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Medicina

蒸汽腔体建设用于公开小鼠酒精在所有三个学期人类发展的等效

Published: July 13, 2014
doi:
10.3791/51839
, , ,
1Department of Neurosciences, School of Medicine,University of New Mexico Health Sciences Center

Summary

我们证明的使用，能同时容纳6鼠笼现成材料酒精蒸气室的建设。我们进一步描述了在胎儿酒精暴露的小鼠模型相当于人类怀孕的所有3个学期的使用。这一范式妊娠和产后1-12天期间暴露的动物。

Abstract

暴露于酒精在开发过程中可能导致的被统称为胎儿酒精谱系障碍（FASDs）的形态和行为异常的星座。在光谱的最严重的到底是胎儿酒精综合症（FAS），其特点是生长发育迟缓，颅面畸形学和神经行为缺陷。研究，动物模型，包括啮齿类动物，已经阐明参与FASDs的病理生理许多分子和细胞机制。乙醇处理对怀孕啮齿动物已被用来在怀孕的第一和第二孕期人体暴露模型。孕晚期乙醇消费量在人类已经使用新生儿啮齿类动物为蓝本。然而，很少有研究啮齿动物有特点乙醇暴露在相当于人类怀孕，曝光就是常见于孕妇的模式的所有三个学期的效果。在这里，我们将展示如何从随手打造蒸汽室Øbtainable材料，可以各容纳6个标准鼠笼。我们描述了一个蒸汽室的范例，可以用来模拟暴露于乙醇中，用最少的处理，在所有的3个三个月。我们的研究表明，怀孕母畜发展显著的代谢耐受乙醇。然而，新生小鼠没有发展代谢宽容和胎儿的数目，胎儿体重，胎盘重量，为幼崽/产仔数，死亡幼仔/产仔数和小狗体重并没有显著影响乙醇暴露。这种模式的一个重要优势就是它的适用性与转基因小鼠的研究。此外，这种模式最大限度地减少处理的动物，在胎儿酒精研究的一个主要变乱。

Introduction

怀孕期间饮酒可能会损害胎儿，造成持续性的改变在许多器官和系统，显著降低生活质量受影响的个人和家庭。据估计，女性约10〜30％的怀孕，在美国期间喝酒，在一个狂欢的模式1,2 1-8％饮用。胎儿发育过程中由乙醇暴露产生影响的范围内被统称为胎儿酒精谱系障碍（FASDs）。最近的估计表明，FASDs与患病率高达美国3 2-5％一个主要的公共卫生问题。 FASDs较严重的表现为胎儿酒精综合症（FAS），其特点是生长发育迟缓，颅面畸形和神经行为缺陷，包括学习障碍。 FAS的患病率估计为0.2-0.7％，在美国3。对于FASDs目前可用的治疗只是部分有效和更有效的治疗方法的发展是由这种复杂疾病的频谱的细胞和分子基础的认识不足的限制。

从全国出生缺陷预防研究（NBDPS）的数据表明，孕妇在第一孕期最常见的饮料，怀孕已检测前，中后妊娠2阶段其次是禁欲。 NBDPS接受还发现，乙醇消费量在妊娠期间的第二个最常见的模式涉及到整个怀孕2的所有孕期饮用。其原因包括缺乏认识胎儿酒精暴露（即使在低剂量），有限的访问产前检查，对神经精神疾病阳性家族史，以及滥用或酒精依赖4的潜在有害影响。有趣的是，NBDPS报道，消费的第三个最常见的模式在1禁欲参与<sup>第一及第二学期其次是消费的第三季度，当它常常想当然地认为饮酒是安全的，因为器官已经大部分完成时。然而， 第三学期是一个时期高易感性乙醇引起的神经系统损害，因为这是当神经回路发生深刻的细化2期。 NBDPS接受还发现酒精消费在怀孕期间发生的其他不太常见的模式，包括整个第一和第二孕期其次是禁欲第三学期2时消耗。

