Zn is an important element in both industrial and biological sense. The great industrial importance of Zn has made this element a potential hazard to vegetable consuming humans. In this review, the important biological role of Zn and the human Zn dietary requirement as well as its toxicity are discussed. The Zn in various commonly consumed vegetables have also been reviewed. Based on a range to previous studies, it is confirmed that human activities such as metal mining and smelting as well as the application of manure fertilizer could contribute to Zn enrichment in both cultivation soil and the vegetable tissues. Zn in vegetable tissues also been discovered to have a strong and positive correlation with some element such as K, Fe, Mn and Cd. Due to Zn’s industrial importance, it will always be a possibility of the occurrence of high Zn enrichment due to anthropogenic activities. Despite the biological importance, the constant monitoring of Zn in various food crops should not be neglected.
The ability of human to discover and utilize natural heavy metal resources has been an indispensable factor in advancement of human civilization. The term “heavy metal” can be scientifically defined as the metal (e.g. copper, zinc, iron, cadmium, lead as well as various rare earth elements) and metalloid (e.g. arsenic) elements comprised in Groups 3 to 16 that are in periods 4 and greater in periodic table . Ecological and human health risks is imminent due to continuous and chronic exposure of these elements [2,3]. Since metals are exists in form of chemical element, these metal and metal containing compounds are non-biodegradable and may accumulate and magnified in concentration up to harmful level along food chain [4,5]. The ecological and biological impact of these elements has been element specific and vary due to their chemical property and their chemical forms .
Zinc is an essential trace element that poses great importance in human dietary nutrition and health [7-9]. Therefore, it is known to be the second most abundant trace metal in human body after iron . It is consisting 2-4 g within a human body mass with plasma concentration of 12-16 µM . The role of zinc on human health was originally observed and reported by Prasad et al. . Since there is no specialized Zn storage system in human body, daily intake of Zn is necessary to maintain a steady state .
The objective of this review is to summarize the role of Zn in human physiology, the hazard of its enrichment and its appearance in commonly consumed vegetables.
Human zinc dietary requirement
The human zinc diet can be affected by the many factors. One of the factors is the type of food consumed. The resorption of Zn will be poorer from vegetarian foods in comparison of meat diet . This is due to the chelation of zinc by non-digestible plant ligands such as dietary fibers, phytates and lignin .The appearance of other cations could also affect zinc availability. The resorption could also be reduced by increased bivalent cations, such as iron, cadmium, nickel, calcium, magnesium and copper [9,11,12].
The recommended daily intake of zinc is dependent to several factors: age, sex, weight and the phytate content of diet . The recommended values are also differing in each country and international regulatory organizations. The United States Food and Nutrition Board recommended daily intake of 11 mg and 8 mg for adult male and female respectively . German Society of Nutrition’s recommendation was set at 10 mg and 7 mg for adult male and female respectively . Due to their impact on zinc availability to human diet, the dietary phytate must not be ignored in assessing zinc bioavailability to human. World Health Organization categorized the potential absorption efficiency of zinc, per phytate zinc molar ratio into three groups; high (<5), moderate (5-15) and low (>15) . European Food Safety Authority (EFSA) have also made similar categorization according to dietary phytate intake .
Due to the difference of dietary zinc requirement by ages, sex, weight and phytate ingestion [9,14,15]. These factors must be taken consideration when the potential health risks of dietary zinc be assessed. The assessment of zinc related health risks must be built upon relevant localized data. The average bodyweight and food ingestion behavior across populations may be vastly different according to their religion, ethnicity and their individuals’ societal norms. These differences must be taken account when health risk assessment will be done.
Biological roles and health benefits
Zinc has been known to be essential to multiple crucial biological processes. Zinc is a major component of protein ligands, it was discovered to present in approximately 3000 human proteins based on zinc signature motif in protein sequences [16-19]. The amount of zinc proteins in human zinc proteome will even be larger when additional functions of zinc in regulation . Zinc is also involving in various cellular functions.
