Document Type : Review Paper


1 Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran

2 Iranian Environmental Mutagen Society (IrEMS), Tehran, Iran


The etiological factors for increased risk of endocrine and reproductive disorders remain largely unclear but huge number of data from in vitro, in vivo and epidemiological studies, support the association of their incidence with long term exposure to endocrine disrupting chemicals /agrochemicals in the modern world. Engineered Nanomaterials (ENMs) could be considered as new alternatives to overcome the environmental challenges of endocrine disrupting pesticides and fertilizers and to reduce human health risks of cancer and endocrine toxicity based on their unique physicochemical properties. Carbon nanotubes (CNTs) are the initiative members of the big family of ENMs used for developing “Nanotechnology Based Agrochemical” but despite remarkable detoxifying effects mediated by CNTs, a number of controversies and key questions address the toxicity and endocrine disrupting properties of these authoritative agents which may introduce to the global markets new generation of as nanofertilizers ,nanoadsorbents and nanopesticides soon .The actual issue stems from limited number of studies in valid toxicology models on CNTs related endocrine disruption and absence of systematic reviews on CNTs exposure-mediated endocrine health hazards especially with respect to epidemiological and human data. In this direction this systematic review focused on the following sub-topics: (1) an overview on CNTs applications as novel agrochemicals (2) environmental risks and benefits of CNTs 3) toxicokinetic and toxicodynamic of CNTs (4) contribution of CNTs in pathogenesis of obesity, diabetes and cardiovascular effects 4) evidence on the involvement of CNTs in developmental and reproductive toxicities from in vitro and in vivo studies (5) conclusions and perspectives.



Endocrine-disrupting chemicals (EDCs) comprise a huge number of synthetic or natural chemicals with industrial, agricultural, pharmaceutical, cosmetic, and hygienic applications. They mimic the activities of natural hormones through lifetime dietary intakes, inhalational exposures, or other possible routes of administration [1] . Extensive increase in the incidence and prevalence of non-infectious environmental induced diseases e.g. breast cancer [2] prostate cancer [3], infertility [4] reproductive disorders [5], congenital abnormalities [6], neurodegenerative diseases [7]and immune dysfunctions [8] , could be the consequence of massive use of EDCs over the past 50 years [9] Fig. 1 describes some of the identifiedhuman health effects of EDCs in both genders.

Most of the agrochemicals (e.g. pesticides and fertilizers) have endocrine-disrupting properties based on their anti-androgenic and/or estrogenic effects [10] Nowadays massive use of pesticides and fertilizers in the chain of food production/preservation and uncontrolled human exposure to these hazardous chemicals, have become a very big challenge for global health systems. The annual estimated cost of uncontrolled exposure to EDCs was determined as $340 billion (2·33% of GDP) in the United States and €163 billion in European Union (EU) (1·28%) due to health-care costs and lost productivity but this cost estimation is limited to the present generations, not to the intergenerational and trans-generational epigenetic inheritance [11]. The structural diversity of agrochemicals as well as their presence in most environmental sources at undetectable levels by conventional analytical methods, bioaccumulation, biopersitance, and unknown metabolic fate, make the environmental detection and risk assessment of endocrine disrupting agrochemicals more complicated.

Research into nanotechnology applications in the development of novel agrochemicals in the form of “nano fertilizers”, “nano adsorbents” and “nano pesticides”to overcome current health challenges of routine agrochemicals (e.g. organophosphates, carbamates, organochlorines, synthetic pyrethroids) and improvement of crop protection, has become increasingly popular over the past decade. Unfortunately, a large number of risk assessment studies on engineered nanomaterials have characterized the endocrine-disrupting properties for CNTs because they mimic the natural body hormones and interact with hormone receptors in humans and wildlife [12]. Therefore several controversies and key questions address endocrine disrupting properties of CNTs which may soon introduce to future market of novel agrochemicals. This review aims to identify existing knowledge gaps regarding the endocrine-disrupting properties of CNTs and provide directions for future studies in parallel to regulatory activities for the development and promotion of safer nano agrochemicals.


