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ISSN: 1547-691X (print), 1547-6901 (electronic)
J Immunotoxicol, Early Online: 19
! 2013 Informa Healthcare USA, Inc.
DOI: 10.3109/1547691X.2013.791734

PAPERS FROM MEETINGS

M. A. Altamirano-Lozano1, L. Alvarez-Barrera1, R. A. Mateos-Nava1, T. I. Fortoul2, and J. J. Rodrguez-Mercado1

1

Unidad de Investigacion en Genetica y Toxicologa Ambiental, UMIEZ, Campo II, FES-Zaragoza, Universidad Nacional Autonoma de Mexico,
Mexico, D.F. and 2Departamento de Biologa Celular y Tisular, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Mexico, D.F.

Abstract

Keywords

Research on the biological effects of vanadium in humans has shown that acute poisoning in
workers can manifest itself in a number of symptoms. There are no reports in humans about
reproductive and developmental effects induced by vanadium compounds in humans;
however, some studies with rats and mice indicate that vanadium can cross the placental
barrier and accumulate in fetal membranes rather than the fetus itself. In this case, probably
most consequences of administration of vanadium to pregnant females like reabsorptions,
fetal death and reduction in size can be the result of maternal toxicity. Concerning genetic and
related effects in humans exposed to different vanadium compounds, data are controversial.
Data on genotoxic effects in workers exposed to vanadium indicate that they can have an
increased risk to develop cancer, and DNA instability can give rise to an onset of genetic
syndromes, fetal malformations, and cancer. This paper presents materials presented at the
8th International Symposium on Vanadium Chemistry, Biological Chemistry, and Toxicology in a
session titled Relationship between occupational and environmental exposure to vanadium
compounds and the reprotoxic and genotoxic effects.

Chromosomal aberrations, comet assay, fetal

malformations, micronuclei, teratology,
vanadium pentoxide

Introduction
The use of metals has been a decisive step in cultural and technological development. Several metals perform various, necessary
biological functions, while other metals are not required by living
organisms. Most metals, however, tend to accumulate in biological systems, and organisms display little adaptability when
metals accumulate in high concentrations, causing various
alterations.
In unicellular organisms, such disturbances can lead to changes
in DNA synthesis and repair, genetic instability, changes in
cell proliferation, or cell death. In multicellular organisms
(including humans), in addition to the effects mentioned above,
the alterations may cause cellular aging, changes in differentiation
or cell cycle progression, and the triggering of degenerative
processes, which compromise the integrity of cells and tissues.
A metal that has acquired special importance for its therapeutic
applications and toxicity is vanadium.

Address for Correspondence: Altamirano-Lozano, MA, Unidad de

Investigacion en Genetica y Toxicologa Ambiental, UMIEZ, Campo II,
FES-Zaragoza, UNAM., Mexico, D.F. Tel: 5255-56230760. Fax:
525557736330. E-mail: maal@unam.mx

History
Received 1 December 2012
Revised 21 March 2013
Accepted 28 March 2013
Published online 10 May 2013

Vanadium: Physicochemical properties and biochemical

behavior
Vanadium (V) is the first transition metal in Group 5 of the
periodic table, followed by niobium (Nb) and tantalum (Ta).
Vanadium naturally occurs in low concentrations and, although
this metal is essential for many organisms, its requirement in
humans has yet to be determined (Rydzynski & Pakulska, 2012).
However, the widespread use of vanadium and its release into
the environment has led to an increased presence in various
ecosystems and in food chains. Thus, humans and other
living organisms are in near-constant contact with this metal
(Rodrguez-Mercado & Altamirano-Lozano, 2006).
The most common oxidation states for vanadium, which also
have well-known biological functions, are III, IV, and V; however,
vanadium can exist in lower, very strongly reducing, states.
Usually, in biological systems, V(III), V(IV), and V(V) convert
from one to another by transfer of an electron; in cells, the metal
can most often be found in the form of a metal cation as V3 and
as anions/cations as [VO(OH)3], [(VO)2(OH)5], or VO2 in the
2
3

case of V(IV) and H2 VO

4 , HVO4 , VO4 , or VO2 for V(V). In
2
is one of the most stable diatomic molecules
general, VO
(Crans et al., 2004; Hirao, 2000; Rehder, 1991, 2003; Tracey
et al., 2007). The inter-conversion of chemical species is complex;
for example, V(III) species are unstable in the presence of oxygen
and physiological pH, and under physiological conditions, V(IV)
species are oxidized to V(V). The latter can easily enter a cell via

20
13

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Potential for genotoxic and reprotoxic effects of vanadium compounds

due to occupational and environmental exposures: An article based on
a presentation at the 8th International Symposium on Vanadium
Chemistry, Biological Chemistry, and Toxicology, Washington DC,
August 1518, 2012

M. A. Altamirano-Lozano et al.

ion channels, such as those for phosphate and sulfate; this feature
renders V(V) very toxic. Furthermore, metabolic processes can
transform V(V) to V(IV) inside the cell (Rehder, 2003; Tracey
et al., 2007).
More detailed information about other sources of exposure are
described in other articles from the 8th International Symposium
on Vanadium Chemistry and Toxicology (August 2012). The
remainder of this paper only describes effects of vanadium agents
on genetic material and reproduction.

