Epidemiological aspects of prenatal exposure to high doses of vitamin a in Spain

Reports of the human teratogenicity of retinoids have raised concern about the potential human teratogenicity of high doses of vitamin A. Nevertheless, there are few human case reports of excess intake of vitamin A during pregnancy and defective outcomes. No epidemiological studies have been carried out on this subject. Here we present the results of an epidemiological study of prenatal exposure to high doses of vitamin A in Spain, using data from the Spanish hospital-based, case-control registry. Although it is difficult to reach conclusions with such a very low exposure level (1.3 per 1,000 livebirths), our results suggest that a teratogenic effect might exist for exposures to high doses of vitamin A (OR = 0.5, p = 0.15 for less than 40,000 FU and OR = 2.7, p = 0.06 for 40,000 1U or more). As we might expect, this effect also seems to be related to the organogenetic status (OR = 5.4, p = 0.1 for 1^st –2^nd month, OR = 1.8, p = 0.4 for 3^rd onwards) at the time of exposure.     

丙烯酰胺对大鼠胚胎神经细胞分化的影响

用细胞微团培养法研究丙烯酰胺对大鼠胚胎神经细胞分化的影响。结果表明，当细胞培养物中丙烯酰胺浓度大于６０μｇ／ｍｌ时，可明显抑制细胞分化，表现为细胞集落数目减少，细胞表面突起和集落间神经纤维束减少，细胞形态改变。其半数分化抑制浓度（ＩＣｄ５０）为７５μｇ／ｍｌ，半数存活抑制浓度（ＩＣｖ５０）为９０μｇ／ｍｌ，两者较为接近。认为丙烯酰胺对细胞分化的抑制作用可能被其细胞毒作用所掩盖，其致畸作用不可忽视。     

Preliminary Report on Teratogenic Effects of Zonisamide in the Offspring of Treated Women with Epilepsy

Summary: Purpose: We wished to assess the risk of terato-genicity of zonisamide (ZNS) in humans.
Methods: Pregnant epileptic women treated with ZNS and their offspring were prospectively monitored from June 1989 to December 1994. The outcome of pregnancy and status of neonates were examined based on the same standardized protocol.
Results: Twenty-six offspring exposed to ZNS with or without other antiepileptic drugs (AEDs) were studied. Malformations were detected in 2 offspring (7·7%) exposed to ZNS polypharmacy. Anencephaly was detected in one case at 16 weeks of gestation (case 1, artificial abortion), and atrial septa1 defect was detected in another case at 37 weeks of gestation (case 2, delivery by cesarean section). Serum concentrations of ZNS during the first trimester of pregnancy were 6·1 μg/ml in case 1 and 6·3μ/ml in case 2; in both cases, the levels were below the therapeutic concentration range of ZNS.
Conclusions: Teratogenic effects of ZNS were not clearly defined from these results since malformations were detected in two polypharmacy cases but not in four monopharmacy cases. The present data do not indicate that the risk of ZNS teratogenicity is greater than that of other conventional AEDs. However, such risk cannot be neglected even at therapeutic dosages or concentrations of ZNS, especially in patients receiving polypharmacy.     

二噁英的毒性与三致性及其控制措施

二噁英是目前人们十分关注的一种毒性很强的环境污染物。本文介绍了二噁英的理化特性、污染来源、暴露吸收途径、毒性、致突变性、致癌性和致畸性以及控制措施等。     

Reproductive toxicity and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin

Possible effects on the next generation after long-term exposure (subcutaneous administration) of male rats to very high doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied. Two dose regimes were applied: TCDD-25 (initial dose: 25 g/kg body wt; maintenance dose: 5 g/kg body wt, once weekly) and TCDD-75 (initial dose: 75 g/kg body wt; maintenance dose: 15 g/kg body wt). Male rats were treated for 10 weeks before mating and then throughout the entire 12 week mating period. They were mated to unexposed virgin females. One group of pregnant females was used for teratological evaluations, and another group was allowed to deliver. No significant differences were observed in the number of implantations or fetuses per litter, and resorption rate, and fetal weight between the controls and TCDD-treated groups. No gross-structural anomalies occurred in any of the fetuses sired by TCDD-treated males. In the TCDD-25 group an increased frequency of two types of variations was observed which also occur in controls: incompletely ossified fingers (TCDD-25=5.1%, controls=2.6%), and incompletely ossified ossa zygomatica (TCDD-25=1.8%, controls=0.5%). In the TCDD-25 group a slight but statistically significant increase was observed in the rate of stillbirths (TCDD-25=1.3%, controls=0.1%), apparently due to an unusually low frequency occurring in the controls (overall historical controls=0.6%). There was no difference in postnatal mortality (TCDD-25=1.3%, controls=1.3%). Taken together, despite the very high doses of TCDD used, the data do not provide evidence for biologically significant paternally-mediated developmental toxicity in the fetuses and newborn.     

