Review Article Cadmium and Its Neurotoxic Effectsdownloads.hindawi.com/journals/omcl/2013/898034.pdfReview Article Cadmium and Its Neurotoxic Effects BoWang 1 andYanliDu 2 Department

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2013 Article ID 898034 12 pageshttpdxdoiorg1011552013898034

Review ArticleCadmium and Its Neurotoxic Effects

Bo Wang1 and Yanli Du2

1 Department of Pathology The Second Clinical Medical School of Inner Mongolia University for the Nationalities(Inner Mongolia Forestry General Hospital) Yakeshi 022150 Inner Mongolia China

2Department of Neurosurgery The Second Clinical Medical School of Inner Mongolia University for the Nationalities(Inner Mongolia Forestry General Hospital) Yakeshi 022150 Inner Mongolia China

Correspondence should be addressed to Yanli Du 13804705515163com

Received 24 April 2013 Revised 28 June 2013 Accepted 30 June 2013

Academic Editor Renata Santos

Copyright copy 2013 B Wang and Y Du This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Cadmium (Cd) is a heavy metal that has received considerable concern environmentally and occupationally Cd has a longbiological half-life mainly due to its low rate of excretion from the body Thus prolonged exposure to Cd will cause toxic effectdue to its accumulation over time in a variety of tissues including kidneys liver central nervous system (CNS) and peripheralneuronal systems Cd can be uptaken from the nasal mucosa or olfactory pathways into the peripheral and central neurons forthe latter Cd can increase the blood brain barrier (BBB) permeability However mechanisms underlying Cd neurotoxicity remainnot completely understood Effect of Cd neurotransmitter oxidative damage interaction with other metals such as cobalt and zincestrogen-like effect and epigenetic modification may all be the underlying mechanisms Here we review the in vitro and in vivoevidence of neurotoxic effects of Cd The available finding indicates the neurotoxic effects of Cd that was associated with bothbiochemical changes of the cell and functional changes of central nervous system suggesting that neurotoxic effects may play a rolein the systemic toxic effects of the exposure to Cd particularly the long-term exposure

1 Introduction

Cadmium (Cd) is a toxic nonessential transition metal andclassified as a human carcinogen by the National ToxicologyProgram [1] There are several sources of human exposureto Cd including employment in primary metal industriesproduction of certain batteries some electroplating processes(about 29 of year production) and consumption of tobaccoproducts [2] It is also of interest since the natural bio-geochemical cycle of Cd has been overwhelmed First theconcept of provisional tolerable weekly intake (PTWI) wasestablishedThe Joint FAOWHOExpert Committee on FoodAdditives defines the PTWI for a chemical with no intendedfunction as an estimate of the amount of the chemical thatcan be ingested weekly over a lifetime without appreciablehealth risk [3]The first Cd PTWIwas 400ndash500120583g per personper week This level was based on a critical concentrationof 200mg Cdg kidney cortex attainable after a dietary Cdintake of 140ndash260120583gd for over 50 years or 2000mg over alifetime For several decades the PTWI has been expressedmore rationally in terms of the intake per kg body weight

and the value was constantly changed (Table 1) In 2010 theConsumer Product Safety Commission (CPSC) released astaff report recommending new guidance on Cd that is anacceptable daily intake level of 01 120583g kgminus1 body weight perday for chronic exposure [4] In most studies the half-lifeof Cd in humans is estimated at a range of 15 to 20 years[5] Epidemiological and experimental studies have linkedthe occupational Cd exposure with lung cancer and othercancers such as the prostate renal liver hematopoietic sys-tem urinary bladder pancreatic testis and stomach cancers[6ndash8] Exposure to Cd also severely affects the functionof the nervous system [9 10] with symptoms includingheadache and vertigo olfactory dysfunction parkinsonian-like symptoms slowing of vasomotor functioning peripheralneuropathy decreased equilibrium decreased ability to con-centrate and learning disabilities [11ndash13]Theneurotoxicity ofCd in children was investigated in several studies in the 1970sand 1980s but has received little attention since then In case-control studies in which the hair concentration of Cd in aclinically defined groupwas comparedwith that of a referencegroup higher concentrations of hair Cd were reported in

2 Oxidative Medicine and Cellular Longevity

Table 1 Summary of the ldquosaferdquo level for human contacted of Cd

OrganizationAuthors Year Approach Dose ReferenceFAOWHO 1988 Intake 400ndash500 120583gweek [3]WHO 1992 Intake 7120583gsdotkgminus1 bwweek or 1 120583gsdotkgminus1 bwday [38]FAOWHO 1993 Intake 7120583gsdotkgminus1 bwweek [39]Satarug et al 2000 Intake 30120583gday [40]Nasreddine and Parent-Massin 2002 Intake 10ndash30120583gday [41]WHO 2004 Drinking-water 3120583gL [42]FAOWHO 2006 Food 04mgkg of the BMDL of R-Cd standard [43]ACGIH 2007 Blood 5120583gL [44]EFSA 2009 Intake 25120583gsdotkgminus1 bwweek [45]FAOWHO 2010 Intake 58120583gsdotkgminus1 bwweek [46]CPSC 2010 Intake 01 120583gsdotkgminus1 bwday [4]ACGIH American conference of governmental industrial hygienists CPSC Consumer Product Safety Commission FAO Food andAgriculture OrganizationWHO World Health Organization bw body weight

children withmental retardation [14] and learning difficultiesor dyslexia [11 15] In cohort studies Thatcher et al reportedthat the concentration of Cd in hair was inversely related toadjust Intelligence Quotient (IQ) [16 17] Other investigators[18] also reported associations between hair Cd concen-trations and childrenrsquos performance on visual-motor tasksThese studies clearly indicate the association of increasedtotal Cd concentration with mental retardation and reducedvisualmotor abilities Effect ofCdneurotransmitter oxidativedamage interaction with other metals such as cobalt andzinc estrogen-like effect and epigenetic modification maybe the underlying mechanisms (Figure 1) However the exactmechanism(s) through which Cd elicits its neurotoxic effectsis still unresolved In this review therefore we focus on recentevidence from experimental and epidemiological studiesshowing that Cd exposure can induce its neurotoxin effects

2 The Absorption of Cd in the NervousSystem and Distribution

The Cd exposure rate (based on meconium analysis) ininfants was 85 and the median concentration of the pol-lutants in the positive samples was 1337mgmL In most ofthese studies the concentration of Cd in hair was measuredThe CNS is especially vulnerable to damage during earlyneonatal development Cd is able to readily pass to the fetusvia the placenta and was detected in milk during lactation[19] Cd can be uptaken from the nasal mucosa or olfactorypathways into the CNS thus the CNS is subjected to Cdtoxicity [20ndash22] Under normal conditions Cd barely reachesthe brain in adults due to the presence of the blood brainbarrier (BBB) however this structure is not fully developedin young animals [23] The anatomical and physiologicalbases on which the choroids plexus becomes the target ofxenobiotics have been examined Cd tends to accumulatein the choroids plexus at concentrations much greater thanthose found in the cerebrospinal fluid (CSF) and elsewherein brain tissues A postmortem human study revealed thatthe Cd concentration in the choroids plexus was about 2-3

times higher than that found in the brain cortex [24] Asa general choroids plexus toxicant Cd can directly damagethe choroids plexus ultrastructure Due to differences in theBBB integrity [25] Cd is thus more toxic to newborn andyoung rats than to adult rats Cd can increase permeabilityof the BBB in rats [26] to penetrate and accumulate in thebrain of developing and adult rats [27 28] leading to brainintracellular accumulation cellular dysfunction and cerebraledema

As a barrier the choroidal epithelia are often the first andthemost frequent ones to encountermetal insults frombloodTwo mechanisms may aid resistance of choroids plexus toblood-borne toxicities First the choroids plexus containsabundant metal binding ligands that effectively sequestermetal ions Moreover the concentration of cystine in thechoroids plexus is 4-fold higher than that in the brain cortex[29] Second the choroids plexus owns an active defense sys-tem The activities of superoxide dismutase and catalase aresignificantly higher in the choroids plexus than in cerebrumand cerebellum Taken together the choroids plexus likelyforms the first line of defense against neurotoxicants It mustbe kept in mind however that none of the cellular defensemechanisms would operate in an unlimited capacity Thepathophysiological changes can occur either as the thresholdabove which the protective capacity of the choroids plexusis exceeded or saturated or as a direct result of barrierdysfunction Thus the need arises for a more comprehensiveunderstanding of the detoxification mechanisms such asantioxidant systems induction of protective macromolecules(heat shock proteins etc) formation of specific metalinclusion bodies or binding proteins and biotransformationreactions (methylation conjugation etc) that operate in thechoroids plexus

Cd is transported along the primary olfactory neurons totheir terminations in the olfactory bulbs thereby bypassingthe intact BBB The olfactory route could therefore be alikely way to reach the brain and should be taken intoaccount for occupational risk assessments for this metal[30ndash32] Occupational inhalation of Cd can be toxic to theolfactory sense [30] Primary olfactory neurons are regularly

