Humans have throughout their development been exposed to various environmental genotoxicants through food, air, water, and soil. Environmental exposure to genotoxic compounds may induce damage to human health and thereby increase risks of human cancers and other diseases. Environmental genotoxic chemicals have the ability to induce mutations. Such mutations can give rise to cancer in somatic cells. However, when germ cells are affected, the damage can also have an effect on the next and successive generations. Because of the potential health hazard represented by exposure to genotoxic chemicals, it is important that all chemicals for which there is possible human exposure be screened for genotoxic activity. If genotoxic hazard is detected, then the risks of exposure can be assessed and the use of the chemical controlled and when appropriate eliminated from the market and the environment. In this chapter, a general overview of the genotoxicity and the genotoxicity of some environmental genotoxicants are discussed. This is followed by a description of the genotoxic properties of some environmental genotoxicants such as bisphenols and mycotoxins, which are prominent environmental contaminates, and is believed to be genotoxic agents that contribute to the high incidence of carcinogenicity among populations.
- Environmental genotoxicants
- mode of action
- risk assessments
DNA is constantly damaged by both endogenous and exogenous sources, and genotoxicity can be considered as an imbalance between DNA damage and DNA repair mechanisms. Maintenance of DNA integrity is essential for proper cellular and organismal function, and the capacity to withstand genotoxic challenge is important to avoid long-term genetic instability and population vulnerability. Unrepaired DNA damage can lead to mutations, cellular senescence, apoptosis, progression of cancer, and the process of aging . Mutation is a broad term covering a whole range of changes to the informational molecule, DNA packaged into chromosomes, of an organism from gene changes to modifications of the number and/or structure of chromosomes. Mutagenicity in normal cells is one of the most serious problems due to the possibility of inducing secondary malignancies and abnormal reproductive outcomes such as Down, Klinefelter, and Turner syndromes . Such changes can be assessed directly by measuring the interaction of agents with DNA or more indirectly through the assessment of DNA repair or the production of gene mutations or chromosome alterations.
Genotoxicity covers a broader spectrum of endpoints than mutagenicity. For example, unscheduled DNA synthesis, sister chromatid exchanges, and DNA strand breaks are the measures of genotoxicity, not mutagenicity, because they are not themselves transmissible from cell to cell or generation to generation. Mutagenicity on the other hand refers to the production of transmissible genetic alterations. Although all cells of an organism contain the same DNA, somatic cells in different organs and tissues of the adult body become specialized to perform defined functions so that only some parts of the genome are expressed. A common feature of mutations in cancer-causing genes, such as those controlling cell division and proliferation, is that this results in genes being expressed in the wrong tissue at the wrong time. The effect of a mutation will depend upon the position of the mutation within the DNA and the location and activity of the particular gene in which the mutation has been induced. Mutations in the many genes that have been implicated in the multistage events leading to cancer can be produced by a variety of mechanisms and interactions and modifications of the genetic material [2, 3].
With the recent focus on environmental problems, increasing awareness of the harmful effects of industrial and agricultural pollution has created a demand for progressively more sophisticated pollutant and toxicity detection methods. In recent years, there has been a growing concern about the increasing number of environmental pollutants that may disrupt normal endocrine function in exposed humans and animals. Endocrine disrupting compounds comprise a large group of synthetic chemicals that mimic the actions of natural hormones, act as antagonist, or block their synthesis, release, or metabolism. The xenoestrogen bisphenols have received much attention due to their high production volume and widespread human exposure. Recent research in various animal models has shown the genotoxic activity of bisphenols using
Many important agricultural products, especially those rich in carbohydrates, are attractive colonization sites for fungi. Some toxic secondary metabolites of fungal growth are identified as mycotoxins and may be found to contaminate agricultural products . Mycotoxins are virtually ubiquitous at some concentration in the average human diet. Mycotoxins are able to resist decomposition or being broken down by mammalian digestion, even by ruminant livestock, allowing these compounds to persist in meat and even dairy products . This gives rise to certain partially metabolized mycotoxins, such as aflatoxin M1, which are present in milk from cows or humans that consumed feed or food contaminated by aflatoxins. Even temperature treatments, such as cooking and freezing, do not inactivate some mycotoxins. This section broadly discusses the genotoxic properties of the environmental genotoxicants bisphenols and aflatoxins, which are prominent environmental contaminates, and is believed to be genotoxic agents that contributes to the high incidence of genotoxicity and carcinogenicity among populations.
