Computational modeling reveals key molecular properties and dynamic behavior of disruptor of telomeric silencing 1-like (DOT1L) and partnering complexes involved in leukemogenesis.

Disruptor of telomeric silencing 1-like (DOT1L) is the only non-SET domain histone lysine methyltransferase (KMT) and writer of H3K79 methylation on nucleosomes marked by H2B ubiquitination. DOT1L has elicited significant attention because of its interaction or fusion with members of the AF protein family in blood cell biology and leukemogenic transformation. Here, our goal was to extend previous structural information by performing a robust molecular dynamic study of DOT1L and its leukemogenic partners combined with mutational analysis. We show that statically and dynamically, D161, G163, E186, and F223 make frequent time-dependent interactions with SAM, while additional residues T139, K187, and N241 interact with SAM only under dynamics. Dynamics models reveal DOT1L, SAM, and H4 moving as one and show that more than twice the number of DOT1L residues interacts with these partners, relative to the static structure. Mutational analyses indicate that six of these residues are intolerant to substitution. We describe the dynamic behavior of DOT1L interacting with AF10 and AF9. Studies on the dynamics of a heterotrimeric complex of DOT1L1-AF10 illuminated describe coordinated motions that impact the relative position of the DOT1L HMT domain to the nucleosome. The molecular motions of the DOT1L-AF9 complex are less extensive and highly dynamic, resembling a swivel-like mechanics. Through molecular dynamics and mutational analysis, we extend the knowledge previous provided by static measurements. These results are important to consider when describing the biochemical properties of DOT1L, under normal and in disease conditions, as well as for the development of novel therapeutic agents.

Sterol regulation of developmental and oncogenic Hedgehog signaling.

The Hedgehog (Hh) family of lipid-modified signaling proteins directs embryonic tissue patterning and postembryonic tissue homeostasis, and dysregulated Hh signaling drives familial and sporadic cancers. Hh ligands bind to and inhibit the tumor suppressor Patched and allow the oncoprotein Smoothened (SMO) to accumulate in cilia, which in turn activates the GLI family of transcription factors. Recent work has demonstrated that endogenous cholesterol and oxidized cholesterol derivatives (oxysterols) bind and modulate SMO activity. Here we discuss the myriad sterols that activate or inhibit the Hh pathway, with emphasis on endogenous 24(S),25-epoxycholesterol and 3ß,5α-dihydroxycholest-7-en-6-one, and propose models of sterol regulation of SMO. Synthetic inhibitors of SMO have long been the focus of drug development efforts. Here, we discuss the possible utility of steroidal SMO ligands or inhibitors of enzymes involved in sterol metabolism as cancer therapeutics.

Environmental Carcinogenesis at the Single-Cell Level.

Elucidating the mechanisms behind how exposure to environmental chemicals can lead to cancer is not easy due to the complex natures of these compounds and the challenges to establish biologically relevant experimental models to study them. Environmental chemicals often present selective mechanisms of action on different cell types and can be involved in the modulation of targeted cells and their microenvironment, including immune cells. Currently, the limitations of traditional epidemiologic correlation analyses, in vitro cell-based assays, and animal models are that they are unable to comprehensively examine cellular heterogeneity and the tissue-selective influences. To this end, we propose utilizing single-cell RNA-sequencing (scRNA-seq) to more effectively capture the subtle and complex effects of environmental chemicals and how their exposure could lead to cancer. scRNA-seq's capabilities for studying gene expression level data at a significantly higher resolution relative to bulk RNA-sequencing (RNA-seq) enable studies to evaluate how environmental chemicals regulate gene transcription on different cell types as well as how these compounds impact signaling pathways and interactions between cells in the tissue microenvironment. These studies will be valuable for evaluating environmental chemicals' carcinogenic properties at the individual cell level.See all articles in this CEBP Focus section, "Environmental Carcinogenesis: Pathways to Prevention."

Lycopene enriched tomato extract suppresses chemically induced skin tumorigenesis in mice.