诺司咪唑对小鼠致畸性的研究

目的：观察抗组织胺新药诺司咪唑对小鼠的致畸作用。方法：在小鼠妊娠致畸敏感期(6—15天)分别连续灌胃给予诺司咪唑29．2、58．4和116．8mg／kg，于妊娠第18天解剖动物并记录孕鼠体重、活胎数、死胎数、吸收胎数、胎仔体重、身长、尾长、胎盘重及外观、骨骼和内脏畸形胎仔数。结果：诺司咪唑使孕鼠体重生长缓慢，但对生殖能力无明显影响，高剂量组对胎仔体重、身长和尾长有一定影响，各组均未见胎仔有外观、骨骼和内脏畸形。结论：诺司咪唑对胎仔发育有一定影响，但无致畸作用。     

二氧化氯消毒液的致畸性和亚急性毒性研究

目的研究二氧化氯消毒液的致畸性和亚急性毒性。方法设0.1、0.3和1.0g/kg体重三剂量组,进行致畸研究;设0.04、0.2和1.0g/kg体重三个剂量组,进行亚急性毒性试验,观察二氧化氯消毒液对妊娠大鼠的致畸胎性和对大鼠的蓄积毒性作用。结果三个剂量组各项指标均未见有明显的母体毒性和胚胎毒性、致畸性和亚急性毒性。结论在本实验条件下,二氧化氯消毒液无致畸性和亚急性毒性。     

From cutting edge to guideline: A first step in harmonization of the zebrafish embryotoxicity test (ZET) by describing the most optimal test conditions and morphology scoring system

In the last couple of years, the interest in the zebrafish embryotoxicity test (ZET) for use in developmental toxicity assessment has been growing exponentially. This is also evident from the recent proposal for updating the ICHS5 guideline. The methodology of the ZET used by the different groups varies greatly. To further evaluate its successfulness and to take the ZET to the next level, harmonization of procedures is crucial. In the present study, based on literature and empirical data, the most optimal study design regarding temperature, test chamber, exposure period, presence of chorion, solvent use, exposure method, choice of concentrations, and teratogenic classification is proposed. Furthermore, our morphology scoring system is reported in detail as protocol to further enhance study design harmonization.     

Focus on germ-layer markers: A human stem cell-based model for in vitro teratogenicity testing

Human induced pluripotent stem cells (hiPSC) were used to develop an assay format that may deliver information on teratogenicity of drugs. A human pluripotent stem cell scorecard panel was used to monitor the expression of 96 marker genes that are indicative of the stem cell state or differentiation into the ectoderm, mesoderm and endoderm lineages. We selected a human episomal iPS cell line for the assay based on karyotype stability, initial pluripotency, differentiation capacity and overall gene expression variability. The assay is based on embryoid body formation and was developed to be simply automated. In this proof of concept study, we used eight reference compounds (valproic acid, all-trans-retinoic acid, thalidomide, methotrexate, hydroxyurea, ascorbic acid, penicillin G and ibuprofen) to test the technical performance of the assay (readout stability) in concentration-response and time-course experiments. We also found that each compound affected marker gene expression in a different way. Various forms of data analysis identified 19 out of 96 early developmental genes as potential predictive markers for teratogenicity. Machine-learning models were run to exemplify how the assay will be developed further. The preliminary results from these analyses suggest that the assay could be suitable for the pre-screening of candidate pharmaceutical compounds. The approach presented here points a way towards development of a human cell-based assay that could replace the murine EST currently used to screen for early indications of potential teratogenicity of drug candidates.