在试图建模乙醇消耗量的不同图案的孕妇观察到，一些发育乙醇曝光范式已经建立了采用不同的动物物种，与大鼠和小鼠是最常见的5,6。怀孕在这些动物中的停留时间通常拉斯TS约3周，其对应于1 次和人类妊娠的第二个三个月。许多啮齿动物的研究已经评估不同剂量和乙醇曝光模式在这一时期的影响。通过液体的饮食7,8，加入乙醇到饮用水9,10，糖精增甜的解决方案的自愿饮用11，灌胃12，蒸气吸入13经常用于施用乙醇怀孕小鼠的方法和大鼠的例子包括管理和皮下或腹膜内注射14。这些研究的结果都概括几个在人类与FASDs观察到的赤字，在怀孕的早期阶段表明曝光足够整个大脑（在6,15审阅）损坏的神经元回路。

实验用啮齿类动物也显示出，等效于3 次时的曝光</sup>人类妊娠，这大致对应于第一1-2周出生后的大鼠和小鼠中，中晚期可以显著影响大脑的发育。暴露在此期间进行了建模通过施用乙醇新生大鼠或小鼠。使用各种方法，包括通过胃造口术在人工饲养的动物16-18，胃内插管19， ​​皮下注射20馈送，并且蒸气吸入21,22乙醇已被施用给这些动物。这些研究令人信服地证明，大脑的井喷式增长是高发期易受乙醇6发育的影响。

正如上面提到的，在怀孕的各个孕期饮酒是酒精消费的女性2的通用模式。然而，相对很少有研究评估了利用动物模型曝光此模式的影响。一些研究已经采取advantagË大型动物，其中第三学期相当于在子宫内 ，而不是在新生儿期出现在大鼠和小鼠的情况下。这些动物模型包括非人类的灵长类23,24和羊25-27。然而，这些动物模型中没有得到广泛使用，因为成本高，需要专门的护理设施中FASDs研究，部分。鼠害已较常用的表征对胎儿发育5全孕期酒精暴露的影响。豚鼠在这方面给出了大脑的成熟其广泛的产前发展和相似之处，人类28,29的是特别有利的。用豚鼠，它有可能为乙醇曝光的效果刻画在子宫内 ，其中包括人类第三孕期的等效发展时期。这些动物中的相对较高的成本，以及其怀孕的时间比较长（〜67天），已经它们的使用仅限于工作FASDs研究的几个实验室。

因为在生物医学研究中的成本效益和广泛应用，研究者用大鼠在妊娠的各个孕期暴露于酒精模型。在最初的研究中，大鼠在怀孕期间通过流质饮食其次是乙醇行政胃经人工饲养的新生儿（出生后的天数（P）1-10），导致血峰乙醇含量（BEC）在0.08克/分升的大坝暴露而在幼崽0.16克/分升。这种模式引起持久的改变在视神经髓鞘形成和减少贝格曼神经胶质纤维在小脑30-32的数目。同样，使用在第三孕期当量（P4-9）33,34的一部分，通过胃内插管后新生儿的管理给予乙醇孕鼠水坝在狂欢般的方式人工饲养条件下迈尔和合作者。 PEAK孕产妇和小狗建筑物能源效益守则分别为0.3克/分升在两个孕20天，小六。这一切孕期曝光模式导致生长迟缓，这是显著大于在妊娠期间33选择的期间暴露幼仔观察。此外，大鼠相当于所有孕期期间暴露于乙醇中表现出小脑浦肯野和颗粒细胞，显着高于在动物其他时段34暴露观察到的数量的减少。在海马细胞数量的减少也报告了这一模式，但这种影响似乎主要是暴露的后果第三学期相当于35时。涉及行政乙醇通过灌胃既孕鼠及新生小鼠的方法也被用来模拟所有孕早期接触36。这种方法，取得了0.13克/分升的水坝（孕17天）和0.24克/分升小六的幼崽，引起离子的BEC克持久的改变中单胺神经递质的水平在海马和下丘脑，和DNA甲基转移酶和甲基CpG结合蛋白2在海马37,38的表达增加。使用类似的曝光模式（BEC = 0.14-0.2克/分升的水坝和0.2克/分升的幼崽），吉尔- Mohapel 等 39检测增加了新的未成熟的神经元在成年大鼠海马齿状回的数可能代表一种代偿机制，在成年出生的神经元的成熟乙醇诱导的神经元损伤或改变。研究者也试图透过液体饮食暴露水坝或怀孕和哺乳期间9,40饮水来模拟所有的孕期酒精暴露。然而，通过他们的母亲的乳汁露出幼崽的效用是有限的，因为它通常会导致较低的小狗建筑物能源效益守则（ 例如 ，0.002〜0.05克/分升; 41,42）。

