ETHANOL EFFECTS ON BONE FORMATION IN PREGNANCY

描述(申请人提供)：众所周知，女性比男性更容易受到酒精不良影响的影响。据估计，5%-20%的美国女性在怀孕期间饮酒。然而，几乎没有研究考察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，支持怀孕期间的额外营养需求。利用TEN系统，我们做了几个重要的观察：第一，在持续输注乙醇的情况下，雄性和未怀孕雌性大鼠的血和尿乙醇浓度在几乎为零和超过500 mg/dl之间循环，频率为每5-7天一个脉冲。其次，在怀孕的雌性大鼠中，这些乙醇脉冲的幅度显著降低(80%)，这表明怀孕期间乙醇代谢显著增加。这将是保护性的，因为在给定的乙醇摄入量下，乙醇新陈代谢的速度决定了母亲血液中乙醇的浓度和毒性。第三，我们观察到妊娠期营养不良显著地将搏动性乙醇浓度的幅度提高到更高的水平。这预计会增加母体的毒性。第四，长期摄入乙醇会导致未怀孕动物的骨形成和强度降低。这种作用可被TNFa和IL-1f3阻滞剂逆转。第五，妊娠期间酒精治疗导致妊娠结束时骨小梁和皮质骨密度显著降低，这不仅是怀孕本身的影响，而且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，生育不会增加患骨质疏松症的风险。然而，我们假设乙醇将在妊娠后期骨转换高峰期抑制骨形成，增加哺乳期间的骨丢失，并抑制哺乳期母亲在没有母乳喂养或断奶后发生的产后骨重建的合成代谢阶段。这可能会导致永久性的骨矿化和强度不足。营养不良可能会加剧这些影响。TEN系统将用来确定酒精/营养相互作用对怀孕和哺乳期间母亲骨骼以及产后骨骼重建的影响。在此期间，我们还将研究CYP2E1和自由基在乙醇骨骼毒性中的作用。

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.