Vanadium genotoxicity

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Human studies
Although humans are exposed to vanadium compounds either
occupationally by inhalation or via ingestion of food, few
epidemiological studies have been designed to evaluate DNA
damage in human populations (IARC, 2006). In one of the few
human studies, Ivancsits et al. (2002) evaluated the genotoxic
effects of exposure to V2O5. Forty-nine workers at a factory
producing this metal participated in the study, and it was
determined that the V concentrations in the workers serum
(7.73 mg V/L) and urine (14.57 mg V/g creatinine) were higher
than in the control group, 3.43 mg/L and 1.13 mg V/g creatinine,
respectively. However, when researchers assessed DNA damage
in blood cells using a sister chromatid exchange (SCE) assay and
single-cell gel electrophoresis (Comet assay) under alkaline
conditions, they did not observe any increase in chromatid
exchanges or DNA migration, concluding that vanadium does not
cause DNA damage in vivo.
Similarly, in another epidemiological study involving 52
workers who were exposed to V2O5, the metal concentration
in plasma was 2.2 mg V/L, which was higher than in the control
group (0.3 mg V/L). In addition, when leukocytes from whole
blood were subjected to the Comet assay, no increase in
DNA damage was observed. However, testing of micronuclei
(MN) in lymphocytes with cytokinesis blockade yielded an
observable increase in the number of micronucleated cells
and in the percentage of necrotic cells. Therefore, it was
concluded that occupational exposure might increase the risk
of contracting certain chronic degenerative diseases and that
protective measures for workers should, thus, be improved
(Ehrlich et al., 2008).
Animal studies
Animal studies have demonstrated that the accumulation of
vanadium in the body occurs in the bone, kidney, liver, spleen,
testes, intestines, and stomach, and the intracellular distribution
in these tissues indicates that the nucleus is the organelle that
retains the highest amount of vanadium, which can thus interact
with DNA (Sabbioni & Marafante, 1978; Sabbioni et al., 1991;
Villani et al., 2007). The acute toxicity of vanadium compounds is
low when administered orally, moderate when inhaled, and high
when injected intraperitoneally (IP). In addition, these studies
indicate that small animals such as rats and mice tolerate these
compounds better than do larger animals such as rabbits and
horses (IARC, 2006).
The administration of sodium orthovanadate (Na3VO4),
ammonium metavanadate (NH4VO3), and vanadyl sulfate
(SVO5), at doses of 75, 50, or 100 mg/kg, respectively, to CD-1
strain male mice intragastrically induced an increase in MN
frequency in bone marrow cells evaluated during a 72-h period.
Simultaneously, a second experiment conducted for 24 and 36 h
determined that only SVO5 caused structural chromosomal
aberrations (CAs), but that all the compounds induce numerical
CA (hypo-, hyper-, and polyploid cells), thus confirming that

