BACKGROUND 5-Aza-2'-deoxycytidine (dAZA), causes hindlimb phocomelia in CD-1 mice. Studies in our laboratory have examined the hypothesis that compound- induced changes in gene expression may uniquely affect hindlimb pattern formation. The present study tests the hypothesis that dAZA causes limb dysplasia by inducing cytotoxicity among rapidly proliferating cells in the limb bud mesenchyme. METHODS Pregnant CD-1 mice were given a teratogenic dose of dAZA (i.p.) at different times on GD 10 and fetuses evaluated for skeletal development in both sets of limbs by standard methods. Using general histology and BrdU immunohistochemistry, limb mesenchymal cell death and cell proliferation were then assessed in embryos at various times post dosing, shortly after initial limb bud outgrowth. The effect of dAZA on early limb chondrogenesis was also studied using Northern analysis of scleraxis and Alcian blue staining of whole mount limb buds. RESULTS Compound related hindlimb defects were not restricted to a specific set of skeletal elements but consisted of a range of temporally related limb anomalies. Modest defects of the radius were observed as well. These results are consistent with a general insult to the limb mesenchyme. Mesenchymal cell death and reduced cell proliferation were also observed in both sets of limbs. The timing and location of these effects indicate a role for cytotoxicity in the etiology of dAZA induced limb defects. These effects also agree with the greater teratogenicity of dAZA in the hindlimb because they were more pronounced in that limb. The expression of scleraxis, a marker of early chondrogenesis, was reduced 12 hr after dAZA exposure, a time coincident with maximal cell death, as was the subsequent emergence of Alcian blue stained long bone anlagen. CONCLUSIONS These findings support the hypothesis that cytotoxic changes in the limb bud mesenchyme during early limb outgrowth can induce the proximal limb truncations characteristic of phocomelia after dAZA administration.
{"title":"5-Aza-2'-deoxycytidine-induced cytotoxicity and limb reduction defects in the mouse.","authors":"M. Rosen, N. Chernoff","doi":"10.1002/TERA.10029","DOIUrl":"https://doi.org/10.1002/TERA.10029","url":null,"abstract":"BACKGROUND\u00005-Aza-2'-deoxycytidine (dAZA), causes hindlimb phocomelia in CD-1 mice. Studies in our laboratory have examined the hypothesis that compound- induced changes in gene expression may uniquely affect hindlimb pattern formation. The present study tests the hypothesis that dAZA causes limb dysplasia by inducing cytotoxicity among rapidly proliferating cells in the limb bud mesenchyme.\u0000\u0000\u0000METHODS\u0000Pregnant CD-1 mice were given a teratogenic dose of dAZA (i.p.) at different times on GD 10 and fetuses evaluated for skeletal development in both sets of limbs by standard methods. Using general histology and BrdU immunohistochemistry, limb mesenchymal cell death and cell proliferation were then assessed in embryos at various times post dosing, shortly after initial limb bud outgrowth. The effect of dAZA on early limb chondrogenesis was also studied using Northern analysis of scleraxis and Alcian blue staining of whole mount limb buds.\u0000\u0000\u0000RESULTS\u0000Compound related hindlimb defects were not restricted to a specific set of skeletal elements but consisted of a range of temporally related limb anomalies. Modest defects of the radius were observed as well. These results are consistent with a general insult to the limb mesenchyme. Mesenchymal cell death and reduced cell proliferation were also observed in both sets of limbs. The timing and location of these effects indicate a role for cytotoxicity in the etiology of dAZA induced limb defects. These effects also agree with the greater teratogenicity of dAZA in the hindlimb because they were more pronounced in that limb. The expression of scleraxis, a marker of early chondrogenesis, was reduced 12 hr after dAZA exposure, a time coincident with maximal cell death, as was the subsequent emergence of Alcian blue stained long bone anlagen.\u0000\u0000\u0000CONCLUSIONS\u0000These findings support the hypothesis that cytotoxic changes in the limb bud mesenchyme during early limb outgrowth can induce the proximal limb truncations characteristic of phocomelia after dAZA administration.","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"30 1","pages":"180-90"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73712599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Solvents and color vision.","authors":"A. Scialli, A. Lione, K. Jones","doi":"10.1002/TERA.10030","DOIUrl":"https://doi.org/10.1002/TERA.10030","url":null,"abstract":"","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"36 1","pages":"151; author reply 152"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82650439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUND Since reports on a pattern of multiple sites of fusion of the neural folds in the mouse appeared, it has been widely assumed that a similar pattern must be valid for the human. In the absence of embryological evidence, claims have been made that such a pattern can be discerned by classifying neural tube defects. METHODS The neural folds and tube, as well as the neuropores, were reassessed