Objectives and achievements of the HUMN project on its 26th anniversary.

Micronuclei (MN) are a nuclear abnormality that occurs when chromosome fragments or whole chromosomes are not properly segregated during mitosis and consequently are excluded from the main nuclei and wrapped within nuclear membrane to form small nuclei. This maldistribution of genetic material leads to abnormal cellular genomes which may increase risk of developmental defects, cancers, and accelerated aging. Despite the potential importance of MN as biomarkers of genotoxicity, very little was known about the optimal way to measure MN in humans, the normal ranges of values of MN in healthy humans and the prospective association of MN with developmental and degenerative diseases prior to the 1980's.

Tetraploidy as a metastable state towards malignant cell transformation within a systemic approach of cancer development.

Tetraploidy, a condition in which a cell has four homologous sets of chromosomes, may be a natural physiological condition or pathophysiological such as in cancer cells or stress induced tetraploidisation. Its contribution to cancer development is well known. However, among the many models proposed to explain the causes, mechanisms and steps of malignant cell transformation, only few integrate tetraploidization into a systemic multistep approach of carcinogenesis.

Towards prevention of aneuploidy-associated cellular senescence and aging: more questions than answers?

The aim of this review is to discuss how aneuploidy contributes to the aging process, and to identify plausible strategies for its prevention. After an overview of mechanisms leading to aneuploidy and the major features of cellular senescence, we discuss the link between (i) aneuploidy and cellular senescence; (ii) aneuploidy and aging; and (iii) cellular senescence and aging. We also consider (i) interactions between aneuploidy, micronuclei, cellular senescence and aging, (ii) the potential of nutritional treatments to prevent aneuploidy-associated senescence and aging, and (iii) knowledge and technological gaps.

Aneuploidy, inflammation and diseases.

This review discusses how numerical aneuploidy may trigger inflammation in somatic cells and its consequences. Therefore we: i) summarized current knowledge on the cellular and molecular pathological effects of aneuploidy; ii) considered which of these aspects are able to trigger inflammation; iii) determined the genetic and environmental factors which may modulate the link between aneuploidy and inflammation; iv) explored the rôle of diet in prevention of aneuploidy and inflammation; v) examined whether aneuploidy and inflammation are causes and/or consequences of diseases; vi) identified the knowledge gaps and research needed to translate these observations into improved health care and disease prevention. The relationships between aneuploidy, inflammation and diseases are complex, because they depend on which chromosomes are involved, the proportion of cells affected and which organs are aneuploid in the case of mosaic aneuploidy.

Inflammatory cytokine storms severity may be fueled by interactions of micronuclei and RNA viruses such as COVID-19 virus SARS-CoV-2. A hypothesis.

In this review we bring together evidence that (i) RNA viruses are a cause of chromosomal instability and micronuclei (MN), (ii) those individuals with high levels of lymphocyte MN have a weakened immune response and are more susceptible to RNA virus infection and (iii) both RNA virus infection and MN formation can induce inflammatory cytokine production. Based on these observations we propose a hypothesis that those who harbor elevated frequencies of MN within their cells are more prone to RNA virus infection and are more likely, through combined effects of leakage of self-DNA from MN and RNA from viruses, to escalate pro-inflammatory cytokine production via the cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) and the Senescence Associated Secretory Phenotype (SASP) mechanisms to an extent that is unresolvable and therefore confers high risk of causing tissue damage by an excessive and overtly toxic immune response. The corollaries from this hypothesis are (i) those with abnormally high MN frequency are more prone to infection by RNA viruses; (ii) the extent of cytokine production and pro-inflammatory response to infection by RNA viruses is enhanced and possibly exceeds threshold levels that may be unresolvable in those with elevated MN levels in affected organs; (iii) reduction of MN frequency by improving nutrition and life-style factors increases resistance to RNA virus infection and moderates inflammatory cytokine production to a level that is immunologically efficacious and survivable.

"Micronuclei and Disease" special issue: Aims, scope, and synthesis of outcomes.

The purpose of the "Micronuclei and Disease" special issue (SI) is to: (i) Determine the level of evidence for association of micronuclei (MN), a biomarker of numerical and structural chromosomal aberrations, with risk of specific diseases in humans; (ii) Define plausible mechanisms that explain association of MN with each disease; (iii) Identify knowledge gaps and research needed to translate MN assays into clinical practice. The "MN and Disease" SI includes 14 papers. The first is a review of mechanisms of MN formation and their consequences in humans.

Micronuclei, reproduction and child health.

The current review looks for relationships between results from biomarker studies with micronucleus and health effects related to reproduction and children. In adults, an age related increase in MN is well known as well as associations with environmental exposures especially air pollution from traffic and smoking. Literature searches in PubMED and SCOPUS were performed with the following keywords reproduction, children, micronuclei, health effects.

Micronuclei, inflammation and auto-immune disease.

Auto-immune diseases (AUD) are characterized by an immune response to antigenic components of the host itself. The etiology of AUD is not well understood. The available evidence points to an interaction between genetic, epigenetic, environmental, infectious and life-style factors.