The present study revealed the effects of Lycopene enriched tomato extract (LycT) on chemically induced skin cancer in mice. Skin tumors were induced by topical application of 7,12-Dimethylbenz(a)anthracene (DMBA) [500 nmol/100 ul of acetone, twice a week for two weeks] and 12-O-tetradecanoyl phorbol-13-acetate (TPA) [1.7 nmol/100 ul of acetone, twice a week for eighteen weeks] and LycT (5 mg/kg b.w.) was administered orally. Male Balb/c mice were divided into four groups (n = 15 per group): control, DMBA/TPA, LycT and LycT + DMBA/TPA. The chemopreventive response of LycT to skin tumorigenesis was evident by inhibition in tumor incidence, number, size, burden and volume in LycT + DMBA/TPA group when compared to DMBA/TPA group. This was associated with inhibition of cell proliferation in LycT + DMBA/TPA group as observed by the decrease in epidermal morphometric parameters and mRNA and protein expression of proliferating cell nuclear antigen when compared to DMBA/TPA group (p ≤ 0.05). LycT decreased (p ≤ 0.05) the mRNA and protein expression of angiogenic genes (vascular endothelial growth factor, angiopoietin-2, basic fibroblast growth factor) in LycT + DMBA/TPA group, suggesting its anti-angiogenic effects. The increase (p ≤ 0.05) in protein expression of connexin-32 and 43 in LycT + DMBA/TPA group suggests improved inter cellular communication when compared to DMBA/TPA group. Histochemical studies demonstrated that the components of extracellular matrix (fibrous proteins and mucopolysaccharides) were also modulated during skin carcinogenesis and its chemoprevention by LycT. The decrease in cell proliferation parameters and expression of angiogenesis associated genes, modulation of ECM components and increase in expression of connexins suggest that LycT improved multiple dysregulated processes during chemoprevention of skin cancer.

The Yin-Yang Regulation of Reactive Oxygen Species and MicroRNAs in Cancer.

Reactive oxygen species (ROS) are highly reactive oxygen-containing chemical species formed as a by-product of normal aerobic respiration and also from a number of other cellular enzymatic reactions. ROS function as key mediators of cellular signaling pathways involved in proliferation, survival, apoptosis, and immune response. However, elevated and sustained ROS production promotes tumor initiation by inducing DNA damage or mutation and activates oncogenic signaling pathways to promote cancer progression. Recent studies have shown that ROS can facilitate carcinogenesis by controlling microRNA (miRNA) expression through regulating miRNA biogenesis, transcription, and epigenetic modifications. Likewise, miRNAs have been shown to control cellular ROS homeostasis by regulating the expression of proteins involved in ROS production and elimination. In this review, we summarized the significance of ROS in cancer initiation, progression, and the regulatory crosstalk between ROS and miRNAs in cancer.

An Electrochemical DNA Biosensor for Carcinogenicity of Anticancer Compounds Based on Competition between Methylene Blue and Oligonucleotides.

A toxicity electrochemical DNA biosensor has been constructed for the detection of carcinogens using 24 base guanine DNA rich single stranded DNA, and methylene blue (MB) as the electroactive indicator. This amine terminated ssDNA was immobilized onto silica nanospheres and deposited on gold nanoparticle modified carbon-paste screen printed electrodes (SPEs). The modified SPE was initially exposed to a carcinogen, followed by immersion in methylene blue for an optimized duration. The biosensor response was measured using differential pulse voltammetry. The performance of the biosensor was identified on several anti-cancer compounds. The toxicity DNA biosensor demonstrated a linear response range to the cadmium chloride from 0.0005 ppm to 0.01 ppm (R2 = 0.928) with a limit of detection at 0.0004 ppm. The biosensor also exhibited its versatility to screen the carcinogenicity of potential anti-cancer compounds.

KDM2B in polycomb repressive complex 1.1 functions as a tumor suppressor in the initiation of T-cell leukemogenesis.

KDM2B together with RING1B, PCGF1, and BCOR or BCORL1 comprise polycomb repressive complex 1.1 (PRC1.1), a noncanonical PRC1 that catalyzes H2AK119ub1. It binds to nonmethylated CpG islands through its zinc finger-CxxC DNA binding domain and recruits the complex to target gene loci. Recent studies identified the loss of function mutations in the PRC1.1 gene, BCOR and BCORL1 in human T-cell acute lymphoblastic leukemia (T-ALL). We previously reported that Bcor insufficiency induces T-ALL in mice, supporting a tumor suppressor role for BCOR. However, the function of BCOR responsible for tumor suppression, either its corepressor function for BCL6 or that as a component of PRC1.1, remains unclear. We herein examined mice specifically lacking the zinc finger-CxxC domain of KDM2B in hematopoietic cells. Similar to Bcor-deficient mice, Kdm2b-deficient mice developed lethal T-ALL mostly in a NOTCH1-dependent manner. A chromatin immunoprecipitation sequence analysis of thymocytes revealed the binding of KDM2B at promoter regions, at which BCOR and EZH2 colocalized. KDM2B target genes markedly overlapped with those of NOTCH1 in human T-ALL cells, suggesting that noncanonical PRC1.1 antagonizes NOTCH1-mediated gene activation. KDM2B target genes were expressed at higher levels than the others and were marked with high levels of H2AK119ub1 and H3K4me3, but low levels of H3K27me3, suggesting that KDM2B target genes are transcriptionally active or primed for activation. These results indicate that PRC1.1 plays a key role in restricting excessive transcriptional activation by active NOTCH1, thereby acting as a tumor suppressor in the initiation of T-cell leukemogenesis.

