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Journal of Environmental Science and Health, Part C: Environmental Carcinogenesis and Ecotoxicology Reviews Publication details, including instructions for authors and subscription information:

Environmental Exposure to Lead (Pb) and Variations in Its Susceptibility a



Jina Kim , Youngeun Lee & Mihi Yang a

Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea Published online: 29 May 2014.

To cite this article: Jina Kim, Youngeun Lee & Mihi Yang (2014) Environmental Exposure to Lead (Pb) and Variations in Its Susceptibility, Journal of Environmental Science and Health, Part C: Environmental Carcinogenesis and Ecotoxicology Reviews, 32:2, 159-185, DOI: 10.1080/10590501.2014.907461 To link to this article:

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Journal of Environmental Science and Health, Part C, 32:159–185, 2014 C Taylor & Francis Group, LLC Copyright  ISSN: 1059-0501 print / 1532-4095 online DOI: 10.1080/10590501.2014.907461

Environmental Exposure to Lead (Pb) and Variations in Its Susceptibility Jina Kim, Youngeun Lee, and Mihi Yang Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women’s University, Seoul, Republic of Korea Based on exposure frequency and intrinsic toxicity, lead (Pb) ranks one of the highest priority toxic materials. Continuous regulation of environmental Pb exposure has contributed to dramatically diminished exposure levels of Pb, for example, blood level of Pb. However, the safety level of Pb is not established, as low-level exposure to Pb still shows severe toxicity in high susceptible population and late onset of some diseases from early exposure. In the present study, we focused on food-borne Pb exposure and found broad variations in Pb exposure levels via food among countries. In addition, there are genetic or ethnical variations in Pb-targeted and protective genes. Moreover, various epigenetic alterations were induced by Pb poisoning. Therefore, we suggest a systemic approach including governmental (public) and individual prevention from Pb exposure with continuous biological monitoring and genetic or epigenetic consideration. Keywords: Lead (Pb); exposure; blood lead level (BLL); susceptibility; variation; genetic polymorphism; epigenetics; ALAD (δ-aminolevulinic acid dehydratase); metallothioneins

INTRODUCTION Lead (Pb) ranks the number 2, following arsenic (As), on the substance priority list of Agency for Toxic Substances and Disease Registry, based on a combination of its frequency, toxicity, and potential for human exposure [1]. It is one of well-known toxic heavy metals, having long history for usages over 6,000 years [2]. Unique properties of Pb, like softness, high malleability, ductility, low melting point, and resistance to corrosion, have resulted in its widespread usage in different industries like automobiles, paint, ceramics, plastics, etc. [3]. Due to Pb ubiquity in environment, its poisoning causes dysfunctions in various organs such as kidneys, bones, hematogenesis, cardiovascular system, and acute

Address correspondence to Mihi Yang, College of Pharmacy, Sookmyung Women’s University, Cheongpa-ro 47-gil 100, Youngsan-Ku, Seoul 140-742, Republic of Korea. E-mail: [email protected]


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J. Kim, Y. Lee, and M. Yang

or chronic damage to the central or peripheral nervous system in human [4]. Particularly, its risk mechanism, for example, late onset of Alzheimer at early exposure, has been emphasized with epigenetic approaches [5–7]. Considering its long latent period and toxic characteristics, endocrine disrupting and encephalopathic risks for children, many researchers have been re-emphasized Pb for high susceptible population [8]. For the highly susceptible population, children have been affected by relatively low levels of exposure to Pb, for example, less than 10 μg/dL of blood level of lead (BLL), and shown diseases in the neuro-, immuno-, reproductive, and cardiovascular systems [8]. The European Food Safety Authority Expert Panel on contaminants identified Pb-reduced intelligence quotient (IQ) levels in young children and high blood pressure in adults as the key health effects on which to base its assessment [9]. In addition, there are large variations in patterns or sources of Pb-exposure and its severity of outcomes among countries. Considering characteristics of Pb exposure in each country, each government should prepare proper strategies to control Pb exposure. In a case of Korea, leaded gasoline began phasing out in 1986 and it brought out dramatic cut of Pb exposure levels [10] with the rapid decline in the early 2000s [11–12]. For example, the overall geometric mean of BLL in the Korea National Health and Nutrition Examination Survey (KNHANES) III 2005 became 2.61 μg/dL, which is less than one-fifth of that in the 1980s of the Korean population [11, 13–14]. The reduction of Pb exposure can be also seen in other countries [15]. However, the reduced amounts of BLL are various among countries. For the reasons of variations in BLL in countries, geographical or environmental conditions including food of each country can be firstly considered [11]. In addition, ethnical variations in Pb-specific toxicokinetics or genetic variations of Pb-targeted or protective enzymes can be thought to bring out various outputs for Pb regulation [16–17]. Pb presents in various environmental media including air, water, sediments, and soil [18]. Major sources of environmental exposure to Pb are drinking water (10–20 μg/L), canned food, and Pb-contaminated soil products [19]. As results of these contaminants, dietary exposure to Pb has attracted considerable interests owing to the well-documented health hazards associated with ingestion [20]. The body burden of Pb among ordinary people mostly depends on the dietary intake of Pb [21]. The World Health Organization (WHO) also reported that more than 80% of the daily intake of Pb was derived from the ingestion of food, dirt, and dust [8]. The amount of Pb in food plants depends on soil concentrations and is highest around mines and smelters. Cereals can contain high levels of Pb. Milk or formula is a significant source of exposure to Pb for infants. The use of Pb-soldered food and beverage cans may considerably increase the lead content, especially in the case of acidic foods or drinks. Pb also comes to unintentionally contaminate food as the result of contamination with soil or from Pb-used machinery to process items, for example, wheels

