GPX1 Pro198Leu polymorphism and GSTM1 deletion do not affect selenium and mercury status in mildly exposed Amazonian women in an urban population
Graphical abstract
Introduction
Mercury is a potent toxicant even in low doses, having adverse effects on the renal, immune, cardiovascular, reproductive and central nervous systems (Zahir et al., 2005). In utero transfer of mercury (inorganic or as the more toxic methylmercury species) from mother to fetus is of particular concern, as neurotoxic effects are most marked in the developing brain, and there is concern that current exposure advisories do not sufficiently take into account the potential damage of chronic, low-level exposure during pregnancy (Brown and Austin, 2012, Cardenas et al., 2015, Hui et al., 2016). Selenium is involved in mercury detoxification (Yoneda and Suzuki, 1997); therefore it is important to understand the genetic and biochemical factors that influence interactions between selenium and mercury in at-risk populations, such as women of child-bearing age, as this can result negative health outcomes for the following generation.
Amazonian populations have some of the highest reported mercury exposure levels in the world (Passos and Mergler, 2008). While a small fraction of mercury in the environment occurs through natural geological events (i.e. volcanic activity), the majority of health effects arise from either occupational exposure (e.g. mining) or anthropogenic release (Holmes et al., 2009). Mercury retention in soil in the Amazon region is partially due to geographic factors, but is exacerbated by excessive and poorly-regulated gold-mining, soil cultivation methods and industrial contamination (Comte et al., 2013, Fostier et al., 2015, Miretzky et al., 2005, Pouilly et al., 2013). Biomagnification and the reliance on the aquatic environment for food make local fish intake the most relevant source of methylmercury contamination in this area for subsistence farmers (Barcelos et al., 2013, de Oliveira et al., 2014, Mazzaron Barcelos et al., 2012). Methylmercury exerts the most significant negative health effects through chronic neurotoxicity, particularly during development (Grandjean and Landrigan, 2006, Grandjean and Landrigan, 2014).
Concurrently, Amazonian populations are also exposed to high levels of selenium, also though agriculture, as the soil in this area is the most selenium-rich in Brazil (Cintra and Cozzolino, 1993, Favaro et al., 1997). The most concentrated and widely-consumed selenium food source are Brazil nuts (Bertholletia excelsa, H.B.K), which are widely cultivated in the Amazon basin (Rita Cardoso et al., 2016, Souza and Menezes, 2004). Selenium is an essential nutrient, though it has a therapeutic window that can be exceeded via high dietary intake (MacFarquhar et al., 2010, Martens et al., 2015). Concomitant mercury and selenium exposure in areas such as the Amazon are of significant interest, as selenium is able to partially mitigate mercury toxicity in both animals and humans (Falnoga and Tušek-Žnidarič, 2007). The proposed protective mechanism involves the formation of an inert selenium-mercury complex (Naganuma and Imura, 1983, Yoneda and Suzuki, 1997) that is effective against both inorganic and methylmercury intoxication (Whanger, 1992). However, studies have demonstrated that certain polymorphisms to genes encoding the selenoproteome, a collection of 25 identified selenium-containing proteins (Cardoso et al., 2015) may alter response to dietary intake, thus increasing susceptibility to both mercury intoxication and nutritional selenium deficiencies. In regions like the Amazon, where environmental exposure is practically endemic, assessing these previously identified effects in at-risk populations is an important population health concern.
The Pro198Leu polymorphism (rs1050450) to the selenoprotein glutathione peroxidase 1 gene (GPX1) is characterized by a variant T-allele, encoding leucine (Leu) instead of proline (Pro) at codon 198 (Forsberg et al., 1999, Ravn-Haren et al., 2006). This polymorphism has been associated with changes to selenium status and the selenoprotein hierarchy (Combs et al., 2011, Jablonska et al., 2009, Karunasinghe et al., 2012, Xiong et al., 2010), although its effects in response to selenium supplementation remain unclear (Jablonska et al., 2015, Miller et al., 2012, Soares et al., 2016).