Catalytic and Signaling Role of Peroxiredoxins in Carcinogenesis.

Cancer cells experience strong oxidative stress caused by disorders in cell metabolism and action of external factors. For survival, cancer cells have developed a highly efficient system of antioxidant defense, some of the most important elements of which are peroxiredoxins (Prxs). Prxs are an evolutionarily ancient family of selenium-independent peroxidases that reduce a wide range of organic and inorganic hydroperoxides in the cell and the extracellular space. In addition, some Prxs exhibit chaperone and phospholipase activities. Prxs play an important role in the maintenance of the cell redox homeostasis; they prevent oxidation and aggregation of regulatory proteins, thereby affecting many cell signaling pathways. Prxs are involved in the regulation of cell growth, differentiation, and apoptosis. Due to their versatility and wide representation in all tissues and organs, Prxs participate in the development/suppression of many pathological conditions, among which cancer occupies a special place. This review focuses on the role of Prxs in the development of various forms of cancer. Understanding molecular mechanisms of Prx involvement in these processes will allow to develop new approaches to the prevention and treatment of cancer.

Iron-dependent CDK1 activity promotes lung carcinogenesis via activation of the GP130/STAT3 signaling pathway.

Iron dysregulation is associated with several diseases, including lung cancer, but the underlying mechanism is yet unknown. Iron directly binds CDK1, which is upregulated in several cancers, thereby promoting JAK1 phosphorylation and activation of STAT3 signaling to promote colorectal carcinogenesis. This study aimed to investigate the role of iron/CDK1/STAT3 signaling in lung carcinogenesis. We found that iron-dependent CDK1 activity upregulated IL-6 receptor subunit GP130 post-transcriptionally via phosphorylation of 4E-BP1, which is critical for activation of JAK/STAT3 signaling. CDK1 and STAT3 are essential for iron-mediated colony formation in lung cancer cell lines. CDK1 knockdown and iron chelator DFO decreased tumorigenicity and GP130/STAT3 signaling in vivo. Moreover, CDK1/GP130/STAT3 signaling were elevated in lung cancer tissues compared with adjacent normal lung tissues. Altogether, the present results suggest that CDK1 inhibition and iron deprivation are potential strategies to target GP130/STAT3 signaling to suppress lung cancer.

Participation of selenoproteins localized in the ER in the processes occurring in this organelle and in the regulation of carcinogenesis-associated processes.

The functions performed by the ER are diverse: synthesis of steroid hormones, synthesis of proteins for the plasma membrane, lysosomes, as well as proteins meant for exocytosis, protein folding, formation of disulfide bonds, N-linked glycosylation, etc. Selenoproteins localized in this organelle are definitely involved in the processes occurring in it, and the most common of them include participation in protein degradation, regulation of ER stress and redox metabolism. ER stress has been registered in many types of cancer cells. The ability to persist under prolonged ER stress increases their survival, resistance to drugs and immunity. Disturbances in the redox regulation of the cell cycle, which result in the accumulation of misfolded proteins in the ER, viral infection, disruption of Ca2+ regulation, are known to cause an evolutionarily conserved reaction - unfolded protein response (UPR) and, ultimately, lead to ER stress. Since selenoproteins, as oxidoreductases, possess antioxidant properties, and their role in the regulation of important processes, such as carcinogenesis and ER stress, has been actively studied in the recent decades, the subject of this review is highly relevant.

Multiproteomic and Transcriptomic Analysis of Oncogenic ß-Catenin Molecular Networks.