Exposure to Lead via Food

for flour that are coated with Pb. As alcoholic drinks tend to be acidic, the use of any Pb-containing products in their manufacture or distribution can raise Pb levels. In the present study, we focused on (1) food-borne Pb exposure in different countries, (2) genetic variations in Pb-targeted or protective enzymes, (3) epigenetic alterations as Pb-toxic mechanisms, and (4) prevention of Pb poisoning.

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VARIATIONS IN FOOD-BORNE EXPOSURE TO Pb Pb can be accumulated in fish and shellfish and can be found at higher levels in the offal (liver and kidney) of food animals. Therefore, consumers with diets rich in these foods may be exposed to an unacceptable level of Pb. A further source of Pb in the diet is food containers incorporating Pb, for example, storage in Pb-soldered cans, and ceramic vessels with Pb glazed and crystal glass. Finally, the past use of Pb as a material for water pipes in many older houses may result in unacceptably high levels of Pb in water supplies [9]. Recently, 15 European countries submitted approximately 140,000 results of Pb concentrations in various food commodities and tap water [22]: Considerable variation between and within countries existed in the contribution of different food categories/groups. When food items were separated into 15 categories, Demark and Poland showed the highest levels of Pb intake (∼0.7 μg/kg bw/day) and Slovakia showed the lowest levels of Pb intake-approx. half of the highest country’s level (∼0.3 μg/kg bw/day). Estimated adult means of Pb dietary exposure across European countries were in the range of 0.36 to 1.24 μg/kg bw/day. Major contributors to Pb exposure were cereal products, followed by potatoes, cereal grains (except rice), cereal-based mixed dishes, leafy vegetables, and tap water. Game meat, offal, and algae food supplements showed the highest levels of Pb (3.15, 1.26, 1.07 mg/kg, respectively). Demark and Finland showed higher proportion in “miscellaneous products and products for special dietary use” (including algae, supplement, infant food, etc.) of daily intake of Pb. However, Italy and Poland showed higher proportion of Pb in “vegetables, nuts, and pulses” than that of other countries. The U.K. Total Diet Study (TDS) reported contribution (%) of each food group to total population dietary exposures to Pb, 2006 (23). The offal group had the highest Pb concentration (0.065 mg/kg) and the greatest contributions to the population dietary exposure were made by the beverages (17%) and the bread and other vegetables groups (16%) (23). In French populations, the highest concentrations of Pb were found in crustaceans and mollusks (0.113 mg/kg) and chocolate (0.023 mg/kg) (24). The main contributors of Pb exposure in adults were alcoholic beverages, bread and dried bread products and water. Milk was the main contributor in children (24). Concerning the Saudi diet, Othman et al. carried out a study to determine Pb contamination in 104 of the representative food items and to estimate the