Additionally, glutathione-S-transferases (GSTs) are a family of phase II biotransformation enzymes that are also involved in mercury detoxification and elimination by mediating conjugation of mercury and glutathione (GSH), which is then excreted in bile and by the kidneys (Clarkson and Magos, 2006). The human GST family is subdivided into eight separate classes: alpha, mu, kappa, omega, pi, sigma, theta and zeta; which are encoded by the GSTA, GSTM, GSTK, GSTO, GSTP, GSTS, GSTT, and GSTZ genes, respectively (Hayes and Strange, 2000, Josephy, 2010). These genes are highly polymorphic, and deletion of GSTM (GSTM1) and GSTT (GSTT1) are significant as they result in a complete loss of activity of the enzymes, and studies have associated this deficiency with increased cancer risk and mercury retention (Barcelos et al., 2013, Barcelos et al., 2015, de Oliveira et al., 2014, Goodrich et al., 2011, Jain et al., 2006, Klautau-Guimarães et al., 2005), as well as increased maternal blood mercury levels (Lee et al., 2010). However, other reports have failed to find a link between GSTM1 concentration or activity and an outcome-biomarker of mercury retention (Wang et al., 2012), and thus further studies are required to determine the precise role of this deletion polymorphism on mercury detoxification.
Therefore, considering the importance of mercury exposure in the Amazon region and the interaction between this toxic metal and selenium, this pilot study aimed to evaluate the effect of Pro198Leu polymorphism and GSTM1 deletion on mercury levels, taking into account the previously reported role these mutations play in generalized selenium metabolism. In the context of the Amazonian region, where isolated populations are fast becoming juxtaposed with densely populated urban regions, it is valuable to understand the interaction between exposure to this environmental toxicant and individual genetic susceptibility; a necessity highlighted at the National Institutes of Health Gene-Environment Interplay Workshop (Bookman et al., 2011). Because of the established toxic effect on fetus in addition to the mother, we conducted this study in a female cohort from Porto Velho, representing a diverse urban population in Amazon region.
Section snippets
Study participants
This study was conducted according to the Declaration of Helsinki guidelines and approved by Ethics Committee of the Faculty of Pharmaceutical Sciences at the University of São Paulo (protocol number 574). Written informed consent was obtained from all participants. Sample size calculation, based on prevalence of the variant allele of Pro198Leu (32%) estimated that c.a. 200 participants would be required to test the effects of GSTM1 deletion and Pro198Leu variants of GPX1 on biological selenium
General information
The mean age of participants was 26.6 ± 7.8 years. According to BMI classification (World Health Organisation, 2000), 80.5% were eutrophic, 15.4% were overweight and 4% were underweight. Waist circumference was adequate in 88% of the population indicating low risk for cardiovascular diseases. Full population demographics are shown in Table 1.
Dietary assessment suggested the observed selenium deficiency was due to inadequate intake in 42% of the participants. Dietary recalls revealed that the main
Discussion
Environmental exposure to mercury represents one of the major public health concerns related to chemical pollution and because this metal is especially toxic in utero (Hui et al., 2016, Karagas et al., 2012) it is important to evaluate women in a reproductive age from an area of known high mercury exposure (the Amazon basin). Furthermore, studies have demonstrated the role of gene-environment interaction in regard to susceptibility to mercury toxicity (Julvez and Grandjean, 2013, Llop et al.,
Conclusions
For the first time, our study showed that Pro198Leu does not influence mercury levels in an established biomarker of exposure within a mildly exposed population. We also observed that GSTM1 deletion had no effect on mercury levels in mildly exposed people, suggesting that the isolate deletion of GSTM gene has impact only in highly exposed populations.
Acknowledgments
We are extremely grateful to the Alphaclin Lab which provided the locale for sample collection.
References (81)
- et al.
Mercury contamination in human hair and fish from Cambodia: levels, specific accumulation and risk assessment
Environ. Pollut.
(2005) Total mercury concentrations in human hair from 13 countries in relation to fish consumption and location
Sci. Total Environ.
(1983)- et al.
Relationships between trace element concentrations in human blood and serum
Toxicol. Lett.
(2002) - et al.
Polymorphisms in glutathione-related genes modify mercury concentrations and antioxidant status in subjects environmentally exposed to methylmercury
Sci. Total Environ.
(2013) - et al.
Effects of genetic polymorphisms on antioxidant status and concentrations of the metals in the blood of riverside Amazonian communities co-exposed to Hg and Pb
Environ. Res.
(2015) - et al.
Determination of various nutrients and toxic elements in different Brazilian regional diets by neutron activation analysis
J. Trace Elem. Med. Biol.
(1997) - et al.
Litter mercury deposition in the Amazonian rainforest
Environ. Pollut.
(2015) - et al.
Glutathione enzyme and selenoprotein polymorphisms associate with mercury biomarker levels in Michigan dental professionals
Toxicol. Appl. Pharmacol.
(2011) - et al.
Developmental neurotoxicity of industrial chemicals
Lancet
(2006) - et al.
Neurobehavioural effects of developmental toxicity
Lancet Neurol.
