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Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. AMD is a multifactorial disorder but complement-mediated inflammation at the level of the retina plays a pivotal role. Oral zinc supplementation can reduce the progression of AMD but the precise mechanism of this protective effect is as yet unclear. We investigated whether zinc supplementation directly affects the degree of complement activation in AMD and whether there is a relation between serum complement catabolism during zinc administration and the complement factor H (CFH) gene or the Age-Related Maculopathy susceptibility 2 (ARMS2) genotype. In this open-label clinical study, 72 randomly selected AMD patients in various stages of AMD received a daily supplement of 50 mg zinc sulphate and 1 mg cupric sulphate for three months. Serum complement catabolism-defined as the C3d/C3 ratio-was measured at baseline, throughout the three months of supplementation and after discontinuation of zinc administration. Additionally, downstream inhibition of complement catabolism was evaluated by measurement of anaphylatoxin C5a. Furthermore, we investigated the effect of zinc on complement activation in vitro. AMD patients with high levels of complement catabolism at baseline exhibited a steeper decline in serum complement activation (p<0.001) during the three month zinc supplementation period compared to patients with low complement levels. There was no significant association of change in complement catabolism and CFH and ARMS2 genotype. In vitro zinc sulphate directly inhibits complement catabolism in hemolytic assays and membrane attack complex (MAC) deposition on RPE cells. This study provides evidence that daily administration of 50 mg zinc sulphate can inhibit complement catabolism in AMD patients with increased complement activation. This could explain part of the mechanism by which zinc slows AMD progression. The Netherlands National Trial Register NTR2605.

Honey bees are important plant pollinators and honey producers. Contamination of the environment with metals can lead to a decline in honey bee populations. Copper (Cu) and zinc (Zn) salts are commonly used as fungicides and foliar fertilizers. In this study, we investigated the effects of 10-day chronic oral exposure to different concentrations of Cu (CuSO4) and Zn (ZnCl2) on survival and feeding rates of Carniolan honey bees in laboratory conditions. We found that mortality in honey bee workers increased in a concentration-dependent manner and that Cu (lethal concentration [LC50] = 66 mg/l) was more toxic than Zn (LC50 = 144 mg/l). There was no difference in the feeding rate of Cu-treated bees for the different concentrations tested, but the feeding rate decreased with the increase in Zn concentration. To determine feeding preference or avoidance for Cu and Zn, we conducted 2-choice 24-h feeding experiments. We demonstrated that honey bees preferred Zn-containing solutions compared to the control diet. A two-choice experiment with Cu showed a tendency for honey bees to be deterred by Cu at high concentrations; however, it was not statistically significant. In summary, our results suggest that honey bee workers may suffer adverse effects when exposed to ecologically relevant concentrations of Cu and Zn.

Chronic copper exposure impaired spermatogenesis in adult male mice. The aim of this study was to determine whether chronic copper exposure can induce apoptosis of testicular cell and hypospermatogenesis via disturbing testosterone synthesis in adult male mice. In the present study, sixty CD-1 male mice were randomly divided into four groups, and were continuously administered for 8 weeks by oral gavage with copper sulfate at a dose of 0, 25, 100, and 150 mg/kg/day, respectively. We determined the content of serum and testicular copper, testicular coefficient, testicular histopathology, sperm count and motility, the mRNA and protein levels of Caspase-3, Bax, and Bcl-2, Leydig cell count, testosterone content, testosterone synthetase, and testosterone synthesis–related genes. The results showed that the copper levels in serum increased in a dose-dependent manner, and the copper levels in testes were significantly related to serum copper levels. Male mice given copper sulfate 100 and 150 dosage groups showed significant decreased in sperm motility and sperm number as well as increased in testes damage, and there was no significant change in testicular coefficient in the four groups. The mRNA levels of Bcl-2 decreased and Caspase-3 increased in 150 dosage group, and Bax increased in two higher dosage groups. Meanwhile, Caspase-3 and Bax proteins increased in 150 dosage group, and Bcl-2 protein decreased in three copper treatment groups. Nevertheless, there were no differences on the levels of testosterone content and testosterone synthetase of 3β-HSD, 17β-HSD, 17α-Hyd, and 20α-Hyd, mRNA levels of Cyp11a1, Cyp17a1, and Star, and quantity of Leydig cells in four groups. Overall, these data showed that chronic copper exposure led to copper residues in the testes, and the doses of 100 and 150 mg/kg/day copper sulfate may induce hypospermatogenesis by increasing apoptosis without affecting testosterone secretion.

