Cadmium and male infertility

Abstract

Cadmium (Cd) is a heavy metal to which humans are exposed both occupationally and environmentally. For many years cadmium has been understood as a toxic element to human health, and an elevated level of cadmium exposure has been shown to be related to adverse reproductive effects, especially in men. In this review we studied published data about the toxic effects of this trace element on the total male reproductive system, including gonadal development, testes, testosterone, spermatogenesis and accessory sex glands, to clarify how cadmium causes male fertility problems. For this purpose, in the next sections after introducing this trace element thoroughly, we will separately mention cadmium's effects on each part of male reproductive system.

Full text

Journal of Infertility and Reproductive Biology, 2014, Volume 2, Issue 2, Pages: 62-69
62
Cadmium and male infertility
Alaee S
1*
, Talaiekhozani A
2,3
, Rezaei S
4
, Alaee K
5
, Yousefian E
6
1. Department of Reproductive Biology, School of Advanced Medical Sciences and Technologies, Shiraz
University of Medical Sciences, Shiraz, Iran
2. Institute of Environmental and Water Resources Management, Water Research Alliance, Universiti
Teknologi Malaysia, UTM Skudai, 81310 Johor Bahru, Malaysia
3. Jami Institute of Technology, Department of Civil Engineering, Isfahan, Iran
4. Department of Obstetrics and Gynecology, Shiraz University of Medical Sciences, Shiraz, Iran
5. Department of Radiology, Shiraz University of Medical Sciences, Shiraz, Iran
6. Department of Midwifery, Falavarjan Branch, Islamic Azad University, Isfahan, Iran
Abstract
Cadmium (Cd) is a heavy metal to which humans are exposed both occupationally and environmentally. For
many years cadmium has been understood as a toxic element to human health, and an elevated level of cadmium
exposure has been shown to be related to adverse reproductive effects, especially in men. In this review we studied
published data about the toxic effects of this trace element on the total male reproductive system, including gonadal
development, testes, testosterone, spermatogenesis and accessory sex glands, to clarify how cadmium causes male
fertility problems. For this purpose, in the next sections after introducing this trace element thoroughly, we will
separately mention cadmium’s effects on each part of male reproductive system.
Keywords: Cadmium, Male, Testis, Sperm, Reproduction
1. Introduction
Heavy metals are natural components of the
earth’s crust and cannot be degraded or destroyed.
Cadmium is a heavy metal, used in industrial
activities such as the manufacture of nickel-cadmium
batteries, electroplating, pigments, ceramics, plastic
stabilizers, and fertilizers, as well as in other
industrial, mining, agricultural activities and in the
widespread use of phosphate-based fertilizers (1-3).
Consequently, there is a high level of cadmium
contamination at many locations worldwide, which
leads to pollution of the water and air. After cadmium
enters the environment, it pollutes air and water and
at last is discharged into the food chain, detrimentally
affecting living organisms (4, 5). The toxicity of
cadmium was first described by Friedrich Stromeyer
in 1817. In the 1940s, environmental exposure to
mmm
*
Corresponding Address: Dr. Sanaz Alaee, School
of Advanced Medical Sciences and Technologies,
Shiraz University of Medical Sciences, Shiraz, Iran.
Email: sanazalaee@yahoo.com
cadmium’s toxicity was reported in Japan’s Jinzū
river basin, where a disease called itai-itai tormented
many people. These patients showed a wide range of
symptoms, such as low-grade bone mineralization, a
high rate of fracture, an increased rate of osteoporosis
and intense bone-associated pain. This affliction
occurred because the river basin’s inhabitants had
consumed local rice, which had been grown in fields
irrigated with cadmium-contaminated water (3).
Cadmium has molecular homology with zinc and
calcium and compensates with them for resorption to
the body (6, 7). Studies have shown that in humans,
cadmium can be absorbed into the body through the
gastrointestinal, respiratory and dermal systems (8).
The major source of inhalative cadmium intoxication
is smoking, and the human lung resorbes 40-60% of
the cadmium content in cigarette smoke (9). As a
result, smokers receive a dose of cadmium daily and
generally have cadmium blood levels 4-5 times more
than those of nonsmokers (2, 8, 10). In nonsmokers,
most uptake of cadmium is through cadmium-

Journal of Infertility and Reproductive Biology, 2014, Volume 2, Issue 2, Pages: 62-69
63
contaminated drinking water and food, particularly
cereals, such as rice and wheat, and also potato and
green leafy vegetables (2, 8, 10, 11).
