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Different routes of Cd intake may influence the intestinal distribution of Cd, metallothionein (MT), and trace metals differently. Therefore, we compared the effects of parenteral and enteral administration of Cd on the distribution of trace metals and MT along the small intestine. In a first experiment three groups of rats were employed: a control, one receiving CdCl2 within the drinking water, and another receiving sc injections of CdCl2. In a second experiment, rats were fed three different diets with either 0, 0.3, or 1 mmol CdCl2/kg for one and two weeks to study the time- and dose-dependent effects of orally administered Cd. Metal concentrations (Cd, Zn, Cu, Fe) were measured by atomic emission spectrometry and MT was determined by radioimmunoassay. Intestinal MT levels did not show proximodistal gradients in controls or after sc administration of Cd, but orally administered Cd increased mucosal MT levels longitudinally from the duodenum to the ileum. Cd levels paralleled those of MT. Compared with the metal concentrations in the controls, sc administration of Cd did not change intestinal Zn, Cu, and Fe levels. Oral administration of Cd, however, increased Cu and decreased Fe levels in the intestinal mucosa significantly. The second experiment revealed that only high dietary concentrations of Cd increase intestinal Cd and MT levels longitudinally toward the distal parts, whereas at lower dietary concentration the longitudinal distribution was reversed. This shows that different routes and doses of Cd intake lead to a different trace metal and MT distribution and emphasizes the role of dietary Cd in the local induction of small-intestinal MT.

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Mennonites present cc. 500 years genetic isolation and three bottleneck events that reducedtheir genetic diversity. In order to identify (epi)genetic markers for metabolic syndrome (MS),we used a modified version of the Brazilian National Health Survey to interview 762Mennonites from three settlements, between 2016-2023. We compared 63 vs. 127 exomes(Illumina HiSeq) from Mennonites with/without metabolic syndrome (MS) and genotypedcandidate variants in regulatory regions with mass spectrometry (iPLEX) and sequence-specific amplification (PCR-SSP). We also evaluated DNA methylation of the NR3C1 andFKBP5 genes in peripheral blood mononuclear cells (PBMCs) of up to 66 and 141 individualswith/without MS. MS prevalence was 14.02%, less than half the one reported forNeobrazilians (34.8%, P<0.00001), being paralleled by a three times lower prevalence ofacute myocardial infarction (AMI). Among independent MS risk factors, we found lowermaternal warmth in infancy (OR=1.59, P=0.019) and a higher susceptibility to AMI with theharshest migratory route to Brazil (OR=1.57, P=0.001). Thirty-nine variants of 34 genes wereassociated with MS (p<0.02), 41% create/disrupt CpG sites and 12 were associated withvisceral adipose and/or cardiovascular tissue expression. There were no methylationdifferences between individuals with and without MS in PBMCs with the NR3C1 and FKBP5genes, pointing to other epigenetic causal effects. In conclusion, Mennonites have a peculiarepidemiological profile marked by (epi)genetic founder effects that also affect theirmetabolism, calling for urgent action for prevention and to alleviate the burden ofcomorbidities due to late diagnosis.