Living beings adapt to the environment they live in. Variations in skin color and in a bird’s beak shape are the most famous examples of genetic adaptation. However, adaptation is not restricted to evolution. Biological adaptations to environmental conditions can arise also along the lifespan, and memory of previous events can affect the response to future ones (Stinson, 2009).
Nanomaterials (namely particles where one or more dimensions range between 1 and 100 nm) are routinely commercialized and released in the environment. While it can be argued that particulate matter exposure is nothing new to living beings, modern human-made nanoparticles present an unprecedentedly persistent exposure, especially through air pollution. How do cells and organisms readjust to this changing environment?
Luckily, all cells are equipped with molecular machineries that allow them to respond to stimuli. At first, an acute response is activated to limit immediate damage. If the stimulus persists, the cell will reprogram itself through epigenetic mechanisms such as DNA methylation, histone modifications, and transcription factors binding to regulatory genomic regions. These rewiring mechanisms are a form of adaptation, increasing an organism's fitness and priming the response to subsequent insults.
In our research, we discovered an epigenetic mechanism of adaptation common to several species throughout the tree of life that mediates the long-term cellular responses to particulate matter (del Giudice et al., 2023). Our study proved that the regulation from a specific family of zinc fingers transcription factors (C2H2-ZNF) mediates the molecular adaptation to nanoparticles with various properties and across experimental conditions. A transcription factor is a protein that regulates gene transcription by binding to specific DNA sequences and influencing the rate at which genes are transcribed. They play a crucial role in determining when and to what extent genes are activated or repressed in a cell, contributing to the regulation of various biological processes. C2H2-ZNF specifically, are a well-known conserved family throughout evolution, controlling stress responses, immune functions, and chromatin remodeling, responsible for regulating responses to other exogenous agents, such as viruses and abiotic stress.
Despite nanomaterials growing prevalence, there are still many uncertainties regarding the potential health risks associated with nanoparticulates. As a result, multiple studies have been conducted on humans and the environment (Kinaret et al., 2020). However, the apparent dissimilarity across experimental evidence created a fragmented and often contradictory view of the effects of nanoparticles, requiring each material to be individually tested in varying settings (del Giudice et al., 2023). Our investigation contributes to defining a new generation of tests which are faster and more reliable in assessing the potential toxicity across multiple species and for longer-term consequences. The epigenome, namely all the modification of DNA and DNA associated proteins affecting gene expression without altering the DNA sequence, is extremely conserved in the evolution. Therefore, assessing the impact of substances on the epigenetic layer potentially allows to directly translate hazard considerations and toxicological results across species, contributing to the reduction of animal experimentation and streamlining the process to multiple nanomaterials with disparate physicochemical characteristics.
It is already well known that exposures to environmental factors contribute to disease susceptibility by impacting the epigenome. Indeed, association between DNA modifications (e.g., DNA methylation) and the exposome (the totality of environmental exposures throughout an individual's life ) has been widely investigated and is considered a staple in pharmacological safety assessment (Kringel, Malkusch, & Lötsch, 2021).
The possibility that nanoparticles could somehow epigenetically reprogram biological systems provides an additional dimension to assess health and environmental impact.
Our epigenetic model further suggests that the response to nanoparticles may be a conserved function of the innate immune system, highlighting the link between particulate exposure and immunomodulation. This link is particularly relevant when put in the context of recent findings connecting air pollution to severity of COVID-19, cancer development in non-smokers and spreading of antibiotic resistance (Hill et al., 2023; Sunyer & Dadvand, 2023; Zhou et al., 2023). The potentially detrimental effects of an overactive immune system for extended periods should not be neglected.
Therefore, this study highlights the need to correctly identify potential long-term effects of nanoparticles’ intentional and unintentional exposure, with possibly important epidemiological implications.
Our study revealed that a wide range of species across the tree of life respond to particulate exposure via a common ancestral epigenetic mechanism orchestrated by the C2H2-ZNF, which is present also in non-immunological cells (e.g., fibroblasts) and in simpler organisms (e.g., worms).
Response to ENMs can be assessed at different levels of granularity (e.g., the transcriptome, the metabolome, the epigenome), but not all layers show intra- and interspecies conservation. Stressing the conservation of the epigenetic layer, our study puts toxicoepigenomics in the heart of the One Health framework.
This shift towards a unified approach in safeguarding health and the environment has found support in initiatives like the EU Green Deal Chemicals Strategy for Sustainability and its Systems Biology-based approach (Caldeira et al., 2022). The One Health principle advocates for a comprehensive evaluation of chemicals and materials, including nanoparticles, throughout their entire life cycle. These aspirations align with the principles of the "3Rs" (reduction, refinement and replacement), which aim to reduce and replace animal experimentation.
