Mois : juin 2024

A recent paper has investigated the impact of polystyrene nanoplastics on the molecular processes of male reproductive tissues in mice [1].

Health risks of micro- and nanoplastics

Microplastic and nanoplastic contamination is a worldwide public health concern for a good reason. Numerous research papers have associated microplastics with multiple health risks in the respiratory, immune, digestive, nervous, and reproductive systems, with nanoparticles especially dangerous for reproductive and nervous systems [2-8] due to their ability to “infiltrate biological barriers and have longer retention in tissue”, as the authors point out.

Humans are exposed to microplastics and nanoplastics primarily through food but also through skin contact and air [9, 10]. Studies have reported the presence of microplastics in human blood, the placenta, and the testes [6, 11, 12].

The authors of this study specifically focused on polystyrene nanoplastics and their impact on the male reproductive system. They mentioned that there are some previous studies that have already investigated polystyrene nanoplastics’ impact on reproductive health, showing that polystyrene nanoplastic exposure can lead to changes in sperm count, motility, and morphology [13] and can lead to a reduction in male fertility, including complete infertility [14]. Some studies have noted that an excess of reactive oxygen species (ROS) and premature senescence are part of the toxic effects of polystyrene nanoplastics [15].

Adverse effects of nanoplastics

The researchers exposed the mice to polystyrene nanoplastics for 60 days by delivering them directly to their stomachs. When they analyzed the animals’ tissue morphology after this treatment, they observed changes to male reproductive organ cells and accumulation of exogenous particles in spermatogenic cells. The researchers also referred to their previous, similar study, in which they observed a reduction in reproductive capacity and lower semen quality [16].

The authors also analyzed gene expression in testicular tissues. They noted that in mice exposed to polystyrene nanoplastics, molecular indicators connected to undifferentiated male germ cells (spermatogonia) were downregulated, and the number of spermatogonia was reduced in the group of mice that received a higher nanoplastics dose.

The researchers further evaluated mouse spermatogonia-derived cultured cells by exposing them to various concentrations of polystyrene nanoplastics. They observed suppressed cell proliferation and dose-dependent cell cycle arrest, which can lead to cellular apoptosis or senescence. Through measuring biomarkers, gene expression, and protein levels, the authors demonstrated elevated levels of cellular senescence in mouse spermatogonia that were exposed to polystyrene nanoplastics.

The damage from reactive oxygen species

The researchers aimed to determine exactly how polystyrene nanoplastic exposure leads to cellular senescence. Analysis of gene expression data indicated a role of reactive oxygen species (ROS) metabolism and ROS synthesis processes. Experimental exposure of mouse spermatogonia-derived cultured cells to polystyrene nanoplastics resulted in a dose-dependent increase in ROS levels.

To further investigate the role of ROS, the authors treated the cells with N-acetyl-L-cysteine (NAC), a ROS inhibitor. Exposing cells to NAC reduced the effects of polystyrene nanoplastic-induced changes in senescent biomarkers, gene and protein levels, and cell cycle arrest.

Further investigation into the molecular mechanism behind polystyrene nanoplastics’ impact on male fertility involved extracting data from the male health atlas (MHA) database and other gene expression databases along with a series of experiments. The authors arrived at the conclusion that Sirt1 is, at least partly, responsible for activating polystyrene nanoplastic-induced ROS generation. This “excessive ROS triggers DNA damage response in spermatogenic cells.”

The authors also discuss previous studies that implicated ROS as inducers of senescence and add that their results confirm that suppressing excessive ROS production can blunt the related effects of polystyrene nanoplastics. Taken together, they believe that polystyrene nanoplastic exposure causes excessive ROS production, which leads to a DNA damage response that causes spermatogenic cell senescence.

Potential of pterostilbene

After identifying the problem, the researchers tested pterostilbene as a potential remedy for it. Pterostilbene is a resveratrol-related polyphenol derived from blueberries, and it has potent antioxidant activity and a higher bioavailability than resveratrol.