2.1. Bisphenol A and its analogues
Bisphenols are a group of chemicals known as diphenylmethanes, which contain two benzene rings separated by one central carbon atom, usually with a 4-OH substituent on both benzene rings (e.g., bisphenol A, bisphenol F, bisphenol AF, and bisphenol Z). Bisphenol A is employed to make certain plastics and epoxy resins (Figure 1). In some bisphenols, the central carbon atom is replaced by a sulphone group (e.g., bisphenol S or bisphenol 1) or sulphide moiety (e.g., bisphenol 2). Some bisphenol A analogues seem to be safer alternatives to bisphenol A in industrial applications. For example, the production of bisphenol S, which is stable at high temperatures and resistant to sunlight, is increasing from year to year [7, 8]. The largest US manufacturer of thermal paper has been using bisphenol S as a replacement for bisphenol A since 2006. However, insufficient data are available to tell whether these bisphenol S-containing papers are safer than bisphenol A-containing papers. While bisphenol A is moderately susceptible to environmental breakdown, bisphenol S may be more persistent .
From the viewpoint of biodegradability in the aquatic environment, bisphenol F is more biodegradable under aerobic and anaerobic conditions than bisphenol A and may replace bisphenol A to lower environmental risks . Bisphenol AF also occurs as a monomer of phenol-formaldehyde resin. Bisphenol AF is a component of certain plasters and used as a rubber bridging material, while bisphenol A is a monomer that is polymerized to manufacture polycarbonate plastic products, epoxy, and polyester resins (Figure 2). Polycarbonate plastics have many applications including use in some food and drink packaging such as water and baby bottles, compact discs, impact-resistant safety equipment, and medical devices including those used in hospital settings. Epoxy resins are used to coat metal products such as food cans, bottle tops, and water supply pipes. Bisphenol A can also be found in certain thermal paper products, including some cash register and ATM receipts. Some dental sealants and composites may also contribute to bisphenol A exposure [11, 12].
2.2. Human exposure to bisphenols
Human exposure to bisphenols may occur in the workplace through inhalation during production, but the most common route of exposure is by oral intake. Small amounts of bisphenol A are eluted from canned beverages, foods, and baby bottles, especially when heated . At higher temperatures, longer contact with, and higher pH of the contact medium, bisphenol A monomer can hydrolyse and leach into food and beverages. Recent studies also suggest that the public may be exposed to bisphenol A by handling cash register receipts. In accordance with its widespread use in many applications, bisphenol A has been detected in dietary items  and human biological samples . Moreover, bisphenol A was detected in environmental media as well .
2.3. Risks of exposure to bisphenols
In general, bisphenol A levels in humans have measured well below 50 mg/kg/day, which is the maximum acceptable dose set by the UA EPA . Its ubiquitous presence and widespread distribution have provoked worldwide concerns about its possible association with human diseases such as obesity, diabetes, cardiovascular disease, reproductive disorders, and cancer [17, 18]. Despite its presence in human populations and its association with reproductive and developmental toxicity in animals, most countries have not imposed regulations on the manufacture, import, or sale of bisphenol A products. That has been due largely to conflicting scientific evidence for a direct association between low-level exposure and adverse health effects in humans. Some countries and regions, including Canada, Europe, Sweden, and the United States, on the other hand, have formally banned bisphenol A from infant and children’s products, including, variously, cans of infant formula, baby bottles, and sippy cups. Current efforts are focused on replacing bisphenol A with safer food contact materials. All of these alternative materials need to be assessed for appropriate functionality and safety using state-of-the-art methodology and scientific knowledge.