It has been documented that the total amount of
cadmium uptake to the human body depends on the
consumed dose. Several factors can increase this
uptake, such as low intake of vitamin D, calcium and
iron (8). It has been demonstrated that cadmium
uptake in people with anemia and habitual iron
deficit, such as children or menstruating women, is
higher than in other people (12). In addition, it is
estimated that dietary intake of cadmium is higher in
men than women (13).
A higher level of cadmium intake, more than the
standard level, has an significant adverse effect on
growth rate (14, 15), but its toxic effects on tissues
are not the same in all tissues, i.e., vary from tissue to
tissue and are seen primarily in sensitive tissues such
as liver, kidney, ovary and especially testes (16).
Studies of cadmium toxicity have introduced it as
an ubiquitous environmental human carcinogen (17)
and one of the best-known reproductive toxicants in a
wide variety of animals (18-22). In humans, chronic
exposure to environmentally-relevant cadmium
results in high cadmium level, especially in infertile
men (23, 24). Therefore, in the current study we
reviewed available literature to determine which part
of the male reproductive system is most affected by
cadmium and how cadmium causes male fertility
problems.
2. Effects of cadmium on gonadal development
Collected data showed that cadmium affects the
male reproductive system from embryonic stages to
adulthood, and has adverse effects on gonadal
development (25). In mouse embryos, administration
of cadmium caused reduced genital ridge size and
retarded migration of germ cells into the genital
ridges, resulting in attenuated populations of germ
cells, aberrant maturation of gametes and subfertility
(26). In young rabbits treated with 1.0-2.25 mg/kg
body weight cadmium, significant damage to the
germinal epithelial and basement membrane after 48
hours and a significant reduction in the volume of
epididymis epithelium after 5 months’ treatments
were observed (27).
3. Effects of cadmium on reproductive system
3.1. Testes
Testis is one of the tissues that is very sensitive to
the toxic effects of cadmium. Elevated accumulation
of cadmium in testis has been measured using atomic
absorption spectroscopy technique and confirmed by
the presence of hyperchromatic cadmium precipitants
in histological sections of seminiferous tubules of
adult male mice treated with cadmium (15).
Similarly, gonadal damage has been shown to
develop following administration of cadmium to
adult male rats either orally or subcutaneously (25).
In humans, testicular cadmium levels are age
dependent and elevate after the fourth decade of life
(28). Some studies show that cadmium accumulation
in the testes has no effect on testicular weight (29-
31), but there is some evidence showing that the
weight of testis can be affected by cadmium
accumulation in testicular tissue, rather than by total
body weight; however, this depends on the level of
applied cadmium, duration of treatment and the level
of cadmium concentration in the testis (Table 1) (14,
15, 32, 33). Additionally, cigarette smoking has been
reported to be associated with decreased testis size in
men, related to the cadmium content of cigarettes
(34).
Cadmium enters the seminiferous tubules through
a breach of the blood-testis barrier and causes focal
testicular necrosis and dystrophy with consequent
reduction in germ cell numbers, leading to infertility
(15, 25, 35, 36). Disruption of the blood-testis barrier
by cadmium is a consequence of endothelial cell
damage in testicular blood vessels and separation of
endothelial cells, which has been confirmed by light
and electron microscopy and is mediated by reduced
occludin protein expression, indicating the involve-
ment of cell junction breakdown in blood-testis
barrier disruption (35-37).
Researchers report that high concentration of
reactive oxygen species (ROS), generated by
accumulation of cadmium in testicular tissue, exceeds
the antioxidant capability of the testis cells, leading to
lipid peroxidation, degeneration of seminiferous
tubules, testicular hemorrhage, testicular necrosis,
abnormal Leydig cells, fibrosis and reduced testicular
size. Therefore, severe cellular injury in seminiferous
tubules could be due to a high level of peroxidation
in lipid membrane of testicular cells, observed in
many studies (14, 15, 25, 33, 38-45). In one study by
Monsefi et al., (2010) administration of cadmium
chloride caused severe damage to seminiferous
tubules, resulting in difficulty in identification of
seminiferous tubules by light microscope and also
consequent reduction in spermatogenesis, as there
was no spermatozoid in the lumen of some
seminiferous tubules (15).
