title: Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition.
abstract: For over a decade, folic acid (FA) supplementation has been widely prescribed to pregnant women to prevent neural tube closure defects in newborns. Although neural tube closure occurs within the first trimester, high doses of FA are given throughout pregnancy, the physiological consequences of which are unknown. FA can cause epigenetic modification of the cytosine residues in the CpG dinucleotide, thereby affecting gene expression. Dysregulation of crucial gene expression during gestational development may have lifelong adverse effects or lead to neurodevelopmental defects, such as autism. We have investigated the effect of FA supplementation on gene expression in lymphoblastoid cells by whole-genome expression microarrays. The results showed that high FA caused dysregulation by ≥ four-fold up or down to more than 1000 genes, including many imprinted genes. The aberrant expression of three genes (FMR1, GPR37L1, TSSK3) was confirmed by Western blot analyses. The level of altered gene expression changed in an FA concentration-dependent manner. We found significant dysregulation in gene expression at concentrations as low as 15 ng/ml, a level that is lower than what has been achieved in the blood through FA fortification guidelines. We found evidence of aberrant promoter methylation in the CpG island of the TSSK3 gene. Excessive FA supplementation may require careful monitoring in women who are planning for, or are in the early stages of pregnancy. Aberrant expression of genes during early brain development may have an impact on behavioural characteristics.
authors.affiliation: Department of Developmental Biochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA. mohammed.junaid@opwdd.ny.gov
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Junaid
authors.forename: Salomon
authors.initials: S
authors.lastname: Kuizon
authors.forename: Juan
authors.initials: J
authors.lastname: Cardona
authors.forename: Tayaba
authors.initials: T
authors.lastname: Azher
authors.forename: Noriko
authors.initials: N
authors.lastname: Murakami
authors.forename: Raju K
authors.initials: RK
authors.lastname: Pullarkat
authors.forename: W Ted
authors.initials: WT
authors.lastname: Brown
mesh_terms: D002460:Cell Line; D019175:DNA Methylation / Q000187:drug effects; D004032:Diet; D019587:Dietary Supplements; D005492:Folic Acid / Q000008:administration & dosage*; D015870:Gene Expression / Q000187:drug effects*; D018392:Genomic Imprinting / Q000187:drug effects*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics
chemical_list: D005492:Folic Acid; D017346:Protein Serine-Threonine Kinases; C507394:TSSK3 protein, human