小鼠也被用于EXTENS结构延续表征发育乙醇暴露的影响。这种动物模型股上述许多的大鼠动物模型，具有额外的优势的优势，许多转基因小鼠品系可用5。老鼠已经成功地使用了第一 ， 第二或怀孕43,44的第三学期中乙醇的效果来表征。然而，对这些动物的所有孕早期曝光的影响还没有得到很好的特点，因为它在技术上是比较难在相当于人类怀孕的各个孕期暴露小鼠。例如，人工饲养和灌胃，其已经成功地用于在大鼠中，需要在小鼠45更专门的程序。据我们所知，只有一个研究，迄今已尝试研究利用老鼠进行的所有孕期酒精暴露的影响;这些动物暴露于乙醇溶液中的饮用水杜里纳克怀孕和哺乳46。产妇的BEC分别为0.07克/分升和小狗的BEC没有确定，但预计将那些在堤坝的一小部分。

在这里，我们描述了其中的酒精是通过蒸气吸入室给予双方怀孕母畜和新生儿小鼠的所有孕期酒精暴露的新模式。根据先前的设计47蒸气室建成。我们提供了有关如何构建吸入室，开展曝光程序的详细说明。我们还提供对可达到的的BEC和暴露对幼鼠的存活和生长的影响的信息。

Protocol

所有动物的程序批准了新墨西哥州，健康科学大学的中心机构动物护理和使用委员会。 1，蒸气室总成切聚碳酸酯板与用于顶部，底部，前，后，侧，和门设置在视频（ 图1和表1）的尺寸的圆锯或线锯。 用圆锯或线锯，切于前面板的中间一个开口8英寸高16英寸宽。 测量和由10英寸的聚碳酸酯片材，这将成为腔室的门上的孔的钢琴…

Representative Results

图2A显示了两个孕鼠及新生后代暴露于相对稳定的乙醇蒸气浓度在室内。这些范围。 图2B显示了在妊娠小鼠获得作为时间的函数的的BEC 4-6克/分升之间。的BEC使用标准的醇脱氢酶测定法基于48测量。在G5，能源效益守则迅速上升到〜60毫米2小时暴露后开始见顶，并在4小时暴露期结束。建筑物能源效益守则曝光结束后逐渐下降至〜12毫米的额外4小时后。由G13-14，有一…

Discussion

在这里，我们将详细介绍方法的蒸气吸入室的建设。构建室所需要的材料和工具可容易地从多家商业供应商的步骤和腔室的结构相对简单。我们在这里描述的系统不包含任何直列式止回阀以防止反向流动和混合。我们无法测量任何酒精检测空气中的唯一腔说我们没有任何混合或乙醇回流到空气中只有室。只有腔室应定期检查对乙醇蒸汽的空气（应当指出的是，气室应始终乙醇室之前进行测试，以?…

Declarações

The authors have nothing to disclose.

Acknowledgements

由美国国立卫生研究院支持的授予R01-AA015614，R01-AA014973，T32-AA014127和K12-GM088021。作者感谢萨曼塔L.布基斯特技术援助和博士。凯文·考德威尔和唐纳德·帕特里奇的批判性评估的手稿和视频。

