Effect of nitrilotriacetic acid and tea saponin on the phytoremediation of Ni by Sudan grass (Sorghum sudanense (Piper) Stapf.) in Ni-pyrene contaminated soil.

Phytoremediation is commonly used in the remediation of soils co-contaminated by heavy metals and polycyclic aromatic hydrocarbons (PAHs) because of its economy and effectiveness. Sudan grass (Sorghum sudanense (Piper) Stapf.) has well-developed roots and strong tolerance to heavy metals, so it has been widely concerned. In this study, nitrilotriacetic acid (NTA) and tea saponin (TS) were used as enhancers and combined with Sudan grass for improving the remediation efficiency of Ni-pyrene co-contaminated soil. The results of the pot experiment in soils showed that enhancers promoted the enrichment of Ni in plants. With the function of enhancers, more inorganic and water-soluble Ni were converted into low-toxic phosphate-bonded and residual Ni, so as to reinforce the tolerance of Sudan grass to Ni. In the pot experiment based on vermiculite, it was found that enhancers increased the accumulation of Ni in cell wall by 49.71-102.73%. Enhancers also had the positive effect on the relative abundance of Proteobacteria, Patescibacteria and Bacteroidetes that could tolerate heavy metals at phylum level. Simultaneously, the study found that pyrene reduced the exchangeable Ni in soils. More Ni entered the organelles and transfer to more high-toxic forms in Sudan grass when pynere coexisted. The study manifested that enhancers improved the phytoremediation effect of Ni significantly, yet the co-existence of pyrene weakened the process. Our results provided meaningful references for remediating actual co-contaminated soil of heavy metals and PAHs.

Allosteric effects of sulfonate anions on the rates of iron release from serum transferrin.

Serum transferrin is the protein that transports ferric ion through the bloodstream and is thus a potential target for iron chelation therapy. However, the release of iron from transferrin to low-molecular-weight chelating agents is usually quite slow. Thus a better understanding of the mechanism for iron release is important to assist in the design of more effective agents for iron removal. This paper describes the effect of sulfonate anions on the rates of iron removal from C-terminal monoferric transferrin by acetohydroxamic acid, deferiprone, nitrilotriacetic acid (NTA), and diethylenetriaminepentaacetic acid at 25°C in 0.1M N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (Hepes) buffer at pH 7.4. These ligands remove iron via a combination of pathways that show saturation and first order dependence on the ligand concentration. The kinetic effects of the anions methanesulfonate, methylenedisulfonate, and ethylenedisulfonate were evaluated. All these anions increase the overall rates of iron release, presumably by binding to an allosteric anion binding site on the protein. The two disulfonates produce a larger acceleration in iron release than the monosulfonate. More detailed studies using methylenedisulfonate show that this anion accelerates the rate of iron release via the saturation pathway. The addition of methylenedisulfonate results in the appearance of a large saturation pathway for iron release by NTA, which otherwise removes iron by a simple first-order process. The sulfonate group was selected for these studies because it represents an anionic functional group that can be covalently linked to a therapeutic ligand to accelerate iron release in vivo. The current studies indicate that the binding of the sulfonates to the allosteric site on the protein is quite weak, so that one would not expect a significant acceleration in iron release at clinically relevant ligand concentrations.

Dietary supplementation of silymarin protects against chemically induced nephrotoxicity, inflammation and renal tumor promotion response.

Ferric nitrilotriacetate (Fe-NTA) is a potent nephrotoxicant and a renal carcinogen that induces its effect by causing oxidative stress. The present study was undertaken to explore protective effect of silymarin, a flavonolignan from milk thistle (Silybum marianum), against Fe-NTA mediated renal oxidative stress, inflammation and tumor promotion response along with elucidation of the implicated mechanism(s). Administration of Fe-NTA (10 mg/kg bd wt, i.p.) to Swiss albino mice induced marked oxidative stress in kidney, evident from augmentation in renal metallothionein (MT) expression, depletion of glutathione content and activities of antioxidant and phase II metabolizing enzymes, and enhancement in production of aldehyde products such as 4-hydroxy-2-nonenal. Fe-NTA also significantly activated nuclear factor kappa B (NFkappaB) and upregulated the expression of downstream genes: cyclooxygenase 2 and inducible nitric oxide synthase and enhancing the production of proinflammatory cytokines: tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). However, feeding of 0.5% and 1% silymarin diet conferred a significant protection against Fe-NTA induced oxidative stress and inflammation. It further augmented MT expression, restored the antioxidant armory, ameliorated NFkappaB activation and decreased the expression of proinflammatory mediators. Silymarin also suppressed Fe-NTA induced hyperproliferation in kidney, ameliorating renal ornithine decarboxylase activity and DNA synthesis. From these results, it could be concluded that silymarin markedly protects against chemically induced renal cancer and acts plausibly by virtue of its antioxidant, anti-inflammatory and antiproliferative activities.