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J. Kim, Y. Lee, and M. Yang

dietary Pb intake of Saudi Arabians (25). Sweets, vegetables, legumes, eggs, meat and meat products were the highest sources of Pb (0.011-0.199 mg/kg) (25). Considering the amounts of each food consumed, the major food sources of Pb intake for Saudi can be arranged as follows: Vegetables constituted the highest Pb intake (25.4%), followed by cereal and cereal products, beverages and sweets (25). In addition, a Lebanese study showed the main contributors to the dietary intake of Pb (26): The highest source was vegetables, which constituted 48.7%, followed by breads and cereal-based products, which constituted 31.4%. In Ghanaian markets, the highest Pb content was detected in lettuce (0.56 ± 0.03 mg/kg) among vegetables, whereas the lowest concentration was in watermelon (27). In East Asia including Japan, Korea, and China, the Pb contamination levels in food/water had an obvious descending trend [28]: From 1979 to 2009, the inferred contamination levels decreased from 27.2 to 5.3 μg/day in Japan, from 36.3 to 12.8 μg/day in Korea, and from 35.5 to 20.3 μg/day in China. A Chinese study, which was performed at Xiamen, the southeast coast of China, showed the highest mean concentration of Pb was in carrot, 0.181 mg/kg, followed by offal, and spinach (29). The Pb-high contamination in some vegetable or fruits may be closely related to the pollutants in irrigation water, farm soil, or pollution from the traffic (29–30). In addition, another Chinese group studied environmental contamination and health hazard of Pb around mercury mining deposit in western Hunan Province, South China and found that average daily intake dose (ADD) of Pb via drinking water and rice consumption reached up to 4.63 μg/kg and 2.99 μg/kg, respectively (31): Taking rice consumption and soil ingestion into account, the ADD of Pb via mouth was 7.7 μg/kg/day. In USA- TDS 2006-2008, Pb was not detected in most food (731 items). Only some products had quantifiable concentrations of Pb, namely: chocolate syrup (mean, 0.02 mg/kg) or cake (0.011 mg/kg), candy bar (0.016 mg/kg), and canned food (∼0.01 mg/kg) (32). Therefore, daily intake of Pb in US adults is estimated lower (∼0.0 μg/kg bw) than those in other countries (33). Canadian- TDS 2007 reported that herbs and spices had the highest concentration of Pb (0.39 mg/kg). Chewing gum (0.09 mg/kg), salt, yeast (0.04 um/kg), baking powder (0.02 mg/kg), organ meats, cereal oatmeal, or cooked wheat and rice (0.01 um/kg) followed them [34]. In Korea, Oh and colleagues [35] evaluated the main route of exposure to Pb for the general population with multiroute and multimedia exposure assessment: BLL was statistically higher in the male subjects than in the female subjects (3.39 and 2.22 μg/dL, respectively). People were mainly exposed to Pb via food, respiratory, and drinking water (22.89, 5.06, and 0.002 μg/day, respectively). The Korean FDA (KFDA) recently reported that echinoderms, mushroom, and shellfish belonged to the categories of high concentration of Pb (0.4 mg/kg ∼ 1.1 mg/kg) [36]: In detail, echinoderms (sea squirt and warty sea

Exposure to Lead via Food

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squirt) had 1.1 mg/kg of Pb. In most shellfishes, Pb concentration was higher than 0.3 mg/kg (average, 2.0 mg/kg). In mushroom, manna lichen had the highest concentration of Pb, 10 mg/kg; however, shiitake and oyster mushroom had less than 0.3 mg/kg of Pb. In total Pb intake, farm products constitute 46% in which cereal constituted 28% of whole Pb intake. Taken together, the food items with high concentration of Pb are similar, for example, offal, sea food, or roots and tubers; however, “daily intake of Pb” and “main sources of Pb” are various among countries, maybe due to their different food intake patterns or habits (Table 1).

GENETIC VARIATIONS IN Pb-TARGETED AND PROTECTIVE GENES New molecular evidences have indicated that genetic factors, which were affected by Pb as targets for expression of toxicity, can modify Pb toxicity or might be protective from Pb poisoning. For example, the δ-aminolevulinic acid dehydratase (ALAD), the hemochromatosis gene (HFE), and the vitamin D receptor (VDR) have shown potential as candidate susceptibility genes for Pbtoxicity [17].

