Contributions of dam and conceptus to differences in sensitivity to valproic acid among C57 black and SWV mice
Contributions of dam and conceptus to differences in sensitivity to valproic acid among C57 black and SWV mice
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DOI：
10.1016/s0890-6238(99)00038-6
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发表时间：
1999-09-01
影响因子：
3.3
通讯作者：
Beck, SL
中科院分区：
文献类型：
--
作者：
Beck, SL
为了确定孕鼠和母鼠基因型对丙戊酸（VPA）发育毒性的相对贡献，在耐药的C57 BL/6 JBk（C，C57）和敏感的SWV/Bk（S，SWV）小鼠品系之间建立杂交。这些包括纯系的交配、相互异交和与F1杂种的相互回交。在8 d：12 h +/- 5 h，对于每次交配，ip注射0、500或600 mg/kg VPA水溶液。在妊娠日（gd）Is检查胎仔的露脑畸形（典型异常）、其他异常、死亡率、窝仔数和胎仔体重。在600 mg/kg剂量下，所有情况下对露脑畸形诱导的敏感性均为母体的敏感性，而与父系无关。因此，露脑畸形在很大程度上是母体基因型所产生的子宫环境的一个功能。这一推论在回交后代中得到了证实，F1母畜× S公畜和F1母畜× C公畜产生了相同的结果，而S母畜× F1公畜产生露脑畸形的频率远高于C母畜× F1公畜。胎儿的贡献是从以下观察结果推断的：S-母畜X S-公畜交配产生的死亡率比S-母畜X C-公畜高得多，C-母畜X C-公畜产生的死亡率比C-母畜X S-公畜高。因此，孕体的杂合性具有保护作用。在回交中，胎儿对死亡率的敏感性决定也可以通过观察到F1-母畜X C-公畜产生与C-母畜X F1-公畜相同的胎儿死亡率。子宫环境的贡献被认为是观察到的S-母畜X C-公畜的交配导致更高的胎儿死亡率比那些C-母畜X S-公畜。因此，不同母兽的相同胎仔显示出不同水平的胎仔丢失。因此，露脑畸形的反应似乎在很大程度上是由在母鼠中活跃的基因控制的，而死亡率则是由于孕体和母鼠中活跃的基因导致的多基因结果。这些数据还表明，SWV纯系母鼠的产前死亡率没有看到在C57或F1 dams.Mean窝VPA暴露窝表现出高变异性纯系和异交。在回交中，F1代母鼠比纯系母鼠产生更大的窝仔，认为杂种优势是该参数的一个贡献者。纯系母鼠中VPA暴露导致的窝仔数减少很大，F1母鼠中不存在。与F1公畜杂交的SWV母畜是回交中唯一显示窝仔数减少的组，进一步证实了纯系的敏感性增加（即，胎儿重量似乎是子宫环境的函数，因为雌性SWV在所有杂交中产生具有较低胎儿重量的概念，并且产生归因于VPA暴露的胎儿重量比C57或F1母鼠更大的减少。胎仔体重与窝仔数无密切相关性，表明胎仔体重较低可能是一种品系特征，露脑诱导和产前死亡率也是VPA的反应。对VPA损伤的敏感性差异在所有研究参数中均可见，SWV母鼠最敏感，但许多终点的机制似乎不同。(C)1999 Elsevier Science Inc. All rights reserved.
To ascertain the relative contributions of,genotypes of conceptus and dam to developmental toxicity occasioned by valproic acid (VPA), crosses were established between resistant C57BL/6JBk (C, C57) and susceptible SWV/Bk (S, SWV) strains of mice. These included matings of pure lines, reciprocal outcrosses, and reciprocal backcrosses with Fl hybrids. At 8 d:12 h +/- 5 h, for each mating, 0, 500, or 600 mg/kg aqueous VPA was injected ip. Fetuses were examined on gestation day (gd) Is for exencephaly (the paradigmatic anomaly), other abnormalities, mortality, litter size, and fetal weight.At 600 mg/kg, sensitivity to exencephaly induction in all cases was that of the dam, regardless of sire. Thus exencephaly here seems to be largely a function of the uterine environment produced by the maternal genotype. This inference is confirmed in backcrosses where F1-dams x S-sires and F1-dams X C-sires produced identical outcomes, and S-dams x F1-sires produced much higher frequencies of exencephaly than C-dams X F1-sires.For prenatal mortality, the genotypes of both dam and conceptus appear to be important determinants. Fetal contribution is inferred from the observations that S-dam X S-sire matings produced a much higher frequency of mortality than S-dams X C-sires, and C-dams X C-sires produced higher mortality than C-dams X S-sires. Therefore, heterozygosity of the conceptus was protective. Among backcrosses, fetal determination of sensitivity to mortality is also seen by the observation that F1-dams X C-sires produces the same fetal mortality as C-dams x F1-sires. The contribution of uterine environment is seen in the observation that matings of S-dams X C-sires resulted in higher fetal mortality than did those with C-dams X S-sires. Therefore, identical conceptuses in different dams showed different levels of fetal loss. Thus exencephaly response appears to be largely controlled by genes active in the dam, and mortality as a result of a multigenic outcome with contributing genes active in both conceptus and dam. The data also suggest that SWV pure-line dams make a contribution to prenatal mortality not seen in C57 or Fl dams.Mean litter size among VPA-exposed litters showed high variability in pure lines and outcrosses. In backcrosses, Fl dams produced larger litters than pure line dams, arguing for heterosis as a contributor to this parameter. Reduction in litter size occasioned by VPA exposure was great in pure line dams and nonexistent in Fl dams. The SWV dams crossed with Fl sires were the only group among the backcrosses to show reduction of litter size, providing further confirmation of the increased sensitivity of pure-line (i.e., homozygous) SWV dams to VPA exposure.Fetal weight seems to be a function of uterine environment because female SWV produced conceptuses with lower fetal weight in all crosses, and produced a greater reduction in fetal weight attributable to VPA exposure than C57 or Fl dams. Fetal weight did not correlate closely with litter size, suggesting that a lower fetal weight may be a strain characteristic, as are exencephaly induction and prenatal mortality in response to VPA. Differences in sensitivity to VPA insult are seen for all parameters investigated with SWV dams being the most sensitive, but mechanisms seem to differ for a number of the endpoints. (C) 1999 Elsevier Science Inc. All rights reserved.