3.2. Testosterone
Testosterone is the principle male sex hormone
produced by Leydig cells, located in interstitial tissue
of testis. Presence and function of this hormone is

Journal of Infertility and Reproductive Biology, 2014, Volume 2, Issue 2, Pages: 62-69
64
crucial for accurate spermatogenesis process of
seminiferous tubules, and evaluation of the plasma
testosterone level is considered a useful indicator of
testicular function (46, 47).
While many studies have been suggested that
cadmium increases testosterone level (29, 48, 49),
others showed that cadmium administration
attenuates it (14, 15, 21, 50-54). However, according
to Table 1, it can be concluded that the effect of
cadmium on testosterone level is dependent on dose,
duration and method of cadmium administration. In
addition, modified Leydig cells in the interstitial
tissue of testes of mice exposed to cadmium chloride
have been reported (15). Nevertheless, we should
mention that except for serum, the evaluation of testi-
testic
cular testosterone is important, and testicular
testosterone levels are approximately one hundred
fold higher than serum testosterone levels, and this
high level is required to support spermatogenesis (55,
56).
Consequently, it is possible that testicular
testosterone level can be more sensitive to the effects
of cadmium than serum level, as was observed in rats
treated with cadmium (14). Telisman et al. (2000)
showed that cadmium has the ability to impair male
fertility without effects on the male reproductive
endocrine function (57). So it is concluded that
cadmium affects testosterone synthesis through
various mechanisms that depend upon experimental
conditions.
Table 1. Studies about effects of cadmium on weight of testes, accumulation of cadmium in testes and plasma
testosterone level.
Model of
research
Cadmium
administration
method
Doses of
cadmium
Duration
of
treatment
Weight of
testes
Accumulation
of cadmium in
testes
Plasma
testosterone
level Reference
Adult Wistar
male rats Subchronic
exposure to Cd (CdCl2, 40 mg/l,
per os) 30 days S Decrease NE S Decrease in
plasma and
testis (14)
Adult
BALB/c male
mice
Orally
administration
by gavage
CdCl
2,
23 mg/kg
BW 45 days NS Decrease NS Increase S Decrease (15)
CdCl
2,
50 mg/kg
BW once per day S Decrease S Increase S Decrease
Adult Wistar
male rats Orally CdCl
2
(0.2
mg/kg) 15 days NE S Increase S Decrease (21)
Adult Wistar
male rats
Cadmium-
contaminated
radish bulb
1.1 µg Cd/g of
diet
4 weeks No change S Increase NS Increase
(29)
8 weeks No change S Increase S Increase
12 weeks No change S Increase NS Decrease
Adult
Sprague
Dawley male
rats
Subcutaneously 0.6 mg Cd/kg
once per day 6 weeks No Change S Increase NE (31)
Adult
Sprague
Dawley male
rats
Orally,
administration
by gavage
CdCl
2
, 5 mg/kg
BW 15 days S Decrease NE NE (33)
Adult Swiss
Webster male
mice
Intraperitoneal
injection once a
day
CdCl
2,
0.1 mg/kg
BW once per
week
4, 10, 26,
and 52
weeks NE S Increase NS Increase (48)
S= Significant; NS= Non significant; NE= Not examined.
3.3. Spermatogenesis and semen parameters
Besides being detected in blood, cadmium can be
identified in seminal plasma of cigarette smokers
(58), but no relationship was reported between the
levels of cadmium in blood and seminal plasma (59,
60).
In the literature, conflicting evidence exists
regarding the correlation between the cadmium
content of seminal plasma and semen parameters (20,
60-63). Where some studies demonstrated positive
correlation between the cadmium content of semen
and seminal quality (60, 64), others reported that
seminal plasma cadmium level is unrelated to semen
parameters and also fertility status (64-66).
Studies suggest that different cell populations within
the testis can be as targets of cadmium toxicity (67,
68), and cadmium is able to be accumulated in
germinal cells such as spermatogonia, spermatocytes,

Journal of Infertility and Reproductive Biology, 2014, Volume 2, Issue 2, Pages: 62-69
65
spermatid and spermatozoa after the entrance of
cadmium to testicular tissue (31, 44, 48). In one
study, Sprague Dawley rats subcutaneously injected
with daily 0.6 mg/kg doses of cadmium over a 6-
week period developed an accumulation of cadmium
in the testes, mainly in spermatogonia and
spermatocytes, with consequent reduction in both of
these cell types (31). However, in one study which
used atomic absorption spectroscopy and particle-
induced x-ray emission analyses, the presence of
cadmium in germinal cells was not observed (48).