J Immunotoxicol, Early Online: 19

vanadium exerts more aneuploidogenic effects than clastogenic

effects in vivo (Ciranni et al., 1995).
This effect was also observed in germ cells when female ICR
mice were treated IP once with 5, 15, or 25 mg of Na3VO4/kg and
subsequently (i.e. 18 h later) evaluated for cytogenetic oocyte
abnormalities and for frequencies of hypo-, hyper-, hap-, di-, eu-,
and tetraploid cells in their bone marrow (Mailhes et al., 2003).
The marrow samples from the treated hosts exhibited increased
numbers of tetra- and hyperploid cells, and premature centromere
separations, whereas oocytes displayed an increased number of
early anaphase cells. These alterations, in turn, led to poor
segregation of chromosomes during subsequent cell divisions.
In another study, male 102/E1 x C3H/E1 mice were treated
IP with Na3VO4 in doses similar to those of the previous
investigation. The effect on cellular proliferation in germ cells
was evaluated, and the frequency of hyperploidy and diploidy
was determined by fluorescence in situ hybridization (FISH).
By specifically marking chromosomes X, Y, and 8, it was
observed that the vanadium compound did not induce cell cycle
delay but increased the number of hyper-haploids after treatment
with the highest doses (i.e. 15 and 25 mg/kg). YY8 and XX8
were the most common aneuploidies in the sex chromosomes,
indicating that poor segregation of chromosomes occurs during
the second meiotic division by non-disjunction of sister chromatids (Attia et al., 2005).
Furthermore, induction of genotoxic and cytotoxic effects on
bone marrow cells has not been demonstrated by the MN assay.
In these two studies, it was demonstrated that Na3VO4 does
not arrest meiotic divisions completely during either male or
female meiosis. It was also proposed that male germ cells
are more sensitive than somatic cells to the aneugenic effects of
orthovanadate (Attia et al., 2005; Mailhes et al., 2003).
Similarly, the ability of V2O5 to induce primary DNA lesions,
such as single-strand breaks, in testicular cells from male CD-1
mice was evaluated by a Comet assay 24 h after IP administration
of 5.75, 11.50, or 23 mg of V2O5/kg. The data revealed
that this compound has a dose-dependent genotoxic effect
(Altamirano-Lozano et al., 1996). Using the same protocol,
Altamirano-Lozano et al. (1999) evaluated this function of V2O5
in liver, kidney, lung, spleen, heart, and bone marrow cells, noting
that treatment induced DNA damage in all organs, with the liver,
kidneys, and heart being most susceptible. The investigation also
revealed bone marrow cells are less sensitive to damage induced
by vanadium (as noted in other studies), indicating that dividing
cells can repair this type of damage better than cells with low
proliferation rates can.
Studies have been conducted using CD-1 male mice administered Na3VO4 orally in drinking water for 5 weeks at concentrations of 7.5, 75, 750, or 1500 mg/L. Genetic damage was
evaluated in various tissues employing MN assays in bone
marrow cells and peripheral blood reticulocytes. Primary lesions
were evaluated by the Comet assay in splenocytes, testicular
cells, and bone marrow; the sperm chromatin structure was also
analyzed. The results revealed no significant damage in the germ
cells, indicating that oral exposure to vanadium is not genotoxic
in these cells; however, damage was observed in the somatic
cells only at the highest doses, possibly because of the low
bioavailability of vanadium in these cells (Leopardi et al., 2005).
Villani et al. (2007) evaluated the effects of oral administration
of VOSO4 on male CD-1 mice at doses of 10, 100, 500, or
1000 mg/L for 5 weeks, using the Comet assay and MN test,
which yielded no treatment-related changes; thus, this metal
(as V[IV]) was not genotoxic in somatic and germ cells. However,
given the various biological effects on cellular mechanisms,
the authors recommend caution in applying these results to the
evaluation of other vanadium compounds.

DOI: 10.3109/1547691X.2013.791734

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Vanadium reproductive toxicity

Human, animal, and in vitro studies suggest that heavy metals
may exert adverse effects on the reproductive health of males,
even at relatively low concentrations. Heavy metals can affect the
male reproductive system, altering the hypothalamic-pituitarygonadal axis or directly affecting spermatogenesis, thus diminishing the semen quality (Leopardi et al., 2005; Mendiola et al.,
2011). Of the toxic metals, arsenic, cadmium, chromium, lead,
mercury, and vanadium have been identified as highly significant
in environmental and occupational exposures, as studies have
shown that these metals can accumulate in the testis and/or
epididymis, altering reproductive and endocrine function
(Castellini et al., 2009; Clarkson et al., 1985; Danielsson et al.,
1984; Thompson & Bannigan, 2008).
As with many metal agents, effects of vanadium on reproduction
depend on several factors, such as the chemical form of the
compound, state or oxidation number of vanadium in the
compound, route of exposure, duration of administration, and
dosage (Domingo, 1996) (Table 1). Information on reproductive
toxicity caused by vanadium compounds is limited and is nonexistent in humans; however, interest in vanadium coordination
compounds (e.g. oxovanadates) has increased in recent years due to
the pharmacological properties of the compounds, which can be
employed for treating diabetes mellitus or controlling cholesterol
levels. Other areas of increased attention are the effects of these
coordination complexes in cancer treatment and their spermicidal
activities (Less et al., 2006). However, a serious caveat in the latter
application is suggested by the laboratory animal data revealing
that vanadium can permanently damage reproductive function.
Effect in males
Epidemiological studies and occupational exposure studies have
reported that certain metals exert direct effects on sperm cells,
reducing their motility and/or affecting their morphology (Kumar,
2004; Xu et al., 1993). In addition, animal studies and in vitro
studies have, in most cases, demonstrated a positive correlation
between effects on sperm and the metal concentration in semen
(Aragon & Altamirano-Lozano, 2001; Castellini et al., 2009;
Sakhaee et al., 2012) (Table 2).
In vitro studies
In many in vitro studies, Leydig cells and germ cells have been
identified as the main targets of cytotoxicity, reducing steroidogenesis, and disrupting spermatogenesis (Laskey & Phelps, 1991).
Furthermore, metals can affect the junction between Sertoli cells,
altering the viability of sperm in the epididymis. The exact cause
is unknown, but proposed mechanisms of metal toxicity include
oxidative stress, inflammation, induced apoptosis, and ionic or
molecular mimicry. Vanadium produces reactive oxygen species
(ROS), causing structural lipid peroxidation and alteration of the
anti-oxidant activity of some enzymes, mainly superoxide
dismutase (SOD), catalase (CAT), and glutathione peroxidase
(GPx) (Aragon et al., 2005; Byczkowski & Kulkarni, 1998;
Marouane et al., 2011).
Although exact mechanisms by which vanadium compounds
immobilize sperm are unknown, human spermatozoa are sensitive
to oxidative stress because of the high content of polyunsaturated
fatty acids in their cell membrane. These cells also have low
levels of cytoplasmic enzymes to trap the ROS, which causes
lipid peroxidation and reduces the activity of enzymes that repair
oxidative damage. DCruz et al. (1999) reported that several
coordination complexes containing V(IV) (vanadocenes)
exhibit potent activities in human spermatozoa as spermicides.
The authors found that the spermicidal activity exhibited by these