Oxidative Medicine and Cellular Longevity 3

Cd2+

MARKmTORJAK pathway

Hypothalamus

Pituitary

Ovarytestis

Testosterone

LH

Epigenetic effect

Neurogenesis

Neuron gene expression

ROS

Apoptosis

FSHminus

minus

+

+

+

Ca2+Ca2+

Figure 1 Mechanistic illustration of the neuronal toxicity of Cd (1) Cd-induced neuron cell apoptosis and ROS (reactive oxygen species)are mediated through Ca2+-mitochondria signaling and Ca2+-membrane channels (2) Cd impaired neurogenesis (3) Cd accumulation inthe brain leads to the altered gene expression and epigenetic effect (4) Cd has estrogen-like effect which can induce endocrine disruptionby affecting the hypothalamic-pituitary-gonadal (HPG) axis in different aspects Meanwhile these potential mechanisms have possibleinteractions The solid black arrows represent the stimulation the solid black line segments indicate the inhibition and the dotted linesrepresent the negative feedback control of the HPG axis

replaced throughout the life span Functional recovery andregeneration of olfactory neurons has been demonstratedin laboratory animals but not confirmed in humans [33]Intranasal exposure to Cd has been related to olfactorydysfunction in humans and to nasal epithelial damage andaltered odorant-guided behavior in rodent models Thepathophysiology underlying these deficits has been partlyelucidated Optical imaging revealed significant reductionsin odorant-evoked release from the olfactory nerve at a Cdchloride dose two orders of magnitude less than that requiredto induce morphological changes in the nerve in the sameanimals demonstrating that it is a more sensitive techniquefor assessing the consequences of intranasal neurotoxicantexposureThis approach is potentially useful in exploring theeffects of any putative neurotoxicant that can be deliveredintranasal [32]

3 The Influence of Cd to Central NervousSystem (CNS)

31 The Morphology Change of CNS in Response to CdCd-treated embryos developed a smaller head with unclearboundaries between the brain subdivisions particularly inthe mid-hindbrain region Embryos display normal anteriorto posterior regionalization however the commitment ofneural progenitor cells was affected by Cd [34] Cd hasbeen shown to produce free radicals in the brain whichmay potentially damage both neurons and oligodendrocytes(OLG) OLGs are the glial cells which myelinate axons inthe CNS An early study reported that Cd toxicity affectedCNSwhitematter [35] and one laboratory demonstrated thatOLGs are direct targets of this structure [36] Experimentalstudies have shown that Cd can be a potent neurotoxicantfor the peripheral nervous system Moreover Cd has a half-life of more than 15 years in humans Elderly workers may bemore susceptible to an increased Cd body burden and maydevelop a peripheral polyneuropathy (PNP) over time [37]The primary olfactory neuron is the only sensory cell directly

in contact with the environment and therefore potentiallyexposed to airborne toxicants so olfactory damage mayrepresent the early action of a toxicant on the nervous systemthe primary olfactory neuron may represent the early targetfor airborne Cd toxic action

In cortical neurons cell culture from fetal rats at 19 daysof gestation Cd modified the neuronal morphology after a6 h treatment in a serum-free medium with 10 120583M of Cdwhereas at 24 h it showed a great loss of neuronal integritymainly evidenced by the almost complete disappearance ofthe axons Lower concentrations of Cd than 1120583M couldinduce cell apoptosis and higher concentrations of Cd than1 120583M could induce necrotic cell death [9] Cd affected thecell morphology the morphological changes were mainlylocated in the neural extensions (axons and dendrites) whichalmost disappeared after 24 h of treatment with 1 120583M ofCd in a serum-free medium [9 47] Such morphologicalchanges induced by Cd have also been described in othercells [48] Cd inhibited neurite outgrowth at concentrationsthat decreased viability in Neuroscreen-1 cells (NS-1) modelsa subclone of PC12 cells using high content screening Theprevious studies have shown that cultured oligodendrocytesare directly damaged by Cd exposure and continuous expo-sure (18ndash48 h) of OLPs to low micromolar concentrations(0001ndash25 120583M) of Cd significantly decreased mitochondrialmetabolic activity increased LDH leakage starting at 5mMandmaximally activated caspase-3These results suggest thatCd induces OLP cell deathmainly by apoptosis and at higherconcentrations or with prolonged exposure to the heavymetal there is an increase in cytoplasmic membrane damagean index of necrosis More importantly transient exposureto Cd is sufficient to damage OLPs and could in principleimpairmyelination in the neonate Although the effects of Cdon neuronal cells in culture have been described in severalpapers its effects on human central nervous system neuronsin vivohave not yet been demonstratedHowever the recentlydescribed Cd-induced apoptosis of the motor neurons of theventral horns in cultured explants from human fetal spinal


cords (10-11 weeks gestational age) [49] suggests that theeffects observed in vitro could actually occur also in vivo

Increasing evidence has demonstrated that Cd is a pos-sible etiological factor of neurodegenerative diseases such asAlzheimerrsquos disease (AD) and Parkinsonrsquos disease (PD) [5051] Cerebral cortical neurons have been identified as targetsof Cd-mediated toxicity and Cd-induced cell apoptosis [5253] Apoptotic morphological changes induced by Cd incerebral cortical neurons were assessed in some studies [5354]

In vivo study the age and species of experimental animalscould be effected the CNS results of damage Perinatalexposure to Cd (50 ppm in drinking water) reduced thebrain weights of pups and inhibited the activities of enzymesin nervous system for example acetylcholine esterase K+-ATPase CNP (cyclic nucleotide phosphodiesterase) and 50-nucleotidase [55] The Cd concentration in the choroidsplexuswas about 2-3 times higher than that found in the braincortex Cd-produced deterioration of the plexus structure canbe characterized by the loss of microvilli a rupture of theapical surface and an increased number of blebs Cellulardebris present in the ventricular lumen may result from thebreaking of the apical membrane The epithelial cells displayan abnormally high number of cytoplasmic vacuoles andlysosomes with condensed or irregular nuclei As a generalchoroids plexus toxicant Cd directly destroys the plexusultrastructure In both chronic (22 weeks) and acute (1ndash24days) exposuremodels the levels of Cd in the choroids plexuswere high while Cd in the CSF fell below the detection limit[29]

32 The Biochemical Changes of CNS in Response to CdThe cholinergic system with acetylcholine (ACh) as theneurotransmitter is involved in cognitive processes throughthe activation of metabotropic muscarinic and ionotropicnicotinic cholinergic receptors The reaction responsiblefor the maintenance of levels of ACh is catalyzed by twocholinesterases (ChE) acetylcholinesterase (AChE) andbutyrylcholinesterase (BuChE) AChE is an important bio-marker for several environmental contaminants in zebrafish[56 57] In addition it is also known that this enzyme playsan important role in diseases with an increasing incidence inthe elderly population such as Alzheimer disease Zebrafish(Danio rerio) is an emergent vertebrate model for studyingseveral biological events such as neurochemical alterationspromoted by heavy metal toxicity This teleost possesses onlythe gene for AChE which is responsible for the whole AChdegradation being the BuChE absent The AChE gene hasalready been identified cloned and functionally detectedin the zebrafish brain The recently reported on the effectsof long-term dietary-induced exposure to Cd on the AChEactivity of adult rodentsrsquo brain regions The authors studiedthe changes in the activities of AChE and Na+ K+-ATPasein the cerebral cortex hippocampus hypothalamus cerebel-lum and striatum of adult Wistar rats following a 5-month(long-term) exposure to an experimental diet supplementedwith low levels of Cd salt or with Cd-contaminated potatotubers The authors also assessed the behavioral (cognitive- motor- and anxiety-related) outcomes following the

above-mentioned treatment [58] But the other research termqueried that their study can be ldquoregarded as a significantcontribution to the field as there is paucity of information onthe AChE activity in brain regions following exposure to Cdrdquoand ldquothe experimental protocol used in the aforementionedstudy [58] is exceptionally well designed in order to simulatelong-term dietary-induced exposure to Cdrdquo [59]

Cd can affect the degree and balance of excitation inhibi-tion in synaptic neurotransmission as well as the antioxidantlevels in animal brain [28] Cd increases the serotonin sensi-bility in the CNS [60] Cd inhibits the release of acetylcholineprobably by interfering with calcium metabolism [61] Aremarkable reduction in the concentration of brain galac-tosylceramide (30ndash43) and 31015840-sulphogalactosylceramide(24ndash37) at 21 30 and 45 days of age was observedfollowing pre- and postnatal exposure of Cd in comparisonto the respective controls The ontogenic profile of differentbrain phospholipids in the Cd-exposed group showed anincrease in the levels of phosphatidylethanolamine at 21(31) 30 (25) and 45 (19) days of age the phosphatidyl-choline contents increased at day 21 (14) followed by asignificant decrease at 30 (14) and 45 (19) days com-pared to age-matched controls Brain phosphatidylinositolphosphatidylserine and sphingomyelin did not show anyalteration at early periods of exposure but decreased signif-icantly following continued exposure by 34 45 and 21respectively at 45 days of age [62]

Numerous studies have shown that cadmium causeda decrease in depolarization-evoked exocytotic release ofglutamate (as well as other neurotransmitters) from nerveterminals [73] Cd2+ can stimulate [3H]-glutamate binding inhuman platelets Cd2+ can increase lipid peroxidation levelsand reactive oxygen species (ROS) measurement in plateletsGlutamatergic system may be used as a potential biomarkerfor neurotoxic action of Cd in humans [74]

33 The Central Activity Changes in Response to Cd Cdmay alter the stimulus properties of morphine in adultmale rat model [75] As shown in Table 2 perinatal Cdexposure has been shown to alter behaviors and reducelearning ability In addition high levels of Cd and leadin childrenrsquos hair were associated with learning disabilitiesMotor and perceptual abilities of children exposed to Cdin uteri were significantly affected [76] Behavioral defectsneurochemical changes and brain lesions were reported inexperimental animals while in humans acute Cd poisoningproduced Parkinsonism symptoms [50] Blood Cd in motorneuron disease (MND with limited disability) was higherthan controls [77 78] Plasma Cd levels in the sporadicmotor neuron disease (SMND) group were significantlyincreased compared to controls [78] A recent study usinga fully automated observer-independent procedure to studymorphological alterations of the central nervous systemdemonstrated thatmyalgic encephalomyelitischronic fatiguesyndrome (MECFS) patients had an average decrease of thevolume of the gray matter of about 8 compared to matchedhealthy controls [79] The gray matter volume reduction wassignificantly associated with objective reduction of physicalactivity in MECFS patients Deficits in learning and altered