Oxidative changes in the rat brain by intraperitoneal injection of ferric nitrilotriacetate.

Iron is known to be involved in neuronal diseases such as neurodegenerative diseases, brain ischemia and epilepsy. However, it is unclear if a high level of peripheral iron induces these pathological conditions. Since ferric nitrilotriacetate (Fe-NTA), a low molecule iron chelate, causes kidney carcinoma and diabetes in animals due to its strong and unique oxidative stress, it is also considered to cause pathological conditions in the brain. Therefore, we studied brain changes after intraperitoneal (i.p.) injection of Fe-NTA. We investigated iron distribution in the brain and evaluated heme oxygenase (HO)-1 mRNA, IL-6 mRNA and 4-hydroxy-2-nonenal (4-HNE) quantitatively. In addition, changes in muscarinic acetylcholine receptor mRNAs were measured. It was found that iron was localized in the cortex and the hypothalamus, but not in other areas of the brain. HO-1 was induced in both the cortex and hypothalamus, and the levels of IL-6 and 4-HNE were raised in the hypothalamus, but not in the cortex. In the cortex, expression in M1 and M2 mAChRs were suppressed. In conclusion, iron reached the brain parenchyma after i.p. injection of Fe-NTA, and Fe-NTA caused oxidative reactions and suppression of mAChRs in the brain.

Use of proliferation tests to evaluate the effects of complexing agents on beryllium toxicity.

Occupational exposure to beryllium may cause chronic beryllium disease (CBD), a granulomatous interstitial pneumonitis caused by a cell-mediated immune response with delayed hypersensitivity initiated by an electrostatic interaction with the MHC class II human leukocyte antigen (HLA). Increased research efforts focus on the development of a CBD treatment by chelation therapy. This work presents an in vitro evaluation of the beneficial effects of beryllium chelation with different organic substrates. We have used a standard beryllium lymphocyte proliferation test (BeLPT) adapted for mouse splenocytes. Three complexing agents, 4,5-dihydroxy-1,3-benzenedisulfonic acid (tiron), nitrilotripropionic acid (NTP) and nitrilotriacetic acid (NTA), were tested using different protocols of the splenocyte proliferation test (SPT). We studied their corrective effect (beryllium pre-exposed splenocytes), their protective effect (ligand pre-exposed splenocytes) and their combined effects at fixed Be:L ratio of 1:2, at fixed Be concentration and at fixed L concentration. We also studied the effect of tiron in preventing splenocyte sensitization to beryllium. All three complexing agents showed a corrective effect and proved efficient in the combined effects, except NTA in the fixed Be:L ratio. Only NTP and tiron showed a significant protection at lower beryllium concentrations, while NTA was not significant. Splenocytes pre-exposed to chelated beryllium did not show sensitization while splenocytes pre-exposed to beryllium were sensitized. We observed a strong correlation between the efficiency of the complexing agent and its affinity towards beryllium. Both tiron and NTP showed a similar affinity towards the beryllium ion that is 10(7) higher than that of NTA.

Lycopene and beta-carotene protect in vivo iron-induced oxidative stress damage in rat prostate.