As shown in Table 2, treatment with different
doses and durations of cadmium leads to sperm
concentration reduction (14, 15, 21, 29, 31, 33).
Haouem et al. (2008) observed that by increasing the
duration of cadmium administration, sperm
concentration decreases in male rats mainly because
of high apoptosis of sperm cells (29), which was seen
in male cigarette smokers, too, especially in heavy
smokers. Therefore, cadmium could be a possible
causative agent for the low sperm density among
smokers (69).
Besides sperm concentration, sperm motility is
also severely affected by cadmium. Sperm motility is
recognized to be more sensitive to this trace element,
as reduced sperm motility has been observed at a
dose far below the dose affecting sperm production.
However, it is concluded that cadmium accumulation
in germinal cells and cadmium effects on sperm
count and sperm motility are dose- and time-
dependent (Table 2) (14, 24, 25, 27, 31, 70). Taha et
al. (2012) observed that men with idiopathic male
infertility had higher seminal cadmium levels (71),
which was correlated with impairment of sperm
motility, especially progressive sperm motility, lower
percentages of viable sperms and more important,
with higher sperm DNA fragmentation and semen
ROS level (71).
Regarding the adverse effects of this heavy metal
on sperm motility, some studies have suggested that
motility of sperm can be used as an early and
sensitive endpoint for the assessment of cadmium
toxicity in the male reproductive system (59).
Table 2. Effects of cadmium on semen parameters.
Model of
research
Cadmium
administration
method Doses of cadmium Duration
of
treatment Sperm count Sperm motility Reference
Adult Wistar
male rats
Subchronic exposure
to CdCl
2
40 mg/l, per os 30 days S Decrease S Decrease (14)
Adult BALB/c
male mice Orally administration
of CdCl
2
23 mg/kg BW, once per
day 45 days NS Decrease NS Decrease (15)
50 mg/kg WB, once per
day
45 days S Decrease S Decrease
Adult Wistar
male rats Oral administration of
CdCl
2
(0.2
mg/kg) 15 days S Decrease NE (21)
Adult Wistar
male rats Cd-contaminated
radish bulb 1.1 µg Cd/g of diet
4 weeks NS Decrease NE
(29)
8 weeks NS Decrease NE
12 weeks S Decrease NE
Adult Sprague
Dawley male
rats
Subcutaneous
injection 0.6 mg Cd/kg once per day 6 weeks S Decrease in
testicular SG
and SC NE (31)
Adult Sprague
Dawley male
rats
Oral administration of
CdCl
2
5 mg/kg BW 15 days S Decrease S Decrease (33)
Adult male rats CdCl
2
,
1 mg kg 3 days S Decrease S Decrease (45)
S= Significant; NS= Non significant; NE= Not examined; SG= Spermatogonia; SC= Spermatocyte.
3.4 Sperm chromatin integrity and DNA stability
C
hromatin condensation and DNA stability are
indices of sperm quality, which can be identified
through aniline blue and acridine orange,
respectively, to reflect the possible disorders in sperm
DNA and sperm maturation. Damage to sperm DNA
seems to affect embryo and increases the risk of
infertility, miscarriage, or serious diseases in the
offspring (72, 73). Through the use of acidic aniline
blue staining, it has been revealed that cadmium can
inhibit the chromatin condensation process, which is
important for sperm maturation. This is a significant

Journal of Infertility and Reproductive Biology, 2014, Volume 2, Issue 2, Pages: 62-69
66
limiting factor in fertility potential; but incorporation
of cadmium into sperm chromatin was not confirmed
using Acridine orange staining (15).
3.5. Prostate and Seminal Vesicle
Although some studies have suggested the
carcinogenic potential of cadmium on prostate tissue
(17, 74), a critical study by Sahmoun et al. (2005) has
shown that in contrast to laboratory animals,
epidemiological analyses do not convincingly
implicate cadmium as a cause of prostate cancer (75).
Exposure of rats to Cd resulted in a significant
reduction in seminal vesicle (14, 15). Monsefi et al.
(2010) showed that administration of cadmium to
male mice causes reduced weight of seminal vesicles
and high serum prostatic acid phosphatase activity.
These effects may be due to hypertrophy or
hyperplasia of the prostate gland, leading to increased
synthesis or expression of this enzyme (15).