The dysregulation of Wnt signaling is a frequent occurrence in many different cancers. Oncogenic mutations of CTNNB1/ß-catenin, the key nuclear effector of canonical Wnt signaling, lead to the accumulation and stabilization of ß-catenin protein with diverse effects in cancer cells. Although the transcriptional response to Wnt/ß-catenin signaling activation has been widely studied, an integrated understanding of the effects of oncogenic ß-catenin on molecular networks is lacking. We used affinity-purification mass spectrometry (AP-MS), label-free liquid chromatography-tandem mass spectrometry, and RNA-Seq to compare protein-protein interactions, protein expression, and gene expression in colorectal cancer cells expressing mutant (oncogenic) or wild-type ß-catenin. We generate an integrated molecular network and use it to identify novel protein modules that are associated with mutant or wild-type ß-catenin. We identify a DNA methyltransferase I associated subnetwork that is enriched in cells with mutant ß-catenin and a subnetwork enriched in wild-type cells associated with the CDKN2A tumor suppressor, linking these processes to the transformation of colorectal cancer cells through oncogenic ß-catenin signaling. In summary, multiomics analysis of a defined colorectal cancer cell model provides a significantly more comprehensive identification of functional molecular networks associated with oncogenic ß-catenin signaling.

Single-cell bioluminescence imaging of deep tissue in freely moving animals.

Bioluminescence is a natural light source based on luciferase catalysis of its substrate luciferin. We performed directed evolution on firefly luciferase using a red-shifted and highly deliverable luciferin analog to establish AkaBLI, an all-engineered bioluminescence in vivo imaging system. AkaBLI produced emissions in vivo that were brighter by a factor of 100 to 1000 than conventional systems, allowing noninvasive visualization of single cells deep inside freely moving animals. Single tumorigenic cells trapped in the mouse lung vasculature could be visualized. In the mouse brain, genetic labeling with neural activity sensors allowed tracking of small clusters of hippocampal neurons activated by novel environments. In a marmoset, we recorded video-rate bioluminescence from neurons in the striatum, a deep brain area, for more than 1 year. AkaBLI is therefore a bioengineered light source to spur unprecedented scientific, medical, and industrial applications.

A new enzyme immunoassay for the determination of highly sialylated and fucosylated human α1-acid glycoprotein as a biomarker of tumorigenesis.

BACKGROUND: Upon initiation and progression of cancer, α1-acid glycoprotein (AGP) possessing highly sialylated and fucosylated glycans appears in the serum, and recently has attracted a great deal of attention, as a potential biomarker of tumorigenesis in humans. METHODS: To establish a rapid and precise method for the quantitative assay of fucosylated AGP in serum samples, we developed an enzyme immunoassay (EIA) bearing an anti-AGP antibody and a fucose-binding lectin, Aleuria aurantia (AAL) with additional endeavor to improved sample handling, and antibody preparations. RESULTS: The amounts of fucosylated AGP could be determined by the present method with a good performance feature in all tested samples from both cancer patients and healthy controls. From cancer patients under chemotherapy we show that fucosylated AGP could be a clinically relevant biomarker for cancer progression or prognosis as well as for an early assessment of clinical response and treatment outcomes. Furthermore, in a different setting, fucosylated AGP also showed relevance in patients who received immunotherapy with an anti-programmed cell death-1 (PD-1) antibody. CONCLUSIONS: α1,3fucosylated AGP is a potential biomarker of cancer initiation, progression and response to treatment in cancer patients.

Tracing overlapping biological signals in mid-infrared using colonic tissues as a model system.

AIM: To understand the interference of carbohydrates absorbance in nucleic acids signals during diagnosis of malignancy using Fourier transform infrared (FTIR) spectroscopy. METHODS: We used formalin fixed paraffin embedded colonic tissues to obtain infrared (IR) spectra in the mid IR region using a bruker II IR microscope with a facility for varying the measurement area by varying the aperture available. Following this procedure we could measure different regions of the crypt circles containing different biochemicals. Crypts from 18 patients were measured. Circular crypts with a maximum diameter of 120 µm and a lumen of about 30 µm were selected for uniformity. The spectral data was analyzed using conventional and advanced computational methods. RESULTS: Among the various components that are observed to contribute to the diagnostic capabilities of FTIR, the carbohydrates and nucleic acids are prominent. However there are intrinsic difficulties in the diagnostic capabilities due to the overlap of major absorbance bands of nucleic acids, carbohydrates and phospholipids in the mid-IR region. The result demonstrates colonic tissues as a biological system suitable for studying interference of carbohydrates and nucleic acids under ex vivo conditions. Among the diagnostic parameters that are affected by the absorbance from nucleic acids is the RNA/DNA ratio, dependent on absorbance at 1121 cm-1 and 1020 cm-1 that is used to classify the normal and cancerous tissues especially during FTIR based diagnosis of colonic malignancies. The signals of the nucleic acids and the ratio (RNA/DNA) are likely increased due to disappearance of interfering components like carbohydrates and phosphates along with an increase in amount of RNA. CONCLUSION: The present work, proposes one mechanism for the observed changes in the nucleic acid absorbance in mid-IR during disease progression (carcinogenesis).

