High-dose folic acid supplementation in rats: effects on gestation and the methionine cycle

Abstract

There is new evidence that a good folate status may play a critical role in the prevention of neural-tube defects and in lowering elevated homocysteine concentrations. This adequate folate status may be achieved through folic acid dietary supplementation. Folate is a water-soluble vitamin with a low potential toxicity. However, the possible consequences of long-term high-dose folic acid supplementation are unknown, especially those related to the methionine cycle, where folate participates as a substrate. With the aim of evaluating such possible effects, four groups of Wistar rats were classified on the basis of physiological status (virgin v. pregnant) and the experimental diet administered (folic-acid-supplemented, 40 mg/kg diet v. control, 2 mg folic acid/kg diet). Animals were fed on the diets for 3 weeks. Results showed that gestation outcome was adequate in both groups regardless of the dietary supplementation. However, there were reductions (P < 0·001) in body weight and vertex-coccyx length in fetuses from supplemented dams v. control animals. Folic acid administration also induced a higher (P < 0·01) S-adenosylmethionine : S-adenosylhomocysteine value due to increased S-adenosylmethionine synthesis (P < 0·01). However, hepatic DNA methylation and serum methionine concentrations remained unchanged. Serum homocysteine levels were reduced in supplemented dams (P < 0·05). Finally, pregnancy caused lower serum folate, vitamin B6 and vitamin B12 levels (P < 0·05). Folic acid administration prevented the effect of pregnancy and raised folate levels in dams, but did not change levels of vitamins B12 and B6. These new findings are discussed on the basis of potential benefits and risks of dietary folic acid supplementation.

Chronic hyperhomocysteinemia alters antioxidant defenses and increases DNA damage in brain and blood of rats: Protective effect of folic acid

“…Previous studies showed that folic acid administration did not reduce Hcy levels in brain and plasma from hyperhomocysteinemic rats, suggesting that this vitamin action in independent of Hcy-lowering effect (Matté et al, 2007). These results agree with those of other investigators (Achó n et al, 2000;Bernasconi et al, 2006;Carnicer et al, 2007).…”

Folic acid pretreatment prevents the reduction of Na+,K+‐ATPase and butyrylcholinesterase activities in rats subjected to acute hyperhomocysteinemia

“…As regards to the mechanisms through which folic acid prevented the inhibitory effect of Hcy on the activities of Na + ,K + ‐ATPase and BuChE, although we did not measure brain and blood Hcy levels after folic acid administration, it is possible that pretreatment with this vitamin may have reduced Hcy levels and therefore its inhibitory effects on these enzymes activities as previously demonstrated (Achón et al, 2000; Kim et al, 2002; Mattson et al, 2002; Ho et al, 2003). Therefore, we cannot discard the possibility that folic acid pretreatment provided the cells with sufficient pool of methyl‐tetrahydrofolate, a coenzyme critical in convertion of Hcy to methionine.…”

Folic acid supplements in pregnancy and early childhood respiratory health

“…[18, 19] While there are few data on respiratory and immune outcomes, a methyl-rich diet in pregnant mice has also been found to influence gestational length, coat color and weight of offspring via differential methylation. [20–23] A recent experimental study in mice showed that supplementation with methyl donors, including folic acid, during pregnancy, led to increased gene methylation and allergic asthma phenotypes in offspring via epigenetic mechanisms. [10] Thus it is plausible that a high intake of folate and other methyl donors during pregnancy could influence immune phenotypes in children via epigenetic mechanisms.…”

“…For example, folate participates as a substrate in the methionine cycle which is central in cell metabolism. [20] The impact of altering this cycle is not fully understood. Genetic polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) in the methionine cycle have been suggested to influence development of atopy related outcomes, but findings are conflicting.…”