Table 2 Literature review of Cd neurotoxicity in humans and rats

Year Study design Age group EC (119899) Exposure toCd

Exposepathways Effects Reference

1961 Cross-sectional Male worker 106E84C mdash Occupationalexposure Anosmia [63]

1977 Cross- sectional Children 31E22C CdH Daily life Neurological disorders such aslearning disabilities and hyperactivity [11]

1981 Cross-sectional Children 73E44C CdH Daily life Dyslexic learning disorder [15]

1981 Cross-sectional Workers 49E CdU Occupationalexposure Polyneuropathy [64]

1982 Cross-sectional Children 149 CdH Daily life Effect on verbal IQ [16]1985 Case-control Young men 40 CdH Daily life Behavioural difficulty [65]

1985 Cross-sectional Children 69 CdH Daily lifeNonadaptive classroom behavioraffected behavioral developmentvisuomotor skills darr

[18]

1989 Cross-sectional Male workers 31E CdU Occupationalexposure

darr Attention memory andpsychomotor speed [66]

1992 Cross-sectional Worker 38E CdU Occupationalexposure

90 Headache 42 dizzy spells 21weakness 16 brain atrophy [67]

1992 Cross-sectional Worker 55E16C CdU Occupationalexposure Hyposmia [68]

1997 Case report Old man 1 Multiple organfailure

Occupationalexposureacute

Parkinsonism [50]

1999 Cross-sectional Worker 13E19C CdU Occupationalexposure Polyneuropathy [37]

2000 Cross-sectional Adult worker 42E47C CdU Occupationalexposure

darrMotor speed attention memory uarrequilibrium PNP and concentrationcomplaints

[69]

2006 Case report Adultworkers 1 CdU Inhale the

fumes Peripheral neuropathy [70]

2009 Cross-sectional Children 549 CdH Daily life Withdrawal social problems andattention problems associated [71]

2012 Wistar rats Male 20E20C Intratrachealinstillation

Experimentexposure

Dose- and time-dependent shift fromslower to faster waves [72]

E exposed subjects C control subjects CdU urinary cadmium concentration CdH concentration of cadmium in hair IQ Intelligence Quotient

behaviors and activities were also observed in offspringexposed to Cd during gestational andor lactational periodCd induced neuronal death in cortical neurons through acombined mechanism of apoptosis and necrosis involvingreactive oxygen species generation and lipid peroxidation[80] With regard to the assessment of behavioral disordersthe cross-sectional study by Bao et al from China revealeda higher frequency of withdrawal social problems andattention problems associated with higher levels of cadmiumin hair of children aged 7ndash16 years [71] But another studydid not find any significant association between cadmiumexposure and ADHD [81]

In animal study the role of the nanosized Cd in the cau-sation of nervous system damages and shows the possibilityof modeling human neurotoxic damage in rats [72]

4 The Mechanism by Which Cd Affects CNS

41 Cd and Oxidative Damage Cd-induced injury in thecerebral microvessels is thought to be associated with

oxidative stress Following in vivo Cd exposure there wasan early increase followed by a later decrease in microves-sel enzymes involved in cellular redox reactions such assuperoxide dismutase glutathione peroxidase and catalaseThus a depletion of microvessel antioxidant defense systemsand a resultant increase in lipid peroxidation (LPO) mayprovoke microvessel damage [82] Upon exposure Cd hasbeen shown to induce heavy metal-binding proteins suchas metallothionein (MT) in various organs MT is a low-molecular-weight protein 6500Da with high cysteine con-tent and high metal affinity which plays a major role in thekinetics and metabolism of Cd Four isoforms have beenidentified namely MT-I to MT-IV Metallothionein-3 (MT-III) is specifically expressed in the brain however it is down-regulated and thus deficient in Alzheimerrsquos disease [83] Thechoroids plexus also expresses MT proteins Nishimura et alobserved a strong MT immunostaining in ependymal cellsand choroids plexus epithelium in younger rats (1ndash3 weeksold) poisoned with Cd Thus the sequestration of Cd by MTmay partly contribute to the high accumulation of Cd in the


choroids plexus [84] Cd significantly increases the levels oflipid peroxidation in parietal cortex striatum and cerebel-lumas compared to a control group and dexamethasone (Dx)treatment prevented the increase in LPO levels associated toCd exposure probably through the increase in MT content[85] So MT as a protective mechanism against Cd-inducedneurotoxicity is suggested

In addition mitochondria play a role in stress responsesand can produce ROS when damaged Mitochondria areindeed a major source of ROS The enzyme COX can serveas an indicator of mitochondrial function This is becauseCOX dysfunction increases ROS reduces energy stores andimpairs energy metabolism [86] Accumulating evidencesindicate that Cd-induced neuronal toxicity is due to induc-tion of ROS which leads to oxidative stress [54 87] RecentlyCd induced ROS generation in a time- and concentration-dependent manner in PC12 and SH-SY5Y cells [54] whichcauses apoptosis of neuronal cells via activation of MAPKs(mitogen-activated protein kinases) andmTOR (mammaliantarget of rapamycin) signaling pathways [54 87 88]

42 Interaction andor Impact of Other Metals Including Cal-cium Zinc and Cobalt on CdNeurotoxicity Cerebral corticalneurons have been identified as targets of Cd-mediated toxic-ity [52] And Cd-induced cerebral cortical neurons apoptosisoccurs through Ca2+-mitochondria signaling [52 53] Cddisrupts intracellular free calcium ([Ca(2+)] i) homeostasisleading to apoptosis in a variety of cells including primarymurine neurons Calcium is a ubiquitous intracellular ionwhich acts as a signaling mediator in numerous cellularprocesses including cell proliferation differentiation andsurvivaldeath Few studies have focused on the interactionbetween Cd and Ca-binding molecules such as calmodulin

Cd may block the influx of Ca2+ through membranechannels into the nerve terminal following the action poten-tial these decreases in calcium influx caused by Cd wouldbe associated with an altered transmitter release [89] Of thereceptor agonists tested partially inhibited by Cd2+ [90] Cdions are often used to block high-threshold Ca2+ currents[91] but may also block low-threshold Ca2+ currents [92]When 100 120583MCdwas added to the external solution aminorfraction 86plusmn 89 of the low-threshold current atminus40mV(holding potential minus90mV) was blocked [93] Further studiesare needed to define which molecular effects are indeedelicited by Cd-calmodulin andor whether Cd2+ binds toother regulators of the Ca2+-induced signaling pathways

In a new study Cd-induced apoptosis is associated withcalcium-induced massive production of ROS dissipationof mitochondrial membrane potential (ΔΨm) cleavage ofcaspase-9 caspase-3 and PARP And the results demonstratethat Cd-induced apoptosis is mediated by calcium signalingpathway and calcium-mediated apoptosis occurs through themitochondria-caspase signaling pathway [53]

Although Cd is not accumulated in significant quantitiesinto the brain following exposure it disturbs the metabolismof Cu and Zn Because zinc (Zn) and Cd are cations ofsimilar size and charge and Cd has been shown to inhibitZn uptake in a variety of systems Cd is using transport

systems that normally function to regulate Zn levels in brainMetal analysis in the brain showed a reduction in zinc andcopper levels at 15 and 21 days of age in Cd-exposed animalsIt may be concluded that an early exposure of Cd mayproduce alteration in the development of different lipidswhich may produce CNS dysfunctions with a possibilityof being manifested even in later life [62] The most wellstudied metallothioneins are isoforms of metallothioneins Iand II that are expressed in almost all mammalian tissuesMetallothionein III is expressed in brain and is rich in zincSince the blood-brain barrier keeps Cd outside the CNSreported neurotoxic effects of Cd during development arelikely to be secondary to an interference of Cd with Zn-metabolism and not a direct effect of Cd on brain cells It istherefore of importance to investigate whether neurotoxicityinduced by Cd is related to mechanisms involving MT III inbrain [5]

Very few articles study neurotoxin effects about the effectof cobalt (Co2+) This study addition of inorganic Ca2+channel blockers (Cd2+ or Co2+) was used to demonstrate theCa2+ dependence of Ca2+-activated k+ currents [94] Cd2+andCo2+ were the nonspecific calcium channel antagonists inthe study [95 96] Co2+ did notmodify significantly the ATP-evoked current [97] Application of high potassium media togrowth cones inhibited neurite outgrowth an effect that wasblocked by 2mM cobalt or 100 120583M Cd suggesting that Ca2+influx via voltage-gated channels contributes to glutamate-induced regulation of neuritis outgrowth [98]

