J Infertil Reprod Biol, 2020, Volume 8, Issue 3, Pages: 22-32. https://doi.org/10.47277/JIRB/8(3)/22  
Adverse Effects of some of the Most Widely used  
Metal Nanoparticles on the Reproductive System  
1
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1
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Shahla Abdollahii , Faezeh Jadidi , Marjan Safari , Amir Mohammad Akbari Javar , Nasrin  
4*  
4*  
Beheshtkhoo , Mohammad Amin Jadidi Kouhbanani  
1
Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shahroud University of Medical Sciences,  
Shahroud, Iran  
2
Student Resesrch committee, Zarand school of nursing, Kerman university of medical sciences, kerman,Iran  
3
Department of Mathematics, faculty of Mathematics, Farhangian University, Kerman, Iran  
4
Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran  
Received: 22/03/2020 Accepted: 15/07/2020 Published: 20/09/2020  
Abstract  
Nanotechnology, which allows the manipulation of molecular dimensions, is used in many aspects of human life, from industrial to  
medical and therapeutic aspects. Features of nanoparticles and their unique capabilities have attracted a lot of attention. Among  
nanotechnology structures, metal nanoparticles have been widely used in many aspects of industry and medicine. The unique properties  
of these nanoparticles make possible to produce and expand them on a large scale, thus making the possibility of exposure to these  
nanoparticles more likely. Nanotechnology and nanoparticles like a double-edged sword despite its many benefits, it also has a number  
of disadvantages. One of the most important of these disadvantages is their toxicity. This toxicity may have adverse effects on the  
environment and humans. One of the most important adverse effects of nanoparticles is adverse effects on the reproductive system. In  
this paper, the adverse effects of some of the most widely used metal nanoparticles on the reproductive system are described. These  
adverse effects can be on: sexual behaviors, sexual organs, sperm count, sperm motility, sperm shape, sperm maturity, ovarian and  
follicle maturation, their fertility rate and also the level of sex hormones in men and women. The adverse effects of these nanoparticles  
and their toxicity on a variety of tissues and organs lead us to use safer nanoparticles.  
Keywords: Nanotechnology, Metal nanoparticles, Toxicity, Reproductive system  
Introduction1  
nanodevices (27). Metal nanoparticles have been widely used  
1
in targeted drug delivery, cancer treatment, gene therapy and  
DNA analysis, antibacterial agents (28, 29), biosensors,  
enhancing reaction rates, separation science, and magnetic  
resonance imaging (MRI) (30). Some metal nanoparticles, such  
as gold and silver nanoparticles, due to their unique and tunable  
optical properties on account of their surface plasmon  
resonance (SPR), are widely used in molecular-specific  
imaging and sensing, photo-diagnostics, and selective  
Nanotechnology is defined as the use and manipulation of  
devices, materials, and systems in nanometer scale, 100  
nanometer scale, where the resulting material has new physical  
and chemical properties that are not seen in its Balk  
counterparts. Some scientists believe that Nanotechnology is  
one of the key technologies in the 21st century. This technology  
has revolutionized the field of medicine،information  
technology and materials. In the past 30 years, nanotechnology  
has become one of the areas where explosive growth has taken  
place in many dimensions (1-5). Many nanostructures  
include:fullerenes, nanoparticles, nanopowders, nanotubes,  
nanowires, nanorods, nano-fibers, quantum dots, dendrimers,  
nanoclusters, nanocrystals, and nanocomposites are produced  
on a large scale and are used in many aspects of human life (6).  
Nanotechnology potential applications in: cancer treatment (7),  
diagnostics (8), imaging (9), cosmetics(10), anti-aging(11),  
pollutiosensing (12, 13), hyperthermia (14), textile (15),  
catalysis (16-19), water and wastewater treatment (20), food  
industry (21), agriculture fertilizers (22), agriculture (23), drug  
delivery (24), biosensors and biotechnology (25) and many  
more have been proven so far. In many of its applications,  
including pharmacology, this technology has become a  
challenging innovation (26).  
photothermal  
nanotechnology has played  
therapy  
(31).  
Therefore, although  
very important role in  
a
development and progress in many different aspects: from cell  
phones to medicines, but also the negative dimensions of this  
modern technology and its toxic effects must be considered.  