Similar to the NAC treatment, using pterostilbene to treat polystyrene nanoplastic-exposed, mouse spermatogonia-derived cultured cells reduced ROS levels, cell cycle arrest, senescent cell levels, and expression of senescence-associated molecular markers. It also decreased the levels of a critical DNA damage marker.

The researchers concluded that “pterostilbene can alleviate the spermatogenic cell senescence induced by polystyrene nanoplastics.” Pterostilbene achieves this by reducing the detrimental effects of oxidative stress-mediated DNA damage.

Further research into protecting reproductive functions

The authors emphasize the importance of studying environmental pollutants on male reproductive ability. Their results linking polystyrene nanoplastics to cellular senescence align with previous research linking this particular type of nanoplastic to senescence in different types of cells.

Our study provides a scientific foundation for assessing the male reproductive health risks associated with nanoplastics exposure and identifies a promising intervention drug to mitigate the detrimental health effects of nanoplastics on male reproductive health. However, the impact of PS-NPs on male reproductive health still requires further exploration of the specific mechanism by which Sirt1 leads to ROS outbreaks, and further research is needed to combine epidemiological evidence to better explain the impact of PS-NPs on the spermatogenic process.

Literature

[1] Liang, Y., Yang, Y., Lu, C., Cheng, Y., Jiang, X., Yang, B., Li, Y., Chen, Q., Ao, L., Cao, J., Han, F., Liu, J., & Zhao, L. (2024). Polystyrene nanoplastics exposure triggers spermatogenic cell senescence via the Sirt1/ROS axis. Ecotoxicology and Environmental Safety, 279, 116461.

[2] Li, G., Yang, Z., Pei, Z., Li, Y., Yang, R., Liang, Y., Zhang, Q., & Jiang, G. (2022). Single-particle analysis of micro/nanoplastics by SEM-Raman technique. Talanta, 249, 123701.

[3] Zhu, X., Peng, L., Song, E., & Song, Y. (2022). Polystyrene Nanoplastics Induce Neutrophil Extracellular Traps in Mice Neutrophils. Chemical research in toxicology, 35(3), 378–382.

[4] Lin, S., Zhang, H., Wang, C., Su, X. L., Song, Y., Wu, P., Yang, Z., Wong, M. H., Cai, Z., & Zheng, C. (2022). Metabolomics Reveal Nanoplastic-Induced Mitochondrial Damage in Human Liver and Lung Cells. Environmental science & technology, 56(17), 12483–12493.

[5] Shan, S., Zhang, Y., Zhao, H., Zeng, T., & Zhao, X. (2022). Polystyrene nanoplastics penetrate across the blood-brain barrier and induce activation of microglia in the brain of mice. Chemosphere, 298, 134261.

[6] Zhao, Q., Zhu, L., Weng, J., Jin, Z., Cao, Y., Jiang, H., & Zhang, Z. (2023). Detection and characterization of microplastics in the human testis and semen. The Science of the total environment, 877, 162713.

[7] Kopatz, V., Wen, K., Kovács, T., Keimowitz, A. S., Pichler, V., Widder, J., Vethaak, A. D., Hollóczki, O., & Kenner, L. (2023). Micro- and Nanoplastics Breach the Blood-Brain Barrier (BBB): Biomolecular Corona’s Role Revealed. Nanomaterials (Basel, Switzerland), 13(8), 1404.

[8] Jaafarzadeh Haghighi Fard, N., Mohammadi, M. J., & Jahedi, F. (2023). Effects of nano and microplastics on the reproduction system: In vitro and in vivo studies review. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 178, 113938.

[9] Hu, J., Xu, X., Song, Y., Liu, W., Zhu, J., Jin, H., & Meng, Z. (2022). Microplastics in widely used Polypropylene-Made food containers. Toxics, 10(12), 762.

