视黄类受体与视黄酸致畸作用关系

视黄酸（维甲酸）可引起包括人在内的多种动物胚胎畸形,其生物活性是由一系列视黄酸受体及其配体介导的。其中视黄类受体RAR起主要作用,RAR的配体为强致畸物,相对致畸活性由强至弱依次为配体α、配体β和配体γ。视黄酸受体RXR的配体无致畸活性,但是可加强RAR激动剂的某些致畸郊应。视黄酸受体还可通过其它基因的表达而影响胚胎发育。对视黄类受体基因突变和不同视黄类受体及其配体与致畸作用的关系,以及此类受体对其它基因表达的调节作简要综述。 Abstract: Retinoic acid can induce teratogenesis of the fetus of many animals including human, and its biological activities are induced by a serious of different retinoic acid accepters and their ligands. The retinoic acid acceptor RAR plays key roles in the teratogenesis, and the legands of RAR are strong teratogens. The intensity sequence of the relative teratogenesis is ligandα、ligandβ and ligandγ. The ligands of the retinoic acid acceptor RXR cannot induce teratogenesis, but they can enhance the teratogenesis of the RAR stimulus. The retinoic acid acceptors can also affect the development of the fetus by adjusting the expression of the other genes. The relations between the gene mutation of the retinoic acid acceptor, various retinoic acid acceptors and their ligands and teratogenesis of retinoic acid are summarized in this article. In addition, the regulations of the retinoic acid acceptors to the other genes are also discussed.     

Genesis of alcohol-induced craniofacial dysmorphism

The initial diagnosis of fetal alcohol syndrome (FAS) in the United States was made because of the facial features common to the first cohort of patients. This article reviews the development of an FAS mouse model whose craniofacial features are remarkably similar to those of affected humans. The model is based on short-term maternal treatment with a high dosage of ethanol at stages of pregnancy that are equivalent to Weeks 3 and 4 of human gestation. At these early stages of development, alcohol's insult to the developing face is concurrent with that to the brain, eyes, and inner ear. That facial and central nervous system defects consistent with FAS can be induced by more "realistic" alcohol dosages as illustrated with data from an oral alcohol intake mouse model in which maternal blood alcohol levels do not exceed 200 mg/dl. The ethanol-induced pathogenesis involves apoptosis that occurs within 12 hrs of alcohol exposure in selected cell populations of Day 7, 8, and 9 mouse embryos. Experimental evidence from other species also shows that apoptosis underlies ethanol-induced malformations. With knowledge of sensitive and resistant cell populations at specific developmental stages, studies designed to identify the basis for these differing cellular responses and, therefore, to determine the primary mechanisms of ethanol's teratogenesis are possible. For example, microarray comparisons of sensitive and resistant embryonic cell populations have been made, as have in situ studies of gene expression patterns in the populations of interest. Studies that illustrate agents that are effective in diminishing or exacerbating ethanol's teratogenesis have also been helpful in determining mechanisms. Among these agents are antioxidants, sonic hedgehog protein, retinoids, and the peptides SAL and NAP.     

Acid-sensitive channel inhibition prevents fetal alcohol spectrum disorders cerebellar Purkinje cell loss

Ethanol is now considered the most common human teratogen. Educational campaigns have not reduced the incidence of ethanol-mediated teratogenesis, leading to a growing interest in the development of therapeutic prevention or mitigation strategies. On the basis of the observation that maternal ethanol consumption reduces maternal and fetal pH, we hypothesized that a pH-sensitive pathway involving the TWIK-related acid-sensitive potassium channels (TASKs) is implicated in ethanol-induced injury to the fetal cerebellum, one of the most sensitive targets of prenatal ethanol exposure. Pregnant ewes were intravenously infused with ethanol (258+/-10 mg/dl peak blood ethanol concentration) or saline in a "3 days/wk binge" pattern throughout the third trimester. Quantitative stereological analysis demonstrated that ethanol resulted in a 45% reduction in the total number of fetal cerebellar Purkinje cells, the cell type most sensitive to developmental ethanol exposure. Extracellular pH manipulation to create the same degree and pattern of pH fall caused by ethanol (manipulations large enough to inhibit TASK 1 channels), resulted in a 24% decrease in Purkinje cell number. We determined immunohistochemically that TASK 1 channels are expressed in Purkinje cells and that the TASK 3 isoform is expressed in granule cells of the ovine fetal cerebellum. Pharmacological blockade of both TASK 1 and TASK 3 channels simultaneous with ethanol effectively prevented any reduction in fetal cerebellar Purkinje cell number. These results demonstrate for the first time functional significance of fetal cerebellar two-pore domain pH-sensitive channels and establishes them as a potential therapeutic target for prevention of ethanol teratogenesis.     