in 98 human embryos of Stages 8-13; 61 were controlled by precise graphic reconstructions. RESULTS Careful study of an extensive series of staged human embryos shows that two de novo sites of fusion of the neural folds appear in succession: alpha in the rhombencephalic region and beta in the prosencephalic region, adjacent to the chiasmatic plate. Fusion from Site alpha proceeds bidirectionally (rostrad and caudad), whereas that from beta is unidirectional (caudad only). The fusions terminate in neuropores, of which there are two: rostral and caudal. Highly variable accessory loci of fusion, without positional stability and of unknown frequency, may be encountered in Stage 10 but seemingly not later, and their existence has been known for more than half a century. CONCLUSIONS Two sites of fusion (a term preferred to closure) of the neural folds and two neuropores are found in the human embryo. No convincing embryological evidence of a pattern of multiple sites of fusion, such as has been described in the mouse, is available for the human. The construction of embryological details from information derived from other species or from the examination of later anomalies is liable to error. Neural tube defects are reviewed and although they have been considered on the basis of five, four, or three sites of fusion, interpretations based on two sites can as readily be envisaged.
{"title":"The two sites of fusion of the neural folds and the two neuropores in the human embryo.","authors":"R. O'rahilly, F. Müller","doi":"10.1002/TERA.10007","DOIUrl":"https://doi.org/10.1002/TERA.10007","url":null,"abstract":"BACKGROUND\u0000Since reports on a pattern of multiple sites of fusion of the neural folds in the mouse appeared, it has been widely assumed that a similar pattern must be valid for the human. In the absence of embryological evidence, claims have been made that such a pattern can be discerned by classifying neural tube defects.\u0000\u0000\u0000METHODS\u0000The neural folds and tube, as well as the neuropores, were reassessed in 98 human embryos of Stages 8-13; 61 were controlled by precise graphic reconstructions.\u0000\u0000\u0000RESULTS\u0000Careful study of an extensive series of staged human embryos shows that two de novo sites of fusion of the neural folds appear in succession: alpha in the rhombencephalic region and beta in the prosencephalic region, adjacent to the chiasmatic plate. Fusion from Site alpha proceeds bidirectionally (rostrad and caudad), whereas that from beta is unidirectional (caudad only). The fusions terminate in neuropores, of which there are two: rostral and caudal. Highly variable accessory loci of fusion, without positional stability and of unknown frequency, may be encountered in Stage 10 but seemingly not later, and their existence has been known for more than half a century.\u0000\u0000\u0000CONCLUSIONS\u0000Two sites of fusion (a term preferred to closure) of the neural folds and two neuropores are found in the human embryo. No convincing embryological evidence of a pattern of multiple sites of fusion, such as has been described in the mouse, is available for the human. The construction of embryological details from information derived from other species or from the examination of later anomalies is liable to error. Neural tube defects are reviewed and although they have been considered on the basis of five, four, or three sites of fusion, interpretations based on two sites can as readily be envisaged.","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"83 1","pages":"162-70"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76126698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Epeldegui, Á. Peña-Melián, G. Varela-Moreiras, J. Pérez-Miguelsanz
BACKGROUND The formation of the neural tube (neurulation) involves two mechanisms: primary and secondary neurulation. In chicks, there is also an overlap zone, where both mechanisms work together. Homocysteine (Hcy) may have an important teratogenic role in neural tube defects (NTD) when folic acid levels are considered normal. Recently, Hcy capability to generate NTD and modify neural crest cell migration has been demonstrated in chick embryos. This study was aimed to evaluate the effects of Hcy on neurulation and the development of the dorsal root ganglia (DRG). METHODS Chick embryos were treated with L-Hcy thiolactone 20 micromol to produce the highest rate of survival with embryos carrying neural tube defect (NTD) in the spine. Embryos at stages (st) 3-10 were treated and harvested at st 18-23. Only externally normal embryos or those carrying spinal NTD embryos were considered. RESULTS Histological sections of Hcy-treated embryos showed: open spina bifida (39% of embryos), more than one tube forming the spinal cord (26%), disorganized spinal cord (26%), always affecting lumbosacral regions, probably in the overlap zone. Additionally, 32% of embryos had small and continuous DRG, associated with a slimmed roof plate. Three-dimensional reconstruction showed unsegmented DRG until the C8 ganglion level. There was a 75% reduction of C3 DRG cells in treated embryos in comparison to untreated ganglia. CONCLUSION Hcy teratogenicity in avian embryos affected the neural tube in the overlap zone, secondary neurulation and the cervical DRG.
