title: Developmental consequences of in utero sodium arsenate exposure in mice with folate transport deficiencies.
abstract: Previous studies have demonstrated that mice lacking a functional folate binding protein 2 gene (Folbp2-/-) were significantly more sensitive to in utero arsenic exposure than were the wild-type mice similarly exposed. When these mice were fed a folate-deficient diet, the embryotoxic effect of arsenate was further exacerbated. Contrary to expectations, studies on 24-h urinary speciation of sodium arsenate did not demonstrate any significant difference in arsenic biotransformation between Folbp2-/- and Folbp2+/+ mice. To better understand the influence of folate pathway genes on arsenic embryotoxicity, the present investigation utilized transgenic mice with disrupted folate binding protein 1 (Folbp1) and reduced folate carrier (RFC) genes. Because complete inactivation of Folbp1 and RFC genes results in embryonic lethality, we used heterozygous animals. Overall, no RFC genotype-related differences in embryonic susceptibility to arsenic exposure were observed. Embryonic lethality and neural tube defect (NTD) frequency in Folbp1 mice was dose-dependent and differed from the RFC mice; however, no genotype-related differences were observed. The RFC heterozygotes tended to have higher plasma levels of S-adenosylhomocysteine (SAH) than did the wild-type controls, although this effect was not robust. It is concluded that genetic modifications at the Folbp1 and RFC loci confers no particular sensitivity to arsenic toxicity compared to wild-type controls, thus disproving the working hypothesis that decreased methylating capacity of the genetically modified mice would put them at increased risk for arsenic-induced reproductive toxicity.
authors.affiliation: Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, TX 77030, USA.
authors.forename: Ofer
authors.initials: O
authors.lastname: Spiegelstein
authors.forename: Amy
authors.initials: A
authors.lastname: Gould
authors.forename: Bogdan
authors.initials: B
authors.lastname: Wlodarczyk
authors.forename: Marlene
authors.initials: M
authors.lastname: Tsie
authors.forename: Xiufen
authors.initials: X
authors.lastname: Lu
authors.forename: Chris
authors.initials: C
authors.lastname: Le
authors.forename: Aron
authors.initials: A
authors.lastname: Troen
authors.forename: Jacob
authors.initials: J
authors.lastname: Selhub
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Piedrahita
authors.forename: J Michael
authors.initials: JM
authors.lastname: Salbaum
authors.forename: Claudia
authors.initials: C
authors.lastname: Kappen
authors.forename: Stepan
authors.initials: S
authors.lastname: Melnyk
authors.forename: Jill
authors.initials: J
authors.lastname: James
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
mesh_terms: D000818:Animals; D001149:Arsenates / Q000633:toxicity*; D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002678:Chimera; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000097:blood / Q000378:metabolism; D005494:Folic Acid Deficiency / Q000196:embryology*; D005838:Genotype; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019055:No-Observed-Adverse-Effect Level; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D058978:Reduced Folate Carrier Protein; D012098:Reproduction / Q000187:drug effects
chemical_list: D001149:Arsenates; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D026901:Membrane Transport Proteins; D011956:Receptors, Cell Surface; D058978:Reduced Folate Carrier Protein; C548700:Slc19a1 protein, mouse; C009277:sodium arsenate; D005492:Folic Acid