4. Conclusion
According to the literature, cadmium has adverse
effects on the male reproductive system and the testes
are the main target of cadmium.
Cadmium enters the body through contaminated
air, water and food. It then circulates in the blood and
reaches tissues such as testis, where it accumulates.
Cadmium in the testis disrupts the blood-testis
barrier, comes into close contact with different cells
of testis and, by increasing the production of ROS
and decreasing various antioxidants’ levels, enhances
the lipid peroxidation of cell membranes, causes
apoptosis and necrosis of all testicular tissue leading
to disturbance of spermatogenesis, reduces sperm’s
motility and finally leads to infertility.
Also oxidative damage of sperm’s DNA causes
paternal genomic disorder contributed to a variety of
developmental disorders including early or late
embryonic lethality. However, with regard to the
literature, studies have failed to demonstrate the
incorporation of cadmium into sperm chromatin.
In conclusion, subfertility following cadmium
administration might result from penetration of
cadmium to testicular tissue and damage to testicular
tissue, leading to disturbance of the testes’ function,
manifested by disruption of spermatogenesis and
sperm motility, with or without effects on the male
reproductive endocrine function.
References
1. Aziz R, Rafiq MT, Yang J, et al. Impact
Assessment of Cadmium Toxicity and Its
Bioavailability in Human Cell Lines (Caco-2 and
HL-7702). BioMed Res Int. 2014; 839538.
2. El-Dars FMSE, Bakr MHM, Gabre AM. Reduction
of COD in Resin Production Wastewater Using
Three Types of Activated Carbon. J Environ Treat
Tech. 2013; 1(3): 126-136.
3. Fowler BA. Monitoring of human populations for
early markers of cadmium toxicity: a review.
Toxicol Appl Pharm. 2009; 238(3): 294-300.
4. Jamshidi B, Ehrampoush MH, Dehvari M.
Utilization of Olive Kernel Ash in Removal of
RB19 from Synthetic Textile Wastewater. J
Environ Treat Tech. 2013; 1(3): 150-156.
5. Fazeli M, Hassanzadeh P, Alaei S. Cadmium
chloride exhibits a profound toxic effect on
bacterial microflora of the mice gastrointestinal
tract. Hum Exp Toxicol. 2011; 30(2): 152-159.
6. Frías-Espericueta MG, Zamora-Sarabia FK,
Osuna-López JI, et al. Cadmium, Copper, Lead,
and Zinc Contents of Fish Marketed in NW
Mexico. The Scientific World Journal, 2014;
546897.
7. Foulkes E. Interactions between metals in rat
jejunum: implications on the nature of cadmium
uptake. Toxicology. 1985; 37(1): 117-125.
8. Godt J, Scheidig F, Grosse-Siestrup C, et al. The
toxicity of cadmium and resulting hazards for
human health. J Occup Med Toxicol, 2006; 1(22):
1-6.
9. Elinder C-G, Kjellström T, Friberg L, Linnman
BLL. Cadmium in kidney cortex, liver, and
pancreas from Swedish autopsies. Arch Environ
Health.1976; 31(6): 292-302.
10. Järup L, Berglund M, Elinder CG, et al. Health
effects of cadmium exposure–a review of the
literature and a risk estimate. Scand J Work Env
Hea. 1998: 2; 1-51.
11. Jin T, Frech W, Dumont X, et al. Cadmium bio-
monitoring and renal dysfunction among a
population environmentally exposed to cadmium
from smelting in China (ChinaCad). Biometals.
2002; 15(4): 397-410.
12. Flanagan P, McLellan J, Haist J, et al. Increased
dietary cadmium absorption in mice and human
subjects with iron deficiency. Gastroenterology.
1978; 74(5): 841-846.
13. Watanabe T, Shimbo S, Nakatsuka H, et al.
Gender-related difference, geographical variation
and time trend in dietary cadmium intake in Japan.
Sci Total Environ. 2004; 329(1): 17-27.
14. Amara S, Abdelmelek H, Garrel C, et al.
Preventive effect of zinc against cadmium-induced
oxidative stress in the rat testis. Reprod Dev. 2008;
54(2): 129-134.
15. Monsefi M, Alaee S, Moradshahi A, Rohani L.
Cadmium induced infertility in male mice. Environ

Journal of Infertility and Reproductive Biology, 2014, Volume 2, Issue 2, Pages: 62-69
67
Toxicol. 2010; 25(1): 94-102.