[10] Niu, S., Liu, R., Zhao, Q., Gagan, S., Dodero, A., Ying, Q., Ma, X., Cheng, Z., China, S., Canagaratna, M., & Zhang, Y. (2024). Quantifying the Chemical Composition and Real-Time Mass Loading of Nanoplastic Particles in the Atmosphere Using Aerosol Mass Spectrometry. Environmental science & technology, 58(7), 3363–3374. Advance online publication.

[11] Leslie, H. A., van Velzen, M. J. M., Brandsma, S. H., Vethaak, A. D., Garcia-Vallejo, J. J., & Lamoree, M. H. (2022). Discovery and quantification of plastic particle pollution in human blood. Environment international, 163, 107199.

[12] Braun, T., Ehrlich, L., Henrich, W., Koeppel, S., Lomako, I., Schwabl, P., & Liebmann, B. (2021). Detection of Microplastic in Human Placenta and Meconium in a Clinical Setting. Pharmaceutics, 13(7), 921.

[13] Zhou, L., Yu, Z., Xia, Y., Cheng, S., Gao, J., Sun, W., Jiang, X., Zhang, J., Mao, L., Qin, X., Zou, Z., Qiu, J., & Chen, C. (2022). Repression of autophagy leads to acrosome biogenesis disruption caused by a sub-chronic oral administration of polystyrene nanoparticles. Environment international, 163, 107220.

[14] Xu, W., Yuan, Y., Tian, Y., Cheng, C., Chen, Y., Zeng, L., Yuan, Y., Li, D., Zheng, L., & Luo, T. (2023). Oral exposure to polystyrene nanoplastics reduced male fertility and even caused male infertility by inducing testicular and sperm toxicities in mice. Journal of hazardous materials, 454, 131470.

[15] Shiwakoti, S., Ko, J. Y., Gong, D., Dhakal, B., Lee, J. H., Adhikari, R., Gwak, Y., Park, S. H., Jun Choi, I., Schini-Kerth, V. B., Kang, K. W., & Oak, M. H. (2022). Effects of polystyrene nanoplastics on endothelium senescence and its underlying mechanism. Environment international, 164, 107248.

[16] Lu, C., Liang, Y., Cheng, Y., Peng, C., Sun, Y., Liu, K., Li, Y., Lou, Y., Jiang, X., Zhang, A., Liu, J., Cao, J., & Han, F. (2023). Microplastics cause reproductive toxicity in male mice through inducing apoptosis of spermatogenic cells via p53 signaling. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 179, 113970.

For the first time, scientists have shown that the abundance of proteins needed for mitochondrial energy production in human brains is linked to perceived psychosocial experiences [1].

Picking the brains

Negative psychosocial experiences have been linked to health problems by numerous studies. However, not enough is known about the concrete mechanisms at play. In this new study, scientists from Columbia University have provided interesting insights that point to a possible mediatory role of mitochondria in the brain.

The researchers utilized data from two cohorts of several hundred diseased elderly patients who had donated their brains to science. While they were still alive, periodic psychosocial self-assessments had been collected over the course of up to two decades.

How do your mitochondria feel?

Proteomic analysis of the brains revealed a link between psychosocial experiences and mitochondria, the organelles that produce the lion’s share of energy in our cells. Instead of analyzing thousands of mitochondrial genes one by one, the researchers worked with seven generalized aspects of mitochondrial health, such as metabolism and small molecular transport.

One such factor, OxPhos protein abundance, relates to the amount of protein available for oxidation-phosphorylation reactions, which are at the core of mitochondrial energy production. In the dorsolateral prefrontal cortex (DLPFC), a brain area that is involved in executive functions and emotional regulation and is known to be sensitive to psychological stress, this factor showed marked correlation with both positive and negative psychosocial experiences.

The positive psychosocial aspects most associated with increased OxPhos protein abundance were well-being and late-life social activity. On the opposite side of the scale, negative mood and negative life events had the biggest effect sizes. “Thus”, the paper notes, “both individual experiences (well-being and mood) and objectifiable factors (social activity and life events) relate to DLPFC brain mitochondrial biology.”