Study subjects

To specify our focus on the role of CNTs on human endocrine disruption through environmental exposures by food, water, and air contamination, all available original and review articles in PubMed were considered for this review using the following keywords for inclusion and exclusion of selected studies.


Carbon nanotube OR CNTs OR Single-Wall Carbon Nanotubes OR SWCNTs OR Multi-Walled Carbon Nanotubes OR Multi-Wall Carbon Nanotube OR MWNT OR MWCNT


Nanoagrochemicals OR Agriculture OR Pesticide OR Nanopesticide OR Fertilizer OR Nano fertilizer OR Endocrine Disruption OR Aryl Hydrocarbon Receptor OR AhR ORLipid metabolism OR Obesity OR Fat accumulation OR Diabetes OR Cardiotoxicity OR Cardiovascular effects OR cardiovascular diseases OR Sexual development OR, Female Reproductive Health OR Teratogenicity OR Teratogen OR Embryotoxicity OREstrogen OR Progesterone OR Testosterone OR Androgen OR FSH OR LH OR Cortisol OR Ovary OR Ovaries OR Uterine, OR vagina OR Hypothalamus–hypophysis axis OR Reproductive cycles OR Pregnancy OR birth OR Male Reproductive Health effects OR Semen quality OR Hypospadias OR Sperm OR Cryptorchidism OR Prostate


Nanocarrier, Drug Delivery, Medicine, Therapy, Protein Detection, cell and organ transplantation,imaging system, Nanodevice, bone tissue regeneration, cancer diagnosis, Vector, scaffold


Applications of Carbon Nanotubes asnano agrochemicals

CNTs are authoritative members of the big family of ENMs based on their special physicochemical properties, a wide range of agrochemical applications, and a rapid surge of industrial attractions in the last decade. CNTs are classified into the following two categories: SWNCTs – Single-Walled Carbon Nanotubes and MWCNTs – Multiple-Walled Carbon Nanotubes. Table 1 shows the capabilities of CNTs’ efficient fertilizer (plant growth inducer ) by increasing the water uptake of plants and enhancing root/shoot lengths and plant dry biomass [13], [14]. Table 1 shows also the potentials of CNTs as excellent chemicals for the detection and remediation of environmental pollutants e.g. heavy metals, persistent organic pollutants (POPs) especially organochlorine pesticides, dyes, the residue of pharmaceuticals and EDCs based on exhibiting strong adsorptive properties [15] and their antimicrobial and antifungal properties.

Environmental risks and benefits of CNTs applications

Due to the highly porous and hollow structure of CNTs, large specific surface area, excellent adsorptive capacities as well as their short equilibrium times and strong interaction between CNTs and pollutant molecules, these highly available nanomaterials, have been gradually applied for the removal of organic contaminants with endocrine-disrupting effects from wastewater through adsorption process as novel absorbent [16]. Soluble carbon nanotubes (CNTs) have shown promising roles as adsorptive materials against Endocrine-disrupting chemicals(EDCs)such as Bisphenol A (BPA) but the adsorptive capabilities of CNTs to EDCs may change the final toxic properties of the possible complexes in human and other living organisms and cause reproductive toxicity[17].

Besides the above remarkable effects of CNTs in agriculture and remediation, CNTs provide toxic effects on plants by inducing reactive oxygen species (ROS) leading to abnormal cell death. Unusual accumulation of CNTs in soils can cause hazardous effects on soil microbial population, diversity, and composition. They can modify the balance between plant-toxic metals in soil and accelerate the translocation of heavy metals and metalloids into the plant tissues. [18]. CNTs release into water and wastewater treatment systems when it is used as an adsorbent for water and soil treatment [19]. Studies on adsorptive properties of SWCNTs indicate that SWCNTs effectively adsorbed 17β-estradiol and natural hormones in animals and plants which cause hormonal deficiencies [20]. Increasing environmental levels of MWCNTs is dangerous due to their strong affinities to estrogenic compounds ( 17β-estradiol) in aquatic systems. Hormonal affinities of MWCNTs cause definite alterations in estrogenic responses to other EDCs by increasing their bioavailability[21].It seems that other harmful chemicals would be able to bind and activate soluble estrogen receptors (ERs) and make more critical situations for determining the potential health risks of CNTs alone in biological systems.