Micronuclei as biomarkers of DNA damage, aneuploidy, inducers of chromosomal hypermutation and as sources of pro-inflammatory DNA in humans.

Micronuclei (MNi) are among the most widely studied biomarkers of DNA damage and chromosomal instability in humans. They originate from chromosome fragments or intact chromosomes that are not included in daughter nuclei during mitosis. The main reasons for their formation are a lack of functional centromere in the chromosome fragments or whole chromosomes or defects in one or more of the proteins of the mitotic system that, consequently, fails to segregate chromosomes properly.

Micronuclei and disease - Report of HUMN project workshop at Rennes 2019 EEMGS conference.

The "Micronuclei and Disease" workshop was organized by the HUMN Project consortium and hosted by the European Environmental Mutagen and Genomics Society at their annual meeting in Rennes, France, on 23 May 2019. The program of the workshop focused on addressing the emerging evidence linking micronucleus (MN) frequency to human disease. The first objective was to review what has been published and evaluate the level and quality of evidence for the connection between MN frequency and various diseases through all life stages.

50 years existence and active participation of EEMS (now EEMGS) in the scientific community: A driver of European and international scientific collaborations for the protection of the environment and human health from genome stressors.

EEMS and its successor Society EEMGS have provided a dynamic and successful platform to stimulate research and exchanges among the different actors involved in the protection of the environment and of human health from exposure to genome stressors. It includes basic, translational and applied research projects. This was possible due to the enthusiasm, creativity and support of scientists convinced of the importance of these issues.

Chemically induced aneuploidy in germ cells. Part II of the report of the 2017 IWGT workgroup on assessing the risk of aneugens for carcinogenesis and hereditary diseases.

As part of the 7th International Workshops on Genotoxicity Testing held in Tokyo, Japan in November 2017, a workgroup of experts reviewed and assessed the risk of aneugens for human health. The present manuscript is one of three manuscripts from the workgroup and reports on the unanimous consensus reached on the evidence for aneugens affecting germ cells, their mechanisms of action and role in hereditary diseases. There are 24 chemicals with strong or sufficient evidence for germ cell aneugenicity providing robust support for the ability of chemicals to induce germ cell aneuploidy.

Role of aneuploidy in the carcinogenic process: Part 3 of the report of the 2017 IWGT workgroup on assessing the risk of aneugens for carcinogenesis and hereditary diseases.

Aneuploidy is regarded as a hallmark of cancer, however, its role is complex with both pro- and anti-carcinogenic effects evident. In this IWGT review, we consider the role of aneuploidy in cancer biology; cancer risk associated with constitutive aneuploidy; rodent carcinogenesis with known chemical aneugens; and chemotherapy-related malignant neoplasms. Aneuploidy is seen at various stages in carcinogenesis.

Targets and mechanisms of chemically induced aneuploidy. Part 1 of the report of the 2017 IWGT workgroup on assessing the risk of aneugens for carcinogenesis and hereditary diseases.

An aneuploidy workgroup was established as part of the 7th International Workshops on Genotoxicity Testing. The workgroup conducted a review of the scientific literature on the biological mechanisms of aneuploidy in mammalian cells and methods used to detect chemical aneugens. In addition, the current regulatory framework was discussed, with the objective to arrive at consensus statements on the ramifications of exposure to chemical aneugens for human health risk assessment.

Risks of aneuploidy induction from chemical exposure: Twenty years of collaborative research in Europe from basic science to regulatory implications.

Although Theodor Boveri linked abnormal chromosome numbers and disease more than a century ago, an in-depth understanding of the impact of mitotic and meiotic chromosome segregation errors on cell proliferation and diseases is still lacking. This review reflects on the efforts and results of a large European research network that, from the 1980's until 2004, focused on protection against aneuploidy-inducing factors and tackled the following problems: 1) the origin and consequences of chromosome imbalance in somatic and germ cells; 2) aneuploidy as a result of environmental factors; 3) dose-effect relationships; 4) the need for validated assays to identify aneugenic factors and classify them according to their modes of action; 5) the need for reliable, quantitative data suitable for regulating exposure and preventing aneuploidy induction; 6) the need for mechanistic insight into the consequences of aneuploidy for human health. This activity brought together a consortium of experts from basic science and applied genetic toxicology to prepare the basis for defining guidelines and to encourage regulatory activities for the prevention of induced aneuploidy.

Validity of the Lymphocyte Cytokinesis-Block Micronucleus Assay (L-CBMN) as biomarker for human exposure to chemicals with different modes of action: A synthesis of systematic reviews.

Recently fourteen systematic reviews applying the same selection and evaluation criteria analyzed the induction of micronuclei in lymphocytes as biomarker for DNA damage induced by human exposure to a given chemical or chemical mixture. The results obtained in the individual reviews were summarized to evaluate the validity of the Cytokinesis-Block-Micronucleus assay in lymphocytes (L-CBMN) and propose recommendations for its use in occupational and environmental exposure studies. All systematic reviews found consistent increases of MN frequencies in exposed subjects versus controls in all genotoxic compounds or group of chemicals investigated, in the following decreasing order: As/Cr/Ni, vinyl chloride, formaldehyde, Hg/Pb/Cd, "miscellaneous", pesticides, cytostatics/antineoplastics, anaesthetic gasses, dust/asbestos/other fibers, polycyclic aromatic hydrocarbons, ethylene oxide, butadiene, styrene and petroleum/derivatives.