One of the roles of zinc playing in human biology is immunity [21,22]. Zinc deficiency can result in immunodeficiency . Zinc ions are crucial element in the regulation of intracellular signaling pathway in innate and adaptive immune cells . Immune systems is known to be susceptible to alteration in zinc levels and every immunological response by human body is related to zinc in varying extend . There are two immunological mechanisms in human physiology; innate and adaptive immunity. Innate immunity is the first line of human biological defense countering various forms of pathogens. Innate immunity of human consists of polymorphonuclear cells (PMNs), macrophages, and natural killer cell (NK). Zinc deficiency is associated to reduced PMN chemotaxis and phagocytosis. Deficiency as well as excess of zinc could also inhibit the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which functions to destroy pathogens after it was phagocyted [23,24]. Chelation-free zinc was also be observed to abolish the formation of neutrophil extracellular traps (NETs) in vitro. This is a matrix of DNA, chromatin, and granule proteins that capture extracellular pathogenic protein . Zinc also plays a role in the process of adhesion of monocytes to endothelial cells. In the context of human umbilical endothelial cells, its zinc levels were shown as inhibitive to monocyte adhesion to endothelial cells. It was suggested as one of the key factors in the early stages of antherogenesis . Zinc is also heavily involved in production and signaling of various inflammatory cytokines in variety of cells . Overweight and obese adults with low dietary zinc intakes were observed to have lower plasma zinc concentration, intracellular zinc content and intracellular free zinc levels. Upregulated IL-1α, IL-1β and IL-6 genes were also observed for these patients in comparison of those with sufficient zinc intake . Besides these aforementioned cytokines, zinc deficiencies in humans also influencing the production of IL-2 and TNF-α . The supplementation of zinc to patients caused decreased expression of TNF-α, IL-1β in their phytohemagglutinin-p-stimulated mononuclear cells, showing their antagonistic relationship. While zinc supplementation was showed to increase the expression of IL-2 and IL-2Rα . Zinc deficiency is also associated with the damage of lysosome integrity causing the activation of MLRP3 (ACHT, LRR, and PYD domains-containing protein 3) inflammasome, leading to IL-1β activation . Zinc deficiency causes severe impairment of human immune function. On the flip side, excessive zinc could also provoke similar immune impairment as zinc deficiency does. Excessive zinc could cause the suppression of T and B cell function, overload of Treg cell and direct activation of macrophages . Worse inflammatory profile was observed in zinc deficient institutionalized elders .
Besides regulating immunity related cytokine and suppress of inflammation, zinc also have their importance in the function of lipid and glucose metabolism, reduction of oxidative stress, regulation and formation of insulin . The formation of reactive oxygen species (ROS) and also the reactive nitrogen species could be inhibited by physiological concentration of zinc [34,35]. There are a few factors contributing on the antioxidation effect of zinc. These was achieved by: (i) regulate oxidant production and metal-induced oxidative damage; (ii) associating itself with sulfur in protein cysteine cluster, from which metals can be released by nitric oxide, peroxides, oxidized glutathione and other thiol species; (iii) induction of metallothionein, a zinc binding protein that can act as oxidant scavenger; (iv) regulating glutathione metabolism and protein thiol redox status; and (v) regulating redox signaling directly as well as indirectly . As a cofactor of antioxidant enzyme Cu, Zn-super oxide dismutase (SOD1), zinc is an important factor in keeping Cu, Zn-SOD functionable . Glutathione peroxidase expression could also be increased by zinc supplementation . It must be noted that zinc does not always antioxidative, prooxidative properties could also be dominant when intracellular zinc levels are high. Zinc oxide nanoparticle has been shown to increase oxidative stress in 3T3-L1 adipocyte in a dose dependent manner despite increasing the expression of antioxidant enzymes [39,40]. Higher dose of zinc oxide nanoparticle was observed to severely increased oxidative stress at high doses (10 mg/kg) .
Tight interaction between zinc and adipose dysfunction is a major interest in lipid metabolism study . It has been reported that zinc supplementation can results in reduced total cholesterol, LDL cholesterol and triglycerides; as well as increase in HDL cholesterol level in patients [38,42]. Zinc finger protein ZNF202, as the name suggest, is a zinc containing protein that are involving in HDL metabolism . This proteins was suggested as a candidate susceptibility gene for human dyslipidemia . Decrease in zinc plasma concentration has resulted in worse lipid profile in zinc deficient institutionalized elders . Zinc status was tightly associated to adipose tissue in obesity and its pathologies. High fat intake has resulted in decrease of zinc level in adipose tissue of Wistar rats and is tightly related with excessive adiposity, inflammation, insulin resistance and potentially atherogenic changes .