A multitrial analysis was conducted to evaluate the effect of different levels of Cu from either Cu(2-hydroxy-4-(methylthio)butanoic acid [HMTBa])2 or CuSO4 on growth performance in nursery pigs. Six nursery trials were conducted from 2007 to 2012 under the same commercial conditions with initial BW of 5.75 ± 0.41 kg at 21 ± 3 d of age; the trials lasted for 42 d with a 3-phase feeding program (7 d in Phase I, 14 d in Phase II, and 21 d in Phase III). Diets were medicated with antibiotics and supplemented with 3,000 mg/kg Zn as ZnO during phases I and/or II. Treatments included a basal diet without added Cu or according to the NRC (1998) and supplemental levels of Cu (50 to 250 mg Cu/kg diet) from either Cu(HMTBa)2 or CuSO4; HMTBa was supplemented to make diets isomethionine. Treatments from each trial included 6 or 9 replicate pens/treatment with 22 to 25 piglets/pen. Mixed model analysis was conducted in which trial was considered a random effect, Cu level was considered a continuous fixed effect, and Cu source was a fixed effect. The basal diet within trial and statistical tests of the intercept between sources were not different, resulting in fitting a common intercept mixed model to the overall responses across phases. Cumulative ADG and ADFI quadratically responded (P < 0.05) with increasing Cu supplementation; predicted optimal ADG and ADFI occurred at 174 and 119 mg/kg, respectively. Increasing Cu supplementation linearly improved G:F (P = 0.054). No differences between sources were observed in ADG or ADFI. Numerically, pigs fed Cu(HMTBa)2 had higher ADG and lower ADFI compared to pigs fed CuSO4, resulting in better G:F for pigs supplemented with Cu(HMTBa)2 compared to pigs supplemented with CuSO4 (P < 0.01). The linear slope for increasing Cu supplementation on G:F was 2.1-fold higher for Cu(HMTBa)2 than that of CuSO4, with larger differences occurring in Phase II. In conclusion, Cu supplementation in nursery diets resulted in improved performance and Cu(HMTBa)2 is more effective than CuSO4 in improving feed efficiency.

Lysozyme is a 1,4-β-N-acetylmuramidase that has antimicrobial properties. The objective of this experiment was to determine if lysozyme in nursery diets improved growth performance and gastrointestinal health of pigs weaned from the sow at 24 d of age. Two replicates of 96 pigs (192 total; 96 males, 96 females) were weaned from the sow at 24 d of age, blocked by BW and gender, and then assigned to 1 of 24 pens (4 pigs/pen). Each block was randomly assigned 1 of 3 dietary treatments for 28 d: control (two 14-d phases), control + antibiotics (carbadox/copper sulfate), or control + lysozyme (100 mg/kg diet). Pigs were weighed and blood sampled on d 0, 14, and 28 of treatment. Blood was analyzed for plasma urea nitrogen (PUN) and IgA. At 28 d, pigs were killed, and samples of jejunum and ileum were collected and fixed for intestinal morphology measurements. An additional jejunum sample was taken from the 12 pigs with the median BW per treatment to determine transepithelial electrical resistance (TER). Pigs consuming antibiotics or lysozyme grew at a faster rate than control pigs (0.433 ± 0.009 and 0.421 ± 0.008 vs. 0.398 ± 0.008 kg/d, respectively; P < 0.03), which resulted in heavier ending BW (20.00 ± 0.31, 19.8 ± 0.29, and 18.83 ± 0.32 kg, respectively; P < 0.03). Feed intake was not different (P > 0.48), but G:F was improved in pigs consuming antibiotics or lysozyme (0.756 ± 0.014, 0.750 ± 0.021, and 0.695 ± 0.019 kg/kg; P < 0.05). Immunoglobulin A (P < 0.03) and PUN (P < 0.01) increased during the experiment, regardless of dietary treatment (P > 0.48). Dietary treatment did not affect TER (P > 0.37), but gilts had lower TER compared with barrows (P < 0.04). No differences in villi height or crypt depth were observed in the ileum (P > 0.53). However, jejunum villi height was increased and crypt depth was decreased in pigs consuming antibiotics or lysozyme (P < 0.001), resulting in an increased villi height:crypt depth of 72% (P < 0.001). Thus, we concluded that lysozyme is a suitable alternative to carbadox/copper sulfate diets fed to pigs weaned from the sow at 24 d of age.