The lymphocyte cytokinesis block micronucleus test in human populations occupationally exposed to vinyl chloride: A systematic review and meta-analysis.

Vinyl chloride (VC) is widely used in industry in the production of polyvinyl chloride (PVC), which is used to manufacture a large variety of materials. VC was classified as a known (Group 1) human carcinogen by IARC on the basis of increased risk for liver angiosarcoma and hepatocellular cancer, and the carcinogenicity of VC was shown to be mediated by a genotoxic mechanism. Following inhalation, the compound is rapidly absorbed and metabolized in the liver to the electrophilic metabolites chloroethylene-oxide and chloroacetaldehyde, which form DNA adducts that can be processed into point mutations in cancer-related genes detected in humans and rats exposed to VC.

Epigenetic memory in response to environmental stressors.

Exposure to environmental stressors, toxicants, and nutrient deficiencies can affect DNA in several ways. Some exposures cause damage and alter the structure of DNA, but there is increasing evidence that the same or other environmental exposures, including those that occur during fetal development , can cause epigenetic effects that modulate DNA function and gene expression. Some epigenetic changes to DNA that affect gene transcription are at least partially reversible ( they can be enzymatically reversed after cessation of exposure to environmental agents), but some epigenetic modifications seem to persist, even for decades.

The ex vivo L-CBMN assay detects significant human exposure to butadiene.

1,3-Butadiene (BD), an important industrial chemical used in the production of synthetic rubber and resins and a ubiquitous environmental pollutant, was classified as a human carcinogen by IARC. BD requires metabolic activation to different epoxides that are known to bind to DNA, inducing also DNA-DNA and DNA-protein crosslinks. The DNA damage leading to mutations has been identified as the mode of action of BD.

Reprint of "Biomonitoring of genotoxic effects for human exposure to nanomaterials: The challenge ahead".

Exposures to nanomaterials (NMs), with their specific physico-chemical characteristics, are likely to increase over the next years, as their production for industrial, consumer and medical applications is steadily rising. Therefore, there is an urgent need for the implementation of human biomonitoring studies of genotoxic effects after NM exposures in order to monitor and assure safety for workers and the general population. In this review, most commonly used biomarkers of early genetic effects were analyzed for their adequacy after NM exposures.

Molecular mechanisms by which in vivo exposure to exogenous chemical genotoxic agents can lead to micronucleus formation in lymphocytes in vivo and ex vivo in humans.

The purpose of this review is to summarise current knowledge on the molecular mechanisms by which in vivo exposure to exogenous chemical genotoxins in humans induces micronuclei (MNi) and other nuclear anomalies in lymphocytes in vivo and ex vivo after nuclear division in vitro. MNi originate from acentric chromosome fragments and/or whole chromosomes that are unable to engage with the mitotic spindle and/or fail to segregate properly to the daughter nuclei during anaphase. The lagging fragments or whole chromosomes are surrounded by membrane and become MNi.

Towards a New Paradigm in Nano-Genotoxicology: Facing Complexity of Nanomaterials' Cellular Interactions and Effects.

Changes in paradigm contribute to advances in research. The current paradigms for the evaluation of toxicity of chemicals refer to linear or curvilinear dose-response curves with or without threshold and to surface-dependent induction of oxidative damage for particles. The unique physicochemical properties and biological/genotoxic activity of engineered nanomaterials (NMs) require the development of a new paradigm.

Maternal diet during pregnancy and micronuclei frequency in peripheral blood T lymphocytes in mothers and newborns (Rhea cohort, Crete).

Purpose: The study assessed whether diet and adherence to cancer prevention guidelines during pregnancy were associated with micronucleus (MN) frequency in mothers and newborns. MN is biomarkers of early genetic effects that have been associated with cancer risk in adults.

Methods: A total of 188 mothers and 200 newborns from the Rhea cohort (Greece) were included in the study.

Vitamin D insufficient levels during pregnancy and micronuclei frequency in peripheral blood T lymphocytes mothers and newborns (Rhea cohort, Crete).

Background & Aims: Vitamin D deficiency is common among pregnant women and may be associated with several adverse health outcomes including cancer. Micronuclei frequency is a biomarker of early genetic effects and has been used to examine the association between genotoxic exposures and cancer. We examined maternal vitamin D levels during pregnancy in associations with micronuclei frequency in maternal blood and in cord blood.

Biomonitoring of genotoxic effects for human exposure to nanomaterials: The challenge ahead.

Exposures to nanomaterials (NMs), with their specific physico-chemical characteristics, are likely to increase over the next years, as their production for industrial, consumer and medical applications is steadily rising. Therefore, there is an urgent need for the implementation of human biomonitoring studies of genotoxic effects after NM exposures in order to monitor and assure safety for workers and the general population. In this review, most commonly used biomarkers of early genetic effects were analyzed for their adequacy after NM exposures.