43 Cd and Neurogenesis There is evidence that relatesarsenic and manganese exposure with neurodevelopmen-tal problems in children but there is little informationon cadmium exposure Cd-induced neurotoxicity might becaused by impaired neurogenesis resulting in markedlyreduced neuronal differentiation and axonogenesis leadingto neuronal cell death [99] The present study comparesthe sensitivity of human (ReN CX) and mouse (mCNS)neuroprogenitor cell lines to chemicals using a multiplexassay for proliferation and apoptosis endpoints that arecritical for neural development Cells were exposed to 0001ndash100 120583M concentrations of Cd to affect proliferation andorapoptosis Cd decreased proliferation by at least 50 ofcontrol in either the ReN CX or mCNS cells Comparedto control Cd decreased cell viability (ATP levels) by atleast 50 in the ReN CX cells while Cd decreased viabilityby at least 50 in the mCNS cells Based on these resultsBrdU is an appropriate marker for assessing chemical effectson proliferation and human cells are more sensitive thanmouse cells for this endpoint [100] In the mammalian brainthe complex molecular pathways underlying neurogenesisprovide a variety of possible targets thatmight be impacted byCd exposure and identifying which pathways are disrupted isdifficult

Gender-related differences in susceptibility to chemicalexposure to neurotoxicants have not received sufficient atten-tion There is abundant available information on the gender-specific health effects of mercury and lead and exposure tolead seems to affect boys more than girls [101] The internal


cadmium dose is generally higher in women than in mendue to a higher gastrointestinal absorption at low iron storesThis was probably one major reason why Itai-itai diseasewas mainly a womanrsquos disease Yet data are sparse regardingthe risk for women relative to men to develop cadmium-induced kidney damage in populations exposed to low levelsof cadmium [102] Information regarding gender differencesin susceptibility of cadmium is still too scarce to draw anydefinite conclusion More research is highly warranted aboutthismatter Environmental epidemiological studies should bedesigned to quantify differential gender-based exposures andoutcomes and this may provide new insights into preventionstrategies [101]

44 Cd and Gene Expression Cd accumulation prior toand at birth however might cause irreversible or lastingchanges in the brain which in turn leads to the altered geneexpression [103 104] The expression of several proneuronalgenes including ngn1 in cell clusters zash1a in the devel-oping optic tectum and zash1b in the telencephalon andtectum Cd-treated embryos also have fewer differentiatedneurons and glia in the facial sensory ganglia as indicatedby decreased zn-12 expression Also a lower transcriptionlevel of neurogenic genes ngn1 and neuroD is observedin neurons [34] Cd-induced neurotoxicity can be causedby impaired neurogenesis resulting in markedly reducedneuronal differentiation and axonogenesis

By contrast caspase 3 and p53 were altered by environ-mental chemicals inmouse but not in human cellsThereforethese markers are not appropriate to assess the ability ofenvironmental chemicals to induce apoptosis in the ReNCX cells [100] Among the brain-specific genes neurogranin(RC3) andmyelin basic protein (MBP) are regulated by serumthyroid hormones (THs) [105] Since Cd exposure affectsTHs Cd exposure will alter expression of these genes in thebrain and furthermore those effects might be enhanced bya hypothyroid state In conclusion Cd combined with MMIdecreased the RC mRNA expression in the brain of femaleoffspringThe reduced expression of RC3mRNAmay explainthe effect of Cd on brain function Perinatal Cd exposuredisrupted the reproductive function of offspring indicated bythe reduced expression of ERs and PgR mRNA which wasnot considered to be estrogenic action

Cd-induced apoptosis in the neuronal cells has a time-and concentration-dependent manner Cd induces apoptosisof neuronal cells by activation of JNK Erk12 and mTORsignaling network These findings support the notion thatinhibitors of these pathways may be exploited for preventionof Cd-induced Parkinsonrsquos disease Alzheimerrsquos disease andother neurodegenerative disorders [88]

45 Estrogen-Like Effect (Hormones Regulating Shaft) Cdcan modify hormone levels by affecting the hypothalamic-pituitary-testicular axis in different aspects not only viaits effects on Leydig cells Cd affected the circadian pat-tern release of noradrenaline a regulator of hypothalamushormone secretion which resulted in changes in the dailypattern of plasma testosterone and LH levels [106] In addi-tion plasma levels of pituitary hormones (eg LH FSH

prolactin ACTH)were alsomodified afterCd exposure [107]Nevertheless it remains to be investigated if Cd acts as anendocrine modulator by interacting with ERs or ARs in thetestis andor Leydig cells The study of the hypothalamic-pituitary-gonadal (HPG) axis in animals exposed to themetalis of great interest since the levels of Cd in air water soiland foods have increased by several folds in many parts ofthe world as a result of emissions from industrial activitiesCd accumulation increased in the hypothalamus and testesin all the Cd-treated animals whereas the accumulation ofCd in the pituitary was found only in postpubertal ratsThese data suggest that Cd exerts age-dependent effects onthe hypothalamic-pituitary-testicular (HPT) axis functionand a disruption of the regulatory mechanisms of the HPGaxis emerges [108] Previous studies have shown that theheavy metal Cd mimics the effects of estradiol in estrogen-responsive breast cancer cell lines Cd activates ER-alphathrough an interaction with the hormone-binding domainof the receptor [109] Cd globally effects HPT axis functionby acting at the three levels analyzed and that an interactionbetween Cd exposure and age emerge [110] The effects ofCd on sGnRH and rtERa gene expression in the brain inrainbow troutmodel and these genes are strongly involved inreproduction [111] But one study show that the effect of Cdon the ability of medaka gonads to produce steroids withoutthe presence of physiological signals from brain pituitaryor circulating blood was examined in vitro [112] Plasmalevels of luteinizing hormone (LH) were not modified by Cdin both age groups but follicle stimulating hormone (FSH)levels decreased in postpubertal rats and was not alteredin pubertal rats Plasma levels of testosterone increased inpubertal rats but decreased in postpubertal rats [108]

In summary it is important to note that the endocrinedisruption induced byCd is likely to bemulti-factorial medi-ated via its effects on Leydig cells andor the hypothalamic-pituitary-gonadal axis

46 Epigenetic Effect Cd binds DNA in a weak fashionindicating this is not a primary mode of action BecauseDNA sequence is static genetic susceptibility from DNAsequence variation cannot explain the mechanisms by whichprenatal or early childhoodmetal exposures impact cognitionand behavior later in life Cd may well act as an epigeneticor indirectly genotoxic carcinogen since it is in generalpoorly mutagenic [6 113] There is growing evidence thatexposure to toxicants in early life may cause later healtheffects Children of women exposed to Cd during preg-nancy display lower motor and perceptual abilities HighCd body burden in children is also related to impairedintelligence and lowered school achievement One possiblemechanistic pathway for this phenomenon which has yetto be fully explored in humans is epigenetics Epigenetics isthe study of heritable changes in gene expression that occurwithout changes in DNA sequence Such changes can haveinfluences as profound as those exerted by mutations butunlike mutations are reversible and responsive to environ-mental influences DNA methylation is the best studied ofthe epigenetic processes that regulate gene silencing DNAmethylation results in the addition of a methyl group to


the 51015840position of the cytosine ring in the context of CpGdinucleotides (or island) to form 5-methylcytosine (5-MeC)[114] Several studies have demonstrated that DNA methyla-tion was facilitated by long-term exposure to Cd [115 116]Oxidative stress may be a unifying process to explain thesefindings across differentmetals Metals are known to increasereactive oxygen species production in a catalytic fashion viaredox cycling Oxidative DNA damage can interfere withthe ability of methyltransferases to interact with DNA [117]thus resulting in a generalized hypomethylation of cyto-sine residues at CpG sites [118] Cd-induced alterations inmethylation metabolism could initiate a cascade of eventsincluding gene-specific DNA hypo- or hyper-methylation[119] resulting in aberrant gene expression and also indiminished glutathione activity leaving cells more vulnerableto oxidative stress Although the results of these epigeneticchanges on neurodevelopment have remained unexploredgiven the clear importance of DNA methylation to processesof neurodevelopment the metal-induced disruption of DNAmethylation clearly deserves further study Neurotoxicity isa common health endpoint for excess Cd exposure Finallythere is intriguing evidence that epigenetic phenomena mayunderlie observed effects of fetal or early life exposureand late onset of disease In addition Cd inhibited DNAmethyltransferases in amanner that was noncompetitivewithrespect to the DNA substrate This finding is suggestive ofinterference in enzymeDNA interaction possibly through aninteraction of Cd with the methyltransferase DNA bindingdomain [115] Failure of DNA methylation systems in thebrain leads to clinical syndromes such as mental retardationand autistic-like behaviors [120] Animal studies increas-ingly demonstrate that environmental factors can alter DNAmethylation patterns and that these changes correlate withanimal behavior [121] Further research in Cd should includethe role of epigenetics in determining long-term and late-onset health effects from metal exposure

5 Summary

Cd plays a critical role in neurobiology a growing numberof clinical investigations have pointed to Cd intoxication asa possible etiological factor of neurodegenerative diseasesincluding Parkinsonrsquos disease Alzheimerrsquos disease andHunt-ingtonrsquos disease [50 122 123]Many individuals in Europe andAsian already exceed these exposure levels and the marginis very narrow for large groups The question remains openabout the impact of long term low level exposure to Cd onvulnerable subgroups of the general population (foetusespregnant women young children and elderly people) livingin historically polluted areas where nonferrous industriesare or were in operation The neurotoxic effects of Cd werecomplex associated with both biochemical changes of the celland functional changes of central nervous system suggestingthat neurotoxic effects may play a role in the systemic toxiceffects of the exposure to Cd particularly the long-termexposure So the mechanism of Cd neurotoxicity should beenhancing andmeasures should be taken to reduce cadmiumexposure in the general population in order to minimize the

risk of adverse health effects The recent report on toxicitytesting in the 21st century by theNational ResearchCouncil oftheNational Academy of Sciences recommends the use of celllines of human origin The future of environmental researchon Cd should include the role of neurotoxic in determiningthe long-term and late-onset health effects following Cdexposure