Genotoxity and reprotoxicity of vanadium compounds

V(IV) coordination complexes is related to their ability to

catalyze ROS generation and to cause apoptosis.
In vivo studies
When administered intratesticularly to male rats, V(IV) compounds caused necrosis and a reduction in gonadal weight
(Kamboj & Kar, 1964). In addition, these compounds reduced the
number of sperm cells, decreased their motility, and caused
increased frequency of morphological abnormalities while modifying the serum concentrations of hormones such as testosterone,
LH, and FSH (Chandra et al., 2007a). Histopathological examination revealed an inhibition of spermatogenesis; in addition
these authors postulated that increased formation of free radicals
during exposure to vanadium could render the testicle more
susceptible to oxidative damage (Chandra et al., 2007b).
Altamirano-Lozano et al. (1996) studied male CD-1 mice
treated IP with 8.5 mg V2O5/g every 3 d for a period of 60 d; subgroups of mice were then euthanized every 10 d for analyses.
An additional group was mated with untreated females 24 h after
the final V2O5 dose. The results showed that treatment with
vanadium decreased overall fertility, number of fetal implants,
number of live fetuses, and fetal weight, and increased the
incidence of resorptions. Decreased numbers and decreased
motility of spermatozoa, along with an increased frequency of
abnormal sperm morphology after treatments, were also noted.
DNA damage in testicular cells was also evident. In a study of
mice exposed to inhaled V2O5 (at 0.02 M V2O5) twice a week
for 12 weeks, it was found that the compound accumulated in the
testes within 24 h of host exposure and generally reduced
the percentage of a-tubulin in all analyzed testicular cells,
altering microtubules, impairing cell division, and disrupting
spermatogenesis (Mussali-Galante et al., 2005).
Vanadium tetroxide (V2O4), when orally administered to
male CD-1 mice in daily dosages of 9.4 and 18.8 mg/kg for
60 d, induced degenerative changes in the seminiferous tubules
and reduced testosterone levels. In this case, testicular weight
remained unaffected; however, sperm motility and viability were
decreased, changes in the morphology of spermatozoa were
present, and degenerating germ cells in the seminiferous epithelium and increased numbers of apoptotic cells were observed.
The concentration of progesterone and testosterone was not
affected by treatment (Aragon et al., 2005).
Jain et al. (2007) orally administered 100 mg vanadyl sulfate
(VOSO4)/kg to male rats daily for 60 d, and decreases in weight
of the testes and accessory sex organs, numbers and motility of
spermatozoa, and atrophy and/or reduced seminiferous tubule
diameters were determined. At the histopathological level, the
researchers noted that nuclei of Leydig cells were reduced in size.
Furthermore, tissue analysis revealed an altered biochemical
environment in the genitals. Five days prior to the end of
treatment, each male was placed in the same box with two
untreated females. The fertility rate was determined to be
decreased along with the number of offspring per litter. In this
study, the authors propose that the reduced weight of the testis
may have been due to the decreased number of germ cells, and the
reduced number of cells may have been attributable to a failure in
the maturation of sperm and disruption of the secretory function
of the epididymal cells, possibly caused by androgen insufficiency. Alternatively, all of the above-mentioned findings might
have been caused by oxidative stress or by failure to generate
energy for metabolic enzymes.
DCruz & Uckun (2000) evaluated four different vanadocene
compounds in concentrations of 7.5 mg/kg for 28 d by intratesticular administration and found decreased weight and number
of spermatozoa in the epididymis, atrophy and almost complete