Toxicokinetic and toxicodynamic of CNTs as strong endocrine disruptors

3-1Biodistribution: Environmental induced toxic effects of CNTs are highly dependent on the route of exposure which usually happens through the ingestion of possible residues in food resources or inhalation of contaminated air during occupational activities. The toxicity of CNTs, biodistribution, bioaccumulation, and target organ toxicity are complex subjects and mostly related to the structure and physicochemical properties. The number of walls, chirality, diameter and length [22], purity, production method and CNT functionalization [23] fibrogenic properties, hydrophobicity, high surface area and biopersistence [24] is the most important CNTs characteristics that may cause organ toxicity and systemic adverse health in the endocrine system but among mentioned variables, the quality of functionalization is the most important factor which may change the future of CNTs in the body [23]. Covalently functionalized CNTs tend to be excreted through urine, whereas pristine and non-covalently functionalized CNTs tend to accumulate in spleen and liver of exposed organisms and these types of bioaccumulation in liver and spleen may cause short term or long term toxic responses and disease development [25].

Metabolism: After total body intake and making biological effective concentrations of CNTs, some members especially SWCNTs isoforms could act as competitive inhibitors of CYP3A4, CYP3A5, and CYP2D6 and these enzyme inhibitions may potentiate the endocrine-disrupting properties of other xenobiotics in co-exposure models. Computational and animal models showed the interaction of CNTs with CYP3A4, a critical and high abundance drug-metabolizing cytochrome P450 enzyme [26].

3-3Hormonal effects: Dose-dependent inhi-bition of CYP3A4 by CNTs mediates the conversion of testosterone (male steroid hormone) to its major metabolite, 6β-hydroxy testosterone and finally cause male hormonal dysregulation, interfere with the metabolism of other xenobiotics and provides a molecular mechanism for toxic responses [27].Binding assays indicate the binding capacities of SWCNTs to Estrogen receptors (ER) as one of the most important receptors of human reproductive system .Interacting of SWCNTs to estrogen receptor alpha in a very low concentration range ( 26.43 - 259.01 pg/ml) could be considered as a very critical mechanism and the main molecular initiating event leading to endocrine and reproductive toxicity of SWCNTs[28] . Interactions of CNTs with gonadotropins is another key mechanism for endocrine-disrupting effects of CNTs.Strong affinities between blood glycoproteins and CNTs have been described by molecular and experimental studies. Molecular dynamics, structure, and free binding energy of human Follicle Stimulating Hormone ( FSH) on the surface of SWCNT causes that human FSH in aqueous solution strongly adsorbs onto SWCNT and this strong interaction could change the hormonal activity of FSH, causes dysregulations in hypothalamus-hypophysis axis and endocrine and reproductive toxicity [29]. The same interaction could be predictable between other types of CNTs and circulating hormones in the body based on the mentioned physicochemical properties.

Effects on ovaries: The effects of MWCNTs on ovarian function and granulosa cell steroidogenesis showed the inhibitory role of MWCNTs with different lengths on progesterone secretion and the expression of steroidogenic acute regulatory protein based on cytotoxicity, oxidative stress and mitochondria damages mechanisms [30].


