Introduction
Nanotechnology has made great advances in the manipulation of nanomaterials with different shapes, sizes and functionalization. In general, nanoparticles (NPs) have many applications, such as targeted therapy, drug delivery, gene delivery, detection and diagnosis, biomarker mapping, and molecular imaging (Homberger and Simon, Reference Homberger and Simon2010; Zanella, Reference Zanella2012; Sanna et al., Reference Sanna, Pala and Sechi2014; Bayda et al., Reference Bayda, Hadla, Palazzolo, Kumar, Caligiuri, Ambrosi, Pontoglio, Agostini, Tuccinardi, Benedetti, Riello, Canzonieri, Corona, Toffoli and Rizzolio2017; Rizvi and Saleh, Reference Rizvi and Saleh2018). In this context, nanomedicine is nanotechnology applied in the medical field to diagnose, treat and prevent diseases (Doroudian et al., Reference Doroudian, O’ Neill, Mac Loughlin, Prina-Mello, Volkov and Donnelly2021).
The NPs can solubilize and transport insoluble compounds and are considered promising vehicles for delivering drugs to disease sites (Moses et al., Reference Moses, Demessie, Taratula, Korzun, Slayden and Taratula2021). Additionally, they protect unstable drugs from hydrolysis, oxidation, or other degradative processes in systemic circulation (Pavitra et al., Reference Pavitra, Dariya, Srivani, Kang, Alam, Sudhir, Kamal, Raju, Han, Lakkakula, Nagaraju and Huh2021; Wang et al., Reference Wang, Wang, Zhu, Wang, Qing, Zhang, Liu and Liang2021). In recent years, nanomedicine has offered new opportunities to control the adverse side effects of drugs (Doroudian et al., Reference Doroudian, MacLoughlin, Poynton, Prina-Mello and Donnelly2019) and to improve treatments of cancer, infectious, ophthalmic and neurological diseases (Shao et al., Reference Shao, Zhou, Si, Tang, Liu, Wang, Gao, Wang, Xu and Shen2017). Traditional drugs, without association with NPs, have some limitations when they are in the biological environment, for example, they do not have a special selectivity, do not go through some biological barriers, and need to be at the proper concentration and time of administration. Alternatively serious side effects can arise. Conversely, nanomedicines have better bioavailability, can be conjugated with particles and increase specificity for their therapeutic targets, are used at lower concentrations and, consequently, may have low toxicity (Li et al., Reference Li, Lu, Liang and Xu2019, El-Desoky et al., Reference El-Desoky, Hashem, Gonzalez-Bulnes, Elkomy and Abo-Elezz2021). For example, cisplatin-prodrug micelles had reduced multiorgan toxicity, optimized biodistribution, and enhanced antitumor potency, which optimized the delivery of cisplatin into tumour cells and reduced, in 80.4%, the growth of breast cancer xenografts in vivo (Li et al., Reference Li, Lu, Liang and Xu2019).
Specifically in relation to reproductive disorders, polycystic ovary syndrome, azoospermia, endometriosis, as well as acute ovarian failure in patients undergoing chemotherapy are some examples of negative effects on fertility (Letourneau et al., Reference Letourneau, Ebbel, Katz, Oktay, McCulloch, Ai, Chien, Melisko, Cedars and Rosen2012; Vannuccini et al., Reference Vannuccini, Clifton, Fraser, Taylor, Critchley, Giudice and Petraglia2016). As a consequence; many patients with reproductive disorders and/or infertility require assisted reproductive technologies (ART). Recently, Silva et al. (Reference Silva, Barroso, Nascimento, Figueira, Azevedo, Silva and Santos2021) reported the applicability of NPs to deliver antioxidants and hormones to ovarian follicles, oocytes and embryos in vitro. In addition, NPs have been used to improve the selection of sperm (buffaloes: Bisla et al., Reference Bisla, Rautela, Yadav, Saini, Singh, Ngou, Kumar, Ghosh, Kumar, Bag, Mahajan and Srivastava2021), semen sexing (donkey: Domínguez et al., Reference Domínguez, Moreno-Irusta, Castex, Bragulat, Ugaz, Clemente, Giojalas and Losinno2018), and cryopreservation of human semen (Isaac et al., Reference Isaac, Kumari, Nair, Urs, Salian, Kalthur, Adiga, Manikkath, Mutalik, Sachdev and Pasricha2017). The effects of NPs on the reproductive system depend on various characteristics such as dose, nature and surfaces of NPs, as well as association with other substances (Asati et al., Reference Asati, Santra, Kaittanis and Perez2010).