Due to the widespread use of these nanostructures in various  
aspects of human life, human exposure to these nanostructures  
and nanotechnology is inevitable. It is the duty of these  
nanomaterials to enter and affect the various organs and tissues  
of the human body in various ways. These nanoparticles may  
have toxic effects that deformation and inhibition of cell  
growth.And thus cause various diseases in humans and animal  
(6, 32). There is a wealth of evidence to support the toxicity of  
some nanostructures, for example:Titanium oxide  
nanoparticles, which are widely used in cosmetics and skin care  
products, reactive oxygen, they create species and cause  
damage to DNA carbon nanotubes may cause lipide  
eroxidation, oxidative stress, mitochondrialdys function, and  
Metal nanoparticles have received a lot of attention due to  
their electronic and chemical properties, and many scientists  
are willing to use them in the development of new generation  
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Corresponding authors: (a) Nasrin Beheshtkhoo, Department of Medical Nanotechnology, School of Advanced Technologies in  
Medicine, Tehran University of Medical Sciences, Tehran, Iran. E-mail: beheshtkhoo.nano@gmail.com. (b) Mohammad Amin Jadidi  
Kouhbanani, Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical  
Sciences, Tehran, Iran. E-mail: aminjadidi1993@gmail.com.  
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J Infertil Reprod Biol, 2020, Volume 8, Issue 3, Pages: 22-32. https://doi.org/10.47277/JIRB/8(3)/22  
changes in cell morphology upon in vitro incubation with  
keratinocytes and bronchial epithelial cells and thus be  
dangerous. Silver nanoparticles have been shown to be dose-  
dependent toxicity and may cause oxidative stress in alveolar  
macrophages. Quantum dots and fullerenes cause  
inflammatory reactions and may also cause reactive oxygen  
species (33-40).  
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Factors affecting on the toxicity of  
nanoparticles  
Size, shape, chemical composition, surface charge,  
solubility, the type of nanoparticle entry path into the body, the  
exposure time of nanoparticles. surface chemistry (PEGylation,  
ligand conjugation), bio distribution, penetration rate,  
bioavailability and Individual characteristics (age, sex) (63,  
A large number of nanostructures by passing through  
biological barriers, they can have destructive and toxic effects  
on many human organs such as have the brain, liver, and  
kidney. Another important system that is affected by the toxic  
effects of nanoparticles is reproductive systems. There are  
many evidences that some nanoparticles can pass from the  
reproductive barrier systems such as the blood-testis barrier,  
placental barrier, and epithelial barrier, and then accumulate in  
the testis, epididymis, ovary, and uterus and eventually cause  
damage to these organs. The accumulation of nanoparticles in  
the reproductive system can have adverse effects on sperm and  
oocytes. These adverse effects include: adverse effects on  
quantity, quality, motility and sperm morphology, adverse  
effects on oocytes, detrimental effects on the development of  
primary and secondary follicles, negative effects on the number  
of mature oocytes and their reduction, detrimental effects on  
levels of secreted hormones and changes in sexual behavior.  
Although the exact mechanism of toxicity of nanoparticles on  
reproductive organs has not yet been completely elucidated, it  
is possible that some mechanisms, such as oxidative stress,  
apoptosis, inflammation, and genotoxicity play a role in the  
toxicity of nanoparticles and their destructive effects on the  
reproductive system (41-55) .  
6
4).  
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The main ways in which nanoparticles enter  
the reproductive system  
and  
Dermal  
exposure,  
pulmonary  
exposure,  
gastrointestinal exposure are the major pathways for  
nanoparticles to enter the reproductive system.  
Dermal: Some nanoparticles used in cosmetics, such as nano-  
titanium dioxide, can enter the body through skin absorption.  
Various evidence suggests that the skin absorption rate of  
nanoparticles is very low. In this way, nanoparticles can be  
absorbed through the skin without causing significant toxicity  
(65-70).  