Lipid metabolism and obesogenic effects of CNTs

Because of the global increase in the prevalence of obesity [31] and its related syndromes e.g. nonalcoholic fatty liver disease (NAFLD) [32] and metabolic syndrome [33], the metabolic and obesogenic effects of all chemicals and nanomaterials should be concerned by health regulatory agencies before any official approval. For the first time, one study points towards the cardiovascular risks of MWCNTs through inhalational exposures and showed the role of a single intratracheal instillation of MWCNTs in a dose range of 0, 18, 54 or 162μg/mouse on lipid profile of female C57BL/6 mice. Treated animals showed a significant increase in plasma total cholesterol, low-density/very low-density lipoprotein (LDL, VLDL), APR proteins, SAA3 and haptoglobin, and histopathological studies showed abnormal changes in liver morphology following exposure to MWCNTs with different physicochemical properties. The results of this study link the importance of MWCNTs pulmonary exposure with abnormal body weight gain, changes in lipid metabolism, and increased risk of cardiovascular disease [34].

Another parallel study at the same year (2015) revealed the role of intratracheal exposure to two different MWCNTs on development of nonalcoholic steatohepatitis (NASH)-like phenotype, chara-cterized by inflammation, hepatic steatosis, and fibrosis as well as NASH-like phenotype which was consistent with up-regulation of interleukin 6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1). Other abnormalities including overexpression of NF-κB, p65, impaired cholesterol homeostasis, and suppression of peroxisome proliferator-activated receptor-gamma (PPARγ) in the hepatocytes of exposed animals were also detected [35]. The next study confirmed the aggravating role of MWCNTs in nonalcoholic steatohepatitis in Sprague Dawley rats by inducing oxidative injury [36].

Diabetogenic effects of CNTs

The growing use of carbon nanotubes (CNTs) in agrochemicals, emphasizes the importance of studies on biocompatibility evaluation and specific toxic effects of CNTs in the pancreas. In silico studies and computational analysis have provided insights into the toxic response of CNTs which causes Type 2 Diabetes Mellitus (T2DM) because CNTs could be recognized as pathogens by the Toll-like receptors that may induce the expression of inflammatory secretory proteins [37]. A study in three months old BALB/c mice that exposed to CNTs via injectional rout showed the pancreatic uptake of CNTs but the pancreas remained histologically normal, with no tissue damage, inflammatory infiltrate or inorganic deposits despite inducing hepatic, renal, pulmonary and spleen tissue damages[38] .One other study on the effects of SWCNTs on islets and β-cells, demonstrated decreased viability of islets cells in a dose-dependent manner by overproduction of reactive oxygen species (ROS) and raise of oxidative stress biomarkers including activities of superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA);and glutathione (GSH) peroxidase (GSH-Px); and content of GSH and mitochondrial membrane potential (MMP) [39] Direct diabetogenic effects of SWCNTs and MWCNTs should be considered as important subjects for further preclinical evaluations in realistic models by different routes of administration.

Cardiovascular effects CNTs

There are several primary mechanisms to link CNTs’ exposure to cardiovascular toxicity. The first is their inflammatory and oxidative properties, direct particle interactions based on their excellent systemic absorption, bioreactivity, and their capacities for neural and hormonal alterations [40] . Oral administration of SWCNTs could induce cardiovascular diseases in mice and rats after excellent GI absorption and distribution throughout most of the body organs including the liver, lungs, brain, and spleen by inducing oxidative stress and eliminating through kidney and bile duct [41]. SWCNTs induced oxidative stress has investigated rat aortic endothelial cells (RAECs) and showed cellular, DNA, and protein damages and oxidative damage following SWCNT exposure which may result in the progression of many serious diseases especially cardiovascular abnormalities [42].

