Zinc Deficiency Affects DNA Damage, Oxidative Stress, Antioxidant Defenses, and DNA Repair in Rats

Department of Nutrition and Exercise Science and 5Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA.
Journal of Nutrition (Impact Factor: 3.88). 08/2009; 139(9):1626-31. DOI: 10.3945/jn.109.106369
Source: PubMed


Approximately 12% of Americans do not consume the Estimated Average Requirement for zinc and could be at risk for marginal zinc deficiency. Zinc is an essential component of numerous proteins involved in the defense against oxidative stress and DNA damage repair. Studies in vitro have shown that zinc depletion causes DNA damage. We hypothesized that zinc deficiency in vivo causes DNA damage through increases in oxidative stress and impairments in DNA repair. Sprague-Dawley rats were fed zinc-adequate (ZA; 30 mg Zn/kg) or severely zinc-deficient (ZD; <1 mg Zn/kg) diets or were pair-fed zinc-adequate diet to match the mean feed intake of ZD rats for 3 wk. After zinc depletion, rats were repleted with a ZA diet for 10 d. In addition, zinc-adequate (MZA 30 mg Zn/kg) or marginally zinc-deficient (MZD; 6 mg Zn/kg) diets were given to different groups of rats for 6 wk. Severe zinc depletion caused more DNA damage in peripheral blood cells than in the ZA group and this was normalized by zinc repletion. We also detected impairments in DNA repair, such as compromised p53 DNA binding and differential activation of the base excision repair proteins 8-oxoguanine glycosylase and poly ADP ribose polymerase. Importantly, MZD rats also had more DNA damage and higher plasma F(2)-isoprostane concentrations than MZA rats and had impairments in DNA repair functions. However, plasma antioxidant concentrations and erythrocyte superoxide dismutase activity were not affected by zinc depletion. These results suggest interactions among zinc deficiency, DNA integrity, oxidative stress, and DNA repair and suggested a role for zinc in maintaining DNA integrity.