16. Orisakwe O. Lead and cadmium in public health
in Nigeria: physicians neglect and pitfall in patient
management. N Am J Med Sci, 2014; 6(2): 61.
17. Nakamura K, Yasunaga Y, Ko D, et al.
Cadmium-induced neoplastic transformation of
human prostate epithelial cells. Int J Oncol. 2002;
20(3): 543.
18. El-Ebiary EH, Wahbi OM, El-Greisy ZA.
Influence of dietary Cadmium on sexual maturity
and reproduction of Red Tilapia. Egypt J Aquat
Res. 2013; 39(4): 313-317.
19. Wirth JJ, Mijal RS. Adverse effects of low level
heavy metal exposure on male reproductive
function. Syst Biol Reprod Med. 2010; 56(2): 147-
167.
20. Xu D-X, Shen H-M, Zhu Q-X, et al. The
associations among semen quality, oxidative DNA
damage in human spermatozoa and concentrations
of cadmium, lead and selenium in seminal plasma.
Mut Res Gen Tox En. 2003; 534(1): 155-163.
21. Jahan S, Khan M, Ahmed S, Ullah H.
Comparative analysis of antioxidants against
cadmium induced reproductive toxicity in adult
male rats. Syst Biol Reprod Med. 2014; 60(1): 28-
34.
22. Rahman MS, Sasanami T, Mori M. Effects of
cadmium administration on reproductive
performance of Japanese quail (Coturnix japonica).
J Poult Sci. 2007. 44.
23. Stassen MJ, Preeker NL, Ragas AM, et al. Metal
exposure and reproductive disorders in indigenous
communities living along the Pilcomayo River,
Bolivia. Sci Total Environ. 2012; 427: 26-34.
24. Benoff S, Hauser R, Marmar JL, et al. Cadmium
concentrations in blood and seminal plasma:
correlations with sperm number and motility in
three male populations (infertility patients,
artificial insemination donors, and unselected
volunteers). Mol Med. 2009; 15(7-8): 248.
25. Thompson J, Bannigan J. Cadmium: toxic effects
on the reproductive system and the embryo.
Reprod Toxicol. 2008; 25(3): 304-315.
26. Tam P, Liu W. Gonadal development and fertility
of mice treated prenatally with cadmium during
the early organogenesis stages. Teratology, 1985.
32(3): 453-462.
27. Toman R, Massanyi P, Uhrin V. Changes in the
testis and epididymis of rabbits after an
intraperitoneal and peroral administration of
cadmium. Trace Elements Electrolytes. 2002;
19(3): 114-117.
28. Oldereid N, Thomassen Y, Attramadal A, et al.
Concentrations of lead, cadmium and zinc in the
tissues of reproductive organs of men. J Reprod
Fertil. 1993; 99(2): 421-425.
29. Haouem S, Najjar MF, El Hani A, Sakly R.
Accumulation of cadmium and its effects on testis
function in rats given diet containing cadmium-
polluted radish bulb. Exp Toxicol Pathol, 2008;
59(5): 307-311.
30. Foote RH. Cadmium affects testes and semen of
rabbits exposed before and after puberty. Reprod
Toxicol. 1999; 13(4): 269-277.
31. Aoyagi T, Ishikawa H, Miyaji K, et al.
Cadmium‐induced testicular damage in a rat model
of subchronic intoxication. Reprod Med Biol.
2002; 1(2): 59-63.
32. Blanco A, Moyano R, Vivo J, et al. Quantitative
changes in the testicular structure in mice exposed
to low doses of cadmium. Environ Toxicol
Pharmacol. 2007; 23(1): 96-101.
33. El-Demerdash FM, Yousef MI, Kedwany FS, et
al. Cadmium-induced changes in lipid
peroxidation, blood hematology, biochemical
parameters and semen quality of male rats:
protective role of vitamin E and β-carotene. Food
Chem Toxicol. 2004; 42(10): 1563-1571.
34. Jurasović J, Cvitković P, Pizent A, et al. Semen
quality and reproductive endocrine function with
regard to blood cadmium in Croatian male
subjects. Biometals. 2004 ;17(6): 735-743.
35. Chung NP, Cheng CY. Is Cadmium Chloride-
Induced Inter-Sertoli Tight Junction Permeability
Barrier Disruption a Suitable in Vitro Model to
Study the Events of Junction Disassembly during
Spermatogenesis in the Rat Testis?