The potential cardiotoxicity of MWCNT has not been elucidated yet but an initial study demonstrated the bioreactivity of MWCNT by increasing cell permeability in human microvascular endothelial cells (HMVEC). This toxic effect was mediated by reactive oxygen species (ROS) production, actin filament remodeling, and promoting cell migration in HMVEC. Studies supported the role of MWCNT on elevating the levels of monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule 1 (ICAM-1) in HMVEC and elucidated the potential human toxicity of MWCNT at the cellular level [43]. Male C57BL/6J mice, exposed to single doses of three different forms of MWCNTat doses of 0.01 - 100 μg showed myocardial ischemia/reperfusion injuries based on the form of administered MWCNTs [44].Another study in 2014, confirmed previous findings regarding the cardiotoxic effects of MWCNTs following single intratracheal instillation of 1, 10 or 100 μg MWCNT in Sprague-Dawley rats inLangendorff isolated heart model. Increased endothelin-1 (ET-1) release and depression of coronary flow during early reperfusion were observed in exposed rats and the promoting role of MWCNTs on cardiac injury and depressed coronary flow by invoking vasoconstrictive mechanisms involving ET-1, thromboxane, Rho-kinase, and cyclooxygenase was discovered [45]. One more study also indicated that exposure to MWCNT increases the adherence of monocytes onto the endothelium, elevates the levels of oxidative stress-mediated transformation of monocytes to foam cells which are closely correlated with accelerated progression of atherosclerosis [46].

Later studies in 2015 showed the cardiovascular toxicity of long-term exposure to MWCNTs particularly in occupationally exposed workers with preexisting cardiovascular disorders. In this study, four different MWCNTs with different iron contents and length caused a persistent decrease in the heart rate of spontaneously hypertensive (SH) rats by inducing sustain inflammation of the lung and heart of animals as well as morphological lesions after 30 days repeated dose exposures by intratracheal instillation[47] Another study in mice model of atherosclerosis showed that pharyngeal aspiration of 40 μg MWCNT, once a week for 16 consecutive weeks to female apolipoprotein E-deficient (apo E-/-) mice, elevates the levels of total protein and lactate dehydrogenase (LDH), surfactant protein-D, and mucin without any markedly effect on plasma cholesterol levels [48] These in vivo and epidemiological evidence suggest the cardiotoxicity of both types of CNTs and increased risk of myocardial ischemia and atherosclerosis in repeated dose and long term exposures.


The underlying mechanisms of CNTs’ hormonal activities reviewed in the last sections of this paper. As described in Table 2, MWCNTs are embryotoxic in rodent and aquatic models. Collected data show the dose/concentration-dependent developmental toxicity of MWCNTs and SWCNTs with different physicochemical properties in acute and repeated models by inducing early and late resorption of the fetus, decreased fetal weights, fetal malformations, fetal death in rodent and aquatic models.


Despite restricted, conflicted, and inconclusive body of information concerning the real concentrations and behavior of CNTs in vitro and in vivo models and lack of epidemiological studies on CNTs, present evidence suggests the prominent role of CNTs in the pathogenesis of endocrine and reproductive disorders. The fact that CNTs can disrupt the endocrine and reproductive system, which may eventually lead to cardiovascular toxicity, obesity, changes in lipid metabolism, has gathered support from several in vitro and in vivo which described in the present review.This review showed the underlying mechanism following the interference of EDCs with the body’s endocrine system which induces structural and functional abnormalities in gonads and increases the risk of adverse health effects. Differential adverse health effects of CNTs start usually after excellent systemic absorption through direct binding to circulating hormones or hormone receptors, alteration of hormonal activity and synthesis and changing the biological responses of other EDCs therefore beside available data about the CNTs interactions with various cells, tissues, endocrine organs, and organ systems and whole organs as a prerequisite for safety evaluations, special attention to their endocrine-disrupting properties for registered new CNTs based agrochemicals as new candidates for agricultural, medical and industrial applications. This review to show a new picture from CNTs which could be more complicated than described because the wide range of CNTs with different physicochemical properties and unrecognized conformational changes (e.g. agglomeration) with potential impact on bioavailability and endocrine toxicity may cause unpredicted toxicities in human exposure based on their background factors e.g. nutrition, drugs, occupation, and lifestyle factors moreover any Chemical change in CNTs (functionalization) or conformational alteration (agglomeration) can significantly influence their toxicity potential and their receptor interactions.

