Heavy Metals Acting as Endocrine Disrupters

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Georgescu B. et. al./Scientific Papers: Animal Science and Biotechnologies, 2011, 44 (2)In mice, parenteral administration of nickelchloride and subsulfide results in intrauterinedeath of the fetus and severe intrauterine growthrestriction in neonates. Respiratory exposure to Nicarbonyl results in fetal death, intrauterine growthrestriction and congenital anomalies in rats andhamsters. Nickel carbonyl is associated todominant letal mutations in rats. In early studies, itwas reported that nickel chloride or nickel suphategiven parenterally to dogs and rabbits, induceinsulin resistance and hyperinsulinemia. Latter on,the authors observed that i.v. or i.p. injection inrabbits, rats or chicken or p.o. administration inrabbits resulted in an rapid peak of plasma glucoselevels which returned to normal after about 4hours. Histological examination of pancreatic cellsreported distruction of α cells and degranulationand vacuolization of ß Langerhans cells. In ratsfed with nickel acetate, marked lysis of exocrinepancreatic cells and inhibition of amylase release[9] was noticed. In hypophysectomized oradrenalectomized rats, the hyperglycaemic effectwas markedly reduced but not completelyabolished. Indeed, pretreatment with insulin willreduce nickel-induced hyperglycaemia. It appearsthat Ni combinations may inhibit the release ofprolactin, most probably due to hypothalamicdopamine agonistic effects. Other endocrineeffects related to Ni contamination were inhibitionof growth hormone secretion [9], althoughstimulatory effects on growth hormone releasefrom the pituitary were also demonstrated.6. Lead (Pb)Lead is largely found in nature, in rocks, underseveral combinations. The terrestrial crustcontains on average 1-2 ppm lead. However, dueto important pollution, lead is largely spreaded inthe environment in air, water, soil, flora and fauna.Hayfields and animal fodder cultured in thevicinity of industrial buildings using Pb in thefabrication process are at high risk to becontaminated with Pb resulted from vaporprecipitation or the sedimentation of Pb particles.Aerosols may be dispersed on a distance of 2-3km (0,1 mg/m 3 ) and even 10 km (0.01 mg/m 3 )around the contamination source. Spontaneousvegetation and fodder fields around intensivelytrafficked autorays contain 50-60-fold higherconcentrations of Pb.Contamination of the human or animal with Pb ismade by ingestion, respiration or transdermal. Ithas been shown that digestive absorption is highlyspecies specific, as from the intake about 90% isabsorbed in bovine, 1-2% in ovine and 0.8-1% inrabbits. In human, the absorption percent is about50%. In bovines, ingestion of contaminated fodderleads to a 20-fold increase of Pb levels in the liverand a 3-4-fold increase of Pb levels in milk andmeat. If fodder contains 1-6 mg/kg Pb, then themilk content persists at 0.05-0.15 mg/kg for about120 days.Lead toxicity consists of inhibition of cellularenzymes, binding of sulfhydril groups ordissociation of biological active metal ions frommetaloenzymes. Additionally, it affects themembrane stability of erythrocytes, inducesfunctional disturbances in peripheral nerves anddisturbances in the development of the skeleton.Lead is a powerful disruptor of adrenal andovarian steroidogenesis, inhibiting synthesis andactivity of progesterone, 17-hydroxyprogesterone,17,20-dihydroxyprogesterone, deoxycorticosterone,corticosterone and 21-deoxycortisol in adose-dependent manner. Interestingly, its effectson 17β-estradiol, testosterone and cortisol arebiphasic, with stimulatory effects after low-levelsexposure and inhibitory effects after high-leveexposure [10]. Lead exposure results in disturbedfertility in females, as revealed by an in vitrostudy that examined the consequences of Pbexposure on cytochrome P-450 aromatase (P-450ARO) and ß-estradiol receptors, two key proteinsin the function of the pituitary-ovarian axis. It wasshown that the activity of both P-450 ARO andER-β in the granulosa cells of the ovarian follicleswas strongly inhibited in women exposed to Pb[11]. In summary, Pb contamination may alterendocrine-regulated processes such as longevity,development, sexual receptivity, fertility andlocomotion. For example, in Drosophila, Pbinterferes with the expression of about 122 genesinvolved in locomotion. In the larvar state, thesegenes regulate the level of intracellular calciumassociated with neuronal activity at theneuromuscular jonction sinapses [12].7. Zinc (Zn)Zinc is found in several combinations both in theearth crust and vegetal and animal cells. In fact,Zn is one of the most important natural,biologically active constituents, indispensable tolife itself. In all tissues, Zn levels are 2-fold highercompared to iron levels. It was revealed that the92