Bisphenol A is a known endocrine disruptor compound. While initially considered to be a weak environmental estrogen, several recent publications have demonstrated that bisphenol A may be similar in potency to estradiol in stimulating some cellular responses. Furthermore, emerging evidence suggests that bisphenol A may affect multiple endocrine-related pathways . In men, exposure to endocrine disruptors may be associated with decreased fertility and increased risk of testicular or prostate cancer . In women, exposure may increase the risk of endometriosis, reproductive or other endocrine-related cancers, and impaired oocyte competence, ovarian function, or menstrual cycle . Because females have higher levels of natural estrogens in their blood, the impact of estrogen-like compounds on females may be different from that on males. In women, high urinary bisphenol A levels were associated with reduced antral follicle counts in a cohort of 209 women undergoing infertility treatments , whereas no correlation was found between serum bisphenol A levels and antral follicle counts in another study on a smaller cohort of 44 patients . Nevertheless, several data suggest a negative impact of bisphenol A on woman fertility. Urinary bisphenol A levels were negatively correlated with numbers and quality of oocytes retrieved in stimulated cycles for assisted reproduction . Increased urinary or serum bisphenol A concentrations were also associated with decreased peak oestradiol levels . Moreover, a study on 137 patients undergoing assisted reproduction suggested that high urinary bisphenol A levels might be associated with up to 50% higher chance of implantation failures, in comparison with patients with low or no evidence of bisphenol A exposure .
Because the chemical structure of bisphenol A is similar to that of diethylstilbestrol, which is carcinogenic to mammals, the possible genotoxicity of bisphenol A has been widely tested in a variety of
By now, there is increasing evidence supports the notion that low bisphenol A concentrations adversely affect the epigenome of mammalian female germ cells, with functional consequences on gene expression, chromosome dynamics in meiosis, and oocyte development and quality . An epigenetic impact of bisphenol A was demonstrated also on male germ cells. Male offspring of rats perinatally exposed to bisphenol A had reduced sperm counts and other changes in phenotypes not only in the first generation but also in the
While comprehensive information is available about the adverse health impacts of bisphenol A, toxicological properties of alternative bisphenols are yet to be investigated. Alternative bisphenols are structurally similar to bisphenol A, and therefore expected to possess similar biological activities. However, most available toxicological information is limited to endocrine disrupting potentials, and only very little is known about the genotoxicity of alternative bisphenols . In turn, bisphenol F has been reported to induce DNA strand breaks, but not micronuclei, in HepG2 cells . In human HepG2 cells, bisphenol F induced histone H2AX phosphorylation, an indicator of DNA double strand breaks . Moreover, bisphenol F induced metaphase arrest and micronucleus formation in V79 cells . In Syrian hamster embryo cells, bisphenol F did not induce gene mutation or chromosomal aberrations, but induced aneuploidy and morphological changes . Bisphenol A may cause oxidative stress, and induce DNA adduct and aneuploidy in rodents . Nevertheless, eight bisphenols including bisphenol A showed no positive responses based on
3.1. Sources of aflatoxins
With worldwide increases in population, the need for nutrient-rich food is rising. Contamination of foods by toxins, bacteria, viruses, parasites, allergens, and prions may lead to serious diseases; unhealthy foodstuffs are implicated in approximately one-third of cancer cases. Controlled storage conditions, improved packaging, and strict hygiene regulations for food production, preservation, and distribution are essential to diminish such problems. Aflatoxins are toxic metabolites produced by certain fungi in/on foods and feeds. They are probably the best-known and most intensively researched mycotoxins in the world. The occurrence of aflatoxins is influenced by certain environmental factors; hence, the extent of contamination will vary with geographic location, agricultural, and agronomic practices, and the susceptibility of commodities to fungal invasion during pre-harvest, storage, and/or processing periods. Aflatoxin B1 is a prevalent food pollutant, which is found typically in tropical countries. It imposes great costs on the world’s economy and health . Thus, it is important to eliminate aflatoxin B1 from food resources and prevent production of the toxin. Due to lack of infrastructure, poor and third world countries are the major victims of aflatoxin B1. The established carcinogenesis, teratogenesis, and severe multi-organ toxicity associated with aflatoxin B1 have made it a substantial challenge for scientists [46, 47].
