Papers of the Month
By Janelle Weaver
The same toxic molecule underlies both a muscle disorder and absent nose
A protein called double homeobox 4 (DUX4) is not only responsible for a rare muscular disease but also kills the precursors of the human nose, according to NIEHS researchers and their collaborators.
Mutations in the SMCHD1 gene can cause an extremely uncommon condition known as congenital arhinia — the absence of the nose at birth. In separate sets of patients, SMCHD1 mutations sometimes lead to a late-onset neuromuscular disorder called facioscapulohumeral muscular dystrophy type 2 (FSHD2). Yet it has not been entirely clear how mutations in the same gene can result in these two highly distinct disorders.
Using human embryonic stem cells, the researchers showed that SMCHD1 mutations destroy cranial placode cells — evolutionarily ancient cells that give rise to the sensory organs of the head. Specifically, SMCHD1 mutations unleash DUX4 toxicity, leading to placode cell death. Additional results revealed that induced pluripotent stem cells derived from arhinia and FSHD2 patients produce DUX4 when converting to placode cells.
Moreover, the study implicates herpesviruses, which can cause sexually transmitted diseases, as potential environmental modifiers that may exacerbate DUX4 toxicity in cranial placode cells of the developing fetus. According to the authors, more research is needed to determine why arhinia patients, but not FSHD2 patients, are characterized by abnormalities affecting the face or head.
Citation: Inoue K, Bostan H, Browne MR, Bevis OF, Bortner CD, Moore SA, Stence AA, Martin NP, Chen SH, Burkholder AB, Li JL, Shaw ND. 2023. DUX4 double whammy: the transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose. Sci Adv 9(7):eabq7744.
Cholesterol cousin exerts opposite effects in the injured lung
A cholesterol derivative called 25-hydroxycholesterol (25HC) plays dual roles in damaged lungs, according to NIEHS researchers and their collaborators.
25HC is involved in immune responses and is produced through a chemical reaction called oxidation by the enzyme cholesterol-25-hydroxylase (CH25H). Although levels of CH25H are highest in the lungs, its function in lung biology has been unclear.
Using mice with severely injured lungs, the researchers discovered that 25HC and CH25H exacerbated blood-vessel leakage and inflammation — a complex biological response triggered by tissue damage. In patients with acute respiratory distress syndrome, 25HC and CH25H in lung cell and fluid samples were associated with markers of microvascular leak, inflammation, and clinical severity.
Taken together with past findings, the new results suggest that the impact of CH25H-derived 25HC depends on the extent of lung damage, with healing effects during mild inflammation but harmful effects during severe inflammation. These dual roles indicate that pharmacologic targeting of CH25H in human disease is likely to prove challenging. According to the authors, future studies are warranted to better define the functions of CH25H in the lung, and to explore whether manipulating this molecule may offer some therapeutic benefit.
Citation: Madenspacher JH, Morrell ED, McDonald JG, Thompson BM, Li Y, Birukov KG, Birukova AA, Stapleton RD, Alejo A, Karmaus PW, Meacham JM, Rai P, Mikacenic C, Wurfel MM, Fessler MB. 2023. 25-hydroxycholesterol exacerbates vascular leak during acute lung injury. JCI Insight e155448.
Proteins partner up to produce thyroid hormone
A protein called GLI-Similar 3 (GLIS3) coordinates with three other proteins to synthesize thyroid hormone, according to NIEHS researchers and their collaborators.
Congenital hypothyroidism is thyroid-hormone deficiency present at birth. Severe forms of the disease can lead to growth failure and permanent intellectual disability. In both humans and mice, congenital hypothyroidism is triggered by loss of GLIS3 function because this protein plays a critical role in the production of thyroid hormone. Yet it has not been clear how GLIS3 teams up with other proteins called transcription factors to regulate the expression of thyroid genes.
Using rodent thyroid glands and cells, the researchers showed that GLIS3 works in conjunction with three protein partners ― paired box 8 (PAX8), NK2 homeobox 1 (NKX2.1), and forkhead box E1 (FOXE1). All of these proteins control the transcription of genes involved in thyroid hormone synthesis by binding within the same regulatory hub in these genes.