{"title":"Homocysteine modifies development of neurulation and dorsal root ganglia in chick embryos.","authors":"M. Epeldegui, Á. Peña-Melián, G. Varela-Moreiras, J. Pérez-Miguelsanz","doi":"10.1002/TERA.10033","DOIUrl":"https://doi.org/10.1002/TERA.10033","url":null,"abstract":"BACKGROUND\u0000The formation of the neural tube (neurulation) involves two mechanisms: primary and secondary neurulation. In chicks, there is also an overlap zone, where both mechanisms work together. Homocysteine (Hcy) may have an important teratogenic role in neural tube defects (NTD) when folic acid levels are considered normal. Recently, Hcy capability to generate NTD and modify neural crest cell migration has been demonstrated in chick embryos. This study was aimed to evaluate the effects of Hcy on neurulation and the development of the dorsal root ganglia (DRG).\u0000\u0000\u0000METHODS\u0000Chick embryos were treated with L-Hcy thiolactone 20 micromol to produce the highest rate of survival with embryos carrying neural tube defect (NTD) in the spine. Embryos at stages (st) 3-10 were treated and harvested at st 18-23. Only externally normal embryos or those carrying spinal NTD embryos were considered.\u0000\u0000\u0000RESULTS\u0000Histological sections of Hcy-treated embryos showed: open spina bifida (39% of embryos), more than one tube forming the spinal cord (26%), disorganized spinal cord (26%), always affecting lumbosacral regions, probably in the overlap zone. Additionally, 32% of embryos had small and continuous DRG, associated with a slimmed roof plate. Three-dimensional reconstruction showed unsegmented DRG until the C8 ganglion level. There was a 75% reduction of C3 DRG cells in treated embryos in comparison to untreated ganglia.\u0000\u0000\u0000CONCLUSION\u0000Hcy teratogenicity in avian embryos affected the neural tube in the overlap zone, secondary neurulation and the cervical DRG.","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"15 1","pages":"171-9"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81452437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUND The conduct of human research in the teratogenicity of drugs, chemicals, radiation and infections is needed in order to close critical gaps in knowledge. METHODS We reviewed the various aspects of the ethics of conducting prospective human research in teratogenicity. RESULTS Such research should respect the confidentiality of pregnant women and their families. Because this research is observational, interpretation of results is difficult, and the study design should strive to meet the highest possible scientific standards attainable in the particular research conditions. It should also be acknowledged that confidentiality cannot be always adhered to (e.g., if the interview reveals risks to minors). CONCLUSIONS In general, the benefit risk ratio in this type of research is very favorable, although in specific cases the research follow-up may induce fears (e.g., drugs of abuse) in the woman being interviewed.