It has been suggested that iron overload may be carcinogenic. In the present study, we evaluated the effect of plasma and prostate carotenoid concentration on oxidative DNA damage in 12-week-old Wistar rats treated with intraperitoneal (ip) ferric nitrilotriacetate (Fe-NTA) (10 mg Fe/kg). Plasma beta-carotene and lycopene concentrations were measured as a function of time after ip injection of carotenoids (10 mg kg(-1) day(-1) beta-carotene or lycopene) in rats. The highest total plasma concentration was reached 3 and 6 h after ip injection of lycopene or beta-carotene, respectively. After 5 days of carotenoid treatment, lycopene and beta-carotene were present in the 0.10-0.51 nmol/g wet tissue range in the prostate. Using a sensitive method to detected 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) by HPLC/EC, the level of 8-oxodGuo in rat prostate DNA was significantly higher (6.3 +/- 0.6 residues/10(6) dGuo) 3 h after Fe-NTA injection compared with control rats (1.7 +/- 0.3 residues/10(6) dGuo). Rats supplemented with lycopene or beta-carotene for 5 days prior to Fe-NTA treatment showed a reduction of about 70% in 8-oxodGuo levels to almost control levels. Compared with control rats, the prostate of Fe-NTA-treated animals showed a 78% increase in malondialdehyde accumulation. Lycopene or beta-carotene pre-treatment almost completely prevented lipid damage. Epidemiological studies have suggested a lower risk of prostate cancer in men reporting a higher consumption of tomato products. However, before associating this effect with tomato sauce constituents, more information is required. The results described here may contribute to the understanding of the protective effects of carotenoids against iron-induced oxidative stress.

Lycopene and ß-carotene protect in vivo iron-induced oxidative stress damage in rat prostate

It has been suggested that iron overload may be carcinogenic. In the present study, we evaluated the effect of plasma and prostate carotenoid concentration on oxidative DNA damage in 12-week-old Wistar rats treated with intraperitoneal (ip) ferric nitrilotriacetate (Fe-NTA) (10 mg Fe/kg). Plasma ß-carotene and lycopene concentrations were measured as a function of time after ip injection of carotenoids (10 mg kg-1 day-1 ß-carotene or lycopene) in rats. The highest total plasma concentration was reached 3 and 6 h after ip injection of lycopene or ß-carotene, respectively. After 5 days of carotenoid treatment, lycopene and ß-carotene were present in the 0.10-0.51 nmol/g wet tissue range in the prostate. Using a sensitive method to detected 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) by HPLC/EC, the level of 8-oxodGuo in rat prostate DNA was significantly higher (6.3 ± 0.6 residues/10(6) dGuo) 3 h after Fe-NTA injection compared with control rats (1.7 ± 0.3 residues/10(6) dGuo). Rats supplemented with lycopene or ß-carotene for 5 days prior to Fe-NTA treatment showed a reduction of about 70 percent in 8-oxodGuo levels to almost control levels. Compared with control rats, the prostate of Fe-NTA-treated animals showed a 78 percent increase in malondialdehyde accumulation. Lycopene or ß-carotene pre-treatment almost completely prevented lipid damage. Epidemiological studies have suggested a lower risk of prostate cancer in men reporting a higher consumption of tomato products. However, before associating this effect with tomato sauce constituents, more information is required. The results described here may contribute to the understanding of the protective effects of carotenoids against iron-induced oxidative stress.

Adenovirus-mediated expression of Cu/Zn- or Mn-superoxide dismutase protects against CYP2E1-dependent toxicity.

CYP2E1 induction by ethanol is one mechanism by which ethanol creates oxidative stress in the liver. The superoxide dismutases (SODs) are an important antioxidant enzyme defense system against reactive oxygen species (ROS). To investigate the protective role of SOD against CYP2E1-dependent toxicity, a transfected HepG2 cell line overexpressing CYP2E1 (E47 cells) was infected with adenoviral vectors containing Cu/Zn-SOD complementary DNA (cDNA) (Ad.SOD1) and Mn-SOD cDNA (Ad.SOD2). Forty-eight hours after infection, intracellular levels and activity of Cu/Zn-SOD and Mn-SOD were increased about 2- and 3-fold, respectively. Localization of the overexpressed Cu/Zn-SOD in the cytosol and Mn-SOD in the mitochondria was confirmed by assaying the levels and activity of SOD in the corresponding isolated fractions. Arachidonic acid (AA) plus iron-induced cell death was partially prevented in both Ad.SOD1- and Ad.SOD2-infected E47 cells. Overexpression of Cu/Zn-SOD and Mn-SOD also partially protected E47 cells from the increase in reactive oxygen production and lipid peroxidation and the loss of mitochondrial membrane potential induced by AA and iron. Infection with Cu/Zn-SOD and Mn-SOD also protected the E47 cells against AA toxicity or buthionine sulfoximine (BSO)-dependent toxicity. CYP2E1 levels and catalytic activity were not altered by overexpression of Cu/Zn-SOD or Mn-SOD. Cu/Zn-SOD in the cytosol and Mn-SOD in mitochondria each are capable of protecting HepG2 cells expressing CYP2E1 against cytotoxicity induced by pro-oxidants. In conclusion, these enzymes may be useful in the prevention or improvement of liver injury produced by agents known to be metabolized by CYP2E1 to reactive intermediates and to cause oxidative stress.