But GLIS3 does not affect the binding of PAX8 or NKX2.1 to thyroid genes. In addition, GLIS3 does not appear to alter transcription by causing major changes in the structure of chromatin — a DNA-protein complex that forms chromosomes. According to the authors, future studies could establish whether GLIS3 has any effect on chromatin structure, or how the protein might otherwise activate thyroid genes.
Citation: Kang HS, Grimm SA, Jothi R, Santisteban P, Jetten AM. 2023. GLIS3 regulates transcription of thyroid hormone biosynthetic genes in coordination with other thyroid transcription factors. Cell Biosci 13(1):32.
Nicotine may offer some neural protection against SARS-CoV-2
Exposure to nicotine protects the mouse brain from developing certain signs of infection and disease related to severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), according to NIEHS researchers and their collaborators. These results suggest the biological targets of nicotine could be harnessed to help individuals avoid long COVID.
SARS-CoV-2 is the virus that causes coronavirus disease 2019 (COVID-19), which has killed more than six million people worldwide. Individuals infected with SARS-CoV-2 are at risk of developing a neurological disorder known as long COVID. Symptoms of the disease include cognitive dysfunction, loss of smell, sleep disturbances, headaches, dizziness, fatigue, muscle pain, anxiety, and depression.
Even mild cases can change the structure of the brain, but knowledge of the mechanisms and risk factors that enable SARS-CoV-2 to affect the central nervous system is lacking. Disputed epidemiological data suggest that nicotine may reduce the severity of infection. Yet the possible therapeutic effects of nicotine have not been clear.
To address this knowledge gap, the researchers inoculated mice with SARS-CoV-2 and then provided some of them with a nicotine solution instead of drinking water. Nicotine intake did not alter death rates, but it decreased viral RNA and signs of disease in the brains of a subset of infected mice. According to the authors, the findings could be leveraged to prevent or mitigate neurological-related disorders caused by SARS-CoV-2.
Citation: Letsinger AC, Ward JM, Fannin RD, Mahapatra D, Bridge MF, Sills RC, Gerrish KE, Yakel JL. 2023. Nicotine exposure decreases likelihood of SARS-CoV-2 RNA expression and neuropathology in the hACE2 mouse brain but not moribundity. Sci Rep 13(1):2042.
How the most heavily used herbicide affects human cells
The herbicide glyphosate does not appear to pose a hazard to human DNA, according to researchers from the NIEHS Division of Translational Toxicology.
Over the past 30 years, glyphosate has become the most commonly used herbicide in the United States and throughout the world. Past research has suggested that glyphosate and glyphosate-based formulations (GBFs) may damage DNA (i.e., cause genotoxicity), raising concern about their potential health risks, including cancer. But few of these studies directly compared glyphosate to GBFs or effects among GBFs. Chemicals and other substances are routinely tested for genotoxicity because damage to DNA increases the risk of cells becoming cancer cells.
To address this knowledge gap, the researchers tested how human cells are affected by exposure to glyphosate, a microbial metabolite of glyphosate called (aminomethyl)phosphonic acid (AMPA), various GBFs, and additional herbicides. Neither glyphosate nor AMPA appeared to be toxic, even at high concentrations. By contrast, all GBFs and herbicides other than glyphosate injured the cells, and some of these chemicals damaged DNA. Additional analyses suggested that glyphosate is of low toxicological concern for humans.
The observation that glyphosate is not genotoxic in human cells aligns with the National Toxicology Program’s previous findings, published in 1992, that glyphosate was not genotoxic to mice exposed up to 50,000 ppm glyphosate in their food for three months.
Taken together, these results demonstrate that glyphosate does not produce DNA damage in the form of gene mutations, chromosome breaks, or changes in chromosome number, and that cytotoxicity (i.e., cell death) associated with GBFs may be related to other components of these formulations. For example, ingredients such as surfactants and detergents may compromise cell membranes or otherwise lead to cell death.
Citation: Smith-Roe SL, Swartz CD, Rashid A, Christy NC, Sly JE, Chang X, Sipes NS, Shockley KR, Harris SF, McBride SJ, Larson GJ, Collins BJ, Mutlu E, Witt KL. 2023. Evaluation of the herbicide glyphosate, (aminomethyl)phosphonic acid, and glyphosate-based formulations for genotoxic activity using in vitro assays. Environ Mol Mutagen; doi: 10.1002/em.22534 [Online 7 March 2023].