Three experiments were conducted to evaluate the effects of increasing dietary Cu and Zn on weanling pig performance. Diets were fed in 2 phases: phase 1 from d 0 to 14 postweaning and phase 2 from d 14 to 28 in Exp. 1 and 2 and d 14 to 42 in Exp. 3. The trace mineral premix, included in all diets, provided 165 mg/kg of Zn from ZnSO(4) and 16.5 mg/kg of Cu from CuSO(4). In Exp. 1, treatments were arranged in a 2 × 3 factorial with main effects of added Cu from tri-basic copper chloride (TBCC; 0 or 150 mg/kg) and added Zn from ZnO (0, 1,500, or 3,000 mg/kg from d 0 to 14 and 0, 1,000, or 2,000 mg/kg from d 14 to 28). No Cu × Zn interactions were observed (P > 0.10). Adding TBCC or Zn increased (P < 0.05) ADG and ADFI during each phase. In Exp. 2, treatments were arranged in a 2 × 3 factorial with main effects of added Zn from ZnO (0 or 3,000 mg/kg from d 0 to 14 and 0 or 2,000 mg/kg from d 14 to 28) and Cu (control, 125 mg/kg of Cu from TBCC, or 125 mg/kg of Cu from CuSO(4)). No Cu × Zn interactions (P > 0.10) were observed for any performance data. Adding ZnO improved (P < 0.02) ADG and ADFI from d 0 to 14 and overall. From d 0 to 28, supplementing CuSO(4) increased (P < 0.02) ADG, ADFI, and G:F, and TBCC improved (P = 0.006) ADG. In Exp. 3, the 6 dietary treatments were arranged in a 2 × 2 factorial with main effects of added Cu from CuSO(4) (0 or 125 mg/kg) and added Zn from ZnO (0 or 3,000 mg/kg from d 0 to 14 and 0 or 2,000 mg/kg from d 14 to 42). The final 2 treatments were feeding added ZnO alone or in combination with CuSO(4) from d 0 to 14 and adding CuSO(4) from d 14 to 42. Adding ZnO increased (P < 0.04) ADG, ADFI, and G:F from d 0 to 14 and ADG from d 0 to 42. Dietary CuSO(4) increased (P < 0.004) ADG and ADFI from d 14 to 42 and d 0 to 42. From d 28 to 42, a trend for a Cu × Zn interaction was observed (P = 0.06) for ADG. This interaction was reflective of the numeric decrease in ADG for pigs when Cu and Zn were used in combination compared with each used alone. Also, numerical advantages were observed when supplementing Zn from d 0 to 14 and Cu from d 14 to 42 compared with all other Cu and Zn regimens. These 3 experiments show the advantages of including both Cu and Zn in the diet for 28 d postweaning; however, as evident in Exp. 3, when 3,000 mg/kg of Zn was added early and 125 mg/kg of Cu was added late, performance was similar or numerically greater than when both were used for 42 d.

Arsenic and copper, two toxic pollutants, are powerful inducers of oxidative stress. Exposure to copper and arsenic can cause intestinal injury in cockerel. This study was carried out to investigate the effects of these two pollutants on the gastrointestinal tract of cockerels. Experimental results showed that the activity of antioxidant enzymes (catalase and glutathione peroxidase) was inhibited and the ionic balance was destroyed after exposure to copper sulfate (300 mg/kg) and/or arsenic trioxide (30 mg/kg). However, the expression of pro-inflammatory cytokines (nuclear factor kappa-B, cyclooxygenase-2, tumor necrosis factor-α, and prostaglandin E2 synthases) increased markedly. Damages to the biofilm structure and inflammatory cell infiltration were simultaneously observed during histological examination. Heat-shock proteins were also expressed in large quantities after exposure to the poisons. Collectively, exposure to arsenite and/or Cu2+ can cause rectal damage in cockerels, inducing inflammation and an imbalance in immune system responses. Sometimes, exposure to both pollutants can produce even more toxic effects. Heat-shock proteins can protect the tissue from the exotoxins but the specific mechanisms require exploration. After oral ingestion of toxins, the rectum can still be damaged, necessitating attention to the safety of poultry breeding, human food safety, and environmental protection.