Comparative studies on acetazolamide teratogenesis in pregnant rats, rabbits, and rhesus monkeys

Acetazolamide produces a characteristic forelimb reduction deformity when administered to pregnant rodents. Past studies indicated that non-rodent species (rabbit and monkey) are resistant to this effect. The present studies confirmed this fact and demonstrated that transport of acetazolamide into the rabbit embryo was similar to that in sensitive rat embryos. In monkeys, however, the concentrations of acetazolamide within maternal plasma and embryo were much lower than in rats. Carbonic anhydrase activity was also measured since inhibition of this enzyme is the primary pharmacologic effect of acetazolamide. Again the rabbit embryo had carbonic anhydrase specific activity levels similar to that of the rat. Monkey embryos, on the other hand, contained negligible levels of enzyme activity during the presumed sensitive period of development. Thus the resistance of monkey embryos to acetazolamide teratogenesis may be due to low carbonic anhydrase activity and/or the small amount of drug reaching the embryo. No basis for the resistance of rabbit embryos to acetazolamide teratogenesis was uncovered.     

Teratological interaction between the bis-triazole antifungal agent fluconazole and the anticonvulsant drug phenytoin

Previous studies implicated the cytochrome P450 (CYP) system as critical in the teratogenic bioactivation of phenytoin (PHT). Fluconazole (FCZ) is an antifungal bis-triazole with potent inhibitory effect on the principal CYP-dependent metabolic pathway of PHT. In this study an in vivo experimental model was used to evaluate the potential ability of FCZ (2, 10, or 50 mg/kg intraperitoneally) to modulate PHT (65 mg/kg intraperitoneally) teratogenesis on day 12 (plug day = day 1) Swiss mice. PHT alone elicited embryocidal and malformative effects, with cleft palate as the major malformation. Pretreatment with the nonembryotoxic dosage of 10 mg FCZ/kg potentiated PHT-induced teratogenesis, as indicated by a twofold (from 6.2% to 13.3%) increment of cleft palate incidence (P < 0.05). Combined treatment with 50 mg FCZ/kg plus PHT resulted in a statistically significant (P < 0.05) increment of the resorption incidence recorded after PHT-alone exposure, but possibly as a consequence of the increased embryolethality, in the loss of the potentiative effect on PHT teratogenesis. Although the mechanistic nature of teratological interaction between FCZ and PHT remains to be established, these results may not support CYP system-mediated metabolic conversion as the mechanistic component of PHT teratogenesis.     

发育异常机理的某些研究进展

阐明化学物致畸等发育毒性的作用机理,对建立人类致畸物或发育毒物的鉴定手段和防治工作都有重要意义。近年来随着发育基因或发育调控基因的发现和功能的阐明,发育异常的机理研究也取得一些突破。本文简要概述了几个主要进展。长期以来,一直认为哺乳动物发育的着床前胚胎阶段是诱发实验性先天畸形的不敏感期。因此,现行化学物的致畸性测试均规定在胚胎着床后的器官形成期给予受试物。然而,近年来的研究发现,在着床前期给予某些化学物可导致胎儿畸形、生长发育迟缓和出生后行为功能异常等发育毒性,这对传统的概念是一个大的冲击,即胚胎早期可能也是致畸等毒性的敏感期。如果确实如此,将意味着现行化学物致畸性测试方案需修改,而且以往已进行过致畸性安全性评价的化学物就存在潜在的危险性。对于早期胚胎损伤所致发育异常的机理现有两种假设,一种是根据甲基亚硝基脲的研究认为,胚泡阶段发生了微小的非致死性突变;另一种是基于环氧乙烷等化学物对受精卵的损伤,认为原发性损害是非遗传性的,是由于干扰早期胚胎基固表达的原定程序。据估计,人类胚胎至少有６０％在出生前死亡,其中大多发生在妊娠早期,只有约１５％在着床后死亡。但长期以来对出生前死亡的原因所知甚少,仅知道流产儿中染色     