This review discusses the potential of NPs for the treatment of reproductive disorders related to spermatogenesis and ovarian follicle development, for the regulation of levels of reproduction-associated hormones, as well as for the diagnosis and treatment of uterine disease, such as endometriosis. Concerns about the clinical use of NPs are also highlighted.
Nanotechnology and therapeutic applications of nanoparticles
The NPs vary in size from 1 to 1000 nm, but for nanomedical applications the preferential size is less than 100 nm (Biswas et al., Reference Biswas, Islam, Choudhury, Mostafa and Kadir2014; Shao et al., Reference Shao, Zhou, Si, Tang, Liu, Wang, Gao, Wang, Xu and Shen2017; Rizvi and Saleh, Reference Rizvi and Saleh2018). NPs with sizes between 1 nm and 1000 nm are classified as colloidal particles, i.e. they are suspended in a fluid phase (Biswas et al., Reference Biswas, Islam, Choudhury, Mostafa and Kadir2014). Core/shell NPs can be categorized according to the materials of the core, i.e. organic and inorganic substances. There are four combinations considering the core and the shell: inorganic/organic, inorganic/inorganic, organic/inorganic, and organic/organic (Chiozzi and Rossi, Reference Chiozzi and Rossi2020). The coating can bring advantages, such as less cytotoxicity, an increase in cytocompatibility, thermal stability, etc., and makes it possible to control the release of substances from the core (Liu et al., Reference Liu, Hou, Zhang and Wu2010). In this sense, Doroudian et al. (Reference Doroudian, MacLoughlin, Poynton, Prina-Mello and Donnelly2019) reported that NPs are able to transport and deliver therapeutic agents to target organs and help to treat various diseases.
Organic nanomaterials incorporate compatible biopolymers such as carbohydrates, proteins and lipids typically found in human cells (Bhardwaj and Kaushik, Reference Bhardwaj and Kaushik2017). Metallic and inorganic nanomaterials, including gold, silver, platinum, iron and cobalt (Kaushik and Dixit, Reference Kaushik and Dixit2016), are used in phototherapy (Srinivasan et al., Reference Srinivasan, Bhardwaj, Nagasetti, Fernandez-Fernandez and McGoron2016), optogenetics immunomodulation (He et al., Reference He, Zhang, Ma, Tan, Li, Zang, Wu, Jing, Fang, Zhou, Wang, Huang, Hogan, Han and Zhou2015) and diagnostics (Kaushik and Dixit, Reference Kaushik and Dixit2016). Nanostructures with combined properties of two or more inorganic nanomaterials are the first imaging options to improve diagnosis (Dadfar et al., Reference Dadfar, Roemhild, Drude, von Stillfried, Knüchel, Kiessling and Lammers2019) and to complement chemotherapy (Srinivasan et al., Reference Srinivasan, Bhardwaj, Nagasetti, Fernandez-Fernandez and McGoron2016). Some NPs such as liposomes, polymeric micelles, dendrimers and organic and inorganic nanomaterials are widely used for drug delivery and currently can be used in the diagnosis of diseases (Wang et al., Reference Wang, Luo, Wu, Zhang, Liu, Xu, Johnson and Sun2017a, Reference Wang, Luo, Wu, Zhang, Liu, Xu, Johnson and Sun2017b, Reference Wang, Ho, Tsatskis, Law, Zhang, Zhu, Dai, Wang, Tan, Hopyan, McNeill and Sun2019). Silver NPs are commonly used in the medical field due to their safety for in vivo applications and have excellent anti-inflammatory, antibacterial and anti-angiogenic properties (Pourali and Yahyaei, Reference Pourali and Yahyaei2016). Additionally, some studies have shown that NPs with lipid constitutions are well accepted in the body and are already used in clinical practice (Gonzaga et al., Reference Gonzaga, Botelho, Queiroz, Fechine, Freire, Azevedo, Morais, Ruela, Lyra, Gomes, Quintans Júnior and Freire2012; Ahmad et al., Reference Ahmad, Banala, Kushwaha, Karvande, Sharma, Tripathi, Verma, Trivedi and Mishra2016; Prakapenka et al., Reference Prakapenka, Quihuis, Carson, Patel, Bimonte-Nelson and Sirianni2020). Tissue biological barriers can be infiltrated by NPs allowing their penetration into vital organs, and this versatility of translocation can affect their use. Therefore, safety analysis, judicious control over the size of NPs, and the functionality and stability of these nanostructures are necessary to ensure safe biomedical applications in vivo.