Cisplatin is a widely used antitumor agent; however, tumor resistance and severe side effects limit its use. It is well accepted that cisplatin toxicity can be modulated in vitro in cell cultures by copper salts. In the present work, mice with different blood serum copper status were treated with a single intraperitoneal cisplatin injection at a dose of 5 mg/kg, monitored for 3 days in metabolic cages and analyzed for renal function. Both copper-deficient and copper-overloaded mice displayed more severe early proteinuria and retarded platinum excretion than control mice. The effects of copper status on cisplatin-induced nephrotoxicity are discussed.

An experiment was conducted using a total of 420, 1-d-old, Arbor Acres commercial male chicks to compare copper sulfate and tribasic copper chloride (TBCC) as sources of supplemental copper for broilers. Chicks were randomly allotted to 1 of 7 treatments for 6 replicates of 10 birds each and were fed a basal corn-soybean meal diet (11.45 mg/kg copper) supplemented with 0, 150, 300, or 450 mg/kg copper from copper sulfate or TBCC for 21 d. Chicks fed 450 mg/kg copper as copper sulfate had lower (P < 0.01) average daily feed intake and average daily gain than those consuming other diets. Feeding supplemental copper increased linearly (P < 0.0001) liver copper concentrations regardless of copper source. The slopes of regressions of log10 liver copper on different independent variables used in regressions differ (P < 0.05) between the 2 copper sources. Linear regression over nonzero dietary levels of log10 transformed liver copper concentration on added copper intake resulted in a slope ratio estimate of 109.0 +/- 3.4% (with a 95% confidence interval from 102.2 to 115.8) for bioavailability of copper from TBCC compared with 100 for that in copper sulfate. When the feeds were stored at room temperature for 10 or 21 d, the vitamin E content in the feed fortified with 300 mg/kg copper as TBCC was higher (P < 0.01) than that in the feed added with 300 mg/kg copper as CuSO4. The vitamin E contents in liver and plasma of broilers given TBCC were also higher (P < 0.01) than those of birds fed copper sulfate. The results from this study indicate that TBCC is a safer product and more available to broilers than copper sulfate, and it is chemically less active than copper sulfate in promoting the oxidation of vitamin E in feed.

An experiment was conducted to investigate the bioavailability of organic copper (Cu) proteinate relative to inorganic Cu sulfate for broiler chicks fed a conventional corn–soybean meal basal diet. A total of 320 day-old Arbor Acres commercial male chicks were assigned to one of five treatments in a completely randomized design involving a 2 × 2 factorial arrangement with two levels of added Cu (125 or 250 mg Cu/kg) and two Cu sources (Cu proteinate and Cu sulfate) plus a control with no added Cu for an experimental phase of 42 days. Plasma and liver tissue samples were collected at both 21 and 42 days of age, and bile samples were also obtained at 42 days of age for Cu analyses. The Cu concentrations in liver and bile increased linearly (P < 0.001) on both days 21 and 42 as dietary Cu levels increased. No significant (P > 0.17) linear regression relationships were observed between plasma Cu concentrations on days 21 and 42 or log10 liver Cu concentration on day 21 and daily analyzed Cu intake. Therefore, based on the slope ratios from multiple linear regressions of log10 liver and bile Cu concentrations with daily analyzed Cu intake on day 42, when Cu sulfate was set as 100%, the estimated relative bioavailability values of Cu proteinate were 78.8% for log10 liver Cu concentration and 79.3% for log10 bile Cu concentration, respectively. There was no significant (P > 0.08) difference in bioavailability between Cu proteinate and Cu sulfate for broilers chicks in this experiment.