Embryonic Hypotaurine Levels Contribute to Strain-Dependent Susceptibility in Mouse Models of Valproate-Induced Neural Tube Defects.
Embryonic Hypotaurine Levels Contribute to Strain-Dependent Susceptibility in Mouse Models of Valproate-Induced Neural Tube Defects.
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DOI：
10.3389/fcell.2022.832492
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发表时间：
2022
影响因子：
5.5
通讯作者：
Finnell RH
中科院分区：
文献类型：
--
作者：
Steele JW;Lin YL;Chen N;Wlodarczyk BJ;Chen Q;Attarwala N;Venkatesalu M;Cabrera RM;Gross SS;Finnell RH
丙戊酸（VPA，丙戊酸盐，Depakote）是一种常用的抗癫痫药物（ASM），用于治疗癫痫和各种其他神经系统疾病。虽然VPA和其他ASM可有效控制癫痫发作，但它们也会增加不良妊娠结局的风险，包括神经管缺陷（NTD）。因此，这些药物在妊娠期间和有生育能力的女性中的应用是一个持续的公共卫生挑战。阐明VPA影响妊娠的潜在遗传或代谢风险因素可能会导致非致畸性ASM的发展，新的预防策略或更有针对性的癫痫妊娠管理方法。为了应对这一挑战，我们对来自两个近交系的E8.5小鼠胚胎进行了无偏倚的全胚胎代谢组学筛选，这两个近交系对VPA诱导的NTD具有不同的敏感性。我们确定了两种菌株之间差异丰度的代谢物，无论是在VPA暴露和溶剂对照中。值得注意的富集途径包括脂质代谢、肉毒碱代谢和几种氨基酸途径，特别是半胱氨酸和蛋氨酸代谢。在NTD敏感性更高的菌株中，VPA的ω-氧化产物丰度也增加，表明药物的代谢差异。最后，我们发现无论VPA状态如何，敏感品系的亚牛磺酸水平均显著降低。基于这些信息，我们假设母体补充L-肉碱（400 mg/kg）、辅酶A（200 mg/kg）或亚牛磺酸（350 mg/kg）将减少敏感品系中VPA诱导的NTD，并发现在VPA暴露前给予亚牛磺酸可显著降低NTD的发生率，与对照组相比接近三分之一。左旋肉碱和辅酶A降低吸收率，但没有显着降低NTD的风险，在敏感菌株。这些结果表明，影响胚胎亚牛磺酸状态的遗传变异或环境暴露可能是管理暴露于VPA或其他ASM的孕妇的医疗保健需求时确定不良妊娠结局风险的因素。
Valproic acid (VPA, valproate, Depakote) is a commonly used anti-seizure medication (ASM) in the treatment of epilepsy and a variety of other neurological disorders. While VPA and other ASMs are efficacious for management of seizures, they also increase the risk for adverse pregnancy outcomes, including neural tube defects (NTDs). Thus, the utility of these drugs during pregnancy and in women of childbearing potential presents a continuing public health challenge. Elucidating the underlying genetic or metabolic risk factors for VPA-affected pregnancies may lead to development of non-teratogenic ASMs, novel prevention strategies, or more targeted methods for managing epileptic pregnancies. To address this challenge, we performed unbiased, whole embryo metabolomic screening of E8.5 mouse embryos from two inbred strains with differential susceptibility to VPA-induced NTDs. We identified metabolites of differential abundance between the two strains, both in response to VPA exposure and in the vehicle controls. Notable enriched pathways included lipid metabolism, carnitine metabolism, and several amino acid pathways, especially cysteine and methionine metabolism. There also was increased abundance of ω-oxidation products of VPA in the more NTD-sensitive strain, suggesting differential metabolism of the drug. Finally, we found significantly reduced levels of hypotaurine in the susceptible strain regardless of VPA status. Based on this information, we hypothesized that maternal supplementation with L-carnitine (400 mg/kg), coenzyme A (200 mg/kg), or hypotaurine (350 mg/kg) would reduce VPA-induced NTDs in the sensitive strain and found that administration of hypotaurine prior to VPA exposure significantly reduced the occurrence of NTDs by close to one-third compared to controls. L-carnitine and coenzyme A reduced resorption rates but did not significantly reduce NTD risk in the sensitive strain. These results suggest that genetic variants or environmental exposures influencing embryonic hypotaurine status may be factors in determining risk for adverse pregnancy outcomes when managing the health care needs of pregnant women exposed to VPA or other ASMs.
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影响因子：
3.3
作者：
Beck, SL
通讯作者：
Beck, SL
DOI：
10.1002/tera.1420380403
发表时间：
1988-10-01
期刊：
TERATOLOGY
影响因子：
--
作者：
FINNELL, RH;BENNETT, GD;MOHL, VK
通讯作者：
MOHL, VK
影响因子：
3.3
作者：
Fontana, Mario;Giovannitti, Federica;Pecci, Laura
通讯作者：
Pecci, Laura
影响因子：
2.2
作者：
Haznedar, Pinar;Dogan, Ozlem;Eminoglu, F. Tuba
通讯作者：
Eminoglu, F. Tuba
DOI：
10.1016/j.annfar.2011.05.019
发表时间：
2011-10-01
影响因子：
--
作者：
Alluin, A.;Jezequel, J.;Canevet, C.
通讯作者：
Canevet, C.