Zinc is essential in normal synthesis, storage and secretion of insulin in pancreatic β cells [33,46]. Zinc supplementation has been beneficial to the glucose homeostasis of diabetic patients  and vice versa . This metal have been known to playing a role in glycolysis stimulation, gluconeogenesis inhibition and modulation of glucose in adipocytes . The contribution of zinc in insulin biosynthesis and storage is by forming a hexamer with proinsulin molecules along with calcium. This proinsulin hexamer assembly could form a protective structure that protected some polypeptide chain from proteolytic cleavage, while leaving C-peptide segment of pro insulin exposed to processing enzymes. The alteration of solubility of proinsulin hexamer to insulin hexamer and subsequently crystalized insulin hexamers giving further protection of newly formed insulin chains and separating proinsulin from insulin as the conversion to insulin occurring. Insulin hexamers are also enjoys greater chemical and physical stability than its monomer counterpart . Therefore, the formation and crystallization of proinsulin/insulin hexamer with zinc and calcium ions stabilizes insulin and protects it from degradation. Beside taking part in insulin biosynthesis, storage and crystallization, zinc is also known to be inhibitive to glucagon secretion . Glucagon is a hormone that its function is opposite of insulin’s. Zinc supplemented diabetic patients was resulted in elevated insulin and serum zinc coupled with reduced blood glucose, glucagon and glucose-6-phosphatase, indicating the role of zinc in physiological glucose regulation .
Zinc is also a key element in the growth and development of human. Zinc deficiency during embryogenesis may influence the final phenotype of all organs. Fetal growth may also influence by zinc restriction during pregnancy. Sufficient zinc supplementation reduced the risk of pre-term birth .
Zinc toxicity to human
Despite the apparent biological importance of zinc, acute as well as chronic exposure to overly high concentration of zinc could also bring detrimental impact to human health. The manifestation of acute zinc poisoning could include nausea, vomiting, diarrhea, fever and lethargy. While long term chronic exposure to excessive zinc levels could resulting in metabolic interference with other trace elements. Daily intake of 150-450 mg of zinc have been related to reduction of copper utilization, alteration of iron function, reduction of immune function, as well as the reduction of high-density lipoprotein (HDL) level [54,55]. Zinc has been discovered to have an antagonistic relationship with copper. Therefore, zinc has been utilized to treat Wilson disease, an autosomal recessive disorder of copper metabolism since 1960s. However, copper is still an essential element crucial for the survival of human being, imbalance in zinc intake may cause an induction of copper deficiency (hypocupremia) [14,56,57].
Chronic enriched zinc intakes could result in various chronic effects in gastrointestinal, hematological, and respiratory system along with alteration in cardiovascular and neurological systems of human . Human subjects supplemented with 300 mg zinc per day has been characterized to have elevated LDL cholesterol and reduced HDL cholesterol . Cu, Zn SOD antioxidant is very sensitive toward Zn/Cu ratio changes in plasma. Zinc supplementation may result in excess of free radicals that are detrimental to plasma membrane. The competition between zinc and iron will also causing a decrease if serum ferritin and hematocrit concentration .
Zn in vegetables
Vegetable representing a significant portion of recommended human daily diet due to its richness in essential nutrients while low in fat, sodium and calories . As discussed in previous section, Zn is considered as an essential element for human survival. However, an excess of it will jeopardize human health, causing health risk to human being. This review will present some of the recent studies that investigated the concentration of Zn in a variety of commonly consumed vegetables in several locales. These studies have been presented in Table 1.
Table 1. Review of Zn concentrations and notable findings of previous studies
Zn is essential not only to humans, but also to food crops themselves. There are a numerous studies that confirms the positive correlation of Zn in plant tissues and Zn in surrounding habitat [60-62]. An experimental exposure of 5 mM and 10 mM of Zn to common bean, Phaseolus vulgaris, has revealed a positive Zn accumulation in consequence of the exposure . Another study that samples common purslane Portulaca oleracea in Costa da caparica, Portugal, also revealed similar pattern of Zn accumulation. However, due to high Zn contamination in two of their sites, the P. oleracea from those sites were highly contaminated and consumption were deemed unsafe . Ribwort plantain, Plantago lanceolata L., is a roadside and grassland flora that is widely used as food and herbal preparation in various countries. Drava et al. compared the Zn levels in P. lanceolata in a series of sites with varying anthropogenic characteristics. They revealed that samples collected near mines and smelting plants were up to 15 times higher in Zn concentration compared to rural area . A collective of vegetables were also been discovered to have elevated Zn concentration near Zhuzhou Smelter, Zhuzhou, Hunan Province, China .