Apart from these knowledge gaps, some initial properties of CNTs, relevant for their interactions with plants during agricultural applications have been identified and explained in this review. Exposure of plants with CNTs is frequently associated also with internal translocation of CNTs and some systemic effects because they can be taken up by herbs and their absorbed fractions can induce systemic physiological responses. Low plant tissue levels of CNTs (<100 mg L−1) could have beneficial e.g. improved seed germination, hormesis, or lack of toxicity but higher external concentrations usually cause inhibitory effects on plant growth and differentiation. Formation of reactive Oxygen Species (ROS) and oxidative stress are the main common toxic mechanisms of CNTs in plants and animals but despite indicated facts, CNTs have been proposed as the main engineered nanomaterials for developing next generation of nano agrochemicals by industries.

Since the discovery of the first generation of synthetic pesticides during World War II, numerous chemicals have been developed and applied as an insecticide, rodenticide, fungicide, herbicide, fumigants, and disinfectants. Despite overproduction and large scale application of conventional pesticides, a wide variety of them have become practically inefficient because they were unable to reach the specific pests or the targeted strains may become resistant against them [49]. In parallel with the production of old and new molecules, undetermined cases of acute pesticide poisoning (APP), and countless human and animal death via indirect or indirect poisoning through systemic absorption of pesticide residues in contaminated water, air, and food or by occupational routs have happened. Is it possible to have similar tragedies with CNTs as novel agrochemicals in the next decades?

Although the production and application of highly toxic pesticides banned in many countries, widespread use and lack of standardized case definition, risk assessment, risk management, and regulation globally, led to the pollution of ecosystems, a decline in populations of insect pollinators, and increased risk of pesticide-induced human diseases. However, a surprisingly restricted, conflicted, and inconclusive body of information exists concerning the real concentrations and behavior of these materials in biological systems especially in humans and their interactions with various cells, tissues, organs, organ systems, and whole organs as a prerequisite for safety evaluations. Now the critical question is about environmental and human safety regarding their future wide range of applications, their residues in environmental “ Is humanity waiting for a similar or even worse scenario with CNTs as the new generation of agrochemicals for the next decades? " In an optimistic scenario, applications of MWCNTs and SWCNTs in the agriculture sector showing potential impacts on the endocrine system and their efficacy in improvement of plant growth as nano fertilizer, absorption of pollutants as nano adsorbents or pes control as nano pesticides are at a very nascent stage and more risk assessment studies are necessary for their future applications. Evaluation of endocrine disrupting properties of CNTs should be considered as an essential step in risk assessment and management of CNTs through in vivo and in vitro studies using valid biomarkers to emphasize their roles of endocrine systems and hormone-dependent although these models are not always valid or enough for human risk evaluations this is a critical, initial and mandatory step for regulating all new chemicals for health, agricultural or industrial applications especially CNTs which described in this review.


Author declares no conflict of interest.