Georgescu B. et. al./Scientific Papers: Animal Science and Biotechnologies, 2011, 44 (2)Zn atom from the Zn fingers of the estrogenreceptor can be replaced by several heavy metalmolecules such as copper, cobalt, Ni and Cd. Byreplacing the Zn atom with Ni or copper, bindingof the estrogen receptor to the DNA-hormoneresponsiveelements in the cell nucleus isprevented.Zinc contamination results from industrial smoke,with the most relevant compounds represented byZn chloride, Zn chromate, Zn phosphur, Znsulphate and Zn oxide. Contamination is alsopossible by use of zincate containers to heat milkand foods. Moreover, Zn is an important substanceused in the fabrication process of severalpesticides. It may enter the body either by enteralor respiratory way. It is easily absorbed in alltissues and rapidly diffuses. Zinc is excreted byfeces, the bila etc.; it is co-secreted with insulin bythe pancreas. In the presence of As, Zn toxiceffects are 3-4-fold increased.The maximum admitted limit of Zn in our countryis of 25 ppm in vegetables, 40 ppm in dry beans,50 ppm in meat, meat subproducts and conserves,30 ppm in eggs, 5 ppm in milk, beverage, oil andtomato juice. Besides direct toxic effects, Zn saltsact as endocrine disrupters. In a recent study,copper, Cd, Pb, Hg and Zn at 95.4 pM-1 mM,alone or in combination with the natural estrogen,17ß-estradiol, have been tested using the yeastestrogen screen, an estrogen receptor-dependenttranscriptional expression assay. No direct transactivationof the estrogen-responsive elementcould be measured with any of the concentrationof the metals tested. However, Zn, Cd and copperwere able to potentiate the estradiol-inducedresponse in a dose-dependent manner, thusindicating that Zn can act as a potential endocrinedisrupter by modulating the estrogenic activity ofendogenous hormones (xenoestrogen) [13].ConclusionsBesides several man-made chemicals, most ofthem major components of widely used pesticides,recent studies strongly suggest that some heavymetals may exert endocrine-disrupting activities inanimals and human. Of these metals, Zn, Pb andHg and As interfere with sex hormones andadrenal cortex hormones steroidogenesis to alterreproduction and sex differentiation, Cd isinvolved as a risk factor for breast cancer and Niappears to induce pancreatic cell lesions, possiblyincreasing the risk of diabetes mellitus.Nevertheless, further studies are needed toestablish a dose-effect relationship. Futurestrategies in agriculture, animal husbandry andenvironmental health should aim limitation of theendocrine disruption phenomenon induced byheavy metals.References1.Georgescu, C., Georgescu, B., Duncea, I.,Xenoestrogenii: implicatii clinice si metode de evaluarecalitativa si cantitativa, Clujul Medical, 2006, vol.LXXIX, 1, 7-122.Davey, J. C., Bodwell, J. E., Gosse, J. A., Hamilton,J. W., Arsenic as an endocrine disruptor: Effects ofArsenic on estrogen receptor–mediated gene expressionin vivo and in cell culture, Toxicol Sci, 2007, 98, 75-863.Masufumi, T., Schin’Ichi, Y., New Aspects ofCadmium as Endocrine Disruptor, Environ Sci, 2006,13, 107-1164. Heilier, J. F., Donnez, J., Verougstraete, V., Donnez,O., et al., Cadmium, lead and endometriosis, Int ArchOccup Environ Health, 2006, 80, 149-1535. Strumylaite, L., Bogusevicius, A., Abdrachmanovas,O., Baranauskiene, D., Kregzdyte, R., Pranys, D.,Poskiene, L., Cadmium concentration in biologicalmedia of breast cancer patients, Breast Cancer ResTreat, 2011, 125, 511-5176.Tan, S., Mahaffey, K., Evidence for mercurty as anendocrine disrupter: an overview of the literature, 2003,http://www.scribd.com/doc/17905747. Darbre, P. D., Metalloestrogens: an emerging classof inorganic xenoestrogens with potential to add to theoestrogenic burden of the human breast, J ApplToxicol, 2006, 26, pp. 149-1538. Frynn-Aikins, K., Gallagher, E., Ruessler, S., et al.,An evaluation of methyl mercury as and endocrinedisrupter in Largemeouth Bass, SESC Webmaster,2011, http://www. fl. biology. usgs. gov.9.Dormer, R., L., Kerbey, A. L., McPherson, M.,Manley, S. et al., The effect of nickel on secretorysystems. Studies on the release of amylase, insulin andgrowth hormone, Biochem. J, 1973, 140, 135-14210.Chaube, R., Mishra, S., Rahil Singh, K., In vitroeffects of lead nitrate on steroid profiles in the postvitellogenicovary of the catfish Heteropneustesfossilis, Toxicol in vitro, 2010, 24, 1899-190411.Taupeau, C., Poupon, J., Treton, D., et al., Lead(Pb2+) reduces mRNA and protein levels ofcytochrome P-450 aromatase and estrogen receptorbetain human ovarian granulosa cells, Biol Reprod,2003, 68, 1982-198812. Hirsch, H. V., Possidente, D., Possidente, B., Pb 2+ :an endocrine disruptor in Drosophila?, Behaviour andPhysiology, 2010, 99, 254-25913. Denier, X., Hill, E. M., et al., Estrogenic activity ofcadmium, copper and zinc in the yeast estrogen screen,Toxicol in vitro, 2009, 23, 569-57393
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