Fine particulate
matter (PM2.5)

Oil-combustion associated
elements vanadium and
nickel

Sodium metavanadate 0.25, 0.50 mg/ml

Exposure throughout
pregnancy

Gestation

615 d of gestation

Vanadium pentoxide

8.5 mg/kg

615 d of gestation

Pregnant women

Normal and diabetic female

rats

Mice

Mice

Mice

615 d of gestation

Sodium metavanadate 2, 4, 8 mg/kg

Sodium metavanadate 5, 10, 20 mg/kg/day

Vanadyl sulfate
37.5, 75, 150 mg/kg/day
pentahydrate
Sodium
7.5, 15, 30 mg/kg
orthovanadate

Rat

Mice

Rat
Mice

3 or 8 d of gestation

0.9 single dose

Species
Hamster

Males: 60 d before
mating.
Females: 14 d before
mating; through
gestation and
lactation
614 d of gestation
615 d of gestation

510 d of gestation

Period of treatment

0.47, 1.88, 3.75 mg/kg/day

Concentration

Sodium metavanadate 5, 10, 20 mg/kg/day

Ammonium
metavanadate
Vanadium pentoxide

Compound

Inhaled

Drinking water

Intraperitoneally

Intraperitoneally

Drinking water

Drinking water
Drinking water

Drinking water

Intravenous

Intraperitoneally

Route

Carlton et al. (1982)

References

Bell et al. (2010)

Reduced weight, increased embryo Gomez et al. (1992)

lethality, cleft palate at high dose
Both proportion of litters with
Altamirano-Lozano et al. (1993)
abnormal fetuses and number of
altered fetuses was higher. Limb
shortening most frequent
alteration
Not reported
Ganguli et al. (1994)

No significant adverse effects

Paternain et al. (1987)
Decreased fetal weight, increased
Paternain et al. (1990)
embryo lethality, skeletal defects
Delayed skeletal ossification in some Sanchez et al. (1991)
areas

Skeletal ossification decreased

Wide (1984)
(day 8). Broken spinal cord
(9% of fetuses)
Significant decreases in development Domingo et al. (1986)

Skeletal anomalies

Embryo and fetal effects

Vanadate treatment reduced

both conception rate and
ability to carry pregnancy
to term; effects more
severe in diabetic versus
non-diabetic dams
Not reported
Increased risk of low birth weight

No maternal toxicity
observed.

No significant adverse effects

Decreased liver, kidney
weight
Reduced weight gain and
food consumption. Death
in 30 mg.
Decreased weight gain

No adverse effects

No effects reported

No significant effects

Maternal effects

Table 1. Developmental and maternal toxicity produced by different vanadium compounds (studies listed chronologically).

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4
M. A. Altamirano-Lozano et al.
J Immunotoxicol, Early Online: 19

60 d

4 or 6 h

20, 40, 60, 80 mg/kg/day

4.7, 9.4, 18.8 mg/kg

0.751500 mg/l

5, 15, 25 mg/kg

0.02 M

0.4 mg V/kg

100 mg/kg/day

1, 10, or 100 mM

Sodium metavanadate

Vanadium tetroxide

Sodium orthovanadate

Sodium orthovanadate

Vanadium pentoxide

Sodium metavanadate

Vanadyl sulfate

Sodium metavanadate

Daily for 26 d

1 h/twice a week, 12 weeks

Sperm were sampled from

epididymis 22 d after IP
injection of host

5 weeks

60 d

64 d before mating

Male: every second day, from

birth to 21 d.
Female: from day 21 to day
of first vaginal estrus

12.5 mg/kg

Vanadium pentoxide

Single dose
60 d before mating
Every 3 d for 60 d

Dose and period

0.08 mM/kg
5, 10, 20 mg/kg/day
8.5 mg/kg bw

Concentrations

Vanadium sulfate
Sodium metavanadate
Vanadium pentoxide

Compound

Ejaculated sperm samples,

New Zealand White
rabbits

Male Wistar rats

Male Sprague Dawley rats

Male mice

Male mice

Male CD-1 mice

Male mice

Male mice

Pre-pubertal rats

Rats
Rats
CD-1 male mice

Species

Table 2. Reprotoxicity induced in males by vanadium compounds (studies listed chronologically).