[Expression of CD10 in tumor-associated fibroblast of cancerized or recurrent colorectal adenomas].

Objective: To investigate the expression of CD10 in tumor-associated fibroblasts (TAF) in colorectal adenomas and its relation to cancerization and recurrence of adenoma. Methods: Tissue samples of low-grade adenoma (n=50), high-grade adenoma (n=50) and colorectal adenocarcinoma (n=50) were collected, and tissue samples at the distal margin of corresponding colorectal lesions were taken as controls. The expression of CD10 in the stromal TAFs, and the expressions of ß-catenin, Ki-67, p53 and CyclinD1 in tumor cells were detected by immunohistochemistry (Envision). The correlation of CD10 expression in stromal TAFs with the expressions of ß-catenin, Ki-67, p53 and CyclinD1 in tumor cells was analyzed by Spearmen. One hundred samples of low-grade colorectal adenoma were collected, including 57 non-recurrent cases and 43 recurrent cases (16 cases of recurrent adenoma and 27 cases of recurrent adenocarcinoma); the expression of stromal TAF CD10 were determined and compared among groups. Results: There was no TAF in normal colorectal mucosa. The expression rates of TAF CD10 in low-grade adenoma, high-grade adenoma and colorectal adenocarcinoma were 22%, 50% and 78%, respectively (all P<0.05). The expression of Ki-67 and ß-catenin in low-grade adenoma, high-grade adenoma, colorectal adenocarcinoma was on a rising trend (all P<0.01). The expression of CyclinD1 in high-grade adenoma was higher than that in colorectal adenocarcinoma and low-grade adenoma (all P>0.05). The expression of p53 in colorectal adenocarcinoma and high-grade adenoma was higher than that in low grade adenoma (all P<0.01). The expression of TAF CD10 was correlated with the expression of p53, Ki-67 and ß-catenin-nucleus(r=0.264、0.307、0.320, all P<0.01),but not correlated with CyclinD1 and ß-catenin-membrane (r=0.012、-0.073, all P>0.05). The TAF CD10 level was significantly higher in low-grade adenoma with recurrence than that in those without recurrence (P<0.05).The expression of CD10 in recurrent colorectal adenocarcinoma was higher than that in recurrent adenoma (P<0.05). Conclusion: The expression of TAF CD10 is increased gradually in the process of adenoma-cancer, indicating that it may play an important role in the canceration of adenoma. Adenomas with high expression of CD10 TAF are likely to be recurrent and cancerized, and detection of TAF CD10 combined with p53, Ki-67 and ß-catenin may be of value in predicting canceration or recurrence of colorectal adenoma.

Characterization of the Translationally Controlled Tumor Protein (TCTP) Interactome Reveals Novel Binding Partners in Human Cancer Cells.

Translationally controlled tumor protein (TCTP) is a highly conserved housekeeping protein present in eukaryotic organisms. It is involved in regulating many fundamental processes and plays a critical role in tumor reversion and tumorigenesis. Increasing evidence suggests that TCTP plays a role in the regulation of cell fate determination and is a promising therapeutic target for cancer. To decipher the exact mechanisms by which TCTP functions and how all these functions are integrated, we analyzed the interactome of TCTP in HeLa cells by coimmunoprecipitation (IP) and mass spectrometry (MS). A total of 98 proteins were identified. We confirmed the in vitro and in vivo association of TCTP with six of the identified binding proteins using reciprocal IP and bimolecular fluorescence complementation (BiFC) analysis, respectively. Moreover, TCTP interacted with Y-box-binding protein 1 (YBX1), and their interaction was localized to the N-terminal region of TCTP and the 1-129 amino acid (aa) residues of YBX1. The YBX1 protein plays an important role in cell proliferation, RNA splicing, DNA repair, drug resistance, and stress response to extracellular signals. These data suggest that the interaction of TCTP with YBX1 might cooperate or coordinate their functions in the control of diverse regulatory pathways in cancer cells. Taken together, our results not only reveal a large number of TCTP-associated proteins that possess pleiotropic functions, but also provide novel insights into the molecular mechanisms of TCTP in tumorigenesis.

