Ultrafine Particle Pollutants Delay Neurological Cell Differentiation.

[NNadir]

The paper I'll discuss in this post is this one: Ultrafine Particulate Matter Exacerbates the Risk of Delayed Neural Differentiation: Modulation Role of METTL3-Mediated m6A Modification Rui Wang, Yutong Liu, Lifan Fan, Nanxin Ma, Qiqi Yan, Chen Chen, Wenhao Wang, Zhihua Ren, Xia Ning, Tingting Ku, and Nan Sang Environmental Science & Technology 2025 59 (6), 2974-2986.

I'm a proteomics kind of guy, because that's the way I was raised in fits and starts scientifically, after a time, but in recent years I've tried or been encouraged to broaden my "omics" space to the closely related genomics and transcriptomics (RNA vs. DNA) space, to understand molecular biology at a deeper level. (I may be old, but I'm not dead yet.)

Proteomic people tend to think of post transcriptional modification of proteins at the amino acids subject to them (and thus are sometimes dragged kicking and screaming into glycomics as a result of glycans on asparagine, threonine and serine), but we don't think about, and often are not interested in, the effects of modifications on other "omics" molecules all that much. Somewhat lazily, I thus always assumed that the post translational modifications of nucleic acids was limited to, basically, methylation - which is known to have powerful consequences - but recently I've been relieved of my ignorance by a lecture by Benjamin Garcia at Washington University in St. Louis, where he described a wide variety of structural modifications to the basic nucleic acid building blocks which he measured by mass spectroscopy. This sort of thing has been known for some time, but I was ignorant of it.

He has very recently offered a review of the topic:

Xie, Y., Brás-Costa, C., Lin, Z. and Garcia, B.A. (2025), Mass Spectrometry Analysis of Nucleic Acid Modifications: From Beginning to Future. Mass Spectrometry Reviews. (Early Version)

It is useful to think about these things to understand the environmental and health consequences of pollutants, notably smoke which is becoming more of an issue as the planet burns as a result of our extreme indifference to extreme global heating.

Perhaps the title of the paper cited at the outset sounds like gobbledygook, but I assure you it's important. My suspicion, which is growing rapidly, that the observed mass insanity in this country (and others) is a function of rising levels of pollution - of which air pollution is a major deadly part - but hardly the only major part. The issue is neurotoxicology, and neurotoxicology can and does have intellectual consequences, involving but not limited to, severe psychological consequences.

This paper is concerned with neurodevelopment. It does involve methylation.

From the introductory text:

Air pollution is a major global concern, attributed to 7 million annual deaths. (1) Ninety-nine percent of the world’s population lives in areas that surpass the World Health Organization’s air quality standards (less than 5 ug m^-3 per year). (2) Fine particles in the air, particularly ultrafine particles with an aerodynamic diameter of less than _0.1 um (PM_0.1), are known to pose serious long-term health risks by evading the body’s respiratory defenses and penetrating biological barriers (some of the most rigorous defenses to prevent foreign agents from reaching vulnerable organs like the brain and developing fetuses). (3) Epidemiological studies have shown that PM_0.1 is a substantial contributor to neurodevelopmental disorders such as attention deficit hyperactivity disorder and autism spectrum disorder (ASD). (4,5) Notably, a comprehensive representative pregnancy cohort study of 318,078 mother–child pairs in Southern California linked maternal exposure to airplane PM_0.1 during pregnancy to a heightened risk of ASD diagnosis in children by age 5 years. (6) However, owing to the complex nature of particulate matter (PM) exposure, further research is needed to fully comprehend the cause-and-effect relationship. Investigating sensitive biomarkers and underlying molecular mechanisms is crucial for understanding the impact of PM on brain development.

Brain development is a complex and ongoing process that commences with the differentiation of neural progenitor cells and involves considerable structural changes, including neurogenesis and synaptic plasticity. (7,8) The animal assay of early brain development remains a challenge owing to ethical concerns and time constraints. Embryonic stem cell (ESC)-derived neural differentiation assays, conversely, offer valuable and promising methods for studying crucial nervous system developmental processes in vitro, such as patterning, differentiation, neurite outgrowth, synaptogenesis, and myelination. (9) Despite this, no studies have explored the biological processes and potential mechanisms by which PM_0.1 exposure causes abnormal neurodevelopment using an mESC model.