{"title":"Ethical framework for observational studies of medicinal drug exposure in pregnancy.","authors":"G. Koren","doi":"10.1002/TERA.10038","DOIUrl":"https://doi.org/10.1002/TERA.10038","url":null,"abstract":"BACKGROUND\u0000The conduct of human research in the teratogenicity of drugs, chemicals, radiation and infections is needed in order to close critical gaps in knowledge.\u0000\u0000\u0000METHODS\u0000We reviewed the various aspects of the ethics of conducting prospective human research in teratogenicity.\u0000\u0000\u0000RESULTS\u0000Such research should respect the confidentiality of pregnant women and their families. Because this research is observational, interpretation of results is difficult, and the study design should strive to meet the highest possible scientific standards attainable in the particular research conditions. It should also be acknowledged that confidentiality cannot be always adhered to (e.g., if the interview reveals risks to minors).\u0000\u0000\u0000CONCLUSIONS\u0000In general, the benefit risk ratio in this type of research is very favorable, although in specific cases the research follow-up may induce fears (e.g., drugs of abuse) in the woman being interviewed.","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"32 1","pages":"191-5"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78667360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUND Little is known about reproductive outcome risks for Vietnamese women delivering infants and fetuses in the U.S. METHODS Using data from a large population-based registry, we explored risks of selected congenital malformation phenotypes in offspring of Vietnamese women in California. Data were derived from the California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with congenital malformations using multiple source ascertainment. Approximately 3.4 million births (liveborn and stillborn) occurred during the ascertainment period, 1985-97. Information on maternal race/ethnic background was obtained from California birth certificate and fetal death files. Vietnamese women delivered 45,453 births and 1,257,853 births were delivered to non-Hispanic white women. RESULTS The overall prevalence of structural congenital malformations was 1.92 among Vietnamese and 2.63 among non-Hispanic whites per 100 births and fetal deaths. Grouping by 20 3-digit malformation codes of the International Classification of Diseases-Ninth Revision revealed relative risks of 0.8 or less for spina bifida, eye, upper alimentary, genital, urinary, musculoskeletal, "other" limb, and "other" musculoskeletal anomalies, and relative risks of 1.3 or more for anencephaly and chromosomal anomalies. Grouping by the more specific 4-digit malformation codes revealed 50, among 178, malformation groupings with associated relative risks of >or=1.3 or
{"title":"Congenital malformations in offspring of Vietnamese women in California, 1985-97.","authors":"G. Shaw, S. Carmichael, V. Nelson","doi":"10.1002/TERA.10020","DOIUrl":"https://doi.org/10.1002/TERA.10020","url":null,"abstract":"BACKGROUND\u0000Little is known about reproductive outcome risks for Vietnamese women delivering infants and fetuses in the U.S.\u0000\u0000\u0000METHODS\u0000Using data from a large population-based registry, we explored risks of selected congenital malformation phenotypes in offspring of Vietnamese women in California. Data were derived from the California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with congenital malformations using multiple source ascertainment. Approximately 3.4 million births (liveborn and stillborn) occurred during the ascertainment period, 1985-97. Information on maternal race/ethnic background was obtained from California birth certificate and fetal death files. Vietnamese women delivered 45,453 births and 1,257,853 births were delivered to non-Hispanic white women.\u0000\u0000\u0000RESULTS\u0000The overall prevalence of structural congenital malformations was 1.92 among Vietnamese and 2.63 among non-Hispanic whites per 100 births and fetal deaths. Grouping by 20 3-digit malformation codes of the International Classification of Diseases-Ninth Revision revealed relative risks of 0.8 or less for spina bifida, eye, upper alimentary, genital, urinary, musculoskeletal, \"other\" limb, and \"other\" musculoskeletal anomalies, and relative risks of 1.3 or more for anencephaly and chromosomal anomalies. Grouping by the more specific 4-digit malformation codes revealed 50, among 178, malformation groupings with associated relative risks of >or=1.3 or <or=0.8. Seventeen relative risk estimates suggested elevated risks for Vietnamese births, and 33 estimates suggested lowered risks for Vietnamese, relative to non-Hispanic white births. Simultaneous adjustment for maternal age, plurality, and child sex, did not substantially alter observed risks.\u0000\u0000\u0000CONCLUSIONS\u0000These data contribute to a relatively sparse literature about an important subgroup of the U.S. population, but can not elucidate whether increased or decreased risks among Vietnamese are related to potential underlying genetic susceptibilities, to cultural, social, or political differences that could modify exposures, or to the many potential combinations between susceptibilities and exposures.","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"14 1","pages":"121-4"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84327696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUND Single ventricle, a rare congenital cardiac defect, often occurs as part of a complex group of cardiovascular abnormalities. Little is known of its epidemiologic associations. METHODS Using data from the Baltimore-Washington Infant Study [BWIS], (1981-89), a population based case-control study of cardiovascular malformations, infants with single ventricle were evaluated with respect to infant and family characteristics and maternal and paternal exposures. The cases were analyzed according to presence/absence of abnormal cardio-visceral situs. Controls were 3,572 infants without heart defects randomly selected from the regional cohort of live births. Odds ratios and 95% confidence intervals were used as measures of association. RESULTS Single ventricle occurred in 1.25% of infants with congenital cardiovascular defects in the BWIS. Fifty-five infants had single ventricle. In 48 families (87.3%) the parents were interviewed. Thirty-three infants had normal situs and 15 had abnormal situs. Paternal alcohol consumption (OR = 2.0, 95% CI 1.1-3.9) and paternal cigarette smoking (OR = 2.4, 95% CI 1.1-5.1) were associated with all cases of single ventricle. These associations were even stronger in the subset of infants with abnormal situs. Maternal history of a previous induced abortion was also associated with infants born with abnormal situs (OR = 3.2, 95% CI 1.1-11.5). Paternal marijuana use was associated with cases of single ventricle in normal situs (OR = 2.2, 95% CI 1.0-5.2). CONCLUSIONS Potential risk factors included paternal smoking and alcohol consumption, highlighting the need for future studies to consider environmental factors in the pathogenesis of this cardiac defect.