In recent decades, understanding delivering mechanisms of nanostructured drugs has been refined both in the therapeutic field and in diagnostic imaging, improving the accuracy of diagnosis and treatment of diseases (Patra et al., Reference Patra, Das, Fraceto, Campos, Rodriguez-Torres, Acosta-Torres, Diaz-Torres, Grillo, Swamy, Sharma, Habtemariam and Shin2018). For example, the combination of paclitaxel and cisplatin, which together have an anti-lung cancer effect when transported in lipid–polymer hybrid NPs of biodegradable polymers and lipids, has a better effect when compared with free drugs at the same concentration (Wu et al., Reference Wu, Zhang, Wang, Chen, Zhang, Deng, Tang, Mao and Wang2020). This system combines the advantages of liposomes and polymer nanoparticles, including superior biocompatibility, high drug loading, sustained release, and easy modification of targeting molecules (Zhang et al., Reference Zhang, Zhao, Sun, Huang and Li2018). Other anticancer drugs have also been successfully formulated using nanomaterials, such as dimethazone, doxorubicin and 5-fluorouracil (Shafei et al., Reference Shafei, El-Bakly, Sobhy, Wagdy, Reda, Aboelenin, Marzouk, El Habak, Mostafa, Ali and Ellithy2017; Sun et al., Reference Sun, Chen, Zhou, Guo, Fan, Guo, Zheng and Chen2017; Rençber et al., Reference Rençber, Aydın Köse and Karavana2020). These nanodrugs are intelligent systems that can be adapted for the delivery of drugs directly at the specific site to treat a tumour or to block certain cellular receptors to inhibit the progression of atherosclerosis (Yu et al., Reference Yu, Bajorek, Jayade, Miele, Mirza, Rogado, Sundararajan, Faig, Ferrage and Uhrich2017). In addition to these applications, nanomaterials are used in bioactive dressings, suture threads and medical devices with antimicrobial properties (Kamaly et al., Reference Kamaly, Yameen, Wu and Farokhzad2016). The possibility of manipulation of these nanodrugs allows more effective doses to be administered in therapies, enabling a decrease in the frequency of administration by reducing unwanted side effects. Garbuzenko et al. (Reference Garbuzenko, Kbah, Kuzmov, Pogrebnyak, Pozharov and Minko2019) demonstrated that drugs used for the treatment of cystic fibrosis (lumacaftor and ivacaftor) encapsulated in lipid nanocarriers significantly reduced the area of fibrous tissues.
The development of new techniques using nanostructures and new biomaterials with specific sizes and controlled synthesis and stability is an area of research in constant evolution that has great potential to optimize treatments of infertility-related disorders.
Potential of nanoparticles for therapies of spermatogenesis disorders
The advancement of nanoscience has made it possible to achieve the production of new nanostructures and therefore incorporate new properties and apply them in reproductive science and spermatogenesis (Bhat et al., Reference Bhat, Nazir, Ahmad, Pathakota, Chanu, Goswami, Sundaray and Sharma2018; Feugang et al., Reference Feugang, Rhoads, Mustapha, Tardif, Parrish, Willard and Ryan2019; Kim et al., Reference Kim, Kim, Kim, Cho, Shin, Yoon, Lee, Baek, Woo and Ryoo2020). Depending on their size, one of the characteristics of NPs is their ability to cross biological barriers, including the blood–testis barrier (Ong et al., Reference Ong, Lee, Cai, Liu, Ding, Yung, Bay and Baeg2016; Olugbodi et al., Reference Olugbodi, David, Oketa, Lawal, Okoli and Mtunzi2020). Some studies have reported that NPs alone, or carriers of bioactive molecules, can be used for the treatment of disorders related to spermatogenesis and infertility (Ong et al., Reference Ong, Lee, Cai, Liu, Ding, Yung, Bay and Baeg2016; Bhat et al., Reference Bhat, Nazir, Ahmad, Pathakota, Chanu, Goswami, Sundaray and Sharma2018; El-Behery et al., Reference El-Behery, El-Naseery, El-Ghazali, Elewa, Mahdy, El-Hady and Konsowa2019; Kim et al., Reference Kim, Kim, Kim, Cho, Shin, Yoon, Lee, Baek, Woo and Ryoo2020). After the collection of semen, Feugang et al. (Reference Feugang, Rhoads, Mustapha, Tardif, Parrish, Willard and Ryan2019) reported that NPs have the potential to be used in clinical practices to improve sperm-related biotechnologies such as sperm-mediated gene transfer, sperm sorting, sex-sorting, and cryopreservation. In addition, El-Behery et al. (Reference El-Behery, El-Naseery, El-Ghazali, Elewa, Mahdy, El-Hady and Konsowa2019) demonstrated that zinc oxide nanoparticles (ZnO NPs) protected the testes of rats from damage caused by diabetes mellitus. These authors reported the antioxidant potential of these NPs in reversing testicular impairment and, consequently, spermatogenesis.