In the dynamic “epitranscriptome” landscape of mRNA modifications, m⁶A deposition is particularly prevalent within the nervous system, playing a remarkable role in processes such as ESC differentiation, brain development, and the pathogenesis of neurodevelopmental disorders. (10,11) The dynamic regulation of m⁶A modification by various enzymes, including m⁶A methyltransferases, demethylases, and m⁶A-specific binding proteins, (12) is crucial for neural development and brain function. Methyltransferase-like 3 (METTL3) is a principal RNA methyltransferase responsible for m⁶A formation, working in a protein complex with methyltransferase-like 14 (METTL14) and the scaffold protein Wilms’ tumor 1–associating protein (WTAP). (13) Deletion of either METTL3 or METTL14 has been shown to delay the generation of upper-layer neurons in the postnatal mouse cortex by extending cell cycle progression in neural stem cells (NSCs). (14) METTL3-mediated m⁶A methylation also regulates the chromatin state of ESCs, providing a novel regulatory mechanism for gene expression throughout developmental processes. (15) Despite these findings, the precise mechanism of METTL3 regulation of neurodevelopmental processes remains unknown. Additionally, the sources of PM_0.1 vary in composition and content, leading to varying degrees of harm to organisms. (16) Therefore, identifying the strength of toxicity of the components is crucial in understanding neurodevelopmental damage caused by PM_0.1 in different regions.

Herein, we used mESCs as a model to mimic real-world PM_0.1 exposure in Taiyuan to investigate potential neurodevelopmental disorders and their underlying mechanisms. We employed a combination of in silico methods and the adverse outcome pathway (AOP) framework to discern which polycyclic aromatic hydrocarbons (PAHs) present in PM_0.1 were influential in neuronal morphogenesis and contributed to adverse outcomes. This research provides a crucial foundation for understanding the neurotoxic effects of ultrafine particles on biological organisms...

Figures from the text:



The caption:

Figure 3. PM_0.1 mediates m⁶A of neurodevelopment-related transcripts to induce delayed neural differentiation. (A) The top sequence motif was identified from MeRIP-seq in control and PMm_0.1-treated cells by the HOMER database. (B) PM_0.1 influences the distribution of m⁶A peak in all mRNAs. (C) The proportion of m⁶A peak distribution in control and PM_0.1-treated cells. (D) Volcano plot of all genes with differentially methylated m⁶A peaks. (E) Representative GSEA signaling pathways with the highest normalized enrichment score (NES) score in all differentially methylated genes. (F) KEGG analysis of all genes with differentially methylated peaks (P less than 0.05).

Figure 4. Zic1 is a target involved in m⁶A-regulated neural differentiation. (A) Four-quadrant diagram of genes with significant changes in both m6A and overall transcript levels in PM_0.1-treated cells. (B) The relationship between GO terms related to brain development and their annotated genes (gene or pathway count is shown in parentheses). (C) Inference score of 9 neurodevelopmental related genes in congenital abnormalities diseases. (D) Expression of genes enriched in more than seven pathways in the cluster. (E) m6A abundance in Zic1 mRNAs in PM_0.1-treated cells as detected by MeRIP-seq (F) MeRIP-qPCR was performed to confirm m6A modification in Zic1. (G) Expression of Zic1 in cells treated with actinomycin D at varying time points. #P less than 0.05, ##P less than 0.01, ###P less than 0.001 versus Ctrl.

Some additional text from the paper:

Neurogenesis is a critical biological process occurring during the development of the ectoderm. Embryonic neurogenesis is especially important as it contributes to shaping the organization of the brain structure and the overall development of the nervous system. (31) Previous studies have highlighted the connection between air pollutants and nervous system damage, specifically the potential of PM to influence the nervous system at molecular and cellular levels. (28) Of particular concern is the presence of PM_0.1 in the nervous system and its potential to cause neurological damage. (3,32) We hypothesized that PM_0.1 could lead to neurodevelopmental damage during early embryonic development. To investigate the impact of PM_0.1 on early embryonic neurodevelopment in vitro, the neural differentiation of mESC monolayers into neural progenitor cells was observed over a period of 10 days. Throughout the differentiation process, the control group exhibited mESC clones forming a neural network-like structure by day 10. However, exposure to PM_0.1 resulted in a gradual decrease in neurofilaments, with a concentration of 0.1 μg/mL leading to a significant reduction in the number of nerve cells (Figure 2A).

Lovely, isn't it.

I trust you're enjoying the weekend.