Environmental pollutants-dependent molecular pathways and carcinogenesis

BioDiscovery 22: e29242 doi: 10.3897/biodiscovery.22.e29242 Review Article Environmental pollutants-dependent molecular pathways and carcinogenesis Myriam El Helou‡,§, Pascale A. Cohen§, Mona Diab-Assaf|, Sandra E. Ghayad‡ ‡ Department of Biology, Faculty of Science II, EDST, Lebanese University, Fanar, Lebanon § Univ Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, F-69008, Lyon, France | Department of Biochemistry, Faculty of Science II, EDST, Lebanese University, Fanar, Lebanon Corresponding author: Sandra E. Ghayad () Academic editor: Jean-Christophe Bourdon Received: 22 Aug 2018 | Accepted: 07 Feb 2019 | Published: 21 Feb 2019 Citation: El Helou M, Cohen P, Diab-Assaf M, Ghayad S (2019) Environmental pollutants-dependent molecular pathways and carcinogenesis. BioDiscovery 22: e29242. https://doi.org/10.3897/biodiscovery.22.e29242 Abstract Exposure to environmental pollutants can modulate many biological and molecular processes such as gene expression, gene repair mechanisms, hormone production and function and inflammation, resulting in adverse effects on human health including the occurrence and development of different types of cancer. Carcinogenesis is a complex and long process, taking place in multiple stages and is affected by multiple factors. Some environmental molecules are genotoxic, able to damage the DNA or to induce mutations and changes in gene expression acting as initiators of carcinogenesis. Other molecules called xenoestrogens can promote carcinogenesis by their mitogenic effects by possessing estrogenic-like activities and consequently acting as endocrine disruptors causing multiple alterations in cellular signal transduction pathways. In this review, we focus on recent research on environmental chemicals-driven molecular functions in human cancers. For this purpose, we will be discussing the case of two receptors in mediating environmental pollutants effects: the established nuclear receptor, the Aryl hydrocarbon receptor (AhR) and the emerging membrane receptor, G-protein coupled estrogen receptor 1 (GPER1). © El Helou M et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 2 El Helou M et al Keywords environmental pollutants, genotoxic, endocrine disruptors, GPER1, AhR, carcinogenesis 1. Environmental pollutants and cancer progression The environment presents all the elements that surround us (Schmidt 2012). In the environment, humans are exposed to pollutants in many ways, including orally, by inhalation or by the dermal route. Pollution of the environment is suspected to be one of the main causes of cancer (Parsa 2012). The process of carcinogenesis is mainly divided into three stages: initiation, promotion and progression. The initiation step follows a repeated exposure to “initiators” such as oxidative stress, chemical pollutants, virus and X-rays that increase the frequency of genetic mutations. The promotion step requires a non-mutagenic stimulus known as “promoters” such as chronic inflammation, estrogens and xenoestrogens (natural or chemical compounds that imitates estrogens) that promote proliferation of the initiated cells. The progression step comprises the expression of the malignant phenotype characterised by angiogenesis and metastasis (Liu et al. 2015). Exposure to environmental compounds may interfere at all stages of carcinogenesis, in particular at the initiation and promotion stages. Several studies have evaluated the association between widespread environmental pollutants and carcinogenesis. Indeed, epidemiological studies and in vitro approaches suggest that a great number of cancers could be induced via exposure to chemicals that humans are likely to encounter in their environment (Antwi et al. 2015, Boffetta 2006, Braun et al. 2016, Rochefort 2017, Rodgers et al. 2018, Wilde et al. 2018). The International Agency for Research on Cancer (IARC) evaluated the carcinogenic risks to humans and has classified around 120 agents as carcinogenic, where the chemical substances represent the majority (IARC 2018). There are many kinds of environmental pollutants: 1) agriculture chemicals including pesticides such as 1,1,1-trichloro-2,2-bis(4chlorophenyl)ethane (DDT); 2) the industrial chemicals including dioxins such as 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD), metals such as arsenic compounds, plasticisers such as bisphenol A (BPA) and health care products such as phthalates; 3) the air pollutants including polycyclic aromatic hydrocarbons (PAH) such as benzo[a]pyrene (B[a]P), NNitrosamines such as N-Nitrosodimethylamine (NDMA), air microparticles such as sulphur dioxide and carbon monoxide; 4) drugs including exogenous hormones and 5) some natural compounds such as aflatoxines. Pollutants are characterised by their higher persistence and pervasive nature due to high lipid solubility that allows them to remain, bioaccumulate in fatty tissues and interact with the environment for a long period of time (Mathew et al. 2017). These molecules can have different mechanisms of action; they could be genotoxic or non-genotoxic which include molecules that are able to induce epigenetic modifications, to alter the endocrine system, to act as immunosuppressors or inducers of tissue-specific toxicity and inflammatory responses (Caldwell 2012, Hernández Environmental pollutants-dependent molecular pathways and carcinogenesis 3 et al. 2009). In this review, we will be discussing mainly the genotoxic compounds and the endocrine disruptors. A "genotoxic" agent is able to damage the genetic material by inducing DNA damage, mutation or both (Hayashi 1992). Genotoxicity is a key feature of carcinogenesis; it promotes chromosome changes that may be structural (such as translocations, deletions, insertions, inversions, micro-nuclei and changes in telomere length) or numerical, affecting the numbers of chromosomes as in the case of aneuploidy and polyploidy (Smith et al. 2016). Genotoxicity, due to environmental molecules, can alter the oncogenes and tumour suppressor genes that regulate processes such as cell proliferation, cell death, cell differentiation and genomic stability (Hanahan and Weinberg 2011). Endocrine disruptors or endocrine disrupting chemicals (EDC) are pseudo-persistent compounds present in the environment at very low concentrations; however, these low levels are able to interfere with hormonal regulation pathways causing effects leading to a variety of health problems, such as cancer, specifically the hormone-dependent type (breast, ovarian, endometrial, prostate, testicular) (Abaci et al. 2009, Nohynek et al. 2013, Rachoń 2015, Rochefort 2017). Endocrine disruptors act directly with hormone receptors by imitating or preventing the action of natural ho (...truncated)