Endoplasmic Reticulum Chaperones Are Potential Active Factors in Thyroid Tumorigenesis.

The study aimed to evaluate the proteomic changes in benign follicular adenoma versus malignant follicular variant of papillary thyroid carcinoma. Tumor and nontumor adjacent samples were analyzed by liquid nanochromatography mass spectrometry, and protein abundance was evaluated by label-free quantification. Western blotting and quantitative real-time polymerase chain reaction were used to validate and complement the mass spectrometry data. The results demonstrated deregulated expression of four endoplasmic reticulum chaperones (78 kDa glucose-regulated protein, endoplasmin, calnexin, protein disulfide-isomerase A4), glutathione peroxidase 3 and thyroglobulin, all of them involved in thyroid hormone synthesis pathway. The altered tissue abundance of endoplasmic reticulum chaperones in thyroid cancer was correlated with serum expression levels. The identified proteins significantly discriminate between adenoma and carcinoma in both thyroid tissue and corresponding sera. Data are available via ProteomeXchange with identifier PXD004322.

A review of experimental models in colorectal carcinogenesis / Modelos experimentais de carcinogênese colorretal

Colorectal cancer is the leading cause of malignancy of the gastrointestinal tract. A better understanding of the molecular and cellular changes that lead to the disease is necessary to develop early diagnosis and optimal treatment modalities. Rodent models are rapid, reproducible and exhibit an adenoma-carcinoma sequence similar to that found in humans. The objective of this manuscript is to review the most common chemical carcinogens used to induce experimental tumors and the usual methods of evaluation.

O câncer colorretal é a principal neoplasia maligna do trato gastrointestinal. Um melhor entendimento dos processos moleculares e celulares é necessário para o desenvolvimento de estratégias que permitam um diagnóstico precoce e um tratamento mais eficaz. Modelos que utilizam roedores são rápidos, reprodutíveis e permitem o estudo da sequencia adenoma-carcinoma de forma similar a encontrada em humanos. O objetivo desse manuscrito é revisar os principais modelos de carcinogênese química e os métodos mais usuais para avaliação dos resultados.

Genotoxicidad de los nanomateriales, grandes discrepancias y desafíos / Genotoxicity of nanomaterials, discrepancies and challenges

La nanotecnología es el estudio, diseño, creación, síntesis, manipulación y aplicación de materiales a través del control de la materia a escala nanométrica, entre 1 a 100 nanómetros. Se considera que la nanoteconología está revolucionando nuestro mundo. Los nanomateriales son ampliamente utilizados en diferentes campos por sus propiedades únicas pero también pueden causar efectos adversos tanto para la salud humana como para el ambiente, por lo que es necesario conocer los riesgos y los factores que incrementan estos efectos adversos. En esta revisión abordamos los nanomateriales y sus tipos, los aspectos tóxicos con énfasis en el efecto genotóxico, ya que por sus implicaciones de daños en el ADN pueden iniciar y promover la carcinogénesis, o afectar la fertilidad, ciertas consideraciones que deben tomarse en cuenta en el momento de la evaluación genotóxica de los NMs. Aunque existe cierta evidencia de alteraciones al exponer las células a los nanomateriales, todavía existen deficiencias e inconsistencias en la literatura y en las normativas para conocer las características físico-químicas de los nanomateriales, cómo actúan, y sus posibles cambios con el tiempo (AU)

Nanotechnology is the study, design, creation, synthesis, manipulation and application of materials through the control of matter at the nanometer scale, between 1-100 nanometers. Nanotechnology is revolutionizing our world. Nanomaterials are widely used in various fields thanks to their unique properties. However, nanomaterials can also result in adverse health effects and the environment, it is necessary to know the risks and factors that increase these effects. In this review we focus on nanomaterials and their types, the toxic aspects of nanoparticles; with emphasis on the genotoxic effects and DNA damage that can initiate or promote carcinogenesis or affect fertility as well as the guidelines for the application of genotoxicity tests. Although there is some evidence of changes that occur when cells are exposed to nanomaterials, there is still a dearth of consistent results in the literature and in regulatory documents in terms of physicochemical characteristics of nanomaterials, their mechanisms, and exposure (AU)