Abbreviations

5-MeC 5-MethylcytosineACGIH American conference of governmental

industrial hygienistsAch AcetylcholineAChE AcetylcholinesteraseAD Alzheimerrsquos diseaseADHD Attention deficit hyperactivity disorderBBB Blood brain barrierBuChE ButyrylcholinesteraseBW Body weightCd CadmiumChE CholinesterasesCFS Chronic fatigue syndromeCNP Cyclic nucleotide phosphodiesteraseCPSC Consumer product safety commissionCNS Central nervous systemCSF Cerebrospinal fluidDx DexamethasoneFAO Food and Agriculture OrganizationFSH Follicle stimulating hormoneHPG Hypothalamus-pituitary-gonadal axisHPT Hypothalamic-pituitary-testicularIm IntramuscularIQ Intelligence quotientLDH Lactate dehydrogenaseLH Luteinizing hormoneLPO Lipid peroxidationMAPKs Mitogen-activated protein kinasesmTOR Mammalian target of rapamycinMBP Myelin basic proteinMcns Mouse cortical neural stem cellsME Myalgic encephalomyelitisMND Motor neuron diseaseMT MetallothioneinNS-1 Neuroscreen-1 cellsOLP Oligodendrocyte progenitorsPNP PolyneuropathyPTWI Provisional tolerable weekly intakeReN CX Human ReNcell CXSc SubcutaneousSMND Sporadic motor neuron diseaseTHs Thyroid hormonesWHO World Health OrganizationZn Zinc

Conflict of Interests

The authors have no conflict of interests to declare


Acknowledgment

This paper was supported by National Natural Science Foun-dation of China (NSFC no 81260310)

References

[1] ATSDR ldquoGuidanceManual for the Joint Toxic Action of Chem-ical Mixturesrdquo 2004 httpwwwatsdrcdcgovinteraction-profilesipgahtml

[2] ldquoBeryllium cadmium mercury and exposures in the glassmanufacturing industry Working Group views and expertopinionsrdquo IARC Monographs on the Evaluation of CarcinogenicRisks To Humans vol 58 pp 1ndash415 1993

[3] FAOWHO ldquoEvaluation of certain food additives and con-taminants (Thirty-third report of the Joint FAOWHO ExpertCommittee on Food Additives)rdquoWHOTechnical Report SeriesNo 776 WHO Geneva Switzerland 1988

[4] M N Mead ldquoCadmium confusion do consumers need protec-tionrdquo Environmental Health Perspectives vol 118 no 12 ppA528ndashA534 2010

[5] T Jin J Lu andMNordberg ldquoToxicokinetics and biochemistryof cadmium with special emphasis on the role of metalloth-ioneinrdquo NeuroToxicology vol 19 no 4-5 pp 529ndash536 1998

[6] M P Waalkes ldquoCadmium carcinogenesis in reviewrdquo Journal ofInorganic Biochemistry vol 79 no 1ndash4 pp 241ndash244 2000

[7] B Pesch J Haerting U Ranft A Klimpel B Oelschlagel andW Schill ldquoOccupational risk factors for renal cell carcinomaagent-specific results from a case-control study in GermanyMURC Study Group Multicenter urothelial and renal cancerstudyrdquo International Journal of Epidemiology vol 29 no 6 pp1014ndash1024 2000

[8] P Joseph T K Muchnok M L Klishis et al ldquoCadmium-induced cell transformation and tumorigenesis are associatedwith transcriptional activation of c-fos c-jun and c-myc proto-oncogenes role of cellular calcium and reactive oxygen speciesrdquoToxicological Sciences vol 61 no 2 pp 295ndash303 2001

[9] E Lopez S Figueroa M J Oset-Gasque and M P GonzalezldquoApoptosis and necrosis two distinct events induced by cad-mium in cortical neurons in culturerdquo British Journal of Phar-macology vol 138 no 5 pp 901ndash911 2003

[10] Y Cao A Chen J Radcliffe et al ldquoPostnatal cadmium expo-sure neurodevelopment and blood pressure in children at 2 5and 7 years of agerdquo Environmental Health Perspectives vol 117no 10 pp 1580ndash1586 2009

[11] R O Pihl and M Parkes ldquoHair element content in learningdisabled childrenrdquo Science vol 198 no 4313 pp 204ndash206 1977

[12] S D Kim C K Moon S-Y Eun P D Ryu and S A JoldquoIdentification of ASK1 MKK4 JNK c-Jun and caspase-3 as asignaling cascade involved in cadmium-induced neuronal cellapoptosisrdquo Biochemical and Biophysical Research Communica-tions vol 328 no 1 pp 326ndash334 2005

[13] R K Monroe and S W Halvorsen ldquoCadmium blocks receptor-mediated JakSTAT signaling in neurons by oxidative stressrdquoFree Radical Biology and Medicine vol 41 no 3 pp 493ndash5022006

[14] M Marlowe J Errera and J Jacobs ldquoIncreased lead andcadmium burdens among mentally retarded children and chil-dren with borderline intelligencerdquo American Journal of MentalDeficiency vol 87 no 5 pp 477ndash483 1983

[15] I D Capel M H Pinnock and H M Dorrell ldquoComparison ofconcentrations of some trace bulk and toxic metals in the hairof normal and dyslexic childrenrdquo Clinical Chemistry vol 27 no6 pp 879ndash881 1981

[16] RWThatcherM L Lester RMcAlaster and RHorst ldquoEffectsof low levels of cadmium and lead on cognitive functioning inchildrenrdquo Archives of Environmental Health vol 37 no 3 pp159ndash166 1982

[17] R W Thatcher R McAlaster and M L Lester ldquoEvokedpotentials related to hair cadmium and lead in childrenrdquoAnnalsof theNewYorkAcademy of Sciences vol 425 pp 384ndash390 1984

[18] M Marlowe A Cossairt and C Moon ldquoMain and interactioneffects of metallic toxins on classroom behaviorrdquo Journal ofAbnormal Child Psychology vol 13 no 2 pp 185ndash198 1985

[19] H Korpela R Loueniva E Yrjanheikki and A KauppilaldquoLead and cadmium concentrations in maternal and umbilicalcord blood amniotic fluid placenta and amnioticmembranesrdquoAmerican Journal of Obstetrics and Gynecology vol 155 no 5pp 1086ndash1089 1986

[20] A Lafuente and A I Esquifino ldquoCadmium effects on hypotha-lamic activity and pituitary hormone secretion in the malerdquoToxicology Letters vol 110 no 3 pp 209ndash218 1999

[21] A I Esquifino N Marquez E Alvarez-Demanuel and ALafuente ldquoEffects of chronic alternating cadmium exposure onthe episodic secretion of prolactin inmale ratsrdquo Journal of TraceElements in Medicine and Biology vol 12 no 4 pp 205ndash2101999

[22] A Lafuente N Marquez S Piquero and A I EsquifinoldquoCadmium affects the episodic luteinizing hormone secretionin male rats possible age-dependent effectsrdquo Toxicology Lettersvol 104 no 1-2 pp 27ndash33 1999

[23] R Pal R Nath and K D Gill ldquoInfluence of ethanol oncadmium accumulation and its impact on lipid peroxidationand membrane bound functional enzymes (Na+ K+-ATPaseand acetylcholinesterase) in various regions of adult rat brainrdquoNeurochemistry International vol 23 no 5 pp 451ndash458 1993

[24] W I Manton and J D Cook ldquoHigh accuracy (stable isotopedilution) measurements of lead in serum and cerebrospinalfluidrdquo British Journal of Industrial Medicine vol 41 no 3 pp313ndash319 1984

[25] M T Antonio L Corredor and M L Leret ldquoStudy of theactivity of several brain enzymes like markers of the neurotox-icity induced by perinatal exposure to lead andor cadmiumrdquoToxicology Letters vol 143 no 3 pp 331ndash340 2003

[26] G S Shukla and S V Chandra ldquoConcurrent exposure to leadmanganese and cadmium and their distribution to variousbrain regions liver kidney and testis of growing ratsrdquo Archivesof Environmental Contamination and Toxicology vol 16 no 3pp 303ndash310 1987

[27] J F Goncalves A M Fiorenza R M Spanevello et alldquoN-acetylcysteine prevents memory deficits the decrease inacetylcholinesterase activity and oxidative stress in rats exposedto cadmiumrdquoChemico-Biological Interactions vol 186 no 1 pp53ndash60 2010

[28] M Mendez-Armenta and C Rios ldquoCadmium neurotoxicityrdquoEnvironmental Toxicology and Pharmacology vol 23 no 3 pp350ndash358 2007

[29] W Zheng D F Perry D L Nelson and H V AposhianldquoChoroid plexus protects cerebrospinal fluid against toxic met-alsrdquo FASEB Journal vol 5 no 8 pp 2188ndash2193 1991


[30] H Tjalve and J Henriksson ldquoUptake of metals in the brain viaolfactory pathwaysrdquo NeuroToxicology vol 20 no 2-3 pp 181ndash195 1999

[31] J-R Bondier GMichel A Propper and P-M Badot ldquoHarmfuleffects of cadmium on olfactory system in micerdquo InhalationToxicology vol 20 no 13 pp 1169ndash1177 2008

[32] L A Czarnecki A H Moberly T Rubinstein D J Turkel JPottackal and J P McGann ldquoIn vivo visualization of olfactorypathophysiology induced by intranasal cadmium instillation inmicerdquo NeuroToxicology vol 32 no 4 pp 441ndash449 2011

