Early life metal dysregulation in amyotrophic lateral sclerosis

Abstract

ObjectiveDeficiencies and excess of essential elements and toxic metals are implicated in amyotrophic lateral sclerosis (ALS), but the age when metal dysregulation appears remains unknown. This study aims to determine whether metal uptake is dysregulated during childhood in individuals eventually diagnosed with ALS.MethodsLaser ablation‐inductively coupled plasma‐mass spectrometry was used to obtain time series data of metal uptake using biomarkers in teeth from autopsies or dental extractions of ALS (n = 36) and control (n = 31) participants. Covariate data included sex, smoking, occupational exposures, and ALS family history. Case–control differences were identified in temporal profiles of metal uptake for individual metals using distributed lag models. Weighted quantile sum (WQS) regression was used for metals mixture analyses. Similar analyses were performed on an ALS mouse model to further verify the relevance of dysregulation of metals in ALS.ResultsMetal levels were higher in cases than in controls: 1.49 times for chromium (1.11–1.82; at 15 years), 1.82 times for manganese (1.34–2.46; at birth), 1.65 times for nickel (1.22–2.01; at 8 years), 2.46 times for tin (1.65–3.30; at 2 years), and 2.46 times for zinc (1.49–3.67; at 6 years). Co‐exposure to 11 elements indicated that childhood metal dysregulation was associated with ALS. The mixture contribution of metals to disease outcome was likewise apparent in tooth biomarkers of an ALS mouse model, and differences in metal distribution were evident in ALS mouse brains compared to brains from littermate controls.InterpretationOverall, our study reveals direct evidence that altered metal uptake during specific early life time windows is associated with adult‐onset ALS.

Teeth reveal juvenile diet, health and neurotoxicant exposure retrospectively: What biological rhythms and chemical records tell us

“…Studies of their growth and composition play an especially important role in our understanding of ancient human behavior, development, and evolution. [1][2][3][4] Teeth also serve as important records of toxic environmental exposures in living people, [5][6][7][8] perhaps best exemplified by the detection of radiogenic elements in American children following atomic testing in the 1950s. [9,10] In this unprecedented situation, a "Baby Tooth Survey" was launched to assess the amount of a radioactive variant of strontium in children born in St. Louis, Missouri before, during, and after a period of especially heavy nuclear testing in 1953.…”

Estimating Perinatal Critical Windows of Susceptibility to Environmental Mixtures via Structured Bayesian Regression Tree Pairs

“…Our analysis of five pollutants observed weekly throughout pregnancy and birth weight is the first analysis to identify critical windows to a mixture observed at high-temporal resolution within a distributed lag mixture model framework. Previous studies have either estimated critical windows for a mixture observed at high temporal resolution in an additive DLM setting (Figueroa-Romero et al, 2020;Horton et al, 2018) or to a mixture observed at one or a small number of time points (Levin-Schwartz et al, 2019;Chiu et al, 2018;Valeri et al, 2017). Given the sequential nature of fetal development, where changes occur over varying time scales ranging from many months down to a few days, data driven methods that allow for high resolution and precision in identifying critical windows due to environmental mixtures have the potential to open doors to discovery and understanding in biological science (Wright, 2017).…”

The Role of Metals in the Neuroregenerative Action of BDNF, GDNF, NGF and Other Neurotrophic Factors

“…Using the copper complex CuATSM, a safe vehicle of copper selective in cells with damaged mitochondria, they demonstrated that early CuATSM treatment of pups expressing SODG93A with CCS avoided the early mortality and allowed a normal grow [ 118 ]. According to this study, direct evidence reveals that altered metal uptake during specific early lifetime windows is associated with adult-onset ALS [ 85 ]. Thus, copper homeostasis is undeniably crucial in the maintenance and function of motor neurons, and therefore in the pathogenic mechanisms underlying motoneuron degeneration.…”