ETHANOL EFFECTS ON BONE FORMATION IN PREGNANCY

描述（由申请人提供）：众所周知，女性比男性更容易受到酒精的不良影响。据估计，5- 20%的美国女性在怀孕期间饮酒。然而，几乎没有研究检验过乙醇对孕妇和哺乳期妇女的影响。我们开发了一种全肠内营养（TEN）模型，支持怀孕期间额外的营养需求。使用TEN系统，我们做了几个重要的观察：首先，在持续输注乙醇的情况下，雄性和未怀孕的雌性大鼠的血液和尿液乙醇浓度在几乎为零到超过500毫克/分升之间循环，频率为每5-7天一次脉冲。其次，在怀孕的雌性大鼠中，这些乙醇脉冲的幅度显着降低（80%），这表明乙醇代谢在怀孕期间显着增加。这将是保护性的，因为乙醇代谢率，在给定的乙醇摄入量下，决定了母亲血液中的乙醇浓度和毒性。第三，我们观察到，怀孕期间营养不良显著提高了脉动乙醇浓度的振幅到更高的水平。这可能会增加母体毒性。第四，慢性乙醇输注导致未怀孕动物的骨形成和强度降低。这种作用被tnf和IL-1f3阻滞剂逆转。第五，妊娠期乙醇治疗导致妊娠末期骨小梁和皮质骨矿物质密度显著降低，超过妊娠本身的影响。骨质疏松症是一个重要的卫生保健和关注领域。正常情况下，胎次不增加骨质疏松的风险。然而，我们假设乙醇会抑制妊娠后期高骨转换期间的骨形成，增加哺乳期间的骨质流失，并抑制骨重建的合成代谢阶段，这发生在没有母乳喂养或哺乳期母亲断奶后。这可能导致骨矿化和强度的永久性缺陷。这些影响可能因营养不良而加剧。TEN系统将用于确定乙醇/营养相互作用对怀孕和哺乳期母亲骨骼的影响以及对产后骨骼重建的影响。在这些时期，CYP2E1和自由基在乙醇骨骼毒性中的作用也将被研究。

DESCRIPTION (provided by applicant): It is well known that women are more susceptible to the adverse effects of alcohol than men. An estimated 5-20 percent of American women consume alcohol during pregnancy. Yet, almost no research has examined the effects of ethanol on pregnant and lactating women. We have developed a total enteral nutrition (TEN) -model that supports the additional nutritional demands of pregnancy. Using the TEN system we have made several important observations: First, with constant infusion of ethanol, blood and urine ethanol concentrations of male and non-pregnant female rats cycle between almost zero and over 500 mg/dl with a frequency of one pulse every 5-7 days. Second, the amplitude of these ethanol pulses is markedly reduced (80 percent) in pregnant female rats suggesting that ethanol metabolism is significantly increased in pregnancy. This would be protective since the rate of ethanol metabolism, at a given ethanol intake, determines the maternal blood ethanol concentrations and toxicity. Third, we have observed that undernutrition during pregnancy significantly elevates the amplitude of pulsatile ethanol concentrations to higher levels. This would be expected to increase maternal toxicity. Fourth, chronic ethanol infusion results in reduced bone formation and strength in non-pregnant animals. This effect is reversed by TNFa and IL-1f3 blockers. Fifth ethanol treatment during pregnancy results in significant reductions in trabecular and cortical bone mineral density at the end of gestation, over and above the effects of pregnancy itself Osteoporosis is an area of significant health care and concern. Normally there is no increased risk of osteoporosis with parity. However, we hypothesize that ethanol will inhibit bone formation during the period of high bone turnover in the latter part of pregnancy, increase bone loss during lactation and inhibit the anabolic phase of bone rebuilding which occurs post-partum in the absence of breast feeding or post-weaning in lactating mothers. This may result in permanent deficits in bone mineralization and strength. These effects may be exacerbated by undernutrition. The TEN system will used to determine the effects of ethanol/nutritional interactions on maternal bone in pregnancy and lactation and on skeletal rebuilding post-partum. The role of CYP2E1 and free radicals in the skeletal toxicity of ethanol during these periods will also be studied.