[33] P Mascagni D Consonni G Bregante G Chiappino and FToffoletto ldquoOlfactory function in workers exposed to moderateairborne cadmium levelsrdquoNeuroToxicology vol 24 no 4-5 pp717ndash724 2003

[34] E S H Chow M N Y Hui C C Lin and S H ChengldquoCadmium inhibits neurogenesis in zebrafish embryonic braindevelopmentrdquo Aquatic Toxicology vol 87 no 3 pp 157ndash1692008

[35] R Fern J A Black B R Ransom and S G Waxman ldquoCd2+-induced injury in CNS white matterrdquo Journal of Neurophysiol-ogy vol 76 no 5 pp 3264ndash3273 1996

[36] G Almazan H-N Liu A Khorchid S Sundararajan A KMartinez-Bermudez and S Chemtob ldquoExposure of developingoligodendrocytes to cadmium causes HSP72 induction freeradical generation reduction in glutathione levels and celldeathrdquo Free Radical Biology andMedicine vol 29 no 9 pp 858ndash869 2000

[37] M K Viaene H A Roels J Leenders et al ldquoCadmiuma possible etiological factor in peripheral polyneuropathyrdquoNeuroToxicology vol 20 no 1 pp 7ndash16 1999

[38] WHO Cadmium-Environmental Aspects (EnvironmentalHealth Criteria 135) WHO Geneva Switzerland 1992

[39] FAOWHO ldquoToxicology evaluation of certain food additivesand contaminantsrdquo WHO Technical Report Series No 837WHO Geneva Switzerland 1993

[40] S Satarug M R Haswell-Elkins and M R Moore ldquoSafe levelsof cadmium intake to prevent renal toxicity in human subjectsrdquoBritish Journal of Nutrition vol 84 no 6 pp 791ndash802 2000

[41] L Nasreddine and D Parent-Massin ldquoFood contaminationby metals and pesticides in the European Union Should weworryrdquo Toxicology Letters vol 127 no 1ndash3 pp 29ndash41 2002

[42] WHOGuidelines For Drinking-Water Quality Geneva Switzer-land 3rd edition 2004 httpwwwwhointwater sanitationhealthdwqgdwq3en

[43] FAOWHO ldquoCodex Alimentarius Commissionrdquo in Proceedingsof the 29th Session International Conference Centre GenevaSwitzerland July 2006

[44] ACGIH ldquoCadmium Threshold limit values for chemical sub-stances and physical agents and biological exposure indicesrdquoin Proceedings of the American Conference of GovernmentalIndustrial Hygienists p 17 Cincinnati OH USA 2007

[45] EFSA Scientific Opinion of the Panel on Contaminants in theFood Chain on a Request From the European Commission oncadmium in Food 2009

[46] FAOWHO ldquoThe Summary report of the 73rd JECFAmeetingrdquoTech Rep WHO Geneva Switzerland 2010

[47] S Yoshida ldquoRe-evaluation of acute neurotoxic effects of Cd2+on mesencephalic trigeminal neurons of the adult ratrdquo BrainResearch vol 892 no 1 pp 102ndash110 2001

[48] L Bucio V Souza A Albores et al ldquoCadmium and mercurytoxicity in a human fetal hepatic cell line (WRL-68 cells)rdquoToxicology vol 102 no 3 pp 285ndash299 1995

[49] E Sarchielli S Pacini G Morucci et al ldquoCadmium inducesalterations in the human spinal cord morphogenesisrdquo BioMet-als vol 25 no 1 pp 63ndash74 201

[50] B Okuda Y Iwamoto H Tachibana M Sugita et al ldquoParkin-sonism after acute cadmium poisoningrdquo Clinical Neurology andNeurosurgery vol 99 no 4 pp 263ndash265 1997

[51] L-F Jiang T-M Yao Z-L Zhu C Wang and L-N JildquoImpacts of Cd(II) on the conformation and self-aggregationof Alzheimerrsquos tau fragment corresponding to the third repeatofmicrotubule-binding domainrdquoBiochimica et Biophysica Actavol 1774 no 11 pp 1414ndash1421 2007

[52] B Xu S Chen Y Luo et al ldquoCalcium signaling is involved incadmium-induced neuronal apoptosis via induction of reactiveoxygen species and activation of MAPKmTOR networkrdquo PLoSOne vol 6 no 4 Article ID e19052 2011

[53] Y Yuan C-Y Jiang X H Xu et al ldquoCadmium-inducedapoptosis in primary rat cerebral cortical neurons culture ismediated by a calcium signaling pathwayrdquo PLoS One vol 8 no5 Article ID e64330 2013

[54] L Chen L Liu and SHuang ldquoCadmiumactivates themitogen-activated protein kinase (MAPK) pathway via induction ofreactive oxygen species and inhibition of protein phosphatases2A and 5rdquo Free Radical Biology and Medicine vol 45 no 7 pp1035ndash1044 2008

[55] A Gupta and S V Chandra ldquoGestational cadmium exposureand brain development a biochemical studyrdquo Industrial Healthvol 29 no 2 pp 65ndash71 1991

[56] E P Rico D B Rosemberg M R Senger et al ldquoMethanolalters ecto-nucleotidases and acetylcholinesterase in zebrafishbrainrdquo Neurotoxicology and Teratology vol 28 no 4 pp 489ndash496 2006

[57] M R Senger D B Rosemberg E P Rico et al ldquoIn vitro effectof zinc and cadmium on acetylcholinesterase and ectonucleoti-dase activities in zebrafish (Danio rerio) brainrdquo Toxicology inVitro vol 20 no 6 pp 954ndash958 2006

[58] J F Goncalves F T Nicoloso P da Costa et al ldquoBehaviorand brain enzymatic changes after long-term intoxication withcadmium salt or contaminated potatoesrdquo Food and ChemicalToxicology vol 50 no 10 pp 3709ndash3718 2012

[59] A Zarros K Kalopita S Tsakiris and G S Baillie ldquoCan acetyl-cholinesterase activity be considered as a reliable biomarker forthe assessment of cadmium-induced neurotoxicityrdquo Food andChemical Toxicology vol 56 pp 406ndash410 2013

[60] E Herba D Pojda-Wilczek S M Pojda A Plech and R BrusldquoThe effect of serotonin on flash visual evoked potential in therat prenatally exposed to cadmiumrdquoKlinika Oczna vol 103 no2-3 pp 81ndash84 2001

[61] I Desi L Nagymajtenyi and H Schulz ldquoBehavioural andneurotoxicological changes caused by cadmium treatment ofrats during developmentrdquo Journal of Applied Toxicology vol 18no 1 pp 63ndash70 1998

[62] A Gupta and G S Shukla ldquoOntogenic profile of brain lipidsfollowing perinatal exposure to cadmiumrdquo Journal of AppliedToxicology vol 16 no 3 pp 227ndash233 1996

[63] R G Adams and N Crabtree ldquoAnosmia in alkaline batteryworkersrdquo British Journal of Industrial Medicine vol 18 pp 216ndash221 1961

[64] A MNusioł K Szyrocka-Szwed J Wojczuk and E Kudy-bka ldquoEvaluation of the neurological status and EEG findingsin workers chronically exposed to cadmiumrdquo WiadomosciLekarskie vol 34 no 19 pp 1615ndash1620 1981


[65] R E Struempler G E Larson and B Rimland ldquoHair mineralanalysis and disruptive behavior in clinically normal youngmenrdquo Journal of Learning Disabilities vol 18 no 10 pp 609ndash612 1985

[66] R P Hart C S Rose and R M Hamer ldquoNeuropsychologicaleffects of occupational exposure to cadmiumrdquo Journal of Clin-ical and Experimental Neuropsychology vol 11 no 6 pp 933ndash943 1989

[67] S Bar-Sela M Levy J B Westin R Laster and E D RichterldquoMedical findings in nickel-cadmium battery workersrdquo IsraelJournal of Medical Sciences vol 28 no 8-9 pp 578ndash583 1992

[68] C S Rose P G Heywood and R M Costanzo ldquoOlfactoryimpairment after chronic occupational cadmium exposurerdquoJournal of Occupational Medicine vol 34 no 6 pp 600ndash6051992

[69] M K Viaene R Masschelein J Leenders L J V C Swerts MdeGroof andHA Roels ldquoNeurobehavioural effects of occupa-tional exposure to cadmium a cross sectional epidemiologicalstudyrdquo Occupational and Environmental Medicine vol 57 no 1pp 19ndash27 2000

[70] P K Sethi and D Khandelwal ldquoCadmium exposure healthhazards of silver cottage industry in developing countriesrdquoJournal of Medical Toxicology vol 2 no 1 pp 14ndash15 2006

[71] Q-S Bao C-Y Lu H Song et al ldquoBehavioural development ofschool-aged children who live around a multi-metal sulphidemine in Guangdong province China a cross-sectional studyrdquoBMC Public Health vol 9 article 217 2009

[72] A Papp G Oszlanczi E Horvath et al ldquoConsequences ofsubacute intratracheal exposure of rats to cadmium oxidenanoparticles electrophysiological and toxicological effectsrdquoToxicology amp Industrial Health vol 28 no 10 pp 933ndash941 2012

[73] T Borisova N Krisanova R Sivko et al ldquoPresynaptic mal-function the neurotoxic effects of cadmium and lead on theproton gradient of synaptic vesicles and glutamate transportrdquoNeurochemistry International vol 59 no 2 pp 272ndash279 2011

[74] V C Borges F W Santos J B T Rocha and C WNogueira ldquoHeavy metals modulate glutamatergic system inhuman plateletsrdquo Neurochemical Research vol 32 no 6 pp953ndash958 2007

