Wiley
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Platelet‐derived growth factor C plays a role in the branchial arch malformations induced by retinoic acid Abstract BACKGROUND: All‐trans ‐retinoic acid (RA) can produce branchial arch abnormalities in postimplantation rodent embryos cultured in vitro . Platelet‐derived growth factor C (PDGF‐C) was recently identified as a member of the PDGF ligand family. Many members of the PDGF family are essential for branchial arch morphogenesis and can be regulated by RA. The roles of PDGF‐C in branchial arch malformations induced by RA and possible mechanisms were investigated. METHODS: In whole embryo culture (WEC), mouse embryos were exposed to RA at 0, 0.1, 0.4, 1.0, or 10.0 μM , PDGF‐C at 25, 50, or 75 ng/mL, or PDGF‐C at 25, 50, or 75 ng/mL containing 0.4 μM RA. After 48 h of culture, mouse embryos were examined for dysmorphogenesis, and whole‐mount immunohistochemistry was applied to PDGF‐C. In explant cultures, explants were exposed to the same doses of RA and PDGF‐C as WEC. Semiquantitative RT‐PCR, zymography, and reverse zymography were used to evaluate the expressions and activities of matrix metalloproteinase (MMP)‐2, MMP‐14, and tissue inhibitor of metalloproteinase (TIMP)‐2. RESULTS: PDGF‐C was reduced by RA, and exogenous PDGF‐C rescued the branchial arch malformations induced by RA. Moreover, PDGF‐C prevented RA‐induced inhibition of the migratory ability of mesenchymal cells in the first branchial arch, by regulating the expressions of MMP‐2, MMP‐14, and TIPM‐2. CONCLUSIONS: Our results suggest that RA exposure reduces the expression of PDGF‐C. The branchial arch malformations resulting from fetal RA exposure are caused at least partially by loss of PDGF‐C and subsequent misregulations of the expressions of MMP‐2, MMP‐14, and TIMP‐2. Birth Defects Research (Part A), 2007. © 2006 Wiley‐Liss, Inc.
Wiley - Tập 79 Số 3 - Trang 221-230 - 2007
Emerging data on the use of anti‐tumor necrosis factor‐alpha medications in pregnancy Abstract Anti‐tumor necrosis factor (TNF) α medications are used for the treatment of a number of autoimmune diseases. Evaluation of pregnancy safety for these medications is complicated by the contribution of the underlying maternal disease to adverse pregnancy outcomes, such as preterm delivery and reduced birth weight. Placental transport of these medications is thought to be minimal in the first trimester, thereby providing some reassurance regarding theoretical risks for congenital malformations. Available human exposure data are sparse; however, to date there has been no convincing evidence to support an increased risk for a specific pattern of major congenital malformations with any of the drugs in this group for which some data is currently available. As a result of the improvement of symptoms during pregnancy in some women with autoimmune diseases, it may be possible to discontinue treatment before or shortly after conception. However, in some cases the benefits of treatment and concerns for disease flares in pregnancy have warranted continued treatment during pregnancy. Because of the relatively long half‐life of these medications, and theoretical concerns for immune compromise of the infant following exposure in the latter two trimesters, some clinicians recommend discontinuation of treatment in the third trimester to avoid potentially prolonged infant exposure in the postpartum period. Currently ongoing controlled cohort studies for some of the TNF blocker medications will help to provide more definitive answers for clinicians and patients. Birth Defects Research (Part A) 94:607–611, 2012. © 2012 Wiley Periodicals, Inc.
Wiley - Tập 94 Số 8 - Trang 607-611 - 2012
Teratogen update: Methotrexate Abstract Methotrexate and aminopterin are folic acid antagonists that inhibit dihydrofolate reductase, resulting in a block in the synthesis of thymidine and inhibition of DNA synthesis. Methotrexate has been used for the treatment of malignancy, rheumatic disorders, and psoriasis and termination of intrauterine pregnancy. Recently, methotrexate has become a standard treatment for ectopic pregnancy. The misdiagnosis of an intrauterine pregnancy as an ectopic pregnancy can result in exposure of a continuing pregnancy to dose levels of methotrexate of 50 mg/m2 (maternal body surface area). Experimental animal studies have associated methotrexate therapy with embryo death in mice, rats, rabbits, and monkeys. Structural malformations have been most consistently produced in rabbits at a maternal dose level of 19.2 mg/kg. Abnormalities in rabbits include hydrocephalus, microphthalmia, cleft lip and palate, micrognathia, dysplastic sacral and caudal vertebrate, phocomelia, hemimelia, syndactyly, and ectrodactyly. Based on human case reports of methotrexate exposure during pregnancy, a methotrexate embryopathy has been described that includes growth deficiency, microcephaly, hypoplasia of skull bones, wide fontanels, coronal or lambdoidal craniosynostosis, upswept frontal scalp hair, broad nasal bridge, shallow supraorbital ridges, prominent eyes, low‐set ears, maxillary hypoplasia, epicanthal folds, short limbs, talipes, hypodactyly, and syndactyly. This syndrome may be associated with exposures between 6 and 8 weeks after conception and dose levels of 10 mg/week or greater. More recent case reports of methotrexate exposure for the misdiagnosis of ectopic pregnancy involve treatment before 6 weeks after conception and have raised the suggestion of a distinct syndrome due to such early exposures. Tetralogy of Fallot and perhaps other neural crest cell‐related abnormalities may be features of this early syndrome. A disproportionality analysis of methotrexate and aminopterin case reports and series provides support for pulmonary atresia, craniosynostosis, and limb deficiencies as reported more often than expected in methotrexate‐exposed children. Denominator‐based data will be welcome to better define elements of a methotrexate embryopathy and possibly to distinguish an early exposure syndrome from anomalies traditionally associated with methotrexate exposure. Birth Defects Research (Part A), 2012. © 2012 Wiley Periodicals, Inc.
Wiley - Tập 94 Số 4 - Trang 187-207 - 2012
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