The correlation was most notable for complex I, the largest and most upstream mitochondrial OxPhos enzyme. Psychosocial experiences accounted for 18% to 25% of the variance in the abundance of this protein. For reasons not yet fully understood, the brain is exceptionally vulnerable to complex I defects [2].

Not the neurons

Moving from proteomics to single-cell RNA sequencing enabled the researchers to take an even closer look and yielded intriguing results. The correlation between psychosocial scores and complex I was undetectable for neurons but strong for glia, the “helper” cells that facilitate proper neuronal functions, such as microglia, the brain’s resident immune cells.

“This may be why chronic psychological stress and negative experiences are bad for the brain,” said Caroline Trumpff, assistant professor of medical psychology in the Department of Psychiatry at Columbia University and a lead author on the paper, “because they damage or impair mitochondrial energy transformation in the dorsolateral prefrontal cortex, the part of the brain responsible for high-level cognitive tasks.”

These results do not come as a complete surprise. Scientists have already shown that in animal models, stress impairs mitochondrial function [3]. Moreover, this relationship appears to be bidirectional: the same group that authored this new study had found that differences in mitochondrial energy production capacity affect anxiety and social avoidance in rodents [4].

Complex interactions

“We’re showing that older individuals’ state of mind is linked to the biology of their brain mitochondria, which is the first time that subjective psychosocial experiences have been related to brain biology,” said Trumpff.

Yet, the researchers admit that their study has several limitations, such as inability to establish causation. Instead, they propose four “biologically plausible scenarios” to explain their findings. First, that psychosocial experiences affect brain activity and thus mitochondrial biology. Second, that mitochondrial biology affects behavior and perception of psychosocial experiences. Third, a bidirectional relationship, sort of a positive feedback loop. Finally, other factors, such as environmental pollution, could independently affect both mitochondria and psychosocial experiences. “However,” the authors note, “the emerging picture in the literature is that all those pathways are interactive, and thus, our results may reflect the outcome of those complex interactions.”

In this study, we used longitudinal psychosocial data and postmortem DLPFC proteomics in a sample of older adults with and without cognitive impairments to evaluate the association between psychosocial experiences and brain mitochondrial biology. Individuals reporting more positive experiences, such as greater well-being, had greater brain tissue OxPhos complex I protein abundance, while the opposite effect was found for negative psychosocial experiences. Considering their independent contributions (people feeling more positive may report fewer negative experiences), we find that ~18 to 25% of the variance in complex I abundance between individuals was attributable to self-reported psychosocial experiences.

Literature

[1] Trumpff, C., Monzel, A. S., Sandi, C., Menon, V., Klein, H. U., Fujita, M., … & Picard, M. (2024). Psychosocial experiences are associated with human brain mitochondrial biology. Proceedings of the National Academy of Sciences, 121(27), e2317673121.

[2] Quintana, A., Kruse, S. E., Kapur, R. P., Sanz, E., & Palmiter, R. D. (2010). Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome. Proceedings of the National Academy of Sciences, 107(24), 10996-11001.

[3] Batandier, C., Poulet, L., Hininger, I., Couturier, K., Fontaine, E., Roussel, A. M., & Canini, F. (2014). Acute stress delays brain mitochondrial permeability transition pore opening. Journal of neurochemistry, 131(3), 314-322.

[4] Rosenberg, A. M., Saggar, M., Monzel, A. S., Devine, J., Rogu, P., Limoges, A., … & Picard, M. (2023). Brain mitochondrial diversity and network organization predict anxiety-like behavior in male mice. Nature Communications, 14(1), 4726.

Scientists have identified a small molecule that upregulates telomerase reverse transcriptase (TERT) in multiple tissues, improving health and cognition in old mice.