Doxorubicin induces an increase of nitric oxide synthesis in rat cardiac cells that is inhibited by iron supplementation.

Doxorubicin is an anthracycline antibiotic generally used in the treatment of solid tumors, but its use is limited by a severe cardiotoxicity, which has been related to the generation of oxygen- and nitrogen-derived free radicals. We have demonstrated that doxorubicin induces nitric oxide (NO) synthesis in the rat cardiac cells H9c2: the drug, after a 24-h incubation, evoked a dose-dependent increase of both NO synthase (NOS) activity in the cells and nitrite levels in the culture supernatant; the accumulation of nitrite (a stable derivative of NO) was prevented by different NOS inhibitors. The increase of NO production was associated with an increased expression of the inducible NOS isoform gene. These effects were significantly inhibited by the coincubation of doxorubicin with iron nitrilotriacetate, a compound that releases iron into the cells. Our results suggest that doxorubicin could induce NO generation in cardiac cells by modifying the iron homeostasis.

Iron inhibits the nitric oxide synthesis elicited by asbestos in murine macrophages.

Crocidolite fibers stimulated nitric oxide synthase (NOS) activity and expression in glial and alveolar murine macrophages: this effect was inhibited by iron supplementation and enhanced by iron chelation. We suggest that in these cells crocidolite stimulates NOS expression by decreasing the iron bioavailability and activating an iron-sensitive transcription factor.

Protective effect of lycopene on lipid peroxidation and oxidative DNA damage in cell culture.

A high incidence of cancer has been correlated with chronic iron overload, and carotenoids are of interest as possible anticarcinogens. We have investigated the effect of lycopene on lipid peroxidation and on the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) in CV1-P monkey cells exposed to ferric nitrilotriacetate (Fe-NTA) plus ascorbate. Cells supplemented with lycopene (20 pmol/10(6) cells) showed a reduction of 86% in Fe-NTA/ascorbate-induced lipid peroxidation (TBARS). Levels of 8-oxodGuo rose from 1.59+/-0.09 residues/10(6) dGuo in the control cells to 14.02+/-0.41 residues/10(6) dGuo after incubation with (1:4 mM) Fe-NTA/ascorbate (40 microM). Lycopene supplementation decreased in 77% the 8-oxodGuo levels in Fe-NTA/ascorbate-treated cells. These results indicate that lycopene can protect mammalian cells against membrane and DNA damage and possibly play a protective role against tumor promotion associated with oxidative damage.

Ferric nitrilotriacetate induced DNA and protein damage: inhibitory effect of a fermented papaya preparation.

The carcinogen Fe-NTA catalyzes the hydrogen peroxide-derived production of free radicals and possibly acts through a mechanism involving oxidative stress. Fermented papaya preparation (FPP) has been reported as a natural antioxidant able to prevent lipid peroxidation in vitro and in vivo. However, little is known about the antioxidant properties of FPP regarding iron-mediated oxidative damage to DNA and proteins. In the present study FPP protected supercoiled plasmid DNA against Fe-NTA plus H2O2 induced single and double strand breaks. Similar protective effects of FPP were evident when human T-lymphocytes were challenged with Fe-NTA/H2O2 and DNA damage was determined using the Comet assay. Fe-NTA/H2O2 also induced fragmentation of bovine serum albumin (BSA) in vitro and depleted cellular GSH levels in lymphocytes. BSA fragmentation and GSH depletion were dose-dependently counteracted by FPP. EPR spin trapping studies demonstrated that antioxidant properties of FPP are related to both hydroxyl scavenging as well as iron chelating properties.

Iron as a potential co-factor in the pathogenesis of Kaposi's sarcoma?

The role of iron in the pathogenesis of several tumours is being increasingly investigated. In particular, its involvement in the pathogenesis of Kaposi's sarcoma (KS) is suggested by the distribution of the endemic form of KS corresponding to continental rifts and associated iron-oxide-rich volcanic clays. We investigated in vitro to what extent iron supplementation or withdrawal could affect the growth of KS-derived cells, by analysing the effects of adding iron salts (iron chloride and ferric nitrilotriacetate) and/or reducing iron by iron chelators (desferrioxamine) on KS-derived cell cultures. The addition of iron salts strongly stimulated the growth of KS cells, as reflected by increase in thymidine incorporation and cell number. Conversely, desferrioxamine and deferiprone inhibited cell growth. The inhibitory effect of iron chelation was more pronounced on rapidly dividing basic fibroblast-growth-factor-stimulated cells. These results may point to a novel therapeutic approach to KS.