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    • "active metals in membranes (Clegg et al., 2005; Kroncke and Klotz, 2009; Oteiza, 2012). Increased oxidative stress and oxidative damage secondary to Zn deficiency have been reported by numerous investigators using a variety of in vivo and in vitro model systems (Ho et al., 2003; Mackenzie et al., 2006b; Song et al., 2009; Aimo et al., 2010). With respect to in utero development , Zn has been shown to influence fetal redox homeostasis, whereby maternal dietary Zn deficiency was associated with increased oxidative damage in fetal brain, whereas dietary Zn supplementation was shown to mitigate ROS production and anomalies in hearts of diabetic rat fetuses (Aimo et al., 2010; Kumar et al., 2012). "
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    ABSTRACT: BACKGROUND Developmental zinc (Zn) deficiency increases the incidence of heart anomalies in rat fetuses, in regions and structures derived from the outflow tract. Given that the development of the outflow tract requires the presence of cardiac neural crest cells (cNCC), we speculated that Zn deficiency selectively kills cNCC and could lead to heart malformations.METHODS Cardiac NCC were isolated from E10.5 rat embryos and cultured in control media (CTRL), media containing 3 μM of the cell permeable metal chelator N, N, N′, N′-tetrakis (2-pyridylmethyl) ethylene diamine (TPEN), or in TPEN-treated media supplemented with 3 μM Zn (TPEN + Zn). Cardiac NCC were collected after 6, 8, and 24 h of treatment to assess cell viability, proliferation, and apoptosis.RESULTSThe addition of TPEN to the culture media reduced free intracellular Zn pools and cell viability as assessed by low ATP production, compared to cells grown in control or Zn-supplemented media. There was an accumulation of reactive oxygen species, a release of mitochondrial cytochrome c into the cytoplasm, and an increased cellular expression of active caspase-3 in TPEN-treated cNCC compared to cNCC cultured in CTRL or TPEN + Zn media.CONCLUSION Zn deficiency can result in oxidative stress in cNCC, and subsequent decreases in their population and metabolic activity. These data support the concept that Zn deficiency associated developmental heart defects may arise in part as a consequence of altered cNCC metabolism
    Full-text · Article · Feb 2015 · Birth Defects Research Part B Developmental and Reproductive Toxicology
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    • "Antioxidant nutritional interventions may reduce metal-induced toxic responses (Jacquillet et al., 2006; Jemai et al., 2007; Tang et al., 1998). Zinc is a nutritionally critical mineral responsible for the structure and function of proteins like metallothionein and for key enzymes in both DNA repair and antioxidant defense (Song et al., 2009; Tapiero and Tew, 2003). Since zinc and cadmium have very similar chemical properties one might expect zinc to play a role in renal function and influence the nephrotoxicity of cadmium . "
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    ABSTRACT: Background Despite animal evidence suggests that zinc modulates cadmium nephrotoxicity, limited human data are available. Objective To test the hypothesis that low serum zinc concentrations may increase the risk of cadmium-mediated renal dysfunction in humans. Methods Data from 1545 subjects aged 20 or older in the National Health and Nutrition Examination Survey (NHANES), 2011–2012 were analyzed. Renal function was defined as impaired when estimated glomerular filtration rate (eGFR) fell below 60 ml/min/1.73 m2 and/or the urinary albumin-to-creatinine ratio surpassed 2.5 in men and 3.5 mg/mmol in women. Results Within the study cohort, 117 subjects had reduced eGFR and 214 had elevated urinary albumin. After adjusting for potential confounders, subjects with elevated blood cadmium (>0.53 μg/L) were more likely to have a reduced eGFR (odds ratio [OR]=2.21, 95% confidence interval [CI]: 1.09–4.50) and a higher urinary albumin (OR=2.04, 95% CI: 1.13–3.69) than their low cadmium (<0.18 μg/L) peers. In addition, for any given cadmium exposure, low serum zinc is associated with elevated risk of reduced eGFR (OR=3.38, 95% CI: 1.39–8.28). A similar increase in the odds ratio was observed between declining serum zinc and albuminuria but failed to reach statistical significance. Those with lower serum zinc/blood cadmium ratios were likewise at a greater risk of renal dysfunction (p<0.01). Conclusions This study results suggest that low serum zinc concentrations are associated with an increased risk of cadmium nephrotoxicity. Elevated cadmium exposure is global public health issue and the assessment of zinc nutritional status may be an important covariate in determining its effective renal toxicity.
    Full-text · Article · Oct 2014 · Environmental Research
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    • "Thus, zinc has an indirect antioxidant effect[71]. Moreover, zinc deficiency causes DNA damage by increasing oxidative stress and blocking DNA repair[72]. Thus, zinc plays an important role in maintaining DNA integrity. "
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    ABSTRACT: A hypomagnetic field is an extremely weak magnetic field-it is considerably weaker than the geomagnetic field. In deep-space exploration missions, such as those involving extended stays on the moon and interplanetary travel, astronauts will experience abnormal space environments involving hypomagnetic fields and microgravity. It is known that microgravity in space causes bone loss, which results in decreased bone mineral density. However, it is unclear whether hypomagnetic fields affect the skeletal system. In the present study, we aimed to investigate the complex effects of a hypomagnetic field and microgravity on bone loss. To study the effects of hypomagnetic fields on the femoral characteristics of rats in simulated weightlessness, we established a rat model of hindlimb unloading that was exposed to a hypomagnetic field. We used a geomagnetic field-shielding chamber to generate a hypomagnetic field of <300 nT. The results show that hypomagnetic fields can exacerbate bone mineral density loss and alter femoral biomechanical characteristics in hindlimb-unloaded rats. The underlying mechanism might involve changes in biological rhythms and the concentrations of trace elements due to the hypomagnetic field, which would result in the generation of oxidative stress responses in the rat. Excessive levels of reactive oxygen species would stimulate osteoblasts to secrete receptor activator of nuclear factor-κB ligand and promote the maturation and activation of osteoclasts and thus eventually cause bone resorption.
    Full-text · Article · Aug 2014 · PLoS ONE
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