Endocrinology. 2001; 142(5): 1878-1888.
36. Wong C, Mruk DD, Lui W, Cheng CY.
Regulation of blood-testis barrier dynamics: an in
vivo study. J Cell Sci. 2004. 117(5): 783-798.
37. Yan HH, Cheng CY. Blood–testis barrier
dynamics are regulated by an
engagement/disengagement mechanism between
tight and adherens junctions via peripheral
adaptors. Proc Natl Acad Sci U S A. 2005;
102(33): 11722-11727.
38. Tremellen K. Oxidative stress and male infertility:
A clinical perspective. Hum Reprod Update. 2008;
14(3): 243-258.
39. Alaee S. Monsefi M. Effect of cadmium on
oxidative stress of testes in adult male mice. Iran J
Reprod Med. 2013; 11(4): 39.
40. Berliner AF, Jones-Witters P. Early effects of a
lethal cadmium dose on gerbil testis. Biol Reprod.
1975; 13(2): 240-247.
41. Niewenhuis RJ. Effects of cadmium upon regene-
rated testicular vessels in the rat. Biol Reprod.

Journal of Infertility and Reproductive Biology, 2014, Volume 2, Issue 2, Pages: 62-69
68
1980; 23(1): 171-179.
42. Fende PL, Niewenhuis RJ. An electron microsco-
pic study of the effects of cadmium chloride on
cryptorchid testes of the rat. Biol Reprod. 1977;
16(3): 298-305.
43. El-Ashmawy IM, Youssef SA. The antagonistic
effect of chlorpromazine on cadmium toxicity.
Toxicol Appl Pharmacol. 1999. 161(1): 34-39.
44. Kotsonis FN, Klaassen CD. Toxicity and
distribution of cadmium administered to rats at
sublethal doses. Toxicol Appl Pharmacol. 1977;
41(3): 667-680.
45. Oguzturk H, Ciftci O, Aydin M, et al.
Ameliorative effects of curcumin against acute
cadmium toxicity on male reproductive system in
rats. Andrologia. 2012; 44(4): 243-249.
46. Gorbel F, Boujelbene M, Makni-Ayadi F, et al.
Impact of lead given in drinking water on the
endocrine and exocrine sexual activity in
pubescent rats. Determination of an apoptotic
process. C R Biol. 2002; 325(9): 927-940.
47. Lafuente A, González-Carracedo A, Romero A,
et al. Cadmium exposure differentially modifies
the circadian patterns of norepinephrine at the
median eminence and plasma LH, FSH and
testosterone levels. Toxicol Lett. 2004; 146(2):
175-182.
48. Bench G, Corzett M, Martinelli R, Balhorn R.
Cadmium concentrations in the testes, sperm, and
spermatids of mice subjected to long‐term
cadmium chloride exposure. Cytometry. 1999;
35(1): 30-36.
49. Zeng X, Jin T, Zhou Y, Nordberg GF. Changes of
serum sex hormone levels and MT mRNA
expression in rats orally exposed to cadmium.
Toxicology. 2003; 186(1): 109-118.
50. Nordberg G. Effects of long-term cadmium
exposure on the seminal vesicles of mice. J Reprod
Fertile. 1975. 45(1): 165-167.
51. Zylber-Haran, EA, Gershman H, Rosemann E,
Spitz IM. Gonadotrophin, testosterone and
prolactin interrelationships in cadmium-treated
rats. J Endocrinol. 1982; 92(1): 123.
52. Clark JT, Jimenez B, Evans SL, et al.
Reproductive effects of low acute doses of
cadmium chloride in adult male rats. Toxicol Appl
Pharmacol. 1984; 73(2): 250-255.
53. Clark JT, Jimenez B, Evans SL, et al. Cadmium-
induced sexual dysfunction does not involve
increased hepatic metabolism of testosterone nor
increased circulating levels of corticosterone.
Physiol Behave. 1994; 56(5): 975-981.
54. Waalkes MP, Rehm S, Devor DE. The effects of
continuous testosterone exposure on spontaneous
and cadmium-induced tumors in the male Fischer
(F344/NCr) rat: loss of testicular response. Toxicol
Appl Pharmacol. 1997; 142(1): 40-46.
55. Jarow JP, Chen H, Rosner W, et al. Assessment of
the androgen environment within the human testis:
minimally invasive method to obtain intratesticular
fluid. J Androl. 2001; 22(4): 640-645.