3.2. Human exposure to aflatoxins
Aflatoxins are a type of mycotoxin produced by
3.3. Risks of exposure to aflatoxins
Aflatoxins have been reported to have several serious deleterious effects in humans and diverse animals with the species reacting differently to the toxicological effects. The target sites of this toxicant are also diverse and effects include hepatotoxicity, teratogenicity, immunotoxicity, hematological disorders, renal dysfunction, induction of chromosome aberrations, and mutations in somatic and germinal cells of animals and humans [51–53]. Aflatoxin B1, the most toxic, is a potent carcinogen and has been directly correlated with adverse health effects, such as liver cancer, in many animal species. Aflatoxin B1 is one of the major risk factors for the occurrence of liver injury and carcinogenesis, especially when it is combined with hepatitis B infection. Epidemiological investigations revealed that dietary contamination with aflatoxin B1 might be responsible for 5–28% of global hepatocellular carcinoma cases . A great deal of evidence has demonstrated that aflatoxin B1 belongs to the indirect-acting carcinogens. Aflatoxin B1 is mainly metabolized in the liver to produce the genotoxic intermediate aflatoxin B1-exo-8,9-epoxide by the liver-specific cytochrome P450 enzymes, P4501A2, and 3A4. These epoxides can form aflatoxin B1-guanine adducts by binding covalently to DNA, thereby introducing GC-TA transversion that leads to DNA mutations and genomic instability . For instance, a frequent hotspot mutation at codon 249 in the human p53 gene gives rise to a Ser to Arg substitution in the p53 protein that decreases its tumor suppressor activity . Another major detoxification pathway of aflatoxin B1 in mammalian species is the glutathione conjugation of aflatoxin B1-8,9-epoxide, which is catalyzed by glutathione S-transferases . Experimental studies conducted in rats have shown that rGSTA5, barely expressed in adult male liver, exhibits a greater activity toward aflatoxin B1-8,9-epoxide than other glutathione S-transferases subunits .
Aflatoxin B1 is a clastogen that has been tested for genotoxicity
Since the discovery of these deleterious effects induced by aflatoxin B1, a large number of studies have explored the mechanisms and pathways involved in aflatoxin B1-mediated genotoxicity. However, few studies have focused on the epigenetic events involved in the induction of genotoxicity. Recently, several studies reported that cellular epigenetic aberrant changes, such as DNA methylation, histone modifications, and miRNA profiling alterations, also contributed to the hepatotoxicity and genotoxicity induced by chemical toxicants. A genome-wide miRNA-profiling analysis in an acute rat liver injury model induced by aflatoxin B1 predicted that several miRNAs and their potential targets were relevant to acute hepatotoxicity, although functional tests were not performed . However, it is clear from gene expression profiling that the pathways involved in acute poisoning and chronic poisoning are not completely consistent. A recent study investigated alterations in miRNA profiles of rat liver tissues by Illumina deep sequencing and evaluated their roles in aflatoxin B1-induced hepatocellular genotoxicity and hepatotoxicity . The authors demonstrated alterations in the miRNA profile in rat liver tissue, including rnomiR-34a-5p, rno-miR-200b-3p, rno-miR-429, and rno-miR-130a-3p, after aflatoxin B1 exposure. Functional tests showed that the increase in miR-34a-5p by p53 activation after aflatoxin B1 exposure led to cell cycle arrest
As it is realized that absolute safety is never achieved, many countries have attempted to limit exposure to aflatoxins by imposing regulatory limits on commodities intended for use as food and feed . The FDA has established specific guidelines on acceptable levels of aflatoxins in human food and animal feed by establishing action levels that allow for the removal of violate lots from commerce. The action level for human food is 20 ppb total aflatoxins, with the exception of milk, which has an action level of 0.5 ppb for aflatoxin M1. The action level for most feeds is also 20 ppb. However, it is very difficult to accurately estimate aflatoxins concentration in a large quantity of material because of the variability associated with testing procedures; hence, the true aflatoxin concentration in a lot cannot be determined with 100% certainty. However, the ability of aflatoxin-producing fungi to grow on a wide range of food commodities and the stability of aflatoxins in foods mean that control is best achieved by measures designed to prevent the contamination of crops in the field and during storage, or detection and removal of contaminated material from the food supply chain.
This work was funded by the National Plane for Science, Technology, and Innovation (MAARIFAH), King Abdulaziz City for Science and Technology, Kingdom of Saudi Arabia, Award Number (12-MED2648-02).
Cooke MS, Evans MD, Dizdaroglu M, Lunec J. Oxidative DNA damage: mechanisms, mutation, and disease. FASEB Journal. 2003;17(10):1195–214. doi:10.1096/fj.02-0752rev.
Attia SM. Mutagenicity of some topoisomerase II-interactive agents. Saudi Pharmaceutical Journal. 2008;16:1–24.
Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–67.
Peretz J, Vrooman L, Ricke WA, Hunt PA, Ehrlich S, Hauser R, Padmanabhan V, Taylor HS, Swan SH, VandeVoort CA, Flaws JA. Bisphenol a and reproductive health: update of experimental and human evidence, 2007–2013. Environ Health Perspect. 2014; 122(8):775–786. doi: 10.1289/ehp.1307728.
Bennett JW, Klich M. Mycotoxins. Clinical Microbiology Reviews. 2003;16(3):497–516.
Kang’ethe EK, Lang’a KA. Aflatoxin B1 and M1 contamination of animal feeds and milk from urban centers in Kenya. African Health Sciences. 2009;9(4):218–26.
Chen MY, Ike M, Fujita M. Acute toxicity, mutagenicity, and estrogenicity of bisphenol-A and other bisphenols. Environmental Toxicology. 2002;17(1):80–6.
Kuruto-Niwa R, Nozawa R, Miyakoshi T, Shiozawa T, Terao Y. Estrogenic activity of alkylphenols, bisphenol S, and their chlorinated derivatives using a GFP expression system. Environmental Toxicology and Pharmacology. 2005;19(1):121–30. doi:10.1016/j.etap.2004.05.009.
Danzl E, Sei K, Soda S, Ike M, Fujita M. Biodegradation of bisphenol A, bisphenol F and bisphenol S in seawater. International Journal of Environmental Research and Public Health. 2009;6(4):1472–84. doi:10.3390/ijerph6041472.
Ike M, Chen MY, Danzl E, Sei K, Fujita M. Biodegradation of a variety of bisphenols under aerobic and anaerobic conditions. Water Science and Technology: A Journal of the International Association on Water Pollution Research. 2006;53(6):153–9.
Liao C, Liu F, Kannan K. Bisphenol S, a new bisphenol analogue, in paper products and currency bills and its association with bisphenol a residues. Environmental Science & Technology. 2012;46(12):6515–22. doi:10.1021/es300876n.
Biedermann S, Tschudin P, Grob K. Transfer of bisphenol A from thermal printer paper to the skin. Analytical and Bioanalytical Chemistry. 2010;398(1):571–6. doi:10.1007/s00216-010-3936-9.
Lorber M, Schecter A, Paepke O, Shropshire W, Christensen K, Birnbaum L. Exposure assessment of adult intake of bisphenol A (BPA) with emphasis on canned food dietary exposures. Environment International. 2015;77:55–62. doi:10.1016/j.envint.2015.01.008.
Liao C, Liu F, Alomirah H, Loi VD, Mohd MA, Moon HB, et al. Bisphenol S in urine from the United States and seven Asian countries: occurrence and human exposures. Environmental Science & Technology. 2012;46(12):6860–6. doi:10.1021/es301334j.
Huang YQ, Wong CK, Zheng JS, Bouwman H, Barra R, Wahlstrom B, et al. Bisphenol A (BPA) in China: a review of sources, environmental levels, and potential human health impacts. Environment International. 2012;42:91–9. doi:10.1016/j.envint.2011.04.010.
Vandenberg LN, Hunt PA, Myers JP, Vom Saal FS. Human exposures to bisphenol A: mismatches between data and assumptions. Reviews on Environmental Health. 2013;28(1):37–58. doi:10.1515/reveh-2012-0034.
Meeker JD, Yang T, Ye X, Calafat AM, Hauser R. Urinary concentrations of parabens and serum hormone levels, semen quality parameters, and sperm DNA damage. Environmental Health Perspectives. 2011;119(2):252–7. doi:10.1289/ehp.1002238.
Jenkins S, Betancourt AM, Wang J, Lamartiniere CA. Endocrine-active chemicals in mammary cancer causation and prevention. The Journal of Steroid Biochemistry and Molecular Biology. 2012;129(3–5):191–200. doi:10.1016/j.jsbmb.2011.06.003.
Rubin BS. Bisphenol A: an endocrine disruptor with widespread exposure and multiple effects. The Journal of Steroid Biochemistry and Molecular Biology. 2011;127(1–2):27–34. doi:10.1016/j.jsbmb.2011.05.002.
