Receptor- and reactive intermediate-mediated mechanisms of teratogenesis.
Receptor- and reactive intermediate-mediated mechanisms of teratogenesis.
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受体和反应中间体介导的致畸机制。
DOI：
10.1007/978-3-642-00663-0_6
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发表时间：
2010
影响因子：
--
通讯作者：
Harper,PatriciaA
中科院分区：
文献类型：
--
作者：
Wells,PeterG;Lee,CrystalJJ;McCallum,GordonP;Perstin,Julia;Harper,PatriciaA
药物和环境化学物质会在怀孕期间的关键时期对胎儿的发育产生不利影响，导致死亡或存活后代的结构和功能性出生缺陷。这种致畸过程可能在出生后十年或更长时间内不明显。出生后的功能异常包括脑功能缺陷、各种代谢疾病和癌症。由于胎儿细胞高度分裂和分化，以及与成人在许多生化途径上的差异，胎儿对致畸剂高度敏感，通常在不伤害母亲的低暴露水平下。对致畸机制的了解主要来自动物模型和体外系统，涉及受体介导或反应性中间体介导的过程。受体介导的机制涉及异生物质底物与特定受体的可逆结合，在此通过环境化学品2，3，7，8-四氯二苯并-对-二恶英（TCDD或“二恶英”）与胞质芳香烃受体（AHR）结合，所述芳香烃受体（AHR）易位至细胞核，并且与其他蛋白质结合，与许多基因中的AH-反应元件（AHRE）结合，引发基因转录的变化，从而扰乱发育。或者，许多异生物质被胎儿酶如细胞色素P450（CYP）和前列腺素H转移酶（PHSs）生物活化为高度不稳定的亲电或自由基反应性中间体。亲电活性中间体可以共价（不可逆）结合并改变基本细胞大分子（蛋白质，DNA）的功能，导致发育异常。自由基反应性中间体可以增强活性氧（ROS）的形成，导致对细胞大分子的氧化损伤和/或改变信号转导。活性中间体的致畸性在很大程度上取决于胚胎和胎儿生物外源性生物活化途径之间的平衡、生物外源性活性中间体的解毒、ROS的解毒和氧化性大分子损伤的修复。
Drugs and environmental chemicals can adversely alter the development of the fetus at critical periods during pregnancy, resulting in death, or in structural and functional birth defects in the surviving offspring. This process of teratogenesis may not be evident until a decade or more after birth. Postnatal functional abnormalities include deficits in brain function, a variety of metabolic diseases, and cancer. Due to the high degree of fetal cellular division and differentiation, and to differences from the adult in many biochemical pathways, the fetus is highly susceptible to teratogens, typically at low exposure levels that do not harm the mother. Insights into the mechanisms of teratogenesis come primarily from animal models and in vitro systems, and involve either receptor-mediated or reactive intermediate-mediated processes. Receptor-mediated mechanisms involving the reversible binding of xenobiotic substrates to a specific receptor are exemplified herein by the interaction of the environmental chemical 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or “dioxin”) with the cytosolic aryl hydrocarbon receptor (AHR), which translocates to the nucleus and, in association with other proteins, binds to AH-responsive elements (AHREs) in numerous genes, initiating changes in gene transcription that can perturb development. Alternatively, many xenobiotics are bioactivated by fetal enzymes like the cytochromes P450 (CYPs) and prostaglandin H synthases (PHSs) to highly unstable electrophilic or free radical reactive intermediates. Electrophilic reactive intermediates can covalently (irreversibly) bind to and alter the function of essential cellular macromolecules (proteins, DNA), causing developmental anomalies. Free radical reactive intermediates can enhance the formation of reactive oxygen species (ROS), resulting in oxidative damage to cellular macromolecules and/or altered signal transduction. The teratogenicity of reactive intermediates is determined to a large extent by the balance among embryonic and fetal pathways of xenobiotic bioactivation, detoxification of the xenobiotic reactive intermediate, detoxification of ROS, and repair of oxidative macromolecular damage.
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血清中骨骼来源碱性磷酸酶定量测定的改进方法。
影响因子：
9.3
作者：
J. Farley;C. Chesnut;D. Baylink
通讯作者：
D. Baylink
血浆“碱性”磷酸酶活性
DOI：
--
发表时间：
1950
期刊：
影响因子：
--
作者：
L. Clark;E. Beck
通讯作者：
E. Beck
用氟化物和钙治疗原发性骨质疏松症。
DOI：
--
发表时间：
1980
期刊：
Journal of the American Medical Association (JAMA)
影响因子：
--
作者：
B. Riggs;Stephen F. Hodgson;David L. Hoffman;Patrick J. Kelly;Kenneth A. Johnson;Donald R. Taves
通讯作者：
Donald R. Taves
DOI：
10.1210/jcem-39-1-119
发表时间：
1974
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
--
作者：
D. Sherrard;D. Baylink;J. Wergedal;N. Maloney
通讯作者：
N. Maloney
影响因子：
6.7
作者：
Cameron, J R;Mazess, R B;Sorenson, J A
通讯作者：
Sorenson, J A