Cobalt binding to gills of rainbow trout (Oncorhynchus mykiss): an equilibrium model.

Rainbow trout (Oncorhynchus mykiss, 1-5 g) were exposed to approximately 7.5 microM Co in soft water for 2-3 hr at pH approximately 6.5. The water contained either complexing ligands such as nitrilotriacetic acid and natural dissolved organic matter (DOM) or competing cations such as Ca, Na, or H. After exposure, gills were excised and analyzed for total bound Co using a graphite furnace atomic absorption spectrophotometer. A Langmuir isotherm was used to calculate the conditional equilibrium binding constant (K) for Co binding to trout gills plus the concentrations of gill Co binding sites. The calculated binding constant for Co to trout gills was log KCo-gillCo = 5.1, with 88 nmol Co binding sites per g of wet gill tissue. Conditional equilibrium binding constants were also calculated for Ca, Na, and H binding to the gill Co sites and for Co binding to DOM. The experimentally determined binding constants were entered into an aquatic equilibrium chemistry program, MINEQL+, to predict Co binding by fish gills. Predicted and observed results indicate that Co would not accumulate on or in gills of trout held in a series of natural and 1:1 diluted natural waters supplemented with approximately 8.7 microM Co. Model analysis of the reasons for Co being kept off gills of trout held in natural waters indicated that Ca competition and DOM complexation were the most important factors in preventing Co binding by trout gills.

Involvement of phenoxyl radical intermediates in lipid antioxidant action of myricetin in iron-treated rat hepatocyte culture.

Supplementation of rat hepatocyte cultures with the flavonoid myricetin (300 microM) led to the formation of phenoxyl radical intermediates, as detected in intact cells by electron paramagnetic resonance (EPR) spectroscopy. These radicals corresponded to one-electron oxidation products of myricetin. The level of phenoxyl radicals was significantly reduced when myricetin-treated hepatocyte cultures were also supplemented with iron (Fe-NTA 100 microM). This suggested that iron could accelerate the oxidation flux of myricetin. Moreover, myricetin was found to be able to inhibit lipid peroxidation induced by iron in hepatocyte culture. Free malondialdehyde (MDA) levels and the amount of radicals derived from oxidized lipids were greatly reduced when myricetin was added to iron-treated cultures. This showed that myricetin was a good inhibitor of lipid peroxidation in this model and that the intermediate generation of phenoxyl radicals might contribute to the antioxidant mechanism of myricetin.

Protective effects of tea polyphenols against oxidative damage to red blood cells.

Tea polyphenols (TPP) from black and green teas were evaluated for their antioxidant effects on normal red blood cells (RBC) and beta-thalassemic RBC membranes challenged with exogenous oxidants in vitro. The TPP of both types protected RBC against primaquine-induced lysis; they also protected the whole cells and the membranes against H2O2-induced lipid peroxidation so that about 80% protection was reached at [TPP] = 10 microg/mL. TPP from black tea at the same concentration protected normal RBC from morphological alterations caused by the peroxide treatment. The mechanism of the effects of TPP was investigated using a chemical system generating .OH (iron + ascorbic acid). TPP from both black and green teas inhibited the .OH fluxes in a concentration-dependent manner, indicating the possibility of iron chelation by TPP. Spectrophotometric titration revealed that TPP could stoichiometrically bind ferric iron to form a redox-inactive Fe-TPP complex. Quantitative analysis suggests that one or more major catechins from the TPP preparations are the likely iron-binding compounds accounting for the antioxidant effects of TPP on RBC.

Vitamin E inhibits apoptosis, DNA modification, and cancer incidence induced by iron-mediated peroxidation in Wistar rat kidney.