Bhat et al. (Reference Bhat, Nazir, Ahmad, Pathakota, Chanu, Goswami, Sundaray and Sharma2018) produced chitosan-coated eurycomanone NPs and showed an increased reproductive performance in males due to its testosterone-supporting steroid activity, aided by the controlled release of the carrier molecular and decreased toxicity. Recently, Kim et al. (Reference Kim, Kim, Kim, Cho, Shin, Yoon, Lee, Baek, Woo and Ryoo2020) successfully used cationic lipid-coated fibre NPs for in vivo delivery of the intratesticular protein peptidyl-prolyl-isomerase 1, which restored fertility in rats with impaired spermatogenesis. In addition, Afshar et al. (Reference Afshar, Aliaghaei, Nazarian, Abbaszadeh, Fathabadi, Abdi, Raee, Aghajanpour, Norouzian and Abdollahifar2021) reported that the association of iron oxide NPs with curcumin promoted an antioxidant response that improved germ cell proliferation and sperm differentiation in mice that had azoospermia caused by long-term scrotal hyperthermia.
There are also new perspectives on using NPs as a contraceptive. de Brito and Lima (Reference de Brito, Lima, Ansa, Moya, Morais, Azevedo and Lucci2020) showed that intratesticular injection of silver NPs decreased the percentage of motile sperm and increased abnormal sperm in rats. These effects on sperm were reversible and no hepatic bioaccumulation was reported (de Brito et al., Reference de Brito, Lima, Ansa, Moya, Morais, Azevedo and Lucci2020). In another study using gold NPs associated with Carica papaya extract, Mohammad (Reference Mohammad2019) also highlighted that these NPs can be used as an innovative male contraceptive, without compromising body weight, haematological indices, as well as weight of reproductive and vital organs in rats. These authors reported that complete sterility was achieved after 30 days of treatment (50 mg/kg body wt./day oral), i.e. the testes exhibited vacuolization in Sertoli cells, disorganization of germinal epithelium, and eruption of germ cells in treated groups that indicated cessation of spermatogenesis at the level of primary spermatocytes and spermatids. Therefore, NPs have great potential to improve various aspects of spermatogenesis and disorders related to male reproduction. For in vivo applications in humans, however, clinical trials are required beforehand to avoid possible reprotoxic effects. Table 1 shows a summary of the effects of NPs in males.