Zn enrichment could lead to alteration in food crops’ physiology. de Figueiredo et al. study has associated Zn exposure to P. vulgaris with lower phytic level . Lowered phytic level could lead to increase of bioavailability of several micronutrients, including Zn since phytic acid is an antinutritive agent capable of blocking mineral absorption [64-66]. Reduced Zn during pods was also observed .
Zn tolerance differs among plants that are closely related genetically. The physiological impact of Zn exposure of two related vegetable species Brassica juncea and B. napus was investigated by exposing them to varying Zn concentrations up to 300 µM. This study revealed that in term of root damage, and microelement homeostasis alteration, B. juncea is more Zn tolerant than B. natus. The physiology of their root was also observed. It was discovered that the oxidative components were predominant compared with nitrosative component in root .
The impact of Zn to the physiology of a food crops isn’t limited to the elevation of its concentration in response of its exposure. In cooperation with other physiological significant element, varying physiological responses may be revealed. Zn (200 ppm) was co-exposed with varying concentration if potassium (K) to wheat (Triticum aestivum L.). It was observed that in consequence of Zn and K co-exposure, oxidative stress was minimized, root, shoot and root lengths were improved. Another wheat physiological parameter, such as wet and dry biomass, photosynthetic pigments, osmolyte regulators and membrane stability index were also improved. Reduction of MDA content was also observed . Inter-species correlation analysis on the heavy metal contents among wide range of vegetable and fruits also unveiled a strong and positive correlation between Zn and Cd . Zn is also found to have a strong and positive relationship with Fe and Mn, which are another physiological significant nutrient . Zn concentration in soil has also been discovered to be one of the factor influencing Cd accumulation in cabbage .
The utilization of manure as fertilizers is one of the major factors impacting Zn availability to vegetable crops. A collective of closed greenhouse cultivated vegetables in Nanjing, China, was investigated by Chen et al. . It was concluded that the Zn in cultivation soil was originated from chicken manure. The application of manure in agriculture isn’t only contribute to elevation of heavy metal accumulation. The application of cow manure biochar was revealed to be able to reduce the bioavailability and translocation factors of several heavy metals in Zucchini (Cucurbita pepo L.), including Zn. Mining and smelting activity is another major Zn source for vegetable. The Zn level along with Pb and Cd in ribwort plantain (Plantago lanceolate L.) near mines and smelting plants were found to be enriched up to 15 times beyond rural areas in Genoa and province, Liguria, North-Western Italy . Another studies has shown that the soil Zn level has been significantly enriched due to smelting activity nearby Huludao Zinc Plant, Liaoning Province, China .
Several recent studies have been conducted to investigate the potential human health risks of metals in vegetables. The Zn in Bok Choy (Brassica campestris L. ssp. chinensis Makino), Water Spinach (Ipomoea aquatica Forsk.), Shanghai green cabbage (Brassica chinensis L.), leaf lettuce (Lactuca sativa L. var. ramosa Hort.) from Shanghai, China. It was determined that the Zn concentrations in these vagetables were below the food safety limit set in China . The Zn levels in Lettuce (Lactuca sativa var. crispa), Ethiopian mustard (Brassica carinata A. Br) and Beet (Beta Vulgaris var. cicla) from wastewater-irrigated urban vegetable farming site in Addis Ababa, Ethiopia was also investigated for possible human health hazard. There was no Zn hazard discovered . Wastewater irrigated coriander, mint and fenugreek in Faisalabad, Pakistan was found to be a potential hazard to consumers due to their higher-than- permissible-limit Cd, Pb and Zn concentration .
It should be noted that not all of the Zn in a biological tissue is bioavailable. A collective of vegetables (Table 1) was sampled in Jijie Town, Gejiu city, Yunnan Province, China. It was noticed that there are a significant portion of Zn in vegetable tissues were categorized as insoluble metal phosphate . This can be interpreted as the bioavailability of Zn in these vegetables may be low . This factor should be taken account when the human health risk of heavy metals will be assessed.
Zn is crucial for both industries and human physiology. It involves in various important biological processes. However, Zn would be toxic to human health in excessive concentration. Therefore, constant close monitoring of Zn levels in commonly consuming vegetables are crucial in public health viewpoint. The Zn concentration can be elevated due to the application of chicken manure fertilizer, mining and smelting activities. Zn in vegetable tissues were also been discovered to have a correlation with other chemical elements, such as Fe, Mn and Cd, indicating Zn enrichment could impact a vegetable by altering the level of other biologically significant elements. Finally, the human health risk assessment on Zn should take Zn speciation in food biomass into account.
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