Pflieger-Bruss S, Schuppe HC, Schill WB. The male reproductive system and its susceptibility to endocrine disrupting chemicals. Andrologia. 2004;36(6):337–45. doi:10.1111/j.1439-0272.2004.00641.x.
Nicolopoulou-Stamati P, Pitsos MA. The impact of endocrine disrupters on the female reproductive system. Human Reproduction Update. 2001;7(3):323–30.
Souter I, Smith KW, Dimitriadis I, Ehrlich S, Williams PL, Calafat AM, et al. The association of bisphenol-A urinary concentrations with antral follicle counts and other measures of ovarian reserve in women undergoing infertility treatments. Reproductive Toxicology. 2013;42:224–31. doi:10.1016/j.reprotox.2013.09.008.
Bloom MS, Kim D, Vom Saal FS, Taylor JA, Cheng G, Lamb JD, et al. Bisphenol A exposure reduces the estradiol response to gonadotropin stimulation during in vitro fertilization. Fertility and Sterility. 2011;96(3):672–7 e2. doi:10.1016/j.fertnstert.2011.06.063.
Ehrlich S, Williams PL, Missmer SA, Flaws JA, Ye XY, Calafat AM, et al. Urinary bisphenol A concentrations and early reproductive health outcomes among women undergoing IVF. Human Reproduction. 2012;27(12):3583–92. doi:10.1093/humrep/des328.
Fujimoto VY, Kim D, vom Saal FS, Lamb JD, Taylor JA, Bloom MS. Serum unconjugated bisphenol A concentrations in women may adversely influence oocyte quality during in vitro fertilization. Fertility and Sterility. 2011;95(5):1816–9. doi:10.1016/j.fertnstert.2010.11.008.
Ehrlich S, Williams PL, Missmer SA, Flaws JA, Berry KF, Calafat AM, et al. Urinary bisphenol A concentrations and implantation failure among women undergoing in vitro fertilization. Environmental Health Perspectives. 2012;120(7):978–83.
Tsutsui T, Tamura Y, Yagi E, Hasegawa K, Takahashi M, Maizumi N, et al. Bisphenol-A induces cellular transformation, aneuploidy and DNA adduct formation in cultured Syrian hamster embryo cells. International Journal of Cancer. 1998;75(2):290–4.
Parry EM, Parry JM, Corso C, Doherty A, Haddad F, Hermine TF, et al. Detection and characterization of mechanisms of action of aneugenic chemicals. Mutagenesis. 2002;17(6):509–21.
Pfeiffer E, Rosenberg B, Deuschel S, Metzler M. Interference with microtubules and induction of micronuclei in vitro by various bisphenols. Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 1997;390(1–2):21–31. doi:10.1016/S0165-1218(96)00161-9.
Iso T, Watanabe T, Iwamoto T, Shimamoto A, Furuichi Y. DNA damage caused by bisphenol A and estradiol through estrogenic activity. Biological & Pharmaceutical Bulletin. 2006;29(2):206–10.
Xin L, Lin Y, Wang A, Zhu W, Liang Y, Su X, et al. Cytogenetic evaluation for the genotoxicity of bisphenol-A in Chinese hamster ovary cells. Environmental Toxicology and Pharmacology. 2015;40(2):524–9. doi:10.1016/j.etap.2015.08.002.
Schweikl H, Schmalz G, Rackebrandt K. The mutagenic activity of unpolymerized resin monomers in Salmonella typhimurium and V79 cells. Mutation Research. 1998;415(1–2):119–30.
Ivett JL, Brown BM, Rodgers C, Anderson BE, Resnick MA, Zeiger E. Chromosomal aberrations and sister chromatid exchange tests in Chinese hamster ovary cells in vitro. IV. Results with 15 chemicals. Environmental and Molecular Mutagenesis. 1989;14(3):165–87.
Pacchierotti F, Ranaldi R, Eichenlaub-Ritter U, Attia S, Adler ID. Evaluation of aneugenic effects of bisphenol A in somatic and germ cells of the mouse. Mutation Research. 2008;651(1–2):64–70. doi:10.1016/j.mrgentox.2007.10.009.
Kolsek K, Sollner Dolenc M, Mavri J. Computational study of the reactivity of bisphenol A-3,4-quinone with deoxyadenosine and glutathione. Chemical Research in Toxicology. 2013;26(1):106–11. doi:10.1021/tx300411d.