ALAD Porphobilinogen synthase/ALAD is an important enzyme for the heme biosynthesis, because it synthesizes aminolevulinicacid molecules [37]. ALAD, which is encoded in humans by a single gene localized to the chromosome 9q34 region, is a polymorphic enzyme. There are ALAD1 and ALAD2 alleles (rs1800435). The difference between these two alleles lays in a single G→C transversion mutation at nucleotide 177. The allozyme resulting from the ALAD2 allele contains the substitution of a neutral asparagine for a positively charged lysine at residue 59 [38]. Generally, Caucasians have the highest frequency of the ALAD1 homozygote (ALAD 1-1), with approximately 18% of the ALAD1 and ALAD2 heterozygote (ALAD 1-2) and 1% being ALAD2 homozygote (ALAD 2-2) [39]. Using NHANES III, Scinicariello and colleagues [38] reported a significant interaction between BLL and the ALAD2 allele in non-Hispanic whites and non-Hispanic blacks in relation to systolic blood pressure: BLL was associated with systolic BP in non-Hispanic whites and with hypertension and systolic, diastolic BP in non-Hispanic blacks. Non-Hispanic white ALAD2 carriers in the highest BLL quartile (3.8-52.9 μg/dL) had a significantly higher adjusted prevalence odds ratio for hypertension, compared to the ALAD1 homozygous individuals. In contrast, African and Asian populations have low frequencies of the ALAD2 allele with few or no ALAD2 homozygotes [37, 39–40]. A large variation of the mutation rate (0.01–0.20) was found in Asian populations. Korean



Crustaceans and mollusks

Sweets, vegetables, legumes, eggs, meat, and meat products


Saudi Arabia

Canada United States


Ghana China

Lettuce Carrot (followed by offal, and spinach) Echinoderms, mushroom and shellfish Herbs and spices Chocolate syrup and canned food

Offal group



Game meat; game offal; algae food supplements

Highly Pb-Contaminated Food



0.39 0.02; ∼0.01


0.56±0.03 0.181




3.15; 1.26; 1.07

Pb Levels of the Food (mg/kg)

Table 1: Variations in Food-Borne Exposure to Pb among Countries

Farm products constitute 46%

Vegetable (48.7%); breads and cereal-based products (31.4%)

Cereal products, followed, potatoes, cereal grains (except rice), cereal-based mixed dishes and leafy vegetables and tap water Beverages (17%); bread and other vegetables (16%) Alcoholic beverages, bread and dried bread products and water Vegetables (25.4%)

Main Contributors

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[34] [32]


[27] [29]







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Exposure to Lead via Food

researchers found no association between the polymorphism and hypertension in Pb-smelters [41]; however, they observed the protective effect of the ALAD 1-2 or 2-2 genotypes against BLL on higher hematologic parameters [42] and renal function [43]. In addition, Zhao and colleagues [44] performed a meta-regression analysis with 15 publications to evaluate the association between the ALAD−G177C polymorphism and BLL: As a result, the ALAD1 homozygotes showed higher BLL than ALAD2 carriers (0.61 and 1.51 μg/dL, respectively). It suggests the presence of the ALAD1 allele may be more susceptible to Pb poisoning than that of the ALAD2 allele. Another SNP (rs1139488, 14719T>C), the ALAD RsaI-polymorphism, modified the relationship between IQ and blood Pb levels [45]: Increasing BLL with 1 μg/L, the T carriers demonstrated 0.06 score lower IQ than others. It suggests the ALAD RsaI-T carriers are more susceptible than the CC homozygote carriers. Thus, the T-genotype may slow or accelerate the protein synthesis, resulting in different amounts of ALAD protein translated [46, 47]. Recently, not only genetic but also epigenetic studies showed that Pb exposure increased the ALAD methylation and downregulated the ALAD transcription in cell models [48]. We will discuss this issue in detail in the section titled “Epigenetic Alteration by Pb Exposure.” Not only the previously mentioned genetic variations but also their phenotypical results should be further studied whether the polymorphisms influence phenotypes-response or susceptibility to Pb exposure or toxicity. We will further review Pb-related epigenetic alteration.