We have developed an experimental model of iron-induced oxidative nephrotoxicity and renal cancer. Using this model, the effect of vitamin E, a known antioxidant, was investigated. Three-week-old male Wistar rats were fed with vitamin E-sufficient (control) and vitamin E-supplemented diets throughout the experiment. After 1 month of feeding, iron-induced tissue lipid peroxidation, apoptosis, and formation of 8-hydroxydeoxyguanosine, a known DNA oxidative modification, were observed by cold Schiff staining, in situ labeling method (staining by terminal deoxynucleotidyl transferase-mediated nick end labeling), and high-performance liquid chromatography with electrochemical detection system, respectively, in the groups of rats treated with ferric nitrilotriacetate (Fe-NTA; Fe, 10 mg/kg body weight). For the vitamin E intervention study on Fe-NTA-induced renal carcinogenesis, two groups of rats fed vitamin E-sufficient and vitamin E-supplemented diets (30 and 20 rats, respectively) were treated with Fe-NTA (Fe, 7.5 mg/kg body weight once or twice a week) i.p. for 3 months and observed for 9 additional months. Five of the vitamin E-sufficient rats died during the first 3-month period. The results showed that vitamin E could inhibit tissue lipid peroxidation, apoptosis, 8-hydroxydeoxyguanosine formation, and the development of cancer [11 of 25 rats (44%) for vitamin E-sufficient versus 1 of 20 rats (5%) for vitamin E-supplemented rats, respectively]. These studies strongly suggest that in Fe-NTA-induced renal cancer, as with certain other types of cancer, oxidative stress plays an important role in carcinogenesis, and an antioxidant is an effective chemopreventive measure.

Ginseng extract scavenges hydroxyl radical and protects unsaturated fatty acids from decomposition caused by iron-mediated lipid peroxidation.

This study was conducted to investigate whether or not the antioxidation effect of ginseng extract directly inhibits decomposition of unsaturated fatty acid caused by iron and hydrogen peroxide-induced lipid peroxidation, and whether this effect involves a hydroxyl radical-scavenging mechanism. Thiobarbituric acid-reactive substances (TBARS), gas chromatography, and electron spin resonance (ESR) spectrometer were used to measure lipid peroxidation, unsaturated fatty acid, and hydroxyl radical. The results showed TBARS formed and the loss of arachidonic acid during lipid peroxidation, and that hydroxyl radical formed by the Fenton reaction were completely inhibited by ginseng extract. This antioxidant effect of ginseng may be responsible for its wide pharmacological actions in clinical practice by a free radical reaction-inhibition mechanism.

Iron release and uptake by plant ferritin: effects of pH, reduction and chelation.

Ferritins are iron-storage proteins that accumulate in plastids during seed formation, and also in leaves during senescence or iron overload. Iron release from ferritins occurs during growth of seedlings and greening of plastids. Depending on the concentration of the reducing agent ascorbate, either an overall iron release or uptake by ferritins from iron(III) citrate may occur. We have designed methods to measure these simultaneous and independent uptake and release fluxes. Each individual step of the exchange was studied using different iron chelates and an excess of ligand. It is shown that: (i) the chelated form of iron, and not ionic Fe3+, is the substrate for iron reduction, which controls the subsequent uptake by ferritin; (ii) iron uptake by ferritins is faster at pH 8.4 than at pH 7 or 6 and is inhibited by an excess of strongly binding free ligands; and (iii) strongly binding free ligands are inhibitory during iron release by ascorbate. When reactions are allowed to proceed simultaneously, the iron chelating power is shown to be a key factor in the overall exchange. The interactions of iron chelating power, reducing capacity and pH are discussed with regard to their influence on the biochemical mobilization of iron.

The effect of different iron compounds on transferrin receptor expression in term human cytotrophoblast cells.

During pregnancy, the mother is faced with an increased food demand. A good example of this increased demand is iron (Fe). Fe is needed in all growing cells. During pregnancy, the Fe transport to the fetus increases enormously. This amount can easily induce an Fe deficiency in the mother. Fe supplementation is very important for her, but not for the Fe status of the fetus, which is protected against Fe toxicity as well as deficiency. The placenta seems to be autonomous in Fe uptake. Likely there is a regulation mechanism. The human placenta is hemomonochorial. The cell layer of the fetus in contact with the maternal blood is formed by syncytiotrophoblasts. Fe is transported to the placenta by transferrin. Transferrin binds to a transferrin receptor on the trophoblast membrane and is internalized via an endocytic pathway. During this cycle, Fe is released from transferrin and the transferrin-transferrin receptor complex is recycled to the membrane. Isolated trophoblast cells from term placentas form a syncytium in vitro, and transferrin receptors are expressed. Expression depends on the number of cells in culture, culture time, the amount of Fe available, and the Fe compound. By regulation of the number of transferrin receptors, trophoblasts are able to control their Fe uptake.