Apolipoprotein E-deficient mice apoE-/-mice

Acute-phase proteins/ acute-phase

reactant (APR) APR proteins

Carbon Nanotubes CNTs


Cytochrome P450 enzyme Cyp450/CYP

Endocrine-disrupting chemicals EDCs

Endothelin-1 ET-1

Engineered Nanomaterials ENMs

Follicle Stimulating Hormone FSH

Glutathione GSH

Human microvascular endothelial cells HMVEC

Glutathione peroxidase GSH-Px

Interleukin 6 IL-6

Intercellular adhesion molecule 1 ICAM-1

GDP Gross Domestic Product

Single-Wall Carbon Nanotubes SWCNTs

Monocyte chemoattractant protein-1 MCP-1

Multi-Walled Carbon Nanotubes MWCNT

Nonalcoholic steatohepatitis NASH

Nonalcoholic fatty liver disease NAFLD

Reactive Oxygen Species ROS

Serum amyloid A 3 SAA3

Type 2 Diabetes Mellitus T2DM

Lactate dehydrogenaseLDH

Low-density lipoprotein LDL

Luteinizing Hormone LH

Malondialdehyde MDA

Mitochondrial membrane potentialMMP

Plasminogen activator inhibitorPAI-1

Peroxisome proliferator-activated receptor-gamma PPARγ

Rat aortic endothelial cellsRAECs

Spontaneously hypertensive rats SH rats

Superoxide dismutase SOD

Nuclear factor-kappa B NF-κB

Very low-density lipoprotein VLDL



1. S. A. S. M. R. F. A. M. Lauretta R, “Endocrine Disrupting Chemicals:Effects on Endocrine Glands,” Front Endocrinol (Lausanne). , vol. 10, p. 178, 2019.

2. E. T. S. R. Bidgoli SA, “Role of Xenoestrogens and Endogenous Sources of Estrogens on the Occurrence of Premenopausal Breast Cancer in Iran,” Asian Pac J Cancer Prev. , vol. 12:, no. 9, pp. 2425-30., 2011.

3. Bidgoli SA, Jabari N, Zavarhei MD. Prostate-Specific Antigen Levels in Relation to Background Factors: Are there Links to Endocrine Disrupting Chemicals and AhR Expression? Asian Pacific Journal of Cancer Prevention. 2014;15(15):6121-5.

4. Bidgoli SA, Karimi M, Asami Z, Baher H, Djamali Zavarhei M. Association between testicular Aryl hydrocarbon Receptor levels and idiopathic male infertility: A case–control study in Iran. Science of The Total Environment. 2011;409(18):3267-73.

5. Bidgoli SA, Khorasani H, Keihan H, Sadeghipour A, Mehdizadeh A. Role of Endocrine Disrupting Chemicals in the Occurrence of Benign Uterine Leiomyomata: Special Emphasis on AhR Tissue Levels. Asian Pacific Journal of Cancer Prevention. 2012;13(11):5445-50.

6. Skinner MK. Epigenetic transgenerational inheritance. Nature Reviews Endocrinology. 2015;12(2):68-70.

7. Tavakol S, Shakibapour S, Bidgoli SA. The Level of Testosterone, Vitamin D, and Irregular Menstruation More Important than Omega-3 in Non-Symptomatic Women Will Define the Fate of Multiple Scleroses in Future. Molecular Neurobiology. 2016;55(1):462-9.

8. Barroso-Sousa R, Ott PA, Hodi FS, Kaiser UB, Tolaney SM, Min L. Endocrine dysfunction induced by immune checkpoint inhibitors: Practical recommendations for diagnosis and clinical management. Cancer. 2018;124(6):1111-21.

9. Iavicoli I, Leso V, Beezhold DH, Shvedova AA. Nanotechnology in agriculture: Opportunities, toxicological implications, and occupational risks. Toxicology and Applied Pharmacology. 2017;329:96-111.

10. Schug TT, Johnson AF, Birnbaum LS, Colborn T, Guillette LJ, Crews DP, et al. Minireview: Endocrine Disruptors: Past Lessons and Future Directions. Molecular Endocrinology. 2016;30(8):833-47.

11. The Lancet D, Endocrinology. EDCs: regulation still lagging behind evidence. The Lancet Diabetes & Endocrinology. 2019;7(5):325.

12. Iavicoli I, Fontana L, Leso V, Bergamaschi A. The Effects of Nanomaterials as Endocrine Disruptors. International Journal of Molecular Sciences. 2013;14(8):16732-801.

13. G. G. M. I. R. Kumar Das Sh, “Nano-science for Agrochemicals in Plant Protection,” Popular Kheti, vol. 5, no. 4, 2017.