In vitro

Orally

Intraperitoneally

Inhaled

Intraperitoneally

Drinking water

Intraperitoneally

Drinking water

Intraperitoneally

Intratesticular
Orally
intraperitoneally

Route

Effects
Reduction in testis weight and total necrosis
No effects on fertility and reproduction
Decrease in fertility rate. Sperm count, motility,
and morphology were impaired with the
advancement of treatment. Decreased
implantation, live fetuses, and fetal weight
and increased the number of resorption/dam.
Males: increased weight of seminal vesicles,
thymus and submandibular glands
Females: no significant differences in age of
vaginal opening nor first vaginal estrus.
Ovulation rate was lower in treated animals
Reduced body and epididymis weight. Decrease
in sperm count
Increase of apoptosis and ultrastructural changes
of germ cell, but testosterone level was not
modified
No treatment-related effect on sperm chromatin
structure or on testis cell population was
observed
Significant increases in the frequencies of total
hyper-haploid sperm were found with 15 and
25 mg/kg, indicating induced non-disjunction
during male meiosis
Vanadium accumulates in the testes and
decreases the percentage of gamma-tubulin
in testicular cells (Sertoli, Leydig, and germ
cells)
Reduced sperm count associated with decreased
serum testosterone and gonadotropins level
Decreased weights of testes and accessory
reproductive organs. Reduced number and
motility of epididymal sperm. Mating tests
with untreated females revealed a decrease in
pregnancy rate and mean number of pups
delivered
Reduced sperm motility and curvilinear velocity
and numerous folds in the acrosome
membrane

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Castellini et al. (2009)

Jain et al. (2007)

Chandra et al. (2007a)

Mussali-Galante et al.
(2005)

Attia et al. (2005)

Leopardi et al. (2005)

Aragon et al. (2005)

Llobet et al. (1993)

Altamirano et al.
(1991)

Kamboj & Kar (1964)

Domingo et al. (1986)
Altamirano-Lozano
et al. (1996)

References

DOI: 10.3109/1547691X.2013.791734

Genotoxity and reprotoxicity of vanadium compounds

5

M. A. Altamirano-Lozano et al.

vacuolation of the seminiferous tubules, and loss of late

spermatids. These compounds produced germ cell apoptosis.

Maternal toxicity and effects of vanadium on embryo

and fetus

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Animal studies
Vanadium in the form of vanadate is a potent inhibitor of tyrosine
phosphatase inhibitors, including CDC25, in human kidney cells.
ATPase activity is necessary for the assembly and activation of
the mitotic apparatus and spindle fibers. In Xenopus and mouse
oocytes, vanadate decreases the activity of the maturationpromoting factor through inhibition of p34 cdc2 tyrosine dephosphorylation. Apparently, vanadate also inactivates the maturation
factor of porcine oocytes (i.e. vanadate potentially inhibits or
disturbs oocyte maturation and correct assembly of the mitotic
spindle). This effect compromises the segregation of oocyte
chromosomes and damages their descendants (Kim et al., 1999).
Mailhes et al. (2003) found that vanadate administered
intraperitoneally immediately after application of hCG, increased
the occurrence of premature anaphase in oocytes, while, in bone
marrow cells, vanadate also increased the percentage of tetraploids, hyperpolyploids, and premature centromere separation
in bone marrow cells. The researchers postulated that a kinasephosphatase imbalance during oocyte maturation and the
metaphase-anaphase transition produce cytogenetic abnormalities
that differ between oocytes and bone marrow cells.
The embryos of all mammals depend on the mothers system;
thus, the environment in which the mother lives is of great
importance in successful development of the offspring. Naturally,
the age and physical and nutritional status of the mother could
exert significant effects during growth in the uterus; however,
if integrity of the maternal system is altered, the change may
indirectly affect the offspring. Studies of intrauterine development
have revealed that exposure to physical and chemical agents,
infectious diseases, hormonal changes, and nutritional deficiencies or excesses are factors that directly cause abnormal embryonic or fetal development and birth defects (Scialli, 1992).
While there is little information on the reproductive toxicity
of vanadium and developmental toxicity after vanadium inhalational exposure, this metal causes toxicity in the embryo and fetus
when administered orally. However, the toxic effects of vanadate
and vanadyl have been observed only at doses remarkably higher
than the doses that can be ingested through food (Domingo,
1996). Vanadium can cross the placental barrier (Edel &
Sabbioni, 1989; Paternain et al., 1990) but appears to accumulate
in fetal membranes rather than in the fetus itself (Roshchin et al.,
1980; Hackett & Kelman, 1983; IPCS, 1988). However,
Underwood (1977) determined that the metal could accumulate
in the fetal skeleton.
Roshchin et al. (1980) reported that administration of
vanadium (oxidation state undefined) to pregnant rats on
days 21 and 22 of gestation causes accumulation of this metal
in the placenta; however, vanadium does not cross the placental
barrier. Nonetheless, the researchers observed some embryotoxic
effects, like increased mortality, when vanadium was administered on day 10 of pregnancy. Wide (1984) found that intravenous
administration of 0.15 ml of 1 mM V2O5 (V5) to mice on day 8
of gestation caused a decrease in skeletal ossification areas in 71%
of fetuses, with an increased number of non-viable implants, and
9% of fetuses examined on day 17 of gestation had a broken spine.
In hamsters, a mild transplacental effect was reported
after applying ammonium metavanadate (V5, 0.47, 1.88, and
3.75 mg NH4VO3/kg/day) intraperitoneally to pregnant females
from days 510 of gestation. No toxic effects were observed
in the mother at any dose, but skeletal abnormalities occurred,

