Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

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Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: The challenge ahead

The cell cycle inhibitor p21CDKN1A is a protein playing multiple roles not only in the DNA damage response, but also in many cellular processes during unperturbed cell growth. The main, well-known function of p21 is to arrest cell cycle progression by inhibiting the activity of cyclin-dependent kinases. In addition, p21 is involved in the regulation of transcription, apoptosis, DNA repair, as well as cell motility. However, p21 appears to a have a dual-face behavior because, in addition to its tumor suppressor functions, it may act as an oncogene, depending on the cell type and on the cellular localization. As a biomarker of the cell response to different toxic stimuli, p21 expression and functions have been analyzed in an impressive number of studies investigating the activity of several types of chemicals, in order to determine their possible harmful effects on human cells. Here, we review these studies in order to highlight the different roles p21 may play in the cell response to chemical exposure and to better evaluate the information provided by this biomarker.

Biology of the cell cycle inhibitor p21(CDKN1A): molecular mechanisms and relevance in chemical toxicology.

Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis.

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Causes of genome instability: the effect of low dose chemical exposures in modern society

Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis.

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The effect of environmental chemicals on the tumor microenvironment.

Aronia melanocarpa berries (chokeberries) constitute a very rich source of numerous substances exerting a beneficial impact on health, including mainly polyphenols (proanthocyanidins, anthocyanins, flavonoids, and phenolic acids), possessing antioxidative, anti-inflammatory, antiviral, anticancer, antiatherosclerotic, hypotensive, antiplatelet, and antidiabetic properties. Thus, the consumption of products made from chokeberries is of vital importance for health maintenance and protection. Nowadays, due to the growing prevalence of noncommunicable diseases and ubiquitous human exposure to numerous man-made and naturally occurring toxic substances, some of which are dangerous even at low amounts, it is very important to look for effective means of health protection. An important role in this regard may be played by A. melanocarpa berries; however, up to now the attention of scientists, nutritionists, and health practitioners has been focused mainly on the effectiveness of chokeberry products in the prevention and treatment of noncommunicable diseases, while only little attention has been paid to the possibility of their use to counteract the adverse health effects of exposure to xenobiotics. That is why in this review article the main interest has been focused on the possibility of using chokeberries in the protection against unfavorable health effects caused by the action of substances to which humans may be exposed environmentally and/or occupationally. The available experimental data indicate that not only the fruit but also the leaves of A. melanocarpa and their products may be effective means for prevention and treatment of the effects of toxic action of some xenobiotics in humans; however, further studies on this subject are necessary.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/1541-4337.12221

Chokeberries (Aronia melanocarpa) and Their Products as a Possible Means for the Prevention and Treatment of Noncommunicable Diseases and Unfavorable Health Effects Due to Exposure to Xenobiotics.

Paraquat inhibits cell viability via enhanced oxidative stress and apoptosis in human neural progenitor cells.

Compelling evidences have shown that diverse environmental insults arising during early life can either directly lead to a reduction in the number of dopaminergic neurons or cause an increased susceptibility to neurons degeneration with subsequent environmental insults or with aging alone. Oxidative stress is considered the main effect of neurotoxins exposure. In this study, we investigated the oxidative stress effect of Paraquat (PQ) on immortalized human embryonic neural progenitor cells by treating them with various concentrations of PQ. We show that PQ can decrease the activity of SOD and CAT but increase MDA and LDH level. Furthermore, the activities of Cyc and caspase-9 were found increased significantly at 10 μM of PQ treatment. The cytoplasmic Nrf2 protein expressions were upregulated at 10 μM but fell back at 100 μM. The nuclear Nrf2 protein expressions were upregulated as well as the downstream mRNA expressions of HO-1 and NQO1 in a dose-dependent manner. In addition, the proteins expression of PKC and CKII was also increased significantly even at 1 μM. The results suggested that Nrf2/ARE pathway is involved in mild to moderate PQ-induced oxidative stress which is evident from dampened Nrf2 activity and low expression of antioxidant genes in PQ induced oxidative damage.

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Nrf2/ARE Pathway Involved in Oxidative Stress Induced by Paraquat in Human Neural Progenitor Cells.

Objective To investigate effects of paraquat on the mRNA expression of key elements of Notch signaling (Notch1,Jagged1 and DTX1) during differentiation process of human neural stem cells (hNSCs).Mathods hNSCs exposed to PQ at the concentrations 0.10,1.00,10.00 M.Cell proliferation ability was assessed using MTT assay and mRNA expressions of Notch1,Jagged1 and DTX1 were detected by Real-time RT-PCR at 2,4,8,12 d of differentiation.Results Compared with control group,NOTCH1,JAG1 mRNA expression levels exposed to PQ at the concentration of 0.10 M significantly reduced at 2,4,8 d and significantly went up at 12d (P＜0.01).Compared with control group,NOTCH1,JAG1 and DTX1 mRNA expression levels exposed to PQ at the concentration of 10.00 M significantly reduced at 2,8,12 d (P＜0.01).PQ could down-regulate Notch1,Jagged1 and DTX1 mRNA expressions at the early stage of differentiation,then up-regulate Notch1 mRNA expression,and down-regulate Notch1,Jagged1 and DTX1 mRNA expressions at the end of differentiation.Conclusion Notch signaling pathway may be involved in differentiation of neural stem cell exposed to PQ.

Key words: 
Human neural stem cell; Paraquat; Cell differentiation; Notch signaling pathway

Wen Lu

Papers

Paraquat inhibits cell viability via enhanced oxidative stress and apoptosis in human neural progenitor cells.

Nrf2/ARE Pathway Involved in Oxidative Stress Induced by Paraquat in Human Neural Progenitor Cells.

Paraquat involves differentiation of human neural stem cells via Notch signaling