Gastrointestinal: This route is one of the main entry and  
absorption pathways for nanoparticles. Most of the  
nanoparticles that used in food and the drugs that are taken  
orally enter the body through this pathway. The nanoparticles  
mainly enter the bloodstream and secondary organs after  
entering the gastrointestinal tract. The rate of absorption of  
different nanoparticles varies. Different nanoparticles have a  
longer duration in the large intestine and a shorter duration in  
the stomach. After entering and absorbing, nanoparticles are  
distributed through this pathway to various organs, including  
the liver, spleen, and mesenteric lymph nodes (71-74) .  
Lung: Some nanostructures, such as cerium oxide, enter the  
body mainly through inhalation and remain in the lungs. Some  
other nanoparticles enter through inhalation and then enter the  
central nervous system through olfactory neurons (75, 76).  
There are many evidences that nanoparticles are absorbed into  
the bloodstream after entering each of these pathways and  
eventually enter organs such as the liver, spleen, kidney, brain,  
ovaries and testes (76).  
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The reproductive system  
1
.2 The female reproductive system  
The female reproductive system has internal and external  
parts. External sections include labia majora, labia minora,  
Bartholin’s glands, and clitoris. The internal parts also include  
the vagina, uterus, ovaries and fallopian tubes. The most  
important functions of the female reproductive system are:  
oocytes production, which can eventually act as an egg cell and  
play a role in the reproductive process, participation in the  
fertilization process, participation in the implantation process,  
participation in the menstrual cycle And It also produces some  
female sex hormones to maintain the reproductive cycle (56-  
5 Some of the most widely used metal  
nanoparticles and their effect on the  
reproductive system  
5
8).  
5
.1 Titanium dioxide nanoparticles (TiO  
TiO NPs are widely used in medical, diagnostic and  
2
NPs)  
2
.2 The male reproductive system  
2
The male reproductive system also has internal and external  
cosmetic fields. The increasing use of these nanoparticles is  
highly toxic to humans. Some evidence suggests that TiO2 NPs  
lead to damage to follicles. These nanoparticles reduce  
follicular survival and prevent the development and maturation  
of oocyte. TiO2 NPs also have adverse effects on sperm. These  
nanoparticles have an adverse effect on sperm motility. These  
nanoparticles reduce the number of normal sperm but increases  
the number of abnormal sperm. Some other evidence suggests  
that these nanoparticles induce apoptosis in germ cells in the  
testicular mouse (77-81). The table 1 shows some of the effects  
of titanium dioxide nanoparticles on the reproductive system.  
parts. External genitalia include: the penis, scrotum, and  
testicles and the internal genitalia include: epididymis,vas  
deferens, ejaculatoryducts, urethra, seminal vesicles, and  
prostateGland, bulbourethral glands. The most important  
functions of the male reproductive system are: sperm  
production, sperm maintenance and protection. In this device,  
some sex hormones are also produced and secreted to maintain  
the reproductive system (59-62).  
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Table 1: Shows some of the entry routes and adverse effects of TiO NP  
Function  
The entrance route  
Reference  
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J Infertil Reprod Biol, 2020, Volume 8, Issue 3, Pages: 22-32. https://doi.org/10.47277/JIRB/8(3)/22  
Orally  
-
Body weight changes, relative changes in testicular weight and genitals.  
(82)  
Some studies have shown that TiO2 NPs can be found in cytoplasm and nuclei of ovarian cells  
accumulate. Nanoparticles accumulated in the cell can induce apoptosis. In addition, the  
mitochondria and nuclei of ovarian cells were disrupted. Mitochondrial swelling and rupture,  
nuclear chromatin condensation,and irregularity of the nuclear membrane was also observed.  
(83-87)  
Spermatogenesis suppressionThrough alterationsof testicular enzymes and oxidative stress in  
the testes.  
Intragastric  
IP  
(88)  
(89)  
Changes in estrogen and progesterone levels, changes in ovarian tissue, loss of Graafian  
follicles, destruction of follicles wall, reducing the thickness of Granulosa and Thec layers and  
decreased corpus luteum.  
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The direct effect of TiO NPs on ovarian function and consequently ovarian damage, as well  
Intragastric  
Orally  
as these nano particles can cause an imbalance of mineral element distribution and sex (5)  
hormones, decrease fertility or the pregnancy rate and oxidative stress in mice.  
