Hill Denise S, Wlodarczyk Bogdan J, Mitchell Laura E, Finnell Richard H
Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, 77030, USA.
Toxicol Appl Pharmacol. 2009 Aug 15;239(1):29-36. doi: 10.1016/j.taap.2009.05.009. Epub 2009 May 14.
Epidemiological studies have linked environmental arsenic (As) exposure to increased type 2 diabetes risk. Periconceptional hyperglycemia is a significant risk factor for neural tube defects (NTDs), the second most common structural birth defect. A suspected teratogen, arsenic (As) induces NTDs in laboratory animals.
We investigated whether maternal glucose homeostasis disruption was responsible for arsenate-induced NTDs in a well-established dosing regimen used in studies of arsenic's teratogenicity in early neurodevelopment.
We evaluated maternal intraperitoneal (IP) exposure to As 9.6 mg/kg (as sodium arsenate) in LM/Bc/Fnn mice for teratogenicity and disruption of maternal plasma glucose and insulin levels. Selected compounds (insulin pellet, sodium selenate (SS), N-acetyl cysteine (NAC), l-methionine (L-Met), N-tert-Butyl-alpha-phenylnitrone (PBN)) were investigated for their potential to mitigate arsenate's effects.
Arsenate caused significant glucose elevation during an IP glucose tolerance test (IPGTT). Insulin levels were not different between arsenate and control dams before (arsenate, 0.55 ng/dl; control, 0.48 ng/dl) or after glucose challenge (arsenate, 1.09 ng/dl; control, 0.81 ng/dl). HOMA-IR index was higher for arsenate (3.9) vs control (2.5) dams (p=0.0260). Arsenate caused NTDs (100%, p<0.0001). Insulin pellet and NAC were the most successful rescue agents, reducing NTD rates to 45% and 35%.
IPGTT, insulin assay, and HOMA-IR results suggest a modest failure of glucose stimulated insulin secretion and insulin resistance characteristic of glucose intolerance. Insulin's success in preventing arsenate-induced NTDs provides evidence that these arsenate-induced NTDs are secondary to elevated maternal glucose. The NAC rescue, which did not restore maternal glucose or insulin levels, suggests oxidative disruption plays a role.
流行病学研究表明，环境砷（As）暴露与2型糖尿病风险增加有关。孕期高血糖是神经管缺陷（NTDs）的一个重要风险因素，NTDs是第二常见的结构性出生缺陷。砷（As）作为一种疑似致畸物，可在实验动物中诱发NTDs。
我们采用了一种在砷对早期神经发育致畸性研究中常用的成熟给药方案，研究母体葡萄糖稳态破坏是否是砷酸盐诱导NTDs的原因。
我们评估了LM/Bc/Fnn小鼠腹腔内（IP）暴露于9.6mg/kg砷（以砷酸钠形式）的致畸性以及对母体血浆葡萄糖和胰岛素水平的影响。研究了选定的化合物（胰岛素丸、硒酸钠（SS）、N-乙酰半胱氨酸（NAC）、L-甲硫氨酸（L-Met）、N-叔丁基-α-苯基硝酮（PBN））减轻砷酸盐作用的潜力。
在腹腔内葡萄糖耐量试验（IPGTT）期间，砷酸盐导致显著的血糖升高。在葡萄糖激发前（砷酸盐组，0.55ng/dl；对照组，0.48ng/dl）或激发后（砷酸盐组，1.09ng/dl；对照组，0.81ng/dl），砷酸盐组和对照组母鼠的胰岛素水平无差异。砷酸盐组母鼠的HOMA-IR指数（3.9）高于对照组（2.5）（p=0.0260）。砷酸盐导致了NTDs（100%，p<0.0001）。胰岛素丸和NAC是最成功的挽救剂，将NTDs发生率分别降低到45%和35%。
IPGTT、胰岛素检测以及HOMA-IR结果表明，葡萄糖刺激的胰岛素分泌略有不足以及存在葡萄糖不耐受特征性的胰岛素抵抗。胰岛素成功预防砷酸盐诱导的NTDs，这证明这些砷酸盐诱导的NTDs继发于母体血糖升高。NAC的挽救作用并未恢复母体葡萄糖或胰岛素水平，这表明氧化破坏起到了一定作用。