Table 1. Therapeutic potential of NPs in testes, ovaries, uterus, placenta and embryos
Potential of nanoparticles for therapies for ovarian disorders
Various studies have shown that the functionalization of NPs with plant extracts may increase their potential to be used to solve female reproductive disorders (Sak et al., Reference Sak, Soydinc, Sak, Evsen, Alabalik, Akdemir and Gul2013; Behroozi-Lak et al., Reference Behroozi-Lak, Ebrahimpour, Zarei, Pourjabali, Farhad and Mohaddesi2018; Fatemi Abhari et al., Reference Fatemi Abhari, Khanbabaei, Hayati Roodbari, Parivar and Yaghmaei2020; Majidi et al., Reference Majidi, Rezaei, Zare, Dashti, Shafaroudi and Abediankenari2021). Curcumin NPs minimized ischaemia-reperfusion injury in ischaemia-exposed ovarian tissue through the antioxidant and anti-inflammatory action of curcumin, which helped to preserve fertility in rats (Behroozi-Lak et al., Reference Behroozi-Lak, Ebrahimpour, Zarei, Pourjabali, Farhad and Mohaddesi2018). It has been reported in other studies in murine models that curcumin administration led to a decrease in oxidative stress and may have inhibitory actions on inflammatory transcription factors (Sak et al., Reference Sak, Soydinc, Sak, Evsen, Alabalik, Akdemir and Gul2013; Fatemi Abhari et al., Reference Fatemi Abhari, Khanbabaei, Hayati Roodbari, Parivar and Yaghmaei2020). Recently, Fatemi Abhari et al. (Reference Fatemi Abhari, Khanbabaei, Hayati Roodbari, Parivar and Yaghmaei2020) evaluated the beneficial effects of curcumin-loaded superparamagnetic iron oxide NPs in polycystic ovaries of mice. They revealed that animals treated with curcumin NPs had a decrease in expression of BCL2 Associated X (BAX) and Caspase 3 protein, an increase in the levels of B-cell lymphoma 2 (Bcl2), and consequently reduced apoptosis in granulosa cells. In other treatment conditions, diabetic rats co-treated with l-carnitine and zinc oxide NPs had increased sex hormone levels and antioxidant activity, in addition to decreased lipid peroxidation (Majidi et al., Reference Majidi, Rezaei, Zare, Dashti, Shafaroudi and Abediankenari2021), emphasizing the potential of simultaneous use of these two components to preserve ovarian function. The potential beneficial effects of these NPs are through mechanisms such as the suppression of cell apoptosis and reduction of oxidative stress. Recently, El-Desoky et al. (Reference El-Desoky, Hashem, Gonzalez-Bulnes, Elkomy and Abo-Elezz2021) showed a positive role of Moringa leaf ethanolic extract (MLEE) as a supplement in heat-stress tolerance, metabolism and the reproductive performance of rabbit does bred under natural heat-stress conditions. Additionally, these authors showed that the use of the nanoencapsulated MLEE allowed an 80% reduction in the optimal dose without affecting the efficiency of the treatment.
Regarding the effects of NPs on the regulation of reproduction-associated hormones, lipid-based NPs are an alternative for hormonal treatment of menopausal women, as they are well accepted in the body and present a lower risk of toxicity compared with other types of NPs (Gonzaga et al., Reference Gonzaga, Botelho, Queiroz, Fechine, Freire, Azevedo, Morais, Ruela, Lyra, Gomes, Quintans Júnior and Freire2012; Ahmad et al., Reference Ahmad, Banala, Kushwaha, Karvande, Sharma, Tripathi, Verma, Trivedi and Mishra2016; Prakapenka et al., Reference Prakapenka, Quihuis, Carson, Patel, Bimonte-Nelson and Sirianni2020). Recently, Hashem and Gonzalez-Bulnes (Reference Hashem and Gonzalez-Bulnes2021) reported that GnRH-chitosan-tripolyphosphate nanoparticles NPs could be an alternative to equine chorionic gonadotropin (eCG) for stimulating ovarian follicles growth before artificial insemination in rabbits. They showed the ability of these NPs to induce greater follicular growth and formation of ovulation points than equine chorionic gonadotropin. Prakapenka et al. (Reference Prakapenka, Quihuis, Carson, Patel, Bimonte-Nelson and Sirianni2020) evaluated the effects of oestrogen-laden poly(lactic-co-glycolic acid) (PLGA) NPs in ovariectomized middle-aged rats and showed that PLGA-encapsulated NPs improved bioavailability and hormonal biological activity. PLGA-NPs loaded with estradiol also improved the levels of oestrogen in murine plasma (Mittal et al., Reference Mittal, Sahana, Bhardwaj and Ravi Kumar2007). Other compounds, such as quercetin, can also be used and transported by solid lipid NPs to improve their bioavailability. Quercetin inhibits bone loss in ovariectomized rats and can be a preventive option to control postmenopausal osteoporosis (Ahmad et al., Reference Ahmad, Banala, Kushwaha, Karvande, Sharma, Tripathi, Verma, Trivedi and Mishra2016).
It is noteworthy that the NPs increased hormone bioavailability when used as carriers (Mittal et al., Reference Mittal, Sahana, Bhardwaj and Ravi Kumar2007; Gonzaga et al., Reference Gonzaga, Botelho, Queiroz, Fechine, Freire, Azevedo, Morais, Ruela, Lyra, Gomes, Quintans Júnior and Freire2012; Ahmad et al., Reference Ahmad, Banala, Kushwaha, Karvande, Sharma, Tripathi, Verma, Trivedi and Mishra2016; Prakapenka et al., Reference Prakapenka, Quihuis, Carson, Patel, Bimonte-Nelson and Sirianni2020). Therefore, the association of hormones and other compounds with NPs opens new perspectives for the minimization of the menopausal effects in women or in young patients with reproductive problems after undergoing cancer treatments. The effects of NPs on the female reproductive system are shown in Table 1.