J Immunotoxicol, Early Online: 19

e.g. micrognathia, supernumerary ribs, and alterations in ossification of the sternebrae. Despite these abnormalities, it was
suggested that the low incidence and lack of a dose-dependent
response was not definitive proof that NH4VO3 was teratogenic
(Carlton et al., 1982).
Edel & Sabbioni (1989), after applying intravenous injections
of pentavanadate with [48V]-labeled vanadium at doses of 0.1 mg
V5/animal to pregnant rats on day 12 of gestation, found
significant amounts of vanadium in the liver, intestine, and kidney
of fetuses, proving that vanadium in this form crosses the
placental barrier and is metabolized by the fetus. Moreover, V4
crosses the placenta and reaches the fetus, as demonstrated by the
results reported by the same authors when applying vanadyl
sulfate pentahydrate (V4) to pregnant female mice by intragastric
gavage on days 615 of pregnancy. In this case, the authors
postulated that the transport path through the placenta may be
facilitated by the formation of a complex with transferrin or
albumin.
Altamirano et al. (1991) evaluated the effect of V2O5 on the
early reproductive process in newborn rats. The researchers
intraperitoneally injected pre-pubertal male and female rats of the
CII-ZV strain every 2 d (from birth until day 21) at a dose of
12.5 mg/kg and another group of females from day 21 until the
day of the first vaginal estrus. In the pre-pubertal and juvenile
females, no differences were observed in the vaginal opening or
estrous cycle; however, the ovulation rate was decreased in
young females treated with this compound. Notably, when
juvenile females were treated from day 21 post-partum, there
was an increase in weight of the submandibular glands, thymus,
and liver. In the males, an increase was also detected in the
seminal vesicles, thymus, and submandibular glands. These
results demonstrate that, similar to other metals, the toxicology
of vanadium has sex-based differences, with the male pre-pubertal
group being more susceptible than the female group.
As with the majority of toxic agents, the path or route of
exposure is critical to the effect produced, and this phenomenon is
clearly observed in the case of vanadium compounds. The oral
administration of sodium metavanadate (20 mg NaVO3/kg/day) to
rats on days 614 of gestation does not cause embryolethal or
teratogenic effects. However, if the NaVO3 is administered via the
intraperitoneal route to female mice from days 615 of gestation
at doses of 4 or 8 mg/kg/day, then an increase occurs in the
number of resorptions, dead fetuses, and cleft palates (Gomez
et al., 1992). Although the authors of this study reported the
presence of maternal toxicity, they postulated that the effect
observed in fetuses may be caused by direct contact of vanadium
with the tissues from embryos or fetuses and not by maternal
toxicity; however, it is likely that most of the effects produced by
the administration of vanadium compounds to pregnant females
(increased percentage of resorptions, fetal death, and fetal weight
reduction) is the result of maternal toxicity caused by high doses
of the compounds (Leonard & Gerber, 1998).
The oxidation number of vanadium in compounds is also a key
factor explaining the different responses found during assessments
of developmental toxicology. For example, intra-gastric administration of sodium orthovanadate (V5; at 0, 7.5, 15, 30, or 60 mg/
kg) to mice on days 615 of gestation caused maternal toxicity
observed as decreased weight and even death; however, no
teratogenic effects or embryo lethality were observed, although
delayed ossification occurred only at the highest dose (Sanchez
et al., 1991). Furthermore, oral administration of vanadyl sulfate
pentahydrate (V4; up to 150 mg/kg/day) to female mice from
days 615 of gestation caused maternal, embryonic, and fetal
toxicity (including teratogenicity) at all dosesespecially the
highest dosetested, with cleft palate and micrognathia being
the major malformations observed (Paternain et al., 1990).