Eichenlaub-Ritter U, Pacchierotti F. Bisphenol A effects on mammalian oogenesis and epigenetic integrity of oocytes: a case study exploring risks of endocrine disrupting chemicals. BioMed Research International. 2015;2015: 1–11. doi:10.1155/2015/698795.
Salian S, Doshi T, Vanage G. Perinatal exposure of rats to Bisphenol A affects the fertility of male offspring. Life Sciences. 2009;85(21–22):742–52. doi:10.1016/j.lfs.2009.10.004.
Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner MK. Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. Plos One. 2013;8(1):e55387. doi:10.1371/journal.pone.0055387.
Li G, Chang H, Xia W, Mao Z, Li Y, Xu S. F0 maternal BPA exposure induced glucose intolerance of F2 generation through DNA methylation change in Gck. Toxicology Letters. 2014;228(3):192–9. doi:10.1016/j.toxlet.2014.04.012.
Cabaton N, Dumont C, Severin I, Perdu E, Zalko D, Cherkaoui-Malki M, et al. Genotoxic and endocrine activities of bis(hydroxyphenyl)methane (bisphenol F) and its derivatives in the HepG2 cell line. Toxicology. 2009;255(1–2):15–24. doi:10.1016/j.tox.2008.09.024.
Audebert M, Dolo L, Perdu E, Cravedi JP, Zalko D. Use of the gammaH2AX assay for assessing the genotoxicity of bisphenol A and bisphenol F in human cell lines. Archives of Toxicology. 2011;85(11):1463–73. doi:10.1007/s00204-011-0721-2.
Kanai H, Barrett JC, Metzler M, Tsutsui T. Cell-transforming activity and estrogenicity of bisphenol-A and 4 of its analogs in mammalian cells. International Journal of Cancer. 2001;93(1):20–5. doi: 10.1002/Ijc.1303.
Tiwari D, Kamble J, Chilgunde S, Patil P, Maru G, Kawle D, et al. Clastogenic and mutagenic effects of bisphenol A: an endocrine disruptor. Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 2012;743(1–2):83–90. doi:10.1016/j.mrgentox.2011.12.023.
Chen MY, Ike M, Fujita M. Acute toxicity, mutagenicity, and estrogenicity of bisphenol-A and other bisphenols. Environmental Toxicology. 2002;17(1):80–6. doi: 10.1002/Tox.10035
Algul I, Kara D. Determination and chemometric evaluation of total aflatoxin, aflatoxin B1, ochratoxin A and heavy metals content in corn flours from Turkey. Food Chemistry. 2014;157:70–6. doi:10.1016/j.foodchem.2014.02.004.
Partanen HA, El-Nezami HS, Leppanen JM, Myllynen PK, Woodhouse HJ, Vahakangas KH. Aflatoxin B1 transfer and metabolism in human placenta. Toxicological Sciences. 2010;113(1):216–25. doi:10.1093/toxsci/kfp257.
Niknejad F, Zaini F, Faramarzi MA, Amini M, Kordbacheh P, Mahmoudi M, et al. Candida parapsilosis as a potent biocontrol agent against growth and aflatoxin production by Aspergillus species. Iranian Journal of Public Health. 2012;41(10):72–80.
Martins ML, Martins HM, Bernardo F. Aflatoxins in spices marketed in Portugal. Food Additives & Contaminants. 2001;18(4):315–9. doi: 10.1080/02652030120041.
Mohd Redzwan S, Rosita J, Mohd Sokhini AM, Nurul ’Aqilah AR, Wang JS, Kang MS, et al. Detection of serum AFB1-lysine adduct in Malaysia and its association with liver and kidney functions. International Journal of Hygiene and Environmental Health. 2014;217(4–5):443–51. doi: 10.1016/j.ijheh.2013.08.007.
Dohnal V, Wu Q, Kuca K. Metabolism of aflatoxins: key enzymes and interindividual as well as interspecies differences. Archives of Toxicology. 2014;88(9):1635–44. doi:10.1007/s00204-014-1312-9.
Guindon KA, Foley JF, Maronpot RR, Massey TE. Failure of catalase to protect against aflatoxin B1-induced mouse lung tumorigenicity. Toxicology and Applied Pharmacology. 2008;227(2):179–83. doi:10.1016/j.taap.2007.10.015.