Functional role of AhR in the expression of toxic effects by TCDD

Cytochrome P450 1A1 (CYP1A1) is one of the xenobiotic metabolizing enzymes (XMEs), which is induced by polycyclic aromatic hydrocarbons (PAHs). The most potent inducer of CYP1A1 is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In addition, TCDD induces a broad spectrum of biochemical and toxic effects, such as teratogenesis, immunosuppression and tumor promotion. Most, if not all, of the effects caused by TCDD and other PAHs are known to be mediated by AhR (aryl hydrocarbon receptor or dioxin receptor) which has a high binding affinity to TCDD. The liganded AhR translocates from cytoplasm to nuclei where it switches its partner molecule from Hsp90 to Arnt. Thus formed AhR/Arnt heterodimer binds a specific DNA sequence designated XRE in the promoter region of the target genes including CYP1A1, UDP-glucuronosyl transferase and others to enhance their expression. Although it remains to be studied how AhR is involved in the other TCDD-induced biological effects such as teratogenesis and immunosuppression than induction of XMEs, it is believed that these adverse TCDD effects are caused by untimely activation of gene expression by ligand-activated AhR in the biological process. We summarize the present knowledge about functional role of AhR in TCDD-induced biological effects.     

Oxidative stress as a mechanism of teratogenesis

Emerging evidence shows that redox-sensitive signal transduction pathways are critical for developmental processes, including proliferation, differentiation, and apoptosis. As a consequence, teratogens that induce oxidative stress (OS) may induce teratogenesis via the misregulation of these same pathways. Many of these pathways are regulated by cellular thiol redox couples, namely glutathione/glutathione disulfide, thioredoxinred/thioredoinox, and cysteine/cystine. This review outlines oxidative stress as a mechanism of teratogenesis through the disruption of thiol-mediated redox signaling. Due to the ability of many known and suspected teratogens to induce oxidative stress and the many signaling pathways that have redox-sensitive components, further research is warranted to fully understand these mechanisms.     

Zinc deficiency and the developing embryo

The effect ofin utero zinc deficiency on fetal development in rats is reviewed. Attention is paid to the primary biochemical lesion associated with zinc-related teratogenesis and special consideration is given to the central nervous system. Evidence is presented that the thymidine kinase salvage pathway, used for the synthesis of thymidine monophosphate in DNA synthesis, is depressed more in fetal brain tissue than in the liver. In addition, greater reliance appears to be placed on this pathway than onde novo synthesis in the fetal brain than in other tissues. Some consideration is given to the use of in vitro embryo culture in studies relating to neurogenesis, but evidence is presented of a greater capacity of explanted rat embryos to obtain zinc from maternal serum than occurs in vivo. The rapid onset of a teratogenic zinc deficiency following dietary zinc restriction is again highlighted and further studies are described which demonstrate the critical impact of a single feeding cycle, of 4 d duration, on maternal plasma zinc levels and on the extent and nature of the observed fetal abnormalities. Evidence is presented that by shifting the timing of the high dietary intake/low plasma zinc peak to coincide with a particular 48 h period between days 6 and 10 of pregnancy, the pattern of malformations thus obtained reflected the coincidence of the high dietary intake of zinc-deficient diet and the critical time of morphogenesis of several organ systems. Whereas diminished plasma zinc levels at term in zinc-deficient animals are generally well correlated with reduced growth and dysmorphogenesis of the offspring, the same is not always found in human studies. In some cases, elevated plasma zinc levels at parturition are found in mothers with growth-retarded children, or vice versa. Experimental studies with rats are reported that suggest that maternal zinc status at term may be higher in dams bearing pups stunted by exposure to a transient zinc deficiency early in pregnancy, which in turn may have reduced the demand for maternal zinc in the later stages of gestation. The protective effect of zinc on cadmium-induced teratogenesis is discussed, particularly in relation to findings concerning an interaction of these metals in the embryonic yolk sac and thus on preplacental embryonic nutrition. Possible interactions between alcohol and zinc deficiency are also considered and data are presented pointing to increased fetotoxicity and teratogenesis in the presence of both treatments and to a more specific interaction with respect to reduced cell numbers in the developing rat hippocampus. Malondialdehyde levels, which reflect the extent of lipid peroxidation in tissue, are reported to be substantially higher in microsomes from fetal rat livers whenin utero deficiency and gestational alcoholism are combined. The suggestion is made that alcohol and zinc deficiency act independently in the body, but overlap to some extent at the common biochemical locus of membrane lipid peroxidation.     