Glutathione-S-Transferases The glutathione-S-transferases (GSTs) are known as phase II metabolic enzymes that play important roles in detoxification of various toxicants, particularly metals, because glutathione is a key player in metal-induced oxidative stress defenses [49]. Several polymorphisms in GSTs result in phenotypic variations in enzymatic activity and have been suggested to play an important role in susceptibility to the harmful effects of Pb exposure [50, 51]. For neurotoxicity, Eum and colleagues [51] found that the GSTP1-Val105 allele and the GSTM1 deleted type modified Pb-related cognitive function in silver age of VA Normative Aging Study (NAS), USA: Persons with the GSTP1Val105 allele performed worse on cognitive assessments per unit and showed an increase in bone Pb biomarker levels. They also found Pb burden, as measured by bone Pb levels, to be marginally associated with worse cognition among individuals with the GSTM1 deletion polymorphism. Concerning cardiovascular toxicity, Lee and associates [52] found a strong association of the GSTT1 positive allele with hypertension in Pb-exposed Korean male workers: The adjusted odds ratio (OR) for having essential hypertension revealed a strong association between the GSTT1 presence and



J. Kim, Y. Lee, and M. Yang

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hypertension (OR = 1.59; 95% CI = 1.16–2.19), using null genotypes as references. For immune or inflammatory responses, Sirivarasai and coauthors [50] reported that individuals with the null genotypes of GSTM1 and GSTT1 and the GSTP1-Val105 allele were more sensitive to Pb exposure with elevated Creactive protein than others in the Thai population. In the Korean population, Kim and colleagues [53] also reported that BLL was associated with inflammatory responses, which were associated with the polymorphisms at the GSTM1, null /presence, and the tumor necrosis factor-alpha (TNF-α), 308 G/A.

HFE Some epidemiologic studies have shown an association between Pb exposure and cardiovascular disease. Recent reports using data from NHANES III suggested even low BLL (C (rs2239185) and nucleotide 32 of exon 11, T>C (rs731236)] in adolescents of NHANES III subjects. A Portuguese worker study also showed the VDR BsmI polymorphism influenced BLL, since carriers of the variant allele B showed lower BLL than wild-type b homozygotes, although significance was only reached for B/B homozygotes [75]. However, Rezende and associates [76] reported that lower whole blood or plasma Pb and % whole BLL or plasma Pb were found in the subjects with the haplotype combining the a, b, and f alleles for the ApaI, BsmI, and FokI polymorphisms, respectively, compared with the other haplotype groups. In addition, higher Pb dose was associated with worse renal function in current and former Korean Pb- workers with the variant B allele of the BsmI polymorphism [77].

Other Genetic Polymorphisms Among DNA repair genes, the x-ray repair cross-complementing group 3 (XRCC3) codes for a protein involved in homologous recombinational repair

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Exposure to Lead via Food

for double strand breaks of DNA and cross-link repair in mammalian cells [78]. Recently, association between the XRCC3 polymorphisms and susceptibility to Pb was studied [79]. The workers with XRCC3- 241 CT or TT showed significantly higher BLL than those with XRCC3-241CC. In addition, transferrin (TF), a monomeric glycoprotein that facilitates the transport of ferric iron among the sites of absorption, storage, and utilization [80], has been emphasized as a modulator for Pb poisoning. For example, Roy and colleagues [81] suggested that children who carry the TF C2 variant (rs1049296, P589S) are more susceptible to Pb-related lowering IQ. In addition, the carriers of the C2 variant showed increased susceptibility to Pb-induced toxicity on electrocardiographic conduction in the NAS, USA [54]. When the genetic effects of HFE and TF were combined, the TF P570S (P589S) variant carriers showed high BLL among Mexican children [82]: The carriers of both HFE and TF variant alleles had 50% higher BLL than those of the wild alleles. The subjects with the both HFE and TF variants showed significantly higher risk (OR = 2.3: 95% CI = 1.0–5.5) of having high levels of BLL (≥10 μg/dL). Table 2 shows a current summary of the relationship between genetic polymorphisms and Pb- related end points. However, there are some conflict results to support the above results [17]; therefore, it is rushed to conclude the previous genetic variations as the susceptible or risky genetic polymorphisms for Pb poisoning.

EPIGENETIC ALTERATION BY Pb EXPOSURE Growing evidences show that environmental metal exposure results in epigenetic alteration, which may lead to a link between heritable changes in gene expression and disease susceptibility [83]. DNA methylation, undoubtedly the most studied epigenetic mechanism, corresponds to the addition of a methyl group to the 5 carbon position on the cytosine pyrimidine ring [5-methylcytosine (5mC)] via DNA methyltransferases (DNMTs). CpG sites, which are “CpG islands” on the DNA promoter region, are the target sites of DNA methylation, which is most commonly associated with gene silencing or plays a critical role in central developmental events [6]. For example, chronic exposure to Pb showed increase of reactive oxygen species (ROS) [84], which inhibit methyl-CpG binding proteins and alter function of DNMTs [85]. The recent discovery is that methylcytosine dioxygenase, particularly TET proteins, can oxidize 5mC, a global methylation parameter, into 5-hydroxymethylcytosine (5hmC), which has added another layer of regulation to the DNA methylation process [6]: The TET proteins are sensitive to oxidation, while Pb inhibits the TET proteins via oxidative stress. Some studies reported that Pb exposure could change DNA methylation status of ALAD, amyloid precursor protein (APP), collagen type 1 alpha-2



