The C57BL/6J Mouse Exhibits Sporadic Congenital Portosystemic Shunts

Abstract

C57BL/6 mice are the most widely used strain of laboratory mice. Using in vivo proton Magnetic Resonance Spectroscopy (1H MRS), we have repeatedly observed an abnormal neurochemical profile in the brains of both wild-type and genetically modified mice derived from the C57BL/6J strain, consisting of a several fold increase in cerebral glutamine and two fold decrease in myo-inositol. This strikingly abnormal neurochemical “phenotype” resembles that observed in chronic liver disease or portosystemic shunting and appeared to be independent of transgene, origin or chow and was not associated with liver failure. As many as 25% of animals displayed the abnormal neurochemical profile, questioning the reliability of this model for neurobiology. We conducted an independent study to determine if this neurochemical profile was associated with portosystemic shunting. Our results showed that 100% of the mice with high brain glutamine displayed portosystemic shunting by concomitant portal angiography while all mice with normal brain glutamine did not. Since portosystemic shunting is known to cause alterations in gene expression in many organs including the brain, we conclude that portosystemic shunting may be the most significant problem associated with C57BL/6J inbreeding both for its effect on the central nervous system and for its systemic repercussions.

Non‐invasive detection of neurochemical changes prior to overt pathology in a mouse model of spinocerebellar ataxia type 1

“…When neurochemical profiles of the mice were compiled, 1 WT mouse and 3 Sca1 154Q/2Q mice (all from different litters) were found to have an abnormal ‘high Gln’ profile that was previously described in the brains of both WT and genetically modified mice derived from the C57BL/6 strain (Tkáč et al 2011; Cudalbu et al 2013). The abnormal profile consisted of 2–3 fold higher Gln, 15–45% lower myo -Ins and 10–20% lower Tau relative to other WT or Sca1 154Q/2Q mice, respectively, at the same age.…”

“…The abnormal neurochemical profile was observed at all scans throughout the life span of these mice. This profile was recently shown to occur in as many as 25% of the animals from the C57BL/6 background and to be associated with portosystemic shunting in the liver (Cudalbu et al 2013). Since portosystemic shunting causes alterations in gene expression in many organs and an abnormal neurochemical profile in the brain, these four mice were excluded from further analysis.…”

“…In this first MRS study of the line, we had to exclude four mice (1 WT and 3 Sca1 154Q/2Q ) from MRS analysis in order to separate the neurochemical alterations caused by the SCA1 mutation from those associated with portosystemic shunting in mice with the C57BL/6 background. The study that recently described this phenomenon reported the abnormal high Gln profile in three other brain regions (striatum, hippocampus, and cortex) in mice (Cudalbu et al 2013). Together with the current results, the portosystemic shunting appears to affect the neurochemical profile globally in the cerebrum and cerebellum.…”

“…In addition, plasma ammonia and glutamine levels, as well as markers of liver function (total bilirubin, aspartate amino transferase, and alanine amino transferase) are within normal limits in the high Gln mice (Cudalbu et al 2013). …”

Keap1/Nrf2 pathway activation leads to a repressed hepatic gluconeogenic and lipogenic program in mice on a high-fat diet

“…However, further research is warranted to elucidate how Nrf2 can affect Creb levels. Another study using Nrf2 knockout mice showed that 2/3 of these mice have a congenital intrahepatic shunt (a much higher percentage than what is expected in the C57Bl6 mice [42]) that affects the hepatic oxygen and protein expression gradients [43]. In these mice, Pepck showed a more diffused expression not only confined to the periportal zone but expanding to both periportal and centrilobular areas due to the difference in oxygen tension.…”