L1 cell adhesion molecule and fetal alcohol syndrome: The major research focus in my laboratory is the effect of ethanol on the cell adhesion molecule, L1. The neuroanatomy of patients with defects in L1 is similar to that of patients with fetal alcohol syndrome, suggesting a role for L1 in the pathogenesis of the central nervous system abnormalities found in these patients. L1 is a transmembrane glycoprotein that promotes and regulates neuronal adhesion and neurite outgrowth by activation of signaling cascades and clathrin-dependent endocytosis. L1 mediates adhesion by binding homophilically to another L1 on an apposing neuron. Adhesion generates signal transduction involving src and MAP kinases, and possibly the fibroblast growth factor receptor. Inhibition of endocytosis blocks MAP kinase activation, and inhibition of MAP kinase inhibits neurite outgrowth. Interestingly, we found that L1 adhesion was unaffected by ethanol, while L1 mediated neurite outgrowth was inhibited at low physiologic concentrations of ethanol. We are currently investigating the effects of ethanol on L1 signal activation, and endocytosis.

Cerebral palsy (CP) is one of the major neurodevelopmental handicaps of premature infants, yet its etiology remains poorly understood. Currently, severe cranial ultrasound abnormalities are the best predictor for the development of CP. However, in a recent study, 48% of preterm infants who developed CP had a normal ultrasound. To identify infants at risk for CP, better and earlier predictors are needed. CP frequently involves the corticospinal tract. The development of this tract is dependent on the expression of an axon guidance molecule L1. L1 can be detected in cerebrospinal fluid (CSF). We have found that the amount and the pattern of several high molecular weight forms of L1 are dependent on postconceptual age with large amounts of the higher molecular weight forms present in the CSF of preterm infants. We are investigating the normal and abnormal developmental pattern of these forms.

Alcohol use during pregnancy is a significant public health problem. Heavy drinking during pregnancy can cause the fetal alcohol syndrome (FAS), the leading known cause of mental retardation. In addition, drinking during pregnancy can result in a spectrum of effects: alcohol-related birth defects, alcohol-related neurodevelopmental defects and subtle deficits on a variety of behavioral, educational and psychological tests. It is estimated that 1% of all live births suffer some prenatal alcohol damage and cost society anywhere from $75 million to $9.7 billion per year. Identifying the alcohol-exposed newborn is difficult. Early identification of affected infants is desirable to best determine effective secondary prevention strategies. We have developed a technique to measure ethanol metabolites in meconium, the first stools passed by newborns. The amount of these metabolites is highly associated with maternal self-reported drinking. A cutoff value for these metabolites determined in an abstaining population was found to identify infants in a study population who scored significantly lower on the Bayley Test of Infant Intelligence. We are currently developing an ovine animal model to further validate this test, as well as extending these observations in study populations in South Africa, Chile, Utah and Jordan.

1. Tang N, He M, O’Riordan MA, Farkas C, Buck K, Lemmon V, Bearer CF. (2006)
   Ethanol inhibits L1 cell adhesion molecule activation of mitogen-activated protein kinases. J Neurochem. 2006 Mar; 96(5):1480-1490.
   
2. Bearer CF, Santiago LM, O’Riordan MA, Buck K, Lee SC, Singer LT. (2005)
   Fatty Acid ethyl esters: quantitative biomarkers for maternal alcohol consumption. J Pediatr. 2005 Jun; 146(6):824-830.
   
3. Lanphear BP, Bearer CF. (2005)
   Biomarkers in paediatric research and practice. Arch Dis Child. 2005 Jun; 90(6):594-600.
   
4. Moya J, Bearer CF, Etzel RA. (2004)
   Children’s behavior and physiology and how it affects exposure to environmental contaminants. Pediatrics. 2004 Apr; 113(4 Suppl):996-1006.
   
5. Bearer CF, Jacobson JL, Jacobson SW, Barr D, Croxford J, Molteno CD, Viljoen DL, Marais AS, Chiodo LM, Cwik AS. (2003)
   Validation of a new biomarker of fetal exposure to alcohol. J Pediatr. 2003 Oct; 143(4):463-469.
   
6. Bearer CF, Linsalata N, Yomtovian R, Walsh M, Singer L. (2003)
   Blood transfusions: a hidden source of lead exposure. Lancet. 2003 Jul 26; 362(9380):332.
   
7. Noland JS, Singer LT, Arendt RE, Minnes S, Short EJ, Bearer CF. (2003)
   Executive functioning in preschool-age children prenatally exposed to alcohol, cocaine, and marijuana. Alcohol Clin Exp Res. 2003 Apr; 27(4):647-656.
   
8. Bearer CF. (2003)
   Meconium as a biological marker of prenatal exposure. Ambul Pediatr. 2003 Jan-Feb; 3(1):40-43.
   
9. Nagy LE, Lakshman MR, Casey CA, Bearer CF. (2002)
   Ethanol and membrane protein trafficking: diverse mechanisms of ethanol action. Alcohol Clin Exp Res. 2002 Feb; 26(2):287-293.
   
10. Bearer CF. (2001)
    Markers to detect drinking during pregnancy. Alcohol Res Health. 2001; 25(3):210-218.
    
11. Bearer CF. (2001)
    L1 cell adhesion molecule signal cascades: targets for ethanol developmental neurotoxicity. Neurotoxicology. 2001 Oct; 22(5):625-633.
    
12. Bearer CF. (2001)
    Developmental neurotoxicity. Illustration of principles. Pediatr Clin North Am. 2001 Oct; 48(5):1199-213, ix.
    
13. Gitterman BA, Bearer CF. (2001)
    A developmental approach to pediatric environmental health. Pediatr Clin North Am. 2001 Oct; 48(5):1071-1083.
    
14. Bearer CF. (2001)
    Mechanisms of brain injury: L1 cell adhesion molecule as a target for ethanol-induced prenatal brain injury. Semin Pediatr Neurol. 2001 Jun; 8(2):100-107.
    
15. Bearer CF. (2000)
    The special and unique vulnerability of children to environmental hazards. Neurotoxicology. 2000 Dec; 21(6):925-934.
    
16. Bearer CF, O’Riordan MA, Powers R. (2000)
    Lead exposure from blood transfusion to premature infants. J Pediatr. 2000 Oct; 137(4):549-554.
    
17. Claudio L, Bearer CF, Wallinga D. (1999)
    Assessment of the U.S. Environmental Protection Agency methods for identification of hazards to developing organisms, Part II: The developmental toxicity testing guideline. Am J Ind Med. 1999 Jun; 35(6):554-563.
    
18. Claudio L, Bearer CF, Wallinga D. (1999)
    Assessment of the U.S. Environmental Protection Agency methods for identification of hazards to developing organisms, Part I: The reproduction and fertility testing guidelines. Am J Ind Med. 1999 Jun; 35(6):543-553.
    
19. Bearer CF, Swick AR, O’Riordan MA, Cheng G. (1999)
    Ethanol inhibits L1-mediated neurite outgrowth in postnatal rat cerebellar granule cells. J Biol Chem. 1999 May 7; 274(19):13264-13270.
    
20. Bearer CF, Lee S, Salvator AE, Minnes S, Swick A, Yamashita T, Singer LT. (1999)
    Ethyl linoleate in meconium: a biomarker for prenatal ethanol exposure. Alcohol Clin Exp Res. 1999 Mar; 23(3):487-493.
    

1. Bearer CF. Detection of Teratogen Exposure. Awarded September 14, 1999, #5,952,235, United States Patent Office.
2. Bearer CF. Biomarker of Maternal Alcohol Use During Pregnancy. Submitted September 6, 2003