Potential of nanoparticles for therapies of uterine diseases
Wang et al. (Reference Wang, Chen, Yang, Wang, Shen, Sun, Guo and Zhang2016) reported that negatively charged gold NPs in association with glutathione displayed lower excretion and increased tumour uptake, and exhibited great therapeutic potential for U14 cervical cancer in mice models, which may contribute to reducing the adverse effects on reproductive organs and gametes. Clinical investigations in the diagnosis and treatment of endometriosis have also been successfully performed using NPs of a lipid nature (Moses et al., Reference Moses, Demessie, Taratula, Korzun, Slayden and Taratula2021). These NPs have the ability to transport therapeutic agents to target tissues, are absorbed and show low toxicity (Graziani et al., Reference Graziani, Vital, Morikawa, Van Eyll, Fernandes Junior, Kalil Filho and Maranhão2017; Bedin et al., Reference Bedin, Maranhão, Tavares, Carvalho, Baracat and Podgaec2019). According to Savla et al. (Reference Savla, Garbuzenko, Chen, Rodriguez-Rodriguez and Minko2014), endometriotic tissues have overexpression of low-density lipoprotein (LDL) receptors to take up LDL cholesterol into cells to meet rising cholesterol demands. Therefore, lipid-based NPs can be taken up by the tissues of patients with ovarian cancer and deep endometriosis (Moses et al., Reference Moses, Demessie, Taratula, Korzun, Slayden and Taratula2021). Moses et al. (Reference Moses, Demessie, Taratula, Korzun, Slayden and Taratula2021) also reported that PEG-based polymeric NPs efficiently accumulate in endometriotic tissues after intravenous injection into mice bearing sub-cutaneous rhesus macaque endometriotic xenografts. Yuan et al. (Reference Yuan, Ding, Meng, Lu, Shao, Zhang, Yuan and Hu2017) demonstrated that, after tail-vein injection, three different types of nanostructured lipid NPs (chitosan, oligosaccharide-g-stearic acid, and polymer micelles) were detected in human endometriotic tissue subcutaneously implanted in mice. These data indicated that systemically injected NPs can accumulate in endometriotic lesions. Studies in rats and mice have also shown enhanced magnetic resonance images in uterine tissue of rats using ultra-small superparamagnetic iron oxide NPs and improved detection of uterine lesions using magnetic oxide NPs functionalized with hyaluronic acid (Hue et al., Reference Hue, Lee, Jon, Nam, Yun, Kim and Lee2013; Zhang et al., Reference Zhang, Li, Sun, Hu, Zhang, Shen and Shi2014).
Regarding the application of NPs during pregnancy, it was previously reported that NPs could reach the placenta, and embryos and be present in the newborn offspring of females who received NPs during pregnancy and lactation (Melnik et al., Reference Melnik, Buzulukov, Demin, Demin, Gmoshinski, Tyshko and Tutelyan2013). Austin et al. (Reference Austin, Umbreit, Brown, Barber, Dair, Francke-Carroll, Feswick, Saint-Louis, Hikawa, Siebein and Goering2012) showed that when pregnant rats were injected with silver NPs (50 nm), embryos received a very small fraction of NPs. According to these authors, this should be attributed to the visceral yolk sac that seems to minimize the transfer of NPs to embryos, which showed no morphological changes. Conversely, Rattanapinyopituk et al. (Reference Rattanapinyopituk, Shimada, Morita, Sakurai, Asano, Hasegawa, Inoue and Takano2014) reported that gold NPs penetrated the placental cells of mice after intravenous administration and suggested that the mechanism responsible for this process is endocytosis mediated by clathrin and caveolin proteins. No toxic damage to the placenta, maternal and fetal organs was observed. Refuerzo et al. (Reference Refuerzo, Godin, Bishop, Srinivasan, Shah, Amra, Ramin and Ferrari2011) showed that pregnant rats that were administered with silicon nanovectors (greater than > 800 nm) did not penetrate the placenta and, consequently, did not reach the fetus, remaining in the maternal circulation. They suggested that these larger NPs may serve as protectors of fetal exposure when transporting drugs that are harmful to the fetus, but needed by mothers during pregnancy. The effects of NPs on the placenta, uterus and embryos are summarized in Table 1.