(2014)
Glutathione-S-transferase polymorphism, metallothionein expression, and mercury levels among students in Austria
Sci. Total Environ.
Genetic background of lead and mercury metabolism in a group of medical students in Austria
Environ. Res.
Is low-level environmental mercury exposure of concern to human health?
Sci. Total Environ.
Impact of fetal and childhood mercury exposure on immune status in children
Environ. Res.
GSTT1, GSTM1 and GSTP1 genetic polymorphisms and interaction with tobacco, alcohol and occupational exposure in esophageal cancer patients from North India
Cancer Lett.
Role of micronutrients against dimethylmercury intoxication in male rats
Environ. Toxicol. Pharmacol.
Exposure to methylmercury in non-fish-eating people in Sweden
Environ. Res.
Selenium status in preschool children receiving a Brazil nut-enriched diet
Nutrition
Influence of the glutathione peroxidase 1 Pro200Leu polymorphism on the response of glutathione peroxidase activity to selenium supplementation: a randomized controlled trial
Am. J. Clin. Nutr.
Sorption of mercury (II) in Amazon soils from column studies
Chemosphere
Mode of in vitro interaction of mercuric mercury with selenite to form high-molecular weight substance in rabbit blood
Chem. Biol. Interact.
Dietary selenium's protective effects against methylmercury toxicity
Toxicology
Serum selenium and selenoprotein P status in adult Danes – 8-year followup
J. Trace Elem. Med. Biol.
Selenium status and hair mercury levels in riverine children from Rondonia, Amazonia
Nutrition
An investigation of modifying effects of single nucleotide polymorphisms in metabolism-related genes on the relationship between peripheral nerve function and mercury levels in urine and hair
Sci. Total Environ.
Association study between polymorphisms in selenoprotein genes and susceptibility to Kashin-Beck disease
Osteoarthr. Cartil.
Detoxification of mercury by selenium by binding of equimolar Hg-Se complex to a specific plasma protein
Toxicol. Appl. Pharmacol.
Low dose mercury toxicity and human health
Environ. Toxicol. Pharmacol.
Diretrizes brasileiras de obesidade 2009/2010
Hair mercury speciation as a function of gender, age, and body mass index in inhabitants of the Negro River Basin, Amazon, Brazil
Arch. Environ. Contam. Toxicol.
Selection of methodology to assess food intake
Eur. J. Clin. Nutr.
Gene-environment interplay in common complex diseases: forging an integrative model-recommendations from an NIH workshop
Genet. Epidemiol.
Maternal transfer of mercury to the developing embryo/fetus: is there a safe level?
Toxicol. Environ. Chem.
Differential DNA methylation in umbilical cord blood of infants exposed to mercury and arsenic in utero
Epigenetics
Pro198Leu polymorphism affects the selenium status and GPx activity in response to Brazil nut intake
Food Funct.
Glutathione peroxidase 1 Pro198Leu polymorphism in Brazilian Alzheimer's disease patients: relations to the enzyme activity and to selenium status
J. Nutrigenet. Nutrigenomics
Nutritional status of selenium in Alzheimer's disease patients
Br. J. Nutr.
Selenium, selenoproteins and neurodegenerative diseases
Metallomics
Selenium bioavailability in a regional diet of São Paulo
Int. J. Food Sci. Nutr.
The toxicology of mercury and its chemical compounds
Crit. Rev. Toxicol.
Cited by (9)
Genomic investigation on genes related to mercury metabolism in Amazonian indigenous populations
2024, Science of the Total EnvironmentAssociation between genetic variations in GSH-related and MT genes and low-dose methylmercury exposure in children and women of childbearing age: a pilot study
2020, Environmental ResearchCitation Excerpt :Barcelos et al. (2013) suggesting that it may be due to other factors, such as differences in exposure level, as GSTP1 Val allozyme is less sensitive to the inhibition induced by high dose Hg concentrations (Dierickx, 1982). Several studies have investigated the modification effects of GPX1 on body burden of Hg, but significant effects have not been demonstrated before (Rocha et al., 2016). Here we report a possible significant effect of the minor allele of GPX1 on the body burden of Hg.
Current Understanding of Human Polymorphism in Selenoprotein Genes: A Review of Its Significance as a Risk Biomarker
2024, International Journal of Molecular SciencesPlasma Concentration of Essential and Toxic Trace Elements After Brazil Nut Intake: Results from a Randomized Controlled Trial
2023, Biological Trace Element ResearchThe influence of nutrigenetics on biomarkers of selenium nutritional status
2021, Nutrition Reviews