Although critical periods for structural and many behavioral anomalies due to prenatal alcohol exposure have been identified, little is known about the effects of ethanol (EtOH) on preimplantation embryos. Preliminary studies from our laboratory indicate that EtOH exposure during preimplantation can cause implantation to occur earlier than normal, possibly resulting in a disruption of maternal-fetal synchrony. In our proposed project, an in vitro culture system for mouse pre- and peri-implantation embryos will be used to assess the direct effects of EtOH exposure during early pregnancy independent of maternal confounders. Based on our preliminary studies that clearly demonstrate an accelerated rate of embryogenesis among embryos treated with 0.1 to 0.4% (w/v) EtOH, the mechanism underlying this effect will be explored. The effect of this treatment appears to be specific, rather than globally cytotoxic, since treated embryos can develop normally to term. Using this model, we will identify the biochemical events that follow the exposure of cells to EtOH and develop a working model of the physiological effects of EtOH on embryonic cells. Based on our preliminary results, we hypothesize that EtOH accelerates preimplantation development by perturbing the plasma membrane and altering components of the signal-transduction pathway, leading to a precocious change in the expression of genes that regulate subsequent development. This hypothesis will be tested using normal and EtOH-treated embryos by examining selected components of the signal transduction pathway and by identifying those genes that undergo altered expression in response to EtOH. Using immunohistochemistry and micro-enzymatic assays, the activity of growth factor receptors will be measured, and where appropriate, the associated protein tyrosine kinase activity, also. Other aspects of the signal transduction pathway that will be examined include phospholipase C activity, protein kinases C activity, intracellular Ca2+ levels, and the expression of the putative transcription factors, c-myc, c-fos, and c-jun. to identify the gene transcripts that are expressed at increased or decreased levels during EtOH-induced acceleration of embryo development, EtOH-regulated genes will be identified by the technique of subtraction hybridization with normalized cDNA libraries prepared using mRNA isolated from control and ETOH-treated embryos. This technology has the capacity to select treatment-specific cDNAs that are representative of all abundance classes of mRNA in a form amenable to identification and characterization. The unique transcripts will be sequenced and, where possible, identified using databases. In this manner, a catalogue of both known and unidentified, unique sequences modulated by EtOH will be acquired. This resource will be available to us and others to subsequently determine the role of these unique gene products in EtOH perturbation of preimplantation and fetal development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
3P50AA007606-10S1
Application #
6097668
Study Section
Project Start
1998-05-01
Project End
1998-11-30
Budget Start
Budget End
Support Year
10
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Wayne State University
Department
Type
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
Jacobson, Sandra W; Carter, R Colin; Jacobson, Joseph L (2014) Breastfeeding as a proxy for benefits of parenting skills for later reading readiness and cognitive competence. J Pediatr 164:440-2
Carter, R Colin; Jacobson, Joseph L; Dodge, Neil C et al. (2014) Effects of prenatal alcohol exposure on testosterone and pubertal development. Alcohol Clin Exp Res 38:1671-9
Dodge, Neil C; Jacobson, Joseph L; Jacobson, Sandra W (2014) Protective effects of the alcohol dehydrogenase-ADH1B*3 allele on attention and behavior problems in adolescents exposed to alcohol during pregnancy. Neurotoxicol Teratol 41:43-50
Yumoto, Chie; Jacobson, Sandra W; Jacobson, Joseph L (2008) Fetal substance exposure and cumulative environmental risk in an African American cohort. Child Dev 79:1761-76
Cortese, Bernadette M; Moore, Gregory J; Bailey, Beth A et al. (2006) Magnetic resonance and spectroscopic imaging in prenatal alcohol-exposed children: preliminary findings in the caudate nucleus. Neurotoxicol Teratol 28:597-606
Jacobson, Sandra W; Carr, Lucinda G; Croxford, Julie et al. (2006) Protective effects of the alcohol dehydrogenase-ADH1B allele in children exposed to alcohol during pregnancy. J Pediatr 148:30-7
Burden, Matthew J; Jacobson, Sandra W; Jacobson, Joseph L (2005) Relation of prenatal alcohol exposure to cognitive processing speed and efficiency in childhood. Alcohol Clin Exp Res 29:1473-83
Burden, Matthew J; Jacobson, Sandra W; Sokol, Robert J et al. (2005) Effects of prenatal alcohol exposure on attention and working memory at 7.5 years of age. Alcohol Clin Exp Res 29:443-52
Jacobson, Sandra W; Jacobson, Joseph L; Sokol, Robert J et al. (2004) Maternal age, alcohol abuse history, and quality of parenting as moderators of the effects of prenatal alcohol exposure on 7.5-year intellectual function. Alcohol Clin Exp Res 28:1732-45
Das, Utpala G; Cronk, Christine E; Martier, Susan S et al. (2004) Alcohol dehydrogenase 2*3 affects alterations in offspring facial morphology associated with maternal ethanol intake in pregnancy. Alcohol Clin Exp Res 28:1598-606

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