Papers of the Month
By Megan Avakian
Promising therapy for manganese-induced neurological disorder
NIEHS-funded researchers discovered how manganese (Mn) is regulated in the body, pointing to a promising therapy for Mn-induced neurological disorders, which resemble Parkinson’s disease. Until now, treatments have been hindered by a limited understanding of the mechanisms controlling Mn in the body.
The researchers exposed mice to Mn in drinking water from birth to eight weeks of age. They then measured expression of SLC30A10, a protein that plays an important role in eliminating Mn from the body. Compared with unexposed controls, the mice given Mn had increased SLC30A10 levels in the intestines and liver, which are responsible for excreting Mn. In human liver cell cultures genetically modified to block SLC30A10, there were higher levels of Mn and cell death compared with controls, suggesting that upregulation of SLC30A10 is critical to reduce Mn in the body and protect against toxicity.
Mechanistic studies in human liver cell cultures revealed that Mn exposure increased levels of proteins called hypoxia inducible factors (HIFs), and that HIFs were required for SLC30A10 upregulation. Further examination showed that Mn increased HIFs by blocking proteins called prolyl hydroxylases, which are necessary for degrading HIFs.
To examine potential therapies for Mn toxicity, the researchers treated Mn-exposed liver cells and mice with drugs that block prolyl hydroxylases. In cells, drug treatment increased HIF levels, enhanced SLC30A10 expression, and reduced cellular Mn levels. In mice, drug treatment increased SLC30A10 in the intestine, reduced Mn in the brain, and improved neurobehavioral outcomes, compared with mice not given the drug.
Citation: Liu C, Jursa T, Aschner M, Smith DR, Mukhopadhyay S. 2021. Up-regulation of the manganese transporter SLC30A10 by hypoxia-inducible factors defines a homeostatic response to manganese toxicity. Proc Natl Acad Sci USA 118(35):e2107673118.
Plant leaves work as reliable air monitor in citizen-science study
Working with citizen-scientists, NIEHS-funded researchers demonstrated that leaves can be used as a low-cost, reliable method to assess the level of metals in airborne dust. The leaf method yielded similar results as a standard sampling technique that uses an inverted disc. These methods can help assess exposure from former mine sites that emit heavy metals that can be distributed by wind to nearby communities.
After being trained to collect samples, 20 participants from Superior, Arizona, placed both a potted peppermint plant and disc sampler in a self-selected area, usually outside of their home. After one month, they submitted two leaves and the disc for analysis of seven different metals — arsenic, lead, cadmium, copper, aluminum, nickel, and zinc. The researchers assessed differences in metal levels by sampling method. Using enrichment factor calculations, they determined whether metals in dust came from the mine or other human activities.
On both the leaves and discs, levels of all metals decreased as distance from the mine increased. Both methods collected similar levels of all seven metals, although the disc generally collected more dust. Aluminum and iron were the most abundant metals detected. Enrichment factor calculations showed that human activity contributed to levels of metals in dust, further indicating that leaves are a promising method for assessing air quality.
According to the authors, results suggest that plant leaves can serve as a reliable monitor of metal-laden aerosols and that the low-cost technique is applicable to sites where resources are limited.
Citation: Zeider K, Van Overmeiren N, Rine KP, Sandhaus S, Eduardo Saez A, Sorooshian A, Munoz HC Sr, Ramirez-Andreotta MD. 2021. Foliar surfaces as dust and aerosol pollution monitors: an assessment by a mining site. Sci Total Environ. 790:148164.
Combination of a plant-based diet and specific gut microbes may protect against multiple sclerosis
A new NIEHS-funded study in mice showed that a diet rich in the plant-based compound isoflavone may protect against multiple sclerosis (MS). The isoflavone diet was only protective when the mice had gut microbes capable of breaking down isoflavones. MS is a disease in which the immune system attacks nerves in the brain and spinal cord, resulting in muscle weakness and loss of balance or coordination.
The researchers fed mice with MS characteristics an isoflavone-rich or isoflavone-free diet for six weeks. They measured levels of inflammatory cells in the brain and spinal cord, a hallmark of MS, and characterized the makeup of the gut microbiome.
Mice fed an isoflavone-free diet had more severe disease, with greater numbers of inflammatory cells in the brain and spinal cord, than mice fed isoflavone-rich diets. Isoflavone-free mice lacked isoflavone-metabolizing gut bacteria, which were abundant in mice fed the plant-based compounds. When the researchers fed mice isoflavones but removed isoflavone-metabolizing bacteria, the diet no longer protected against MS-like symptoms. When the bacteria were restored, the protective effect of the isoflavone diet returned. Furthermore, the researchers showed that isoflavone-free mice given equol, a metabolite produced when gut bacteria breakdown isoflavone, were also protected against MS.
Results suggest that the development and severity of MS is influenced by both diet and the makeup of the gut microbiome. According to the authors, results can inform therapies for patients with MS.
Citation: Jensen SN, Cady NM, Shahi SK, Peterson SR, Gupta A, Gibson-Corley KN, Mangalam AK. 2021. Isoflavone diet ameliorates experimental autoimmune encephalomyelitis through modulation of gut bacteria depleted in patients with multiple sclerosis. Sci Adv 7(28):eabd4595.
Wildfire smoke linked to increase in COVID-19 cases and deaths
Thousands of COVID-19 cases and deaths in the western U.S. may be attributable to increases in fine particulate matter air pollution (PM2.5) from wildfires, according to NIEHS-funded research. Exposure to wildfire smoke can increase the risk of lung infections, including COVID-19.
The researchers linked publicly available data on daily PM2.5 levels and the number of COVID-19 cases and deaths that occurred between March and December 2020 in 92 counties across California, Oregon, and Washington. They developed a model to estimate the association between daily changes in PM2.5 and percentage increase in COVID-19 cases and deaths up to 28 days after exposure. The scientists adjusted for factors such as weather, population size, and patterns of social distancing.
From August to October 2020, when fire activity was greatest, daily levels of PM2.5 during wildfire days were significantly higher than on non-wildfire days. Wildfires amplified the effect of exposure to PM2.5 on COVID-19 cases and deaths for up to four weeks. On average across all counties, a daily increase of 10 micrograms per cubic meter of PM2.5 for 28 days was associated with an 11.7% increase in COVID-19 cases and an 8.4% increase in deaths. The total number of COVID-19 cases and deaths attributable to daily increases in PM2.5 from wildfires were 19,742 and 748, respectively.
According to the authors, this study identified high levels of PM2.5 during wildfire days as a key factor in worsening the severity of the COVID-19 pandemic in the western U.S.
Citation: Zhou X, Josey K, Kamareddine L, Caine MC, Liu T, Mickley LJ, Cooper M, Dominici F. 2021. Excess of COVID-19 cases and deaths due to fine particulate matter exposure during the 2020 wildfires in the United States. Sci Adv 7(33):eabi8789.