背景:单心室是一种罕见的先天性心脏缺陷，常作为一组复杂的心血管异常的一部分。人们对其流行病学关联知之甚少。方法使用巴尔的摩-华盛顿婴儿研究[BWIS](1981-89)的数据，这是一项基于人群的心血管畸形病例对照研究，评估单心室婴儿的婴儿和家庭特征以及母亲和父亲的暴露情况。根据有无心脏脏器部位异常进行分析。对照组为3572名无心脏缺陷的婴儿，随机从地区活产队列中选出。比值比和95%置信区间作为相关性的度量。结果先天性心血管缺陷患儿中单心室发生率为1.25%。55名婴儿有单心室。对48个家庭(87.3%)的家长进行了访谈。33例患儿位置正常，15例患儿位置异常。父亲饮酒(OR = 2.0, 95% CI 1.1-3.9)和父亲吸烟(OR = 2.4, 95% CI 1.1-5.1)与所有单心室病例相关。这些关联在位置异常的婴儿亚群中甚至更强。母亲既往人工流产史也与出生时胎位异常的婴儿有关(OR = 3.2, 95% CI 1.1-11.5)。父亲使用大麻与正常位置的单心室病例相关(OR = 2.2, 95% CI 1.0-5.2)。结论潜在的危险因素包括父亲吸烟和饮酒，强调未来的研究需要考虑环境因素在这一心脏缺陷的发病机制。
{"title":"Infants with single ventricle: a population-based epidemiological study.","authors":"E. Steinberger, C. Ferencz, C. Loffredo","doi":"10.1002/TERA.10017","DOIUrl":"https://doi.org/10.1002/TERA.10017","url":null,"abstract":"BACKGROUND\u0000Single ventricle, a rare congenital cardiac defect, often occurs as part of a complex group of cardiovascular abnormalities. Little is known of its epidemiologic associations.\u0000\u0000\u0000METHODS\u0000Using data from the Baltimore-Washington Infant Study [BWIS], (1981-89), a population based case-control study of cardiovascular malformations, infants with single ventricle were evaluated with respect to infant and family characteristics and maternal and paternal exposures. The cases were analyzed according to presence/absence of abnormal cardio-visceral situs. Controls were 3,572 infants without heart defects randomly selected from the regional cohort of live births. Odds ratios and 95% confidence intervals were used as measures of association.\u0000\u0000\u0000RESULTS\u0000Single ventricle occurred in 1.25% of infants with congenital cardiovascular defects in the BWIS. Fifty-five infants had single ventricle. In 48 families (87.3%) the parents were interviewed. Thirty-three infants had normal situs and 15 had abnormal situs. Paternal alcohol consumption (OR = 2.0, 95% CI 1.1-3.9) and paternal cigarette smoking (OR = 2.4, 95% CI 1.1-5.1) were associated with all cases of single ventricle. These associations were even stronger in the subset of infants with abnormal situs. Maternal history of a previous induced abortion was also associated with infants born with abnormal situs (OR = 3.2, 95% CI 1.1-11.5). Paternal marijuana use was associated with cases of single ventricle in normal situs (OR = 2.2, 95% CI 1.0-5.2).\u0000\u0000\u0000CONCLUSIONS\u0000Potential risk factors included paternal smoking and alcohol consumption, highlighting the need for future studies to consider environmental factors in the pathogenesis of this cardiac defect.","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"142 1","pages":"106-15"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86779204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUND The purpose of the present study was to investigate the correlation between MeHg developmental toxicity and mitochondrial 16S ribosomal RNA (16S rRNA) expression in the embryonic forebrain and pharmacological intervention with PK11195, a ligand for the mitochondrial peripheral-type benzodiazepine receptor (Bzrp). METHODS Pregnant CD-1 mice were dosed with methylmercury (II) chloride (MeHg) with or without 4 mg/kg PK11195 on Day 9 of gestation. Fetuses were examined on Day 9 (RT-PCR), Day 15 (histology), and Day 17 (teratology). RESULTS MeHg (10 mg/kg) induced microcephaly, microphthalmia and cleft palate. The mean incidences of malformed fetuses were 47.7% with MeHg (P < 0.001) and 19.2% with PK11195 co-treatment (P < 0.01 for rescue). Cleft palates were 12.8% and 1.5%, respectively. An estimate of neurocranial circumference revealed a small (5%) but highly significant (P < 0.001) reduction that was rescued in a subset of co-treated fetuses (P < 0.05). RT-PCR analysis of the Day 9 forebrain revealed inhibition of 16S rRNA expression 3.0 hr after 5 mg/kg MeHg exposure (P < 0.001). This effect was rescued with PK11195 (P < 0.001). Preliminary findings revealed a similar response-rescue in cultured embryos exposed to 1 microM Hg(II) when exogenous 5-aminolevulinic acid (ALA) was added. Protoporphyrin-IX (PP9), the penultimate precursor to heme and an endogenous ligand of the Bzrp, increased in a manner that was ALA-dependent and PK11195-sensitive. CONCLUSION At least some teratological effects of Hg appear linked with late steps in the heme biosynthesis pathway through the Bzrp. PK11195, a ligand for these mitochondrial receptors, significantly lessens the risk of microphthalmia, microcephaly, and cleft palate in Hg-poisoned embryos.
{"title":"Mitochondrial transduction of ocular teratogenesis during methylmercury exposure.","authors":"M. O'Hara, J. Charlap, R. C. Craig, T. Knudsen","doi":"10.1002/TERA.10028","DOIUrl":"https://doi.org/10.1002/TERA.10028","url":null,"abstract":"BACKGROUND\u0000The purpose of the present study was to investigate the correlation between MeHg developmental toxicity and mitochondrial 16S ribosomal RNA (16S rRNA) expression in the embryonic forebrain and pharmacological intervention with PK11195, a ligand for the mitochondrial peripheral-type benzodiazepine receptor (Bzrp).\u0000\u0000\u0000METHODS\u0000Pregnant CD-1 mice were dosed with methylmercury (II) chloride (MeHg) with or without 4 mg/kg PK11195 on Day 9 of gestation. Fetuses were examined on Day 9 (RT-PCR), Day 15 (histology), and Day 17 (teratology).\u0000\u0000\u0000RESULTS\u0000MeHg (10 mg/kg) induced microcephaly, microphthalmia and cleft palate. The mean incidences of malformed fetuses were 47.7% with MeHg (P < 0.001) and 19.2% with PK11195 co-treatment (P < 0.01 for rescue). Cleft palates were 12.8% and 1.5%, respectively. An estimate of neurocranial circumference revealed a small (5%) but highly significant (P < 0.001) reduction that was rescued in a subset of co-treated fetuses (P < 0.05). RT-PCR analysis of the Day 9 forebrain revealed inhibition of 16S rRNA expression 3.0 hr after 5 mg/kg MeHg exposure (P < 0.001). This effect was rescued with PK11195 (P < 0.001). Preliminary findings revealed a similar response-rescue in cultured embryos exposed to 1 microM Hg(II) when exogenous 5-aminolevulinic acid (ALA) was added. Protoporphyrin-IX (PP9), the penultimate precursor to heme and an endogenous ligand of the Bzrp, increased in a manner that was ALA-dependent and PK11195-sensitive.\u0000\u0000\u0000CONCLUSION\u0000At least some teratological effects of Hg appear linked with late steps in the heme biosynthesis pathway through the Bzrp. PK11195, a ligand for these mitochondrial receptors, significantly lessens the risk of microphthalmia, microcephaly, and cleft palate in Hg-poisoned embryos.","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"27 1","pages":"131-44"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73031041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Hyperglycemia and congenital malformations in insulin-dependent diabetes mellitus: a brief summary and evaluation.","authors":"H. Kalter","doi":"10.1002/TERA.10024","DOIUrl":"https://doi.org/10.1002/TERA.10024","url":null,"abstract":"","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"69 1","pages":"97-101"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81748718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Association between maternal diabetes mellitus and major malformations in the offspring: A reply to Dr. Kalter","authors":"M. Greene","doi":"10.1002/TERA.10025","DOIUrl":"https://doi.org/10.1002/TERA.10025","url":null,"abstract":"","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"15 1","pages":"100-101"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89523721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：