Telomere attrition and health

The enzyme telomerase can prevent telomere attrition from happening by extending the length of telomeres. However, in most multicellular organisms, including humans, telomerase expression is switched off, except in germ cells, some types of stem cells, and certain white blood cells. While this might play a role in preventing cancer, as most cancerous cells must switch telomerase expression back on via mutations to enable runaway replication, numerous studies have shown that increasing telomerase through TERT delays aging and increases longevity of model organisms [1].

The small molecule that could

In the lab, this is usually done by introducing genetic vectors carrying a working copy of the gene that codes TERT. It’s this gene that is switched off in somatic cells. However, gene therapies are complex and expensive, and they are just entering the medical mainstream. What if we could do the same using a small molecule?

In a new paper, scientists from the University of Texas MD Anderson Cancer Center report that they have found such a molecule: TERT activator compound (TAC). The researchers started by screening more than 600 thousand molecules and found about 100 that could increase the activity of the human TERT gene. One of them particularly shined.

TAC worked narrowly and precisely, significantly upregulating only TERT and the two genes needed for its derepression.

Excited by these results, the researchers moved to experiments in vivo. TAC was shown to reach numerous tissues and organs, including, importantly, the central nervous system, and to be cleared from the organism in about three hours.

This, according to the researchers, was enough to improve multiple hallmarks of aging. Peripheral mononuclear blood cells (PBMCs), taken from the treated 12-month-old mice, had markedly lower expression levels of p16, an important marker of cellular senescence, as well as several other senescence-associated and pro-inflammatory molecules. Conversely, expression signatures of organism growth and of natural killer cell activation were upregulated.

In genetically modified mice lacking TERT, those changes did not happen, proving that TAC works specifically by upregulating TERT rather than via some other pathway. Interestingly, however, the treatment did not affect the levels of another popular marker of senescence, p21.

Cognitive improvements and more

Chronic TAC administration had a marked effect on the brain health and cognitive abilities in mice, in line with previous research on genetic reactivation of TERT [2]. The treatment increased the creation of new neurons (neurogenesis) and upregulated numerous genes associated with brain function. It also significantly diminished the number of activated microglia, the resident immune cells of the brain. Activated microglia are the primary drivers of neuroinflammation, which, in turn, is a major factor in age-related neurodegeneration. Accordingly, levels of several pro-inflammatory cytokines, including IL-1β, IL-6, and tumor necrosis factor alpha (TNF-α), were significantly downregulated in the hippocampi of the treated mice.

All of this translated into cognitive improvements. Treated old (26-27 months) mice scored better in hippocampus-related cognitive tests compared to controls. Interestingly, the mice also showed improved rotarod performance and grip strength. Unfortunately, the researchers did not investigate possible lifespan extension.

“Epigenetic repression of TERT plays a major role in the cellular decline seen at the onset of aging by regulating genes involved in learning, memory, muscle performance and inflammation,” said Ronald DePinho, professor of Cancer Biology and the corresponding author on the paper. “By pharmacologically restoring youthful TERT levels, we reprogrammed expression of those genes, resulting in improved cognition and muscle performance while eliminating hallmarks linked to many age-related diseases.”

This study highlights the significant regenerative capacity of aging organ systems as well as the ability to pharmacologically modulate aging hallmarks during natural aging. We report the discovery of a novel small-molecule telomerase activator that induces the physiological expression of TERT in both human and mouse somatic tissues. Our findings reinforce the view that TERT exerts anti-aging activity not only by preserving telomere integrity but also by modulating gene expression and cellular signaling pathways governing cellular survival, senescence, neurogenesis, and stress resistance, among other processes.

Literature

[1] Bernardes de Jesus, B., Vera, E., Schneeberger, K., Tejera, A. M., Ayuso, E., Bosch, F., & Blasco, M. A. (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO molecular medicine, 4(8), 691-704.

[2] Shim, H. S., Horner, J. W., Wu, C. J., Li, J., Lan, Z. D., Jiang, S., … & DePinho, R. A. (2021). Telomerase reverse transcriptase preserves neuron survival and cognition in Alzheimer’s disease models. Nature aging, 1(12), 1162-1174.