This study suggests that oral administration of TiO NP may alter ovarian tissue. These  
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changes include:Destruction of follicles, reduction of their number, disruption of follicle  
growth, possibility of ovarian cyst formation, decrease in pregnancy rate, decrease in number (90)  
of births, decrease in oocyte number, decrease in fertilization rate, decrease in fetal growth  
before implantation and also increase in malondyaldehyde hormones and estrogen.  
This study showed that nanosized titanium dioxide reduces body weight, relative ovarian  
weight, reduced fertility, changes in sex hormone levels, atretic follicle increases, (91)  
inflammation, and necrosis.  
Intragastric  
2
This study shows that TiO NPs can lead to premature ovarian failure (POF), decreased levels  
of estradiol hormones, progesterone, increased levels of luteinizing hormone, follicle-  
stimulating hormone, anti-Müllerian hormone, thyroid-stimulating hormone, free  
tetraiodothyronine, anti-nuclear antibody and anti-thyroid peroxidase antibody levels in  
Gavage  
(92)  
(93)  
serum. Thus, TiO  
markers lead to POF.  
According to studies, the findings indicate adverse effects of Titanium dioxide nanoparticles  
TiO  NPs) on sperm. These nanoparticles are able to cross the blood-testis barrier,  
2
nanoparticles can through alterations in hormones and autoimmunity  
(
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inflammation, cytotoxicity, and gene expression changes. In addition, these nanoparticles may  
cause damage to sperm DNA.  
2
This study shows that TiO -NP has been shown to be dose-dependent toxicity. These  
nanoparticles at higher doses can induce autophagy and necrosis in Sertoli cells, and (94)  
consequently negatively affected spermatogenic cells and testicular morphology becomes.  
2
.5 Nano-zinc oxide (ZnO)  
sensing, biological imaging, drug delivery, and cancer  
Zinc oxide nanoparticles have  
a
wide variety of  
treatment (104). Although the unique properties of gold  
nanoparticles provide a wide range of biological applications,  
there is evidence that these nanoparticles are toxic at high  
concentrations (105). Some of these adverse effects are listed  
in Table 4.  
applications in various fields. Numerous studies and evidence  
have shown that zinc oxide nanoparticles have adverse effects  
on the production system. These nanoparticles have the ability  
to cross barriers that protect the reproductive system. These  
nanoparticles have adverse effects on the female reproductive  
system and fertility (95-97). Table 2 shows some of the adverse  
effects of zinc oxide nanoparticles on the reproductive system.  
5.5 Iron oxide nanoparticles  
Iron oxide NPs are used in many fields including: as  
contrast agents in imaging Magnetic resonance imaging (MRI),  
drug delivery, etc. One of the other major applications of these  
nanoparticles is environmental remediation applications. Thus  
these nanoparticles are in a greater risk of human exposures  
(106-115). Table 5 shows some of the risks of this nanoparticle  
associated with the reproductive system.  
3
.5 Silver nanoparticles (AgNPs)  
Silver nanoparticles (AgNPs) have been used extensively  
in areas such as antibiotics, textile , wound dressings, medical  
devices, antibacterial, antifungal, anti-cancer, and antigenic  
applications. But along with its diverse development and  
applications, there are potential risks to human health,  
especially for reproductive system. (98, 99). Table 3 shows  
some of these disadvantages and problems.  
6.5 Nickel nanoparticles (Ni NPs)  
Nickel nanoparticles (Ni NPs) are used in a variety of fields  
due to their unique properties. Some of these features include:  
catalysts, high-density magnetic. These nanoparticles can be  
used to treat cancer (116), catalytic (117), biosensor (118),  
nuclear waste, biochemical products, and cells (119, 120).  
These nanoparticles may cause problems for humans. Some  
studies and evidence have shown that these nanoparticles may  
cause apoptosis, oxidative stress, and DNA damage.  
4
.5 Gold nanoparticles  
Gold nanoparticles have the wide variety of applications.  
Some researchers divide the biological applications of these  
nanoparticles into four main classes: labeling, delivering,  
heating, and sensing (100). These nanoparticles can be used in:  
gene delivery (101), PPTT (102), catalyzed (103), chemical  
Table 2: Shows some of the entry routes and adverse effects of zinc oxide nanoparticles on the reproductive system  
The entrance route Function Reference  
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