Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity.

Genetic variants at the solute carrier family 39 member 8 (SLC39A8) gene locus are associated with the regulation of whole-blood manganese (Mn) and multiple physiological traits. SLC39A8 encodes ZIP8, a divalent metal ion transporter best known for zinc transport. Here, we hypothesized that ZIP8 regulates Mn homeostasis and Mn-dependent enzymes to influence metabolism. We generated Slc39a8-inducible global-knockout (ZIP8-iKO) and liver-specific-knockout (ZIP8-LSKO) mice and observed markedly decreased Mn levels in multiple organs and whole blood of both mouse models. By contrast, liver-specific overexpression of human ZIP8 (adeno-associated virus-ZIP8 [AAV-ZIP8]) resulted in increased tissue and whole blood Mn levels. ZIP8 expression was localized to the hepatocyte canalicular membrane, and bile Mn levels were increased in ZIP8-LSKO and decreased in AAV-ZIP8 mice. ZIP8-LSKO mice also displayed decreased liver and kidney activity of the Mn-dependent enzyme arginase. Both ZIP8-iKO and ZIP8-LSKO mice had defective protein N-glycosylation, and humans homozygous for the minor allele at the lead SLC39A8 variant showed hypogalactosylation, consistent with decreased activity of another Mn-dependent enzyme, ß-1,4-galactosyltransferase. In summary, hepatic ZIP8 reclaims Mn from bile and regulates whole-body Mn homeostasis, thereby modulating the activity of Mn-dependent enzymes. This work provides a mechanistic basis for the association of SLC39A8 with whole-blood Mn, potentially linking SLC39A8 variants with other physiological traits.

Asbestos Fiber Preparation Methods Affect Fiber Toxicity.

To measure the toxic potential of asbestos fibers-a known cause of asbestosis, lung cancer, and malignant mesothelioma-asbestos minerals are generally first ground down to small fibers, but it is unknown whether the grinding condition itself changes the fiber toxicity. To evaluate this, we ground chrysotile ore with or without water for 5-30 min and quantified asbestos-induced reactive oxygen species generation in elicited murine peritoneal macrophages as an indicator of fiber toxicity. The toxicity of dry-ground fibers was higher than the toxicity of wet-ground fibers. Grinding with or without water did not materially alter the mineralogical properties. However, dry-ground fibers contained at least 7 times more iron than wet-ground fibers. These results indicate that grinding methods significantly affect the surface concentration of iron, resulting in changes in fiber-induced reactive oxygen species generation or toxicity. Therefore, fiber preparation conditions should be accounted for when comparing the toxicity of asbestos fibers between reported studies.

Dental morphology and variation in theropod dinosaurs: implications for the taxonomic identification of isolated teeth.

Isolated theropod teeth are common Mesozoic fossils and would be an important data source for paleoecology biogeography if they could be reliably identified as having come from particular taxa. However, obtaining identifications is confounded by a paucity of easily identifiable characters. Here we discuss a quantitative methodology designed to provide defensible identifications of isolated teeth using Tyrannosaurus as a comparison taxon. We created a standard data set based as much as possible on teeth of known taxonomic affinity against which to compare isolated crowns. Tooth morphology was described using measured variables describing crown length, base length and width, and derived variables related to basal shape, squatness, mesial curve shape, apex location with respect to base, and denticle size. Crown curves were described by fitting the power function Y = a + bX(0.5) to coordinate data collected from lateral-view images of mesial curve profiles. The b value from these analyses provides a measure of curvature. Discriminant analyses compared isolated teeth of various taxonomic affinities against the standard. The analyses classified known Tyrannosaurus teeth with Tyrannosaurus and separated most teeth known not to be Tyrannosaurus from Tyrannosaurus. They had trouble correctly classifying teeth that were very similar to Tyrannosaurus and for which there were few data in the standard. However, the results indicate that expanding the standard should facilitate the identification of numerous types of isolated theropod teeth.