Materials

Item Company Cat # Qty
Polycarbonate 1/4" clear 48" x 24" McMaster-Carr 8574K23 10
Foam Rubber bulb seal 3/8"w x 7/32"h  McMaster-Carr 93085K67 10ft
Weld-on #16 McMaster-Carr 7515A11 3
Piano hinge 12" long McMaster-Carr 1658A11 2 x 1ft
Hold-down toggle clamps standard McMaster-Carr 5126A26 8
PEX tubing 1/2" McMaster-Carr 51275K88 10ft
Barbed Tee tube fitting (Black) Pkg 10 McMaster-Carr 5463K608 1
Barbed plug fitting (Black) Pkg 10 McMaster-Carr 5462K79 1
Barbed Elbow tube fitting (Black) Pkg 10 McMaster-Carr 5463K596 1
3/8" Through-Wall Adapters, Tube to Threaded Pipe McMaster-Carr 5463K851 1
Phillips Machine screw 4-40 McMaster-Carr 91772A112 1
Machine screw hex nut 4-40 McMaster-Carr 90480A005 1
Panel-mount flowmeter 2-20 McMaster-Carr 41945K76 3
FLASK, FILTER 1000ML 6/PACK VWR 89001-800 2
Precision Seal Septa VWR 89084-490 1
VWR Black Rubber Stopper #8 1-hole VWR 59581-367 1
TUBE TYGON R3603 3/8X9/16 50' VWR 89068-556 1
TUBE TYGON R3603 1/4X11/16 50' VWR 89068-502 1
Aerator Stone P2120 VWR 32573-007 1
3/8" T-connectors Pk of 20 VWR 46600-060 1
VWR Disconnectors tapered Pk of 10 VWR 46600-110 1
3/8 Hose Barb valved in-line coupling Colder Products Company HFCD17612 1
Air pump medium capacity LMI Manufacturers DB60L 1
Nexelate Wire Shelving 36"W X 24"D X 63"H Global industrial T9A990135 1
Stem Casters Set of (4) 5" Polyurethane Wheel Global industrial T9A500591 1
Breathalyzer Alco-Sensor III Intoximeters, Inc. ASIII 1
Item Company Cat # Qty
Polycarbonate 1/4" clear 48" x 24" McMaster-Carr 8574K23 10
Foam Rubber bulb seal 3/8"w x 7/32"h  McMaster-Carr 93085K67 10ft
Weld-on #16 McMaster-Carr 7515A11 3
Piano hinge 12" long McMaster-Carr 1658A11 2 x 1ft
Hold-down toggle clamps standard McMaster-Carr 5126A26 8
PEX tubing 1/2" McMaster-Carr 51275K88 10ft
Barbed Tee tube fitting (Black) Pkg 10 McMaster-Carr 5463K608 1
Barbed plug fitting (Black) Pkg 10 McMaster-Carr 5462K79 1
Barbed Elbow tube fitting (Black) Pkg 10 McMaster-Carr 5463K596 1
3/8" Through-Wall Adapters, Tube to Threaded Pipe McMaster-Carr 5463K851 1
Phillips Machine screw 4-40 McMaster-Carr 91772A112 1
Machine screw hex nut 4-40 McMaster-Carr 90480A005 1
Panel-mount flowmeter 2-20 McMaster-Carr 41945K76 3
FLASK, FILTER 1000ML 6/PACK VWR 89001-800 2
Precision Seal Septa VWR 89084-490 1
VWR Black Rubber Stopper #8 1-hole VWR 59581-367 1
TUBE TYGON R3603 3/8X9/16 50' VWR 89068-556 1
TUBE TYGON R3603 1/4X11/16 50' VWR 89068-502 1
Aerator Stone P2120 VWR 32573-007 1
3/8" T-connectors Pk of 20 VWR 46600-060 1
VWR Disconnectors tapered Pk of 10 VWR 46600-110 1
3/8 Hose Barb valved in-line coupling Colder Products Company HFCD17612 1
Air pump medium capacity LMI Manufacturers DB60L 1
Nexelate Wire Shelving 36"W X 24"D X 63"H Global industrial T9A990135 1
Stem Casters Set of (4) 5" Polyurethane Wheel Global industrial T9A500591 1
Breathalyzer Alco-Sensor III Intoximeters, Inc. ASIII 1
DOWNLOAD MATERIALS LIST

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Alcohol ExposureFetal Alcohol Spectrum DisordersFASVapor ChamberRodent ModelDevelopmental ToxicologyPrenatal ExposureMetabolic ToleranceGenetic Models

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Morton, R. A., Diaz, M. R., Topper, L. A., Valenzuela, C. F. Construction of Vapor Chambers Used to Expose Mice to Alcohol During the Equivalent of all Three Trimesters of Human Development. J. Vis. Exp. (89), e51839, doi:10.3791/51839 (2014).
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