[75] J R Nation D K Miller and G R Bratton ldquoDietary cadmiumexposure alters characteristics of training substitution andtolerance when morphine is used as a discriminative stimulusrdquoNeuroToxicology vol 21 no 4 pp 553ndash567 2000

[76] C Bonithon-Kopp G Huel and C Grasmick ldquoEffects ofpregnancy on the inter-individual variations in blood levels oflead cadmium and mercuryrdquo Biological Research in Pregnancyand Perinatology vol 7 no 1 pp 37ndash42 1986

[77] M Vinceti D Guidetti M Bergomi et al ldquoLead cadmium andselenium in the blood of patients with sporadic amyotrophiclateral sclerosisrdquo Italian Journal of Neurological Sciences vol 18no 2 pp 87ndash92 1997

[78] R Pamphlett RMcQuilty and K Zarkos ldquoBlood levels of toxicand essential metals inmotor neuron diseaserdquoNeuroToxicologyvol 22 no 3 pp 401ndash410 2001

[79] F P de Lange J S Kalkman G Bleijenberg P Hagoort J WM Van Der Meer and I Toni ldquoGray matter volume reductionin the chronic fatigue syndromerdquoNeuroImage vol 26 no 3 pp777ndash781 2005

[80] E Lopez C Arce M J Oset-Gasque S Canadas and M PGonzalez ldquoCadmium induces reactive oxygen species genera-tion and lipid peroxidation in cortical neurons in culturerdquo FreeRadical Biology and Medicine vol 40 no 6 pp 940ndash951 2006

[81] S Yousef A Adem T Zoubeidi M Kosanovic A A MabroukandV Eapen ldquoAttention deficit hyperactivity disorder and envi-ronmental toxic metal exposure in the United Arab EmiratesrdquoJournal of Tropical Pediatrics vol 57 no 6 Article ID fmq121pp 457ndash460 2011

[82] A Shukla G S Shukla and R C Srimal ldquoCadmium-inducedalterations in bloodmdashbrain barrier permeability and its possiblecorrelation with decreased microvessel antioxidant potential inratrdquoHuman andExperimental Toxicology vol 15 no 5 pp 400ndash405 1996

[83] Y Uchida K Takio K Titani Y Ihara and M TomonagaldquoThe growth inhibitory factor that is deficient in theAlzheimerrsquosdisease brain is a 68 amino acid metallothionein-like proteinrdquoNeuron vol 7 no 2 pp 337ndash347 1991

[84] N Nishimura H Nishimura A Ghaffar and C TohyamaldquoLocalization of metallothionein in the brain of rat and mouserdquoJournal of Histochemistry and Cytochemistry vol 40 no 2 pp309ndash315 1992

[85] M Mendez-Armenta J Villeda-Hernandez R Barroso-Moguel C Nava-Ruız M E Jimenez-Capdeville and C RıosldquoBrain regional lipid peroxidation and metallothionein levelsof developing rats exposed to cadmium and dexamethasonerdquoToxicology Letters vol 144 no 2 pp 151ndash157 2003

[86] I G Onyango J P Bennett Jr and J B Tuttle ldquoEndoge-nous oxidative stress in sporadic Alzheimerrsquos disease neuronalcybrids reduces viability by increasing apoptosis through pro-death signaling pathways and is mimicked by oxidant exposureof control cybridsrdquo Neurobiology of Disease vol 19 no 1-2 pp312ndash322 2005

[87] L Chen B Xu L Liu et al ldquoCadmium induction of reactiveoxygen species activates the mTOR pathway leading to neu-ronal cell deathrdquo Free Radical Biology and Medicine vol 50 no5 pp 624ndash632 2011

[88] L Chen L Liu Y Luo and S Huang ldquoMAPK andmTOR path-ways are involved in cadmium-induced neuronal apoptosisrdquoJournal of Neurochemistry vol 105 no 1 pp 251ndash261 2008

[89] M T Antonio I Corpas and M L Leret ldquoNeurochemicalchanges in newborn ratrsquos brain after gestational cadmium andlead exposurerdquo Toxicology Letters vol 104 no 1-2 pp 1ndash9 1999

[90] S Hayat C B Wigley and J Robbins ldquoIntracellular calciumhandling in rat olfactory ensheathing cells and its role in axonalregenerationrdquoMolecular and Cellular Neuroscience vol 22 no2 pp 259ndash270 2003

[91] A P Fox M C Nowycky and R W Tsien ldquoKinetic and phar-macological properties distinguishing three types of calciumcurrents in chick sensory neuronesrdquo Journal of Physiology vol394 pp 149ndash172 1987

[92] J R Huguenard ldquoLow-threshold calcium currents in centralnervous system neuronsrdquo Annual Review of Physiology vol 58pp 329ndash348 1996

[93] A K Sundgren-Andersson and S Johansson ldquoCalcium spikesand calcium currents in neurons from the medial preopticnucleus of ratrdquo Brain Research vol 783 no 2 pp 194ndash209 1998

[94] T Aoki and S C Baraban ldquoProperties of a calcium-activatedK+ current on interneurons in the developing rat hippocampusrdquoJournal of Neurophysiology vol 83 no 6 pp 3453ndash3461 2000

[95] X Liu J-L Zhou K Chung and J M Chung ldquoIon channelsassociatedwith the ectopic discharges generated after segmentalspinal nerve injury in the ratrdquo Brain Research vol 900 no 1 pp119ndash127 2001

[96] Y-C Hsieh E-L Hsu Y-S Chow and R Kou ldquoEffects ofcalcium channel antagonists on the corpora allata of adult


male loreyi leafworm Mythimna loreyi Juvenile hormoneacids release and intracellular calcium levelrdquo Archives of InsectBiochemistry and Physiology vol 48 no 2 pp 89ndash99 2001

[97] C Acuna-Castillo B Morales and J P Huidobro-Toro ldquoZincand copper modulate differentially the P2X4 receptorrdquo Journalof Neurochemistry vol 74 no 4 pp 1529ndash1537 2000

[98] S K Ryan L R Shotts S-K Hong et al ldquoGlutamate regulatesneurite outgrowth of cultured descending brain neurons fromlarval lampreyrdquo Developmental Neurobiology vol 67 no 2 pp173ndash188 2007

[99] J Son S-E Lee B-S Park et al ldquoBiomarker discovery andproteomic evaluation of cadmium toxicity on a collembolanspecies Paronychiurus kimi (Lee)rdquo Proteomics vol 11 no 11pp 2294ndash2307 2011

[100] M E Culbreth J A Harrill T M Freudenrich W R Mundyand T J Shafer ldquoComparison of chemical-induced changes inproliferation and apoptosis in human andmouse neuroprogen-itor cellsrdquo Neurotoxicology vol 33 no 6 pp 1499ndash1510 2012

[101] S Llop M J Lopez-Espinosa M Rebagliato and F BallesterldquoGender differences in the neurotoxicity of metals in childrenrdquoToxicology 2013

[102] M Vahter A Akesson C Liden S Ceccatelli andM BerglundldquoGender differences in the disposition and toxicity of metalsrdquoEnvironmental Research vol 104 no 1 pp 85ndash95 2007

[103] H Ishitobi K Mori K Yoshida and C Watanabe ldquoEffects ofperinatal exposure to low-dose cadmium on thyroid hormone-related and sex hormone receptor gene expressions in brain ofoffspringrdquo NeuroToxicology vol 28 no 4 pp 790ndash797 2007

[104] H Ishitobi and C Watanabe ldquoEffects of low-dose perinatalcadmium exposure on tissue zinc and copper concentrations inneonatal mice and on the reproductive development of femaleoffspringrdquo Toxicology Letters vol 159 no 1 pp 38ndash46 2005

[105] A Farsetti T Mitsuhashi B Desvergne J Robbins and V MNikodem ldquoMolecular basis of thyroid hormone regulation ofmyelin basic protein gene expression in rodent brainrdquo Journalof Biological Chemistry vol 266 no 34 pp 23226ndash23232 1991

[106] A Lafuente A Gonzalez-Carracedo A Romero P Cano andA I Esquifino ldquoCadmium exposure differentially modifies thecircadian patterns of norepinephrine at the median eminenceand plasma LH FSH and testosterone levelsrdquoToxicology Lettersvol 146 no 2 pp 175ndash182 2004

[107] A Lafuente P Cano and A I Esquifino ldquoAre cadmium effectson plasma gonadotropins prolactin ACTH GH and TSHlevels dose-dependentrdquo BioMetals vol 16 no 2 pp 243ndash2502003

[108] A Lafuente N Marquez M Perez-Lorenzo D Pazo and AI Esquifino ldquoPubertal and postpubertal cadmium exposuredifferentially affects the hypothalamic-pituitary-testicular axisfunction in the ratrdquo Food and Chemical Toxicology vol 38 no10 pp 913ndash923 2000

[109] A Stoica B S Katzenellenbogen andM B Martin ldquoActivationof estrogen receptor-120572 by the heavymetal cadmiumrdquoMolecularEndocrinology vol 14 no 4 pp 545ndash553 2000

[110] A Lafuente N Marquez M Perez-Lorenzo D Pazo andA I Esquifino ldquoCadmium effects on hypothalamic-pituitary-testicular axis in male ratsrdquo Experimental Biology andMedicinevol 226 no 6 pp 605ndash611 2001

[111] A Vetillard and T Bailhache ldquoCadmium an endocrine dis-rupter that affects gene expression in the liver and brain ofjuvenile rainbow troutrdquo Biology of Reproduction vol 72 no 1pp 119ndash126 2005