Concerns about the clinical use of NPs
For clinical use of NPs, some important factors must be taken into account, such as biodistribution, toxicity, therapeutic potential in pathologies, compatibility and bioaccumulation of nanostructures. The size, shape, type of production, dose, and route of exposure are some factors that affect the nanotoxicity of NPs (Ma et al., Reference Ma, Yang, Wang, Liu, Jin, Li and Liang2018).
Considering the entry routes of NPs into the reproductive system, they can be classified as direct, when used as a drug carrier for targeted therapies (nanocarriers), or indirect, when translocation and absorption occur due to exposure to NPs present in cosmetics, food additives, biomedical ceramics and implanted biomaterial paints, wastewater treatment, and sterilization (Wang et al., Reference Wang, Song, Wu, Zhang, Chen and Shao2018). Leso et al. (Reference Leso, Fontana, Marinaccio, Leopold, Fanali, Lucchetti, Sgambato and Iavicoli2018) showed that exposure to palladium NPs, due to wide industrial application, reduced estradiol and testosterone levels but increased luteinizing hormone levels in rats, causing abnormal reproductive axis function. The authors believe that the effects are due to higher doses and physicochemical characteristics, such as particle size. Regarding the accumulation of NPs in fetal tissues, Pourali et al. (Reference Pourali, Nouri, Ameri, Heidari, Kheirkhahan, Arabzadeh and Yahyaei2020) demonstrated that biologically produced silver NPs (30 nm) administered to pregnant rats, depending on the dose, could cross the placenta and accumulate in different organs of the offspring after birth. Dănilă et al. (Reference Dănilă, Berghian, Dionisie, Gheban, Olteanu, Tabaran, Baldea, Katona, Moldovan, Clichici, David and Filip2017) reported that although maternal exposure to the nonbiologically produced NPs induced nitro-oxidative stress and apoptosis in the hippocampus of the rat offspring, these effects were lower for the NPs that were produced using the herb extract (Sambucus nigra).
Studies using male rats and mice as animal models revealed that NPs of titanium dioxide (TiO2) and graphene oxide (GO) caused damage to testicular tissue and sperm deterioration (Morgan et al., Reference Morgan, Ibrahim and Noshy2017; Nirmal et al., Reference Nirmal, Awasthi and John2017). Fathi et al. (Reference Fathi, Hoseinipanah, Alizadeh, Assari, Moghimbeigi, Mortazavi, Hosseini and Bahmanzadeh2019) reported reduced motility and viability, in addition to reducing the number of testicular tubules, sperm cells, Sertoli cells and Leydig cells. Under in vivo conditions, there was an increase in the expression of pro-inflammatory cytokines and significant loss in germ cells in female and male mice (Han et al., Reference Han, Jeong, Gurunathan, Choi, Das, Kwon, Cho, Park, Seo, Park and Kim2016). Some studies have also shown that NPs could accumulate in ovarian and uterine tissues and trigger apoptotic pathways by the activation of caspases (Almeida et al., Reference Almeida, Chen, Foster and Drezek2011; Mohammad Hosseini et al., Reference Mohammad Hosseini, Hossein Moshrefi, Amani, Vahid Razavimehr, Hasan Aghajanikhah, Sokouti and Babaei Holari2019; Kuang et al., Reference Kuang, Zhang, Yang, Aguilar and Xu2021). Depending on their characteristics, NPs can harm germ cells by several mechanisms, such as oxidative stress, cell apoptosis, DNA damage and bioaccumulation in murine (Zhai et al., Reference Zhai, Ge, Wang, Sun, Ma, Liu, Zhao, Feng, Dyce, De Felici and Shen2018; Fatemi Abhari et al., Reference Fatemi Abhari, Khanbabaei, Hayati Roodbari, Parivar and Yaghmaei2020) and human species (Wang et al., Reference Wang, Luo, Wu, Zhang, Liu, Xu, Johnson and Sun2017a). Zhai et al. (Reference Zhai, Ge, Wang, Sun, Ma, Liu, Zhao, Feng, Dyce, De Felici and Shen2018) injected zinc oxide NPs intravenously into pregnant mice and reported disturbances in fetal oogenesis and follicular development due to an increased percentage of secondary follicles, suggesting accelerated follicular development. In rats, titanium dioxide NPs accumulated in the ovaries and caused an imbalance of steroid hormones due to apoptosis in granulosa cells (Tassinari et al., Reference Tassinari, Cubadda, Moracci, Aureli, D’Amato, Valeri, De Berardis, Raggi, Mantovani, Passeri, Rossi and Maranghi2014). Gao et al. (Reference Gao, Ze, Li, Zhao, Zhang, Sheng, Hu, Gui, Sang, Sun, Cheng, Cheng, Wang, Tang and Hong2012) showed that mice ovaries treated with titanium dioxide NPs had 223 genes of known function upregulated, while 65 ovarian genes were downregulated. Due to their characteristics, titanium dioxide NPs are not commonly used for drug delivery. The toxicity of titanium dioxide NPs is associated with their physicochemical properties, such as size, surface area, and crystal phase (Jiang et al., Reference Jiang, Oberdörster, Elder, Gelein, Mercer and Biswas2008).