Heme biosynthesis

Function of Genes

rs28366003, −5 A/G

rs396230, A216 G


rs8052394, A1245G

rs1799945, H63D

rs1800562, C282Y


MT s: Metal-binding proteins MT1A

Iron absorption and deposition in the liver

Normal vs. deficient



Normal vs. deficient

rs947894, Ile105Val

rs1139488, 14719T>C

rs1800435, G177C:



GSTs: Metabolizing enzymes GSTP1




The higher chronic Pb exposure lowered the urine uric acid, especially in workers with the GG genotype [65]. Individuals with the GG genotype had statistically higher BLL than those with AA and AG genotypes [61]; Pb levels of pregnant women with AG genotype were significantly higher than those with AA genotype [67]; Mutation resulted in a marked reduction in the rate of dioxin-induced transcription [69]. Presence of the mutant allele was more susceptible to the toxic effects of Pb on their systolic blood pressure and serum renal function parameters [66].

Val105 allele performed worse on cognitive assessments per unit increase in bone Pb biomarker levels [51]. GSTT1 presence showed high OR for Pb-related hypertension (odds ratio, OR-1.593; 95% confidence interval, CI-1.157-2.194) [52]. GSTM1, GSTT1 null, and GSTP1 Val105 allele were more sensitive to Pb exposure with elevated C-reactive protein than others [50]. Presence of the variant allele showed low bone or blood level of lead [55] and had steeper cognitive decline, compared with wild-type carriers [59]. Presence of the variant allele showed low bone or blood level of lead [55] and had steeper cognitive decline [59] and a negative association between tibia Pb and birth weight [58].

Non-Hispanic white ALAD2 carriers in the highest BLL quartile had a significantly higher OR for hypertension [38]; ALAD2 presence was protective from hematologic [42], and renal disorder [43], and had low BLL levels [44]. T carriers demonstrate 0.06 score lower IQ with increasing B with 1μg/L [45].

Table 2: Relationship Between Genetic Polymorphisms and Pb- Related End Points

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Nuclear hormone receptor

Mutant B or t allele presence showed inverse association rs1544410 (G > A), between cognitive function (full scale IQ) and BLL [45]; Low BLL BsmI (b vs. B) rs731236 (T > C), TaqI was detected in the variant allele B [75], however, was also found in the haplotype combining the a, b, and f alleles [70]; (t vs. T) Higher Pb dose was associated with worse renal function with rs1544410 (T > C), the variant B allele [77]. FokI (f vs. F) rs797523 (A > C), ApaI (a vs. A) rs1049296,, P589S (C > Presence of variant T allele (CT or TT) showed steeper IQ decline T) due to BLL than the wild (CC) type [54]. rs861539, T241M (C > T) Presence of variant T allele showed higher BLL than the wild (CC) type [79].

BLL, blood Pb level; ALAD, δ-aminolevulinic acid dehydratase; VDR, 1,25-dihydroxyvitamin D3 receptor; HFE, hemochromatosis gene; MT, metallothionein; GST, glutathione S-transferases; XRCC3, X-ray repair cross-complementing group 3; TFC2, transferrin C2.

Transportation of ferric iron (Fe(III)) XRCC3 DNA repair



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J. Kim, Y. Lee, and M. Yang

(COL1A2), LINE-1, and p16 [5, 48, 86–88]. Therefore, Pb exposure can alter the DNA methylation, which is associated with biological pathways for human health.

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ALAD Concerning ALAD, Pb-targeted enzymes result in heme deficiency; most studies have focused on its genetic polymorphisms and Pb susceptibility [39]. However, a Chinese group reported that Pb exposure increased the ALAD gene methylation levels and downregulated ALAD transcription [48]: The difference in methylation frequencies between exposures and controls was statistically significant and individuals with methylated ALAD gene showed an increased risk of Pb poisoning (adjusted OR = 3.57, 95% CI, 1.55–8.18). This study suggests a new mechanism of Pb toxicity via Pb-induced ALAD methylation.