Fapohunda SO, Ezekiel CN, Alabi OA, Omole A, Chioma SO. Aflatoxin-mediated sperm and blood cell abnormalities in mice fed with contaminated corn. Mycobiology. 2008;36(4):255–9. doi:10.4489/MYCO.2008.36.4.255.
Anwar WA, Khalil MM, Wild CP. Micronuclei, chromosomal aberrations and aflatoxin-albumin adducts in experimental animals after exposure to aflatoxin B1. Mutation Research. 1994;322(1):61–7.
Liu Y, Wu F. Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment. Environmental Health Perspectives. 2010;118(6):818–24. doi:10.1289/ehp.0901388.
Attia SM. Deleterious effects of reactive metabolites. Oxidative Medicine and Cellular Longevity. 2010;3(4):238–53.
Aguilar F, Hussain SP, Cerutti P. Aflatoxin B1 induces the transversion of G-->T in codon 249 of the p53 tumor suppressor gene in human hepatocytes. Proceedings of the National Academy of Sciences of the United States of America. 1993;90(18):8586–90.
Eaton DL, Gallagher EP. Mechanisms of aflatoxin carcinogenesis. Annual Review of Pharmacology and Toxicology. 1994;34:135–72. doi:10.1146/annurev.pa.34.040194.001031.
Hayes JD, Nguyen T, Judah DJ, Petersson DG, Neal GE. Cloning of cDNAs from fetal rat liver encoding glutathione S-transferase Yc polypeptides. The Yc2 subunit is expressed in adult rat liver resistant to the hepatocarcinogen aflatoxin B1. The Journal of Biological Chemistry. 1994;269(32):20707–17.
Corcuera LA, Vettorazzi A, Arbillaga L, Perez N, Gil AG, Azqueta A, et al. Genotoxicity of Aflatoxin B1 and Ochratoxin A after simultaneous application of the in vivo micronucleus and comet assay. Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association. 2015;76:116–24. doi:10.1016/j.fct.2014.12.003.
Turkez H, Geyikoglu F, Aslan A, Karagoz Y, Turkez O, Anar M. Antimutagenic effects of lichen Pseudovernia furfuracea(L.) Zoph. extracts against the mutagenicity of aflatoxin B1 in vitro. Toxicology and Industrial Health. 2010;26(9):625–31. doi:10.1177/0748233710377779.
Bedard LL, Massey TE. Aflatoxin B1-induced DNA damage and its repair. Cancer Letters. 2006;241(2):174–83. doi:10.1016/j.canlet.2005.11.018.
Zeinvand-Lorestani H, Sabzevari O, Setayesh N, Amini M, Nili-Ahmadabadi A, Faramarzi MA. Comparative study of in vitro prooxidative properties and genotoxicity induced by aflatoxin B1 and its laccase-mediated detoxification products. Chemosphere. 2015;135:1–6. doi:10.1016/j.chemosphere.2015.03.036.
Diaz GJ, Murcia HW, Cepeda SM. Bioactivation of aflatoxin B1 by turkey liver microsomes: responsible cytochrome P450 enzymes. British Poultry Science. 2010;51(6):828–37. doi:10.1080/00071668.2010.528752.
Dohnal V, Wu QH, Kuca K. Metabolism of aflatoxins: key enzymes and interindividual as well as interspecies differences. Archives of Toxicology. 2014;88(9):1635–44. doi:10.1007/s00204-014-1312-9.
Yang WQ, Lian JW, Feng YJ, Srinivas S, Guo ZN, Zhong H, et al. Genome-wide miRNA-profiling of aflatoxin B1-induced hepatic injury using deep sequencing. Toxicology Letters. 2014;226(2):140–9. doi:10.1016/j.toxlet.2014.01.021.
Liu CX, Yu HH, Zhang Y, Li DC, Xing XM, Chen LP, et al. Upregulation of miR-34a-5p antagonizes AFB1-induced genotoxicity in F344 rat liver. Toxicon. 2015;106:46–56. doi:10.1016/j.toxicon.2015.09.016.
Edlayne G, Simone A, Felicio JD. Chemical and biological approaches for mycotoxin control: a review. Recent Patents on Food, Nutrition & Agriculture. 2009;1(2):155–61.