Reduction of uterine blood flow by phenylephrine, an alpha-adrenergic agonist, in the day 11 pregnant rat: relationship to potentiation of acetazolamide teratogenesis

We have demonstrated previously that phenylephrine, a selective postsynaptic alpha-1-adrenergic agonist, significantly potentiates the incidence of acetazolamide-induced right forelimb ectrodactyly in a dose-response manner. As reported herein, phenylephrine also decreases maternal uterine blood flow in a dose-response manner as measured by radioactive microsphere methodology. At the potentiative dose of 12.5 mg/kg phenylephrine decreases uterine blood flow by 86.8% when compared to control. In turn, pretreatment with prazosin, a selective postsynaptic alpha-1-adrenergic antagonist, prevents this large decrease in uterine blood flow and abolishes the potentiation of acetazolamide teratogenesis by phenylephrine. Although the effects of acetazolamide or acetazolamide + phenylephrine on uterine blood flow were not measured the data suggest a correlation between decreased uterine blood flow and potentiation of acetazolamide teratogenesis.     

Environmental carcinogenesis: an integrative model.

An integrative theory is proposed in which environmental carcinogenesis is viewed as a process by which the genetic control of cell division and differentiation is altered by carcinogens. In this theory, carcinogens include physical, chemical, and viral "mutagens," as well as chemical and viral gene modulators. Existing explanations of carcinogenesis can be considered either as somatic mutation theories or as epigenetic theories. Evidence seems to support the hypothesis that both mutations and epigenetic processes are components of carcinogenesis. The mutational basis of cancer is supported by the clonal nature of tumors, the mutagenicity of most carcinogens, high mutation frequencies in cells of cancer-prone human fibroblasts lacking DNA repair enzymes, the correlation of in vitro DNA damage and in vitro mutation and transformation frequencies with in vivo tumorigenesis, age-related incidences of various hereditary tumors, and the correlation between photoreactivation of DNA damage and the biological amelioration of UV-induced neoplasms. Since both mutagens and gene modulators can be carcinogenic it may be that carcinogens affect genes which control cell division. An integration of the mutation and epigenetic theories of cancer with the "two-stage" theory and Comings's general theory of carcinogenesis is proposed. This integrative theory postulates that carcinogens can affect regulatory genes which control a series of "transforming genes." A general hypothesis is advanced that involves a common mechanism of somatic mutagenesis via error-prone repair of DNA damage which links carcinogenesis, teratogenesis, atherosclerosis and aging. Various concepts are presented to provide a framework for evaluating the scientific, medical, and social implications of cancer.     

Transgenic mice expressing a constitutively active retinoic acid receptor in the lens exhibit ocular defects.

Retinoic acid receptors (RARs) modulate gene expression following association with retinoic acid (RA). In transient transfection, an RAR alpha-beta-galactosidase fusion protein (RAR-LacZ) was able to transactivate expression in the absence of RA. When expressed in the ocular lens of transgenic mice, this constitutively active RAR-LacZ fusion gene resulted in founder and progeny animals that exhibited cataracts and microphthalmia, both being characteristics of retinoid-induced teratogenesis. The transgenic phenotypes indicate that retinoid teratogenesis can be mimicked by expression of a constitutively active RAR-LacZ fusion protein in retinoid-sensitive tissues.     

Evolutionary considerations of DNA repair in relation to mutagenesis, teratogenesis and carcinogenesis.

Living organisms have various mechanisms for repairing spontaneous and mutagen-induced damage in DNA. Mutagenesis, teratogenesis, and carcinogenesis are discussed in relation to DNA misrepair. The existence of highly efficient genetic mechanisms for tolerating environmental threats is argued from evolutionary viewpoints.     

Fetal cardiac effects of maternal hyperglycemia during pregnancy

Maternal diabetes mellitus is associated with increased teratogenesis, which can occur in pregestational type 1 and type 2 diabetes. Cardiac defects and with neural tube defects are the most common malformations observed in fetuses of pregestational diabetic mothers. The exact mechanism by which diabetes exerts its teratogenic effects and induces embryonic malformations is unclear. Whereas the sequelae of maternal pregestational diabetes, such as modulating insulin levels, altered fat levels, and increased reactive oxygen species, may play a role in fetal damage during diabetic pregnancy, hyperglycemia is thought to be the primary teratogen, causing particularly adverse effects on cardiovascular development. Fetal cardiac defects are associated with raised maternal glycosylated hemoglobin levels and are up to five times more likely in infants of mothers with pregestational diabetes compared with those without diabetes. The resulting anomalies are varied and include transposition of the great arteries, mitral and pulmonary atresia, double outlet of the right ventricle, tetralogy of Fallot, and fetal cardiomyopathy. A wide variety of rodent models have been used to study diabetic teratogenesis. Both genetic and chemically induced models of type 1 and 2 diabetes have been used to examine the effects of hyperglycemia on fetal development. Factors such as genetic background as well as confounding variables such as obesity appear to influence the severity of fetal abnormalities in mice. In this review, we will summarize recent data on fetal cardiac effects from human pregestational diabetic mothers, as well as the most relevant findings in rodent models of diabetic cardiac teratogenesis. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Hyperthermia as a teratogen: parameters determining hyperthermia-induced head defects in the rat

