Homocysteine levels in A/J and C57BL/6J mice: genetic, diet, gender, and parental effects

Abstract

. Homocysteine levels in A/J and C57BL/6J mice: genetic, diet, gender, and parental effects. Physiol Genomics 21: [404][405][406][407][408][409][410] 2005. First published March 1, 2005; 10.1152/physiolgenomics.00199.2004.-Increased levels of homocysteine in the blood have been associated with various birth defects and adult diseases. However, the extent to which genetic factors control homocysteine levels in healthy individuals is unclear. Laboratory mice are valuable models for dissecting the genetic and environmental controls of total homocysteine (tHcy) levels. We assessed the inheritance of tHcy levels in two inbred strains, A/J and C57BL/6J (B6), under controlled physiological conditions and assessed the relative importance of genetic, diet, gender, and parental effects. Diet affected mean tHcy levels, whereas gender affected both the mean and variance of tHcy levels. Moreover, gender of the parents influenced mean tHcy levels in reciprocal F1 hybrids, suggesting maternal effects. Finally, gene-diet interactions affected heritability of mean tHcy levels. These studies showed that each of these factors contributes to tHcy levels and provided important clues to understanding homocysteine homeostasis in humans.genetics; folate; gene environment HYPERHOMOCYSTEINEMIA, or elevated levels of total homocysteine (tHcy) in the blood, is an independent risk factor for neural tube defects (NTDs) (27a, 37), vascular disease (4,43,46), and Alzheimer's disease (36) and is often associated with diseases such as colon cancer (20), osteoporosis (25, 41), and Down syndrome (3, 16). Although it is unclear whether elevated tHcy levels are a cause or consequence of disease, at least one meta-analysis suggests that hyperhomocysteinemia causes cardiovascular disease (43).Normal tHcy blood levels range from 5 to 12 mol/l (31), and hyperhomocysteinemia is classified into three categories: mild (12-30 mol/l), moderate (30-100 mol/l), and severe (Ͼ100 mol/l) (17, 31). Several environmental and genetic factors affect tHcy levels in the blood. Environmental factors include age (tHcy increases with age), gender (women tend to have lower levels than men), and diet (intake of vitamin cofactors such as folate and vitamin B 6 and B 12 usually reduces tHcy levels) (26). Deficiencies in genes involved in homocysteine and folate metabolism result in hyperhomocysteinemia: these genes include cystathionine ␤-synthase (CBS; Refs. Ref. 9,11,19,21).Homocysteine and folate pathways are tightly linked, and their regulation is complex. tHcy and folate levels are usually inversely related (34). Homocysteine, a sulfur-containing amino acid, is remethylated through the trans-methylation pathway or irreversibly catabolized through the trans-sulfuration pathway (29) and contributes to methylation of DNA, proteins, and lipids and indirectly to glucose metabolism and citric acid cycle. Folate metabolism manages the major pool of single carbon units and participates in purine and pyrimidine biosynthesis and amino acid metabolism (34).Because the levels of h...

Tissue-specific relationship of S-adenosylhomocysteine with allele-specificH19/Igf2methylation and imprinting in mice with hyperhomocysteinemia

“…9,11 The effect of diet on plasma tHcy concentrations in Cast mice has not been reported but it is well known that mouse strain can influence the effect of diet on plasma tHcy concentrations. 27 As such, the extent of the elevation in plasma total homocysteine that we observed in F1 Cast × Cbs +/-mice may not be large enough to…”

Differences in postingestive metabolism of glutamate and glycine between C57BL/6ByJ and 129P3/J mice

“…A few studies published so far indicate that amino acid metabolism is under genetic control in mice (11,24,33). We therefore have begun studies to examine genetic variation in amino acid metabolism.…”

Impaired hydrogen sulfide synthesis and IL-10 signaling underlie hyperhomocysteinemia-associated exacerbation of colitis

“…As in the rats with Hhcy, the IL-10-deficient mice exhibited marked neutropenia, as has been reported to occur in humans with Hhcy (21,22) and in rats with vitamin B 6 deficiency (23). The similarity in phenotype between the rats with diet-induced Hhcy and the IL-10-deficient mice was confirmed by measurements of serum homocysteine levels, which confirmed that these mice had mild to moderate Hhcy (31). Moreover, we confirmed that there is an interplay among IL-10, homocysteine, and H 2 S synthesis, because serum homocysteine levels and colonic H 2 S synthesis could be normalized in the IL-10-deficient mice through administration of recombinant IL-10.…”