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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA012928-01A1
Application #
6541488
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Purohit, Vishnu
Project Start
2002-08-01
Project End
2007-04-30
Budget Start
2002-08-01
Budget End
2003-04-30
Support Year
1
Fiscal Year
2002
Total Cost
$290,250
Indirect Cost
Name
Arkansas Children's Hospital Research Institute
Department
Type
DUNS #
002593692
City
Little Rock
State
AR
Country
United States
Zip Code
72202
Chen, Jin-Ran; Lazarenko, Oxana P; Shankar, Kartik et al. (2010) A role for ethanol-induced oxidative stress in controlling lineage commitment of mesenchymal stromal cells through inhibition of Wnt/beta-catenin signaling. J Bone Miner Res 25:1117-27
Chen, Jin-Ran; Lazarenko, Oxana P; Haley, Rani Lynn et al. (2009) Ethanol impairs estrogen receptor signaling resulting in accelerated activation of senescence pathways, whereas estradiol attenuates the effects of ethanol in osteoblasts. J Bone Miner Res 24:221-30
Shankar, Kartik; Liu, Xiaoli; Singhal, Rohit et al. (2008) Chronic ethanol consumption leads to disruption of vitamin D3 homeostasis associated with induction of renal 1,25 dihydroxyvitamin D3-24-hydroxylase (CYP24A1). Endocrinology 149:1748-56
Shankar, Kartik; Hidestrand, Mats; Liu, Xiaoli et al. (2008) Chronic ethanol consumption inhibits postlactational anabolic bone rebuilding in female rats. J Bone Miner Res 23:338-49
Chen, Jin-Ran; Shankar, Kartik; Nagarajan, Shanmugam et al. (2008) Protective effects of estradiol on ethanol-induced bone loss involve inhibition of reactive oxygen species generation in osteoblasts and downstream activation of the extracellular signal-regulated kinase/signal transducer and activator of transcription 3/ J Pharmacol Exp Ther 324:50-9
Ronis, Martin J J; Wands, Jack R; Badger, Thomas M et al. (2007) Alcohol-induced disruption of endocrine signaling. Alcohol Clin Exp Res 31:1269-85
Shankar, Kartik; Hidestrand, Mats; Haley, Rani et al. (2006) Different molecular mechanisms underlie ethanol-induced bone loss in cycling and pregnant rats. Endocrinology 147:166-78
Chen, Jin-Ran; Haley, Rani Lynn; Hidestrand, Mats et al. (2006) Estradiol protects against ethanol-induced bone loss by inhibiting up-regulation of receptor activator of nuclear factor-kappaB ligand in osteoblasts. J Pharmacol Exp Ther 319:1182-90