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.

Genetic and nutritional deficiencies in folate metabolism influence tumorigenicity in Apcmin/+ mice

“…These findings, which may relate to the background of the strain, are consistent with those of a recent study, which showed that these mice were refractory to folate deficiency with respect to changes in the levels of SAM and SAH -other biomarkers in the homocysteine/methylation cycle [32].…”

“…Developmentally, however, Rfc1 expression may be more critical; homozygous mutants are embryonic lethal [32], and nursing mice receive 5-methyTHF from their mother's breast milk [33]. This is noteworthy for studies involving Apc min/+ mice, since their intestinal cells have an age-specific sensitivity to adenoma formation.…”

Importance of folate-homocysteine homeostasis during early embryonic development

“…The folate transport genes, Folr1, Folr2, and Slc19a1 (26)(27)(28), have been functionally inactivated in mice, and the effect of abnormal folate transport on embryonic development and phenotype has been characterized (2,22,26,(28)(29)(30)(31)(32).…”

Effects of low‐level arsenic exposure on the developmental toxicity of anilofos in rats

“…Inorganic arsenic is considered as an agent that has the potential to be a human developmental toxicant (Donald et al, 1992). It is established that both inorganic arsenite and arsenate readily cross the placenta of mammals and reach the mammalian conceptus following maternal exposure (Hood et al, 1988;Miyazaki et al, 2005;Spiegelstein et al, 2005). Consistent production of malformations was reported in rodents exposed to arsenic by either intravenous or intraperitoneal injections (Golub et al, 1998;DeSesso et al, 1998;NRC, 1999).…”