56. Coviello AD, Bremner WJ, Matsumoto AM, et al.
Intratesticular testosterone concentrations
comparable with serum levels are not sufficient to
maintain normal sperm production in men
receiving a hormonal contraceptive regimen. J
Androl. 2004; 25(6): 931-938.
57. Telisman S, Cvitković P, Jurasović J, et al. Semen
quality and reproductive endocrine function in
relation to biomarkers of lead, cadmium, zinc, and
copper in men. Environ Health Persp. 2000;
108(1): 45.
58. Benoff S, Jacob A, Hurley IR. Male infertility and
environmental exposure to lead and cadmium.
Hum Reprod Update. 2000; 6(2): 107-121.
59. Xu L, Wang S, Yang X, Wang X. Effects of
cadmium on rat sperm motility evaluated with
computer assisted sperm analysis. Biomed Environ
Sci. 2001; 14(4): 312.
60. Pant N, Upadhyay G, Pandey S, et al. Lead and
cadmium concentration in the seminal plasma of
men in the general population: correlation with
sperm quality. Reprod Toxicol. 2003; 17(4): 447-
450.
61. Akinloye O, Arowojolu AO, Shittu OB, Anetor
JI. Cadmium toxicity: a possible cause of male
infertility in Nigeria. Reprod Biol. 2006; 6(1): 17-
30.
62. Wu H-M, Lin-Tan D-T, Wang M-L, et al.
Cadmium level in seminal plasma may affect the
pregnancy rate for patients undergoing infertility
evaluation and treatment. Reprod Toxicol. 2008;
25(4): 481-484.
63. Alexander BH, Checkoway H, Faustman EM, et
al. Contrasting associations of blood and semen
lead concentrations with semen quality among lead
smelter workers. Am J ind Med. 1998; 34(4): 464-
469.
64. Dawson EB, Ritter S, Harris WA, et al.
Comparison of sperm viability with seminal
plasma metal levels. Biol Trace Elem Res. 1998;
64(1-3): 215-219.
65. Keck C, Bramkamp G, Behre HM, et al. Lack of
correlation between cadmium in seminal plasma
and fertility status of nonexposed individuals and
two cadmium-exposed patients. Reprod Toxicol.
1995; 9(1): 35-40.
66. Kasperczyk A, Kasperczyk S, Dziwisz M, et al.

Journal of Infertility and Reproductive Biology, 2014, Volume 2, Issue 2, Pages: 62-69
69
Lead and cadmium concentration in human semen.
Ginekologia polska. 2002; 73(5): 449-453.
67. Jin L, Lou Z, Dong J, Chen X. Effects of
cadmium and mercury on DNA damage of mice
bone marrow cell and testicle germ cell in vitro.
Carcinog Teratog Mutag. 2003; 16(2): 94-97.
68. Yang HS, Han DK, Kim JR, Sim JC. Effects of α-
tocopherol on cadmium-induced toxicity in rat
testis and spermatogenesis. J Korean Med sci.
2006; 21(3): 445-451.
69. Chia S, et al. Effect of cadmium and cigarette
smoking on human semen quality. Int J Fertil
Menopausal Stud. 1994; 39(5): 292.
70. Dixon R, Lee I, Sherins R. Methods to assess
reproductive effects of environmental chemicals:
studies of cadmium and boron administered orally.
Environ Health Persp. 1976; 13: 59.
71. Taha EA, Sayed SK, Ghandour NM, et al.
mmmm
Correlation between seminal lead and cadmium
and seminal parameters in idiopathic oligoastheno-
zoospermic males. Cent Eur J Urol. 2013; 66(1):
84-92.
72. Wellejus A, Poulsen HE, Loft S. Iron-induced
oxidative DNA damage in rat sperm cells in vivo
and in vitro. Free radical Res. 2000; 32(1): 75-83.
73. Aitken RJ, Koppers AJ. Apoptosis and DNA
damage in human spermatozoa. Asian J Androl.
2011; 13(1): 36-42.
74. Julin B, Wolk A, J-E Johansson JE, et al. Dietary
cadmium exposure and prostate cancer incidence:
a population-based prospective cohort study. Brit J
Cancer. 2012; 107: 895-900.
75. Sahmoun AE, Case LD, Jackson SA, Schwartz
GG. Cadmium and prostate cancer: a critical
epidemiologic analysis. Cancer Invest. 2005;
23(3): 256-263.