[112] S C Tilton C M Foran and W H Benson ldquoEffects ofcadmium on the reproductive axis of Japanesemedaka (Oryziaslatipes)rdquo Comparative Biochemistry and Physiology C vol 136no 3 pp 265ndash276 2003

[113] H Koyama H Kitoh M Satoh and C Tohyama ldquoLow doseexposure to cadmiumand its health effects (1) Genotoxicity andcarcinogenicityrdquo Japanese Journal of Hygiene vol 57 no 3 pp547ndash555 2002

[114] O JMillerW Schnedl J Allen and B F Erlanger ldquo5Methylcy-tosine localised in mammalian constitutive heterochromatinrdquoNature vol 251 no 5476 pp 636ndash637 1974

[115] M Takiguchi W E Achanzar W Qu G Li and M P WaalkesldquoEffects of cadmium on DNA-(Cytosine-5) methyltransferaseactivity and DNAmethylation status during cadmium-inducedcellular transformationrdquo Experimental Cell Research vol 286no 2 pp 355ndash365 2003

[116] L Benbrahim-Tallaa R A Waterland A L Dill M M Web-ber and M P Waalkes ldquoTumor suppressor gene inactivationduring cadmium-induced malignant transformation of humanprostate cells correlates with overexpression of de Novo DNAmethyltransferaserdquo Environmental Health Perspectives vol 115no 10 pp 1454ndash1459 2007

[117] V Valinluck H-H Tsai D K Rogstad A Burdzy A Birdand L C Sowers ldquoOxidative damage to methyl-CpG sequencesinhibits the binding of themethyl-CpG binding domain (MBD)of methyl-CpG binding protein 2 (MeCP2)rdquo Nucleic AcidsResearch vol 32 no 14 pp 4100ndash4108 2004

[118] P W Turk A Laayoun S S Smith and S A Weitzman ldquoDNAadduct 8-hydroxyl-21015840-deoxyguanosine (8-hydroxyguanine)affects function of human DNA methyltransferaserdquoCarcinogenesis vol 16 no 5 pp 1253ndash1255 1995

[119] BWang Y Li Y Tan et al ldquoLow-dose Cd induces hepatic genehypermethylation along with the persistent reduction of celldeath and increase of cell proliferation in rats and micerdquo PLoSOne vol 7 no 3 Article ID e33853 2012

[120] M D Shahbazian and H Y Zoghbi ldquoRett syndrome andMeCP2 linking epigenetics and neuronal functionrdquo AmericanJournal of Human Genetics vol 71 no 6 pp 1259ndash1272 2002

[121] B S Schwartz B-K Lee K Bandeen-Roche et al ldquoOccupa-tional lead exposure and longitudinal decline in neurobehav-ioral test scoresrdquo Epidemiology vol 16 no 1 pp 106ndash113 2005

[122] S Johnson ldquoGradual micronutrient accumulation and deple-tion in Alzheimerrsquos diseaserdquo Medical Hypotheses vol 56 no 6pp 595ndash597 2001

[123] A E Panayi N M Spyrou B S Iversen M A White and PPart ldquoDetermination of cadmium and zinc in Alzheimerrsquos braintissue using Inductively Coupled Plasma Mass SpectrometryrdquoJournal of the Neurological Sciences vol 195 no 1 pp 1ndash10 2002

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 Summary of the ldquosaferdquo level for human contacted of Cd

OrganizationAuthors Year Approach Dose ReferenceFAOWHO 1988 Intake 400ndash500 120583gweek [3]WHO 1992 Intake 7120583gsdotkgminus1 bwweek or 1 120583gsdotkgminus1 bwday [38]FAOWHO 1993 Intake 7120583gsdotkgminus1 bwweek [39]Satarug et al 2000 Intake 30120583gday [40]Nasreddine and Parent-Massin 2002 Intake 10ndash30120583gday [41]WHO 2004 Drinking-water 3120583gL [42]FAOWHO 2006 Food 04mgkg of the BMDL of R-Cd standard [43]ACGIH 2007 Blood 5120583gL [44]EFSA 2009 Intake 25120583gsdotkgminus1 bwweek [45]FAOWHO 2010 Intake 58120583gsdotkgminus1 bwweek [46]CPSC 2010 Intake 01 120583gsdotkgminus1 bwday [4]ACGIH American conference of governmental industrial hygienists CPSC Consumer Product Safety Commission FAO Food andAgriculture OrganizationWHO World Health Organization bw body weight

children withmental retardation [14] and learning difficultiesor dyslexia [11 15] In cohort studies Thatcher et al reportedthat the concentration of Cd in hair was inversely related toadjust Intelligence Quotient (IQ) [16 17] Other investigators[18] also reported associations between hair Cd concen-trations and childrenrsquos performance on visual-motor tasksThese studies clearly indicate the association of increasedtotal Cd concentration with mental retardation and reducedvisualmotor abilities Effect ofCdneurotransmitter oxidativedamage interaction with other metals such as cobalt andzinc estrogen-like effect and epigenetic modification maybe the underlying mechanisms (Figure 1) However the exactmechanism(s) through which Cd elicits its neurotoxic effectsis still unresolved In this review therefore we focus on recentevidence from experimental and epidemiological studiesshowing that Cd exposure can induce its neurotoxin effects

2 The Absorption of Cd in the NervousSystem and Distribution

The Cd exposure rate (based on meconium analysis) ininfants was 85 and the median concentration of the pol-lutants in the positive samples was 1337mgmL In most ofthese studies the concentration of Cd in hair was measuredThe CNS is especially vulnerable to damage during earlyneonatal development Cd is able to readily pass to the fetusvia the placenta and was detected in milk during lactation[19] Cd can be uptaken from the nasal mucosa or olfactorypathways into the CNS thus the CNS is subjected to Cdtoxicity [20ndash22] Under normal conditions Cd barely reachesthe brain in adults due to the presence of the blood brainbarrier (BBB) however this structure is not fully developedin young animals [23] The anatomical and physiologicalbases on which the choroids plexus becomes the target ofxenobiotics have been examined Cd tends to accumulatein the choroids plexus at concentrations much greater thanthose found in the cerebrospinal fluid (CSF) and elsewherein brain tissues A postmortem human study revealed thatthe Cd concentration in the choroids plexus was about 2-3

times higher than that found in the brain cortex [24] Asa general choroids plexus toxicant Cd can directly damagethe choroids plexus ultrastructure Due to differences in theBBB integrity [25] Cd is thus more toxic to newborn andyoung rats than to adult rats Cd can increase permeabilityof the BBB in rats [26] to penetrate and accumulate in thebrain of developing and adult rats [27 28] leading to brainintracellular accumulation cellular dysfunction and cerebraledema

As a barrier the choroidal epithelia are often the first andthemost frequent ones to encountermetal insults frombloodTwo mechanisms may aid resistance of choroids plexus toblood-borne toxicities First the choroids plexus containsabundant metal binding ligands that effectively sequestermetal ions Moreover the concentration of cystine in thechoroids plexus is 4-fold higher than that in the brain cortex[29] Second the choroids plexus owns an active defense sys-tem The activities of superoxide dismutase and catalase aresignificantly higher in the choroids plexus than in cerebrumand cerebellum Taken together the choroids plexus likelyforms the first line of defense against neurotoxicants It mustbe kept in mind however that none of the cellular defensemechanisms would operate in an unlimited capacity Thepathophysiological changes can occur either as the thresholdabove which the protective capacity of the choroids plexusis exceeded or saturated or as a direct result of barrierdysfunction Thus the need arises for a more comprehensiveunderstanding of the detoxification mechanisms such asantioxidant systems induction of protective macromolecules(heat shock proteins etc) formation of specific metalinclusion bodies or binding proteins and biotransformationreactions (methylation conjugation etc) that operate in thechoroids plexus

Cd is transported along the primary olfactory neurons totheir terminations in the olfactory bulbs thereby bypassingthe intact BBB The olfactory route could therefore be alikely way to reach the brain and should be taken intoaccount for occupational risk assessments for this metal[30ndash32] Occupational inhalation of Cd can be toxic to theolfactory sense [30] Primary olfactory neurons are regularly


Cd2+

MARKmTORJAK pathway

Hypothalamus

Pituitary

Ovarytestis

Testosterone

LH

Epigenetic effect

Neurogenesis


ROS

Apoptosis

FSHminus

minus

+

+

+

Ca2+Ca2+


























[18]








Parkinsonism [50]




[69]





Experimentexposure






























5 Summary



Abbreviations






Acknowledgment


References





































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Cd2+

MARKmTORJAK pathway

Hypothalamus

Pituitary

Ovarytestis

Testosterone

LH

Epigenetic effect

Neurogenesis


ROS

Apoptosis

FSHminus

minus

+

+

+

Ca2+Ca2+


























[18]








Parkinsonism [50]




[69]





Experimentexposure






























5 Summary



Abbreviations






Acknowledgment


References





































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



































[18]








Parkinsonism [50]




[69]





Experimentexposure






























5 Summary



Abbreviations






Acknowledgment


References





































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























[18]








Parkinsonism [50]




[69]





Experimentexposure






























5 Summary



Abbreviations






Acknowledgment


References





































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






































5 Summary



Abbreviations






Acknowledgment


References





































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























5 Summary



Abbreviations






Acknowledgment


References





































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















5 Summary



Abbreviations






Acknowledgment


References





































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Acknowledgment


References





































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article Cadmium and Its Neurotoxic Effectsdownloads.hindawi.com/journals/omcl/2013/898034.pdfReview Article Cadmium and Its Neurotoxic Effects BoWang 1 andYanliDu 2 Department