It is known that NPs can accumulate in various organs, therefore it is very important to study the consequences (Larson et al., Reference Larson, Carvan, Teeguarden, Watanabe, Taya, Krystofiak and Hutz2014; Abudayyak et al., Reference Abudayyak, Öztaş, Arici and Özhan2017; Luyts et al., Reference Luyts, Van Den Broucke, Hemmeryckx, Poels, Scheers, Casas, Vanoirbeek, Nemery and Hoet2018; Teleanu et al., Reference Teleanu, Chircov, Grumezescu, Volceanov and Teleanu2018). Several in vivo studies have demonstrated NP accumulation in different organs such as the lungs, liver, brain, kidneys and spleen (Dumková et al., Reference Dumková, Smutná, Vrlíková, Le Coustumer, Večeřa, Dočekal, Mikuška, Čapka, Fictum, Hampl and Buchtová2017; Lebedová et al., Reference Lebedová, Hedberg, Odnevall Wallinder and Karlsson2018; Luyts et al., Reference Luyts, Van Den Broucke, Hemmeryckx, Poels, Scheers, Casas, Vanoirbeek, Nemery and Hoet2018; Moradi et al., Reference Moradi, Ziamajidi, Ghafourikhosroshahi and Abbasalipourkabir2019). Smaller NPs can remain in the tissues for long periods, causing some degree of toxicity and damage to biological structures (Pietroiusti et al., Reference Pietroiusti, Magrini and Campagnolo2014). In vivo experimental data suggested that accumulated NPs participate in mechanisms that directly and indirectly induce oxidative stress, which in turn causes inflammation in tissues through the response of inflammatory cells and may also cause physical damage to cells by mimicking native molecules and, finally, DNA damage (reviewed by Pietroiusti et al., Reference Pietroiusti, Magrini and Campagnolo2014). These adverse effects of NPs, however, can be minimized by altering the composition, size, and association of NPs with other substances.
Final considerations
The development of nanomaterials with specific size, shape, ligand density, and charge certainly will contribute to the next generation of therapies to solve fertility problems in humans. Due to the great diversity and versatility of NPs, bioaccumulation and toxicity in reproductive organs and organs related to their metabolization can occur, and special attention is still required to avoid their toxicological effects. Changing the shape, surface and size of NPs allows the formation of NPs with the desired properties, but without a toxic effect. Identifying how the size, shape, and chemistry of NPs influence cells is very important for their redesign to potentiate their beneficial effects. Certainly, understanding the behaviour of NPs and their interactions with biological compounds is crucial for safe implementation in clinical practice.
Data availability
All data searched in this study are included in this publication.
Acknowledgements
We thank the authors and colleagues at the Laboratory of Biotechnology and Physiology of Reproduction (LABIREP), the Nucleus of Research in Animal Experimentation (NUPEX) and the Laboratory of Materials Engineering and Simulation of Sobral (LEMSS), Federal University of Ceará – UFC, Sobral – CE, for their research support. The authors also thank A.W.B. Silva for their suggestions.
Financial support
This research was supported by grants from the National Council for Scientific and Technological Development (CNPq, Brazil) and Coordination for the Improvement of Higher Education Personnel (CAPES). J.R.V. Silva is an investigator for CNPq (grant number 308737/2018-0). P.A.A. Barroso is a recipient of a scholarship from CAPES, Brazil.
Competing interests
The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific study.
Ethics standard
This review article examines past studies and the references used in the text.
