Ethanol alters cell cycle gene expression in human embryonic stem cells

Article type: Research Article

Authors: Krishnamoorthy, Malini^; | Gerwe, Brian A.^; | Heimburg-Molinaro, Jamie | Nash, Rachel J.^; | Arumugham, Jagan | Eilertson, Carmen D. | Stice, Steven L. | Nash, Rodney J.^;

Affiliations: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA | Jeevan Biosciences, Dunwoody, GA, USA | Department of Biochemistry, The University of Georgia, Athens, GA, USA | Macromolecular Therapeutics Development Facility, Albert Einstein College of Medicine, Bronx, NY, USA | Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA | Department of Behavioral Science and Health Education, Emory University School of Public Health, Atlanta, GA, USA | Department of Biology, Georgia State University, Atlanta, GA, USA | Regenerative Bioscience Center, The University of Georgia, Athens, GA, USA

Note: [] Correspondence: Rodney J. Nash, PhD, Jeevan Biosciences, INC. 4722 Kings Down RD, Dunwoody, GA 30338, USA. Tel.: +1 404 316 3046; Fax: +1 404 591 5174; E-mail: [email protected]

Abstract: Ethanol consumption during pregnancy has been shown to promote abnormal development in offspring. These abnormalities include microcephaly, growth retardation, neurological deficits and behavioral and cognitive deficiencies. Cyclins and cyclin dependent kinases (CDKs) are crucial for cell cycle progression, proliferation and differentiation of various cell types. The purpose of our study was to better understand the effects of ethanol on proliferation during early human development by using three human embryonic stem cell (hESC) lines. We found that treatment of ethanol at low doses (20 mM; four days) increased cell proliferation. The expression of key cell cycle regulators, CDKN2B (p15) and CDKN2A (p16) increased in two hESC lines, while CDKN1A (p21) and CDKN1B (p27) gene expression decreased in all cell lines. Western analysis showed a decrease in CDKN2B (p15) and CDKN2A (p16), while CDKN1A (p21) increased and CDKN1B (p27) remained unchanged. The changes in proliferation, gene expression, and protein synthesis suggest that ethanol can have a significant effect on cellular development at an early stage of human development. The correlation of our findings to in vivo conditions remains speculative, but the differential expression of regulators of the cell cycle may be involved in the manifestation of the many phenotypes seen in Fetal Alcohol Spectrum Disorder (FASD).

Keywords: Human embryonic stem cell, proliferation, cell cycle proteins, ethanol, gene expression

DOI: 10.3233/JPB-2010-0026

Journal: Journal of Pediatric Biochemistry, vol. 1, no. 3, pp. 201-208, 2010/2011