Cardiac teratogenicity in mouse maternal phenylketonuria: defining phenotype parameters and genetic background influences.
Cardiac teratogenicity in mouse maternal phenylketonuria: defining phenotype parameters and genetic background influences.
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DOI：
10.1016/j.ymgme.2012.08.001
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发表时间：
2012-12
影响因子：
3.8
通讯作者：
McBride, Kim L.
中科院分区：
文献类型：
--
作者：
Seagraves, Nikki J.;McBride, Kim L.
母亲苯丙酮尿症 (MPKU) 是一种综合征，包括心血管畸形 (CVM)、小头畸形、智力障碍和小于胎龄儿，是由于母亲在子宫内暴露于因 PKU 导致的血清苯丙氨酸 (Phe) 升高而引起的。随着越来越多患有 PKU 的女性达到生育年龄，它正成为一个公共健康问题。尽管 PKU 小鼠模型 BTBR Pahenu2 已问世 20 年，但它尚未被很好地用于研究 MPKU。我们使用该模型来描述 Phe 心血管致畸性的关键参数并研究遗传背景的影响。使用 BTBR Pahenu2 小鼠进行剂量和计时实验。注意到剂量反应曲线，母体血清 Phe 水平 <360 μM（对照）、360 – 600 μM（低）、600 – 900 μM（中）和 >900 μM（高）时的 CVM 率分别为 11.86%、16.67%、30.86% 和 46.67%。 BTBR 背景上注意到多种 CVM，包括右心室双出口 (DORV)、主动脉弓动脉 (AAA) 异常和室间隔缺损 (VSD)。定时暴露实验确定了胚胎第 8.5-13.5 天的致畸窗口，早期暴露时间中圆锥动脉干和瓣膜缺陷发生率较高，而晚期暴露时发生持续性动脉干 (PTA) 和主动脉弓分支异常。与 BTBR 品系相比，C3H/HeJ 背景上的 N10+ Pahenu2 同系基因总体上具有较高的 CVM 发生率和左心室流出道 (LVOT) 畸形倾向，而 C57B/L6 背景具有相似的 CVM 发生率，但主要是 AAA 异常。我们已经描述了 Phe 心血管致畸性的关键参数，证明了该 MPKU 模型在不同小鼠品系上的实用性，并展示了遗传背景如何深刻影响表型。
Maternal phenylketonuria (MPKU) is a syndrome including cardiovascular malformations (CVMs), microcephaly, intellectual impairment, and small for gestational age, caused by in-utero exposure to elevated serum phenylalanine (Phe) due to PKU in the mother. It is becoming a public health concern as more women with PKU reach child bearing age. Although a mouse model of PKU, BTBR Pahenu2, has been available for 20 years, it has not been well utilized for studying MPKU. We used this model to delineate critical parameters in Phe cardiovascular teratogenicity and study the effect of genetic background. Dosing and timing experiments were performed with the BTBR Pahenu2 mouse. A dose response curve was noted, with CVM rates at maternal serum Phe levels <360 μM (control), 360 – 600 μM (low), 600 – 900 μM (mid), and >900μM (high) of 11.86%, 16.67%, 30.86%, and 46.67% respectively. A variety of CVMs were noted on the BTBR background, including double outlet right ventricle (DORV), aortic arch artery (AAA)abnormalities, and ventricular septal defects (VSDs). Timed exposure experiments identified a teratogenic window from embryonic day 8.5-13.5, with higher rates of conotruncal and valve defects occurring in early exposure time and persistent truncus arteriosus (PTA) and aortic arch branching abnormalities occurring with late exposure. Compared to the BTBR strain, N10+ Pahenu2 congenics on the C3H/HeJ background had higher rates of CVMs in general and propensity to left ventricular outflow tract (LVOT) malformations, while the C57B/L6 background had similar CVM rates but predominately AAA abnormalities. We have delineated key parameters of Phe cardiovascular teratogenicity, demonstrated the utility of this MPKU model on different mouse strains, and shown how genetic background profoundly affects the phenotype.
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影响因子：
3.8
作者：
Cho, SB;McDonald, JD
通讯作者：
McDonald, JD
DOI：
10.1002/bdra.20169
发表时间：
2005-08-01
影响因子：
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作者：
McBride, KL;Marengo, L;Belmont, JW
通讯作者：
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影响因子：
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作者：
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通讯作者：
Weglage, J
影响因子：
158.5
作者：
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通讯作者：
LEVY, HL
DOI：
10.1152/ajpheart.00866.2008
发表时间：
2009-07-01
影响因子：
4.8
作者：
Barrick, Cordelia J.;Roberts, Reade B.;Threadgill, David W.
通讯作者：
Threadgill, David W.