD-treated rats. The reduction in EGF binding occurs at a relatively low dose in the guinea pig (a very sensitive species) and at high doses in the hamster (a tolerant species). Among 3 mice strains, TCDD (115 .mu.g/kg, single i.p.) caused 98% reduction in EGF binding in the sensitive strains (C57BL/6J and CBA/J) but only a 50% reduction in the tolerant strain (AKR/J). To relate the above biochemical changes to in vivo effects, TCDD was postnatally administered (through mother''s milk) to mouse neonates. The most prominent toxic manifestations were early eye opening and incisor eruption, loss in body weight gain, and retardation of hair growth. All of these symptoms have been ascribed to EGF effects. TCDD also stimulated phosphorylation of the EGF receptor in the rat hepatic plasma membrane. This phosphorylation effect was observed at day 1 and persisted until the end of the test (day 10). It has long been recognized that agents causing reduction in number of EGF receptors (e.g., phorbol esters) elicit in vivo cellular responses that are similar to those caused by exposure to excess doses of growth factors. Accordingly, a hypothesis was proposed to ascribe some of the EGF-like effects of TCDD, such as fatty infiltration of the liver and hyperplastic proliferation of gastric epithelia and epidermal cells to its action on the EGF receptor.