APP Amyloid precursor protein (APP) is processed sequentially by the β-site APP cleaving enzyme and γ-secretase to generate amyloid β (Aβ) peptides, one of the hallmarks of Alzheimer disease [89]. In addition, developmental exposure of primates and rodents to Pb predetermined the expression of amyloid-β precursor protein (AβPP) later in life. For example, the aging primates exposed to Pb as infants exhibited an overexpression of the Aβ protein precursor (AβPP), Aβ and enhanced pathologic neurodegeneration [90]. In addition to AβPP, the preponderance of genes that were reprogrammed was rich in CpG dinucleotides implicating DNA methylation and chromatin restructuring in their regulation. Increased Aβ can lead to the generation of ROS, and epigenetic modulation in the methylation pattern of cytosines can interfere with the repair or oxidation potential of adjacent oxidized guanines [91]. A female monkey study also showed that the expression of APP and β-site APP cleaving enzyme 1 (BACE1) as well as their transcriptional regulator Sp1 was elevated in the monkeys exposed to Pb, during development [92]. Li and colleagues [93] also showed that four CpG dinucleotide sequences, which were located at positions 2284, 2280, 2261, and 165 among the 41 CpGs in APP promoter, were hypomethylated in the Pb-exposed PC 12 cells.

COL1A2 The collagen type 1 alpha-2 (COL1A2) gene product is an important component of connective tissues, including the chorio-amniotic membranes and the uterine cervix [94, 95]. Hanna and colleagues [94] found that COL1A2P407 CpG site within the promoter region of the COL1A2 was associated with Pb concentrations in women undergoing a first completed in vitro fertilization

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cycle: The methylation (%) of COL1A2-P407 was increased in the lower Pb exposure group ( G polymorphism in the promoter of the human gene for metallothionein IIA. Human Genetics. 2006;120(4):553–560. 70. Rezende VB, Amaral JH, Quintana SM, Gerlach RF, Barbosa F, Tanus-Santos JE. Vitamin D receptor haplotypes affect lead levels during pregnancy. Science Total Environ. 2010;408(21):4955–4960. 71. Krieg EF, Jr., Butler MA, Chang MH, Liu T, Yesupriya A, Dowling N, et al. Lead and cognitive function in VDR genotypes in the third National Health and Nutrition Examination Survey. Neurotoxicol Teratol. 2010;32(2):262–272. 72. GeneCards. Vitamin D (1,25- dihydroxyvitamin D3) receptor. 2011. http:// wwwgenecardsorg/cgi-bin/carddisppl?gene=VDR&search=vdr. 73. Valdivielso JM, Fernandez E. Vitamin D receptor polymorphisms and diseases. Clinica Chimica Acta. 2006;371(1–2):1–12. 74. Jain R. When too much sun is never enough: association of the VDR gene polymorphisms with insulin resistance. Thesis of Auckland University of Technology;2010. 75. Garcia-Leston J, Roma-Torres J, Vilares M, Pinto R, Prista J, Teixeira JP, et al. Genotoxic effects of occupational exposure to lead and influence of polymorphisms in genes involved in lead toxicokinetics and in DNA repair. Environ Int. 2012;43:29–36. 76. Rezende VB, Barbosa F, Jr., Montenegro MF, Sandrim VC, Gerlach RF, TanusSantos JE. Haplotypes of vitamin D receptor modulate the circulating levels of lead in exposed subjects. Arch Tox. 2008;82(1):29–36. 77. Weaver VM, Lee BK, Todd AC, Ahn KD, Shi W, Jaar BG, et al. Effect modification by delta-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase gene polymorphisms on associations between patella lead and renal function in lead workers. Environ Res. 2006;102(1):61–69. 78. Liang HJ, Yan YL, Liu ZM, Chen X, Peng QL, Wang J, et al. Association of XRCC3 Thr241Met polymorphisms and gliomas risk: evidence from a meta-analysis. Asian Pacific journal of cancer prevention. Asian Pac J Cancer Prev. 2013;14(7):4243–4247.

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Environmental exposure to lead (Pb) and variations in its susceptibility.

Based on exposure frequency and intrinsic toxicity, lead (Pb) ranks one of the highest priority toxic materials. Continuous regulation of environmenta...
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