Our findings represent an important step towards the end of the scientific dichotomy that so far has focused on either human or environmental implications of nanoparticle production, and instead embraces the interconnectedness and interdependence of the health of humans, animals, and the environment.
del Giudice, G., Serra, A., Saarimäki, L. A., Kotsis, K., Rouse, I., Colibaba, S. A., Jagiello, K., et al. (2023). An ancestral molecular response to nanomaterial particulates. Nature Nanotechnology, 18(8), 957–966.
Hill, W., Lim, E. L., Weeden, C. E., Lee, C., Augustine, M., Chen, K., Kuan, F.-C., et al. (2023). Lung adenocarcinoma promotion by air pollutants. Nature, 616(7955), 159–167.
Kinaret, P. A. S., Serra, A., Federico, A., Kohonen, P., Nymark, P., Liampa, I., Ha, M. K., et al. (2020). Transcriptomics in toxicogenomics, part I: experimental design, technologies, publicly available data, and regulatory aspects. Nanomaterials (Basel, Switzerland), 10(4).
Kringel, D., Malkusch, S., & Lötsch, J. (2021). Drugs and epigenetic molecular functions. A pharmacological data scientometric analysis. International Journal of Molecular Sciences, 22(14).
Stinson, S. (2009). Ecological diversity and modern human adaptations. In M. J. Marquardt (Ed.), Human Resources and Their Development - Volume II (pp. 25–43). EOLSS Publications. Retrieved October 9, 2023
Sunyer, J., & Dadvand, P. (2023). Air pollution and COVID-19 severity. The European Respiratory Journal, 62(1).
Zhou, Z., Shuai, X., Lin, Z., Yu, X., Ba, X., Holmes, M. A., Xiao, Y., et al. (2023). Association between particulate matter (PM)2·5 air pollution and clinical antibiotic resistance: a global analysis. The Lancet. Planetary Health, 7(8), e649–e659.
Caldeira, C., Farcal, R., Garmendia Aguirre, I., Mancini, L., Tosches, D., Amelio, A., Rasmussen, K., Rauscher, H., Riego Sintes, J. and Sala, S., Safe and sustainable by design chemicals and materials - Framework for the definition of criteria and evaluation procedure for chemicals and materials, EUR 31100 EN, Publications Office of the European Union, Luxembourg, 2022, ISBN 978-92-76-53280-4, doi:10.2760/404991, JRC128591.
Dario Greco (b. 1978) is professor of bioinformatics at the Faculty of Medicine and Health Technology, Tampere University, and the director of FHAIVE, The Finnish Hub for Development and Validation of Integrated Approaches (https://www.fhaive.fi). He is also professor of pharmaceutical bioinformatics, Faculty of Pharmacy, University of Helsinki, principal investigator at the Institute of Biotechnology, University of Helsinki, Finland, and the coordinator of the Finnish 3R Centre (https://www.fin3r.fi). To date, he published over 180 peer reviewed articles, reviews, and book chapters in the areas of nanotoxicology, toxicogenomics, drug discovery, network biology, data modeling and bioinformatics which were cited over 10,500 times (h-index 48). To date, he has completed the supervision of 9 PhD theses. FHAIVE is currently composed of over 30 people, including senior scientists, postdoctoral fellows, PhD and MSc students, technicians, and administrative staff. As principal investigator, Greco received funding from the Academy of Finland, the EU (HE, H2020, Green Deal, ERC, and IMI2 programs), the Novo Nordisk Foundation, the Finnish Red Cross, the Finnish Government for a total of over 13 M€ for the period 2013 – 2023. Among the ongoing projects, he leads the European Research Council (ERC Consolidator) project ARCHIMEDES (2022-2027), focused on developing in vitro and computational NAMs and IATA for pulmonary fibrosis. Moreover, Greco is the coordinator of the EU HE INSIGHT project (2024 – 2028), focused on the development of an integrated SSbD framework and NAMs to replace animal experiments in biomedicine, toxicology, and pharmacology.
M.Sc. Giusy del Giudice is a Ph.D. student at the Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), hosted in the Faculty of Medicine and Health Technology of the Tampere University, Finland. She holds a Bachelor in Biotechnology for human health (2017) and a M.Sc. in Medical Biotechnology (2019). Her areas of expertise are the analysis and modeling of toxicogenomics and pharmacogenomics data, with a focus on systems biology approaches and epigenetics.
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