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DOI: 10.3109/1547691X.2013.791734

Regarding sodium metavanadate (NaVO3), in the literature,

there was only one study reporting a significant increase in
number of reabsorbed fetuses (Paternain et al., 1987). In a
subsequent study with V2O5 by Altamirano-Lozano et al. (1993),
among female CD-1 mice that were injected daily from days 615
of gestation with 8.5 mg V2O5/kg IP, vanadium did not cause a
change in the numbers of live versus dead fetuses or the number
of implants; however, it did lead to decreases in fetal weights
at day 18 of gestation and caused significant delays in skeletal
ossification (i.e. there were decreased numbers of ossification
centers in extremities). No maternal toxicity was noted at this
dose; nevertheless, the authors concluded that vanadium altered
the fetal development process.
In contrast, oral administration of V2O5 (V5) to weanling rats
(10200 mmol/kg) for 3 d resulted in increased alkaline phosphatase activity and DNA content in the femoral diaphysis of treated
animals. These data indicate that vanadium plays a role in bone
formation (Yamaguchi et al., 1989), a finding consistent with
reports of vanadium affinity for bone in developing animals.

Effects of vanadium on reproduction and fetal

development in diabetics
Human studies
One use of vanadium is diabetes treatment, as certain compounds
have proven to be insulin-mimetic, helping to control the disease.
However, there is limited data in humans, although research
performed on laboratory animals has yielded significant results.
Manci et al. (1989) and Al-Attas et al. (1995), who analyzed
placentas of diabetic and non-diabetic women, measured lower
vanadium levels (as vanadate compounds) in the case with
gestational diabetes mellitus (7.62 mg V/g) compared with the
control (8.73 mg V/g), which was attributable to decreased intake
or absorption and increased utilization or excretion of vanadium.
The researchers proposed that the binding of vanadium to the
maternal tissue in humans is increased in diabetes mellitus when
insulin is deficient. Under this hypothesis, recent studies in vitro
have revealed that the binding of vanadate to insulin receptors
increases in the placenta of women with gestational diabetes
mellitus.
Animal studies
Given the interest in the possible use of vanadium to treat diabetes
during pregnancy, the effect of oral administration of vanadate on
the reproductive process was evaluated in normal and diabetic
rats. Vanadate was administered in the drinking water of animals
at concentrations of 0.25 and 0.50 mg/ml, and the data revealed
that vanadium did not normalize blood glucose levels in diabetic
pregnant rats; however, the metal was found to alter certain
reproductive parameters, such as the pregnancy rate and the
ability to sustain the pregnancy to term in normal and diabetic
rats. The authors postulated that these results were most likely due
to changes in the estrous cycle, as polycystic ovaries were
observed in the females that did not become pregnant. Postmortem analysis of the females that did not reach term revealed
highly vascular and fluid-filled uteri, indicating that these animals
had conceived and perhaps had experienced early, spontaneous
abortions (Ganguli et al., 1994).
In another study, normal and diabetic rats received
0.25 mg NaVO3/ml in drinking water during gestation. The
presence of vanadium in maternal blood had a negative effect
on fetal development, namely, a marked reduction in the number
of live fetuses per litter in both diabetic animals and normal
animals. This toxicity may have been caused by a transplacental
transfer of a significant amount of vanadate from the maternal to

Genotoxity and reprotoxicity of vanadium compounds

fetal compartments. Alternatively, the negative effect of vanadium

in the blood of developing fetuses might be a consequence of the
excessive generation of free radicals and reactive species, as it has
been documented that high levels of reactive species can result
in embryonic death (Eriksson & Borg, 1991). Based on these
above-noted results, oral treatment with vanadate is toxic and
ineffective for gestational diabetes because it reduces the reproductive capacity and interferes with fetal growth and development
in normal animals and diabetic animals. Therefore, vanadium
treatment may be contraindicated for diabetic females of reproductive age (Ganguli et al., 1994).

Conclusion
Metals can operate through hormonal or genotoxic pathways,
and some metals can penetrate the bloodtestis barrier, affecting
spermatogenesis by altering the integrity of the genetic material,
altering hormone production, or affecting the cell cycle in certain
cases (e.g. during meiotic non-disjunction). This damage can
cause adverse effects in the offspring. At high doses, vanadium
compounds can damage a developing organism in the uterus, but,
apparently, this effect is mainly due to maternal toxicity. Because
vanadium salts are inefficiently transferred to the fetus itself, fetal
malformations are found only at very high doses (specific agents
and corresponding doses reviewed in Leonard & Gerber, 1998).
The available data indicate the necessity for more studies
of the effects of vanadium in occupationally-, environmentally-,
or pharmacologically-exposed human populations. As demonstrated in the present review, animal models have been shown to
indicate that the reproductive toxicity of various vanadium
compounds depends on the dose, duration of treatment, route of
administration, sex, and species that is encountered.

Declaration of interest
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of the paper.

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