This study determined the relationship between the duration and extent of temperature elevation, during a critical period of rat embryonic development, and the induction of congenital malformations. Pregnant Sprague-Dawley rats, at 9 days 12 hours gestation (gastrulation stage), were partially immersed in a water bath until their core temperature, monitored by a rectal thermistor probe, was elevated to a nominated temperature. Seven temperatures were tested from 40.5 degrees C to 43.5 degrees C, elevations of 2.0-5.0 degrees C in core temperature. Various durations at each of these temperatures were tested for potential teratogenicity. A single elevation of 5.0 degrees C or 4.5 degrees C needed only a "spike" in duration to be teratogenic, 4.0 degrees C was teratogenic within 5 minutes, 3.5 degrees C within 10 minutes, 3.0 degrees C within 20 minutes, and 2.5 degrees C within 1 hour. An elevation of 2.0 degrees C for 8 hours was not teratogenic. Microphthalmia was the most common malformation at all teratogenic temperatures and was frequently the only malformation seen at the shortest time exposure for a particular temperature. Encephalocele, facial clefting, and maxillary hypoplasia were the other frequently seen malformations. Five control rats were placed in the water bath for 2 hours at 38 degrees C so that their core temperature was not elevated. All the control fetuses were normal. An elevation of 2.5 degrees C for 1 hour was the threshold combination for teratogenesis. As the temperature increased above a 2.5 degrees C elevation the necessary duration of exposure for teratogenesis decreased.     

Genetically mediated induction of drug-metabolizing enzymes associated with congenital defects in the mouse.

Various polycyclic aromatic compounds induce certain monooxygenase activities, including aryl hydrocarbon (benzo[a]pyrene) hydroxylase (EC 1.14.14.2), and cytochrome P1-450 in the liver and many nonhepatic tissues of the mouse. This induction process is controlled by the Ah locus. Genetic differences that have been shown in the past to be associated with the Ah locus include an increased susceptibility to chemical carcinogenesis, mutagenicity in vitro, and drug toxicity--manifested as hepatic necrosis, aplastic anemia, or shortened survival time. Pregnant mice received a single injection of 3-methylcholanthrene or 7,12-dimethylbenz[a] anthracene between day 5 and day 13 of gestation, and the uterine contents were examined on day 18. Striking increases were observed in the incidence of MC-1 and DMBA-induced resorptions and congenital malformations in the aromatic hydrocarbon "responsive" C57BL/6N inbred strain, and of DMBA-induced resorptions in the "responsive" C3H/HeN and BALB/cAnN strains--when compared with the similarly treated genetically "nonresponsive" AKR/N strain. These data suggest but do not prove that an association exists between the Ah locus and developmental toxicity, i.e., teratogenesis. Although numerous teratogenic differences among inbred mouse strains have previously reported, this study is unique in that the genetic differences in teratogenicity observed were predicted in advance on the basis of known differences among these strains in polycyclic hydrocarbon metabolism regulated by the Ah locus.     

Teratogenic action and embryo lethality of AY 9944R. Prevention by a hypercholesterolemia-provoking diet.

Embryomortality and teratogenesis provoked by inhibitors of cholesterol synthesis are well demonstrated. Teratogenic action is particularly reflected by holoprosencephalies, but also by uro-genital abnormalities. A hypercholesterolemia-provoking diet has been shown to be completely effective for preventing holoprosencephaly, but only partially so for preventing the uro-genital malformations and fetal mortality. It is thus possible that the two types of abnormalities are governed by different mechanisms. In addition, the diet itself, whose hypercholesterolemic effect is considerable, has certain disadvantages. It seems to have a certain effect on fetal mortality and could be responsible for several uro-genital malformations. This deserves further study.     

Problems and terminology of functional teratology.

Possible causes for the teratogenesis of fundamental processes of life are explained. Hence, it is suggested that traditional teratology, i.e. teratomorphology (developmental pathomorphology) should be completed by teratophysiology (developmental pathophysiology), teratopsychology (developmental pathopsychology), and teratoimmunology (developmental pathoimmunology), as developmental biology can be also subdivided into developmental morphology, developmental physiology, developmental psychology and developmental immunology.