14. D. E. M. M. X. Y. L. Z. W. F. B. A. Khodakovskaya M, “Tomato Seed Coat Permeability to Selected Carbon Nanomaterials and Enhancement of Germination and Seedling Growth,” ACS Nano., vol. 3, no. 10, pp. 3221-7., 2009.

15. Pyrzynska K. Carbon nanotubes as sorbents in the analysis of pesticides. Chemosphere. 2011;83(11):1407-13.

16. Z. X.-H. Y. H. C. X.-H. Y. Q. Y. L.-Y. J. J.-H. C. X.-Q. Yu J.-G., “Aqueous adsorption and removal of organic contaminants by carbon nanotubes. Sci. Total Environ.,” Sci. Total Environ. , vol. 482, no. 483, p. 241–251., 2014.

17. Wang W, Jiang C, Zhu L, Liang N, Liu X, Jia J, et al. Adsorption of Bisphenol A to a Carbon Nanotube Reduced Its Endocrine Disrupting Effect in Mice Male Offspring. International Journal of Molecular Sciences. 2014;15(9):15981-93.

18. Vithanage M, Seneviratne M, Ahmad M, Sarkar B, Ok YS. Contrasting effects of engineered carbon nanotubes on plants: a review. Environmental Geochemistry and Health. 2017;39(6):1421-39.

19. Zhang M, Wang X, Du T, Wang H, Hao H, Wang Y, et al. Effects of carbon materials on the formation of disinfection byproducts during chlorination: Pore structure and functional groups. Water Research. 2019;162:1-10.

20. R. S. L. C. N. T. C. B. C. H. L. K. D. D. P.-T. J. S. N. F. P. D. N. S.-A. T. Bisesi JH Jr, “Influence of the Gastrointestinal Environment on the Bioavailability of Ethinyl Estradiol Sorbed to Single-Walled Carbon Nanotubes,” Environ Sci Technol. , vol. 51, no. 2, pp. 948-957. , 2017.

21. Yan Z, Liu Y, Sun H, Lu G. Influence of multiwall carbon nanotubes on the toxicity of 17β-estradiol in the early life stages of zebrafish. Environmental Science and Pollution Research. 2017;25(8):7566-74.

22. Laurent C, Flahaut E, Peigney A. The weight and density of carbon nanotubes versus the number of walls and diameter. Carbon. 2010;48(10):2994-6.

23. Madani SY, Mandel A, Seifalian AM. A concise review of carbon nanotube’s toxicology. Nano Reviews. 2013;4(1):21521.

24. Simon A, Maletz SX, Hollert H, Schäffer A, Maes HM. Effects of multiwalled carbon nanotubes and triclocarban on several eukaryotic cell lines: elucidating cytotoxicity, endocrine disruption, and reactive oxygen species generation. Nanoscale Research Letters. 2014;9(1):396.

25. Cui H-F, Vashist SK, Al-Rubeaan K, Luong JHT, Sheu F-S. Interfacing Carbon Nanotubes with Living Mammalian Cells and Cytotoxicity Issues. Chemical Research in Toxicology. 2010;23(7):1131-47.

26. Asai Y, Sakakibara Y, Inoue R, Inoue R, Nadai M, Katoh M. Effect of single-walled carbon nanotubes on cytochrome P450 activity in human liver microsomes in vitro. Biopharmaceutics & Drug Disposition. 2018;39(5):275-9.

27. El-Sayed R, Bhattacharya K, Gu Z, Yang Z, Weber JK, Li H, et al. Single-Walled Carbon Nanotubes Inhibit the Cytochrome P450 Enzyme, CYP3A4. Scientific Reports. 2016;6(1).

28. Liu X, Liu T, Song J, Hai Y, Luan F, Zhang H, et al. Understanding the interaction of single-walled carbon nanotube (SWCNT) on estrogen receptor: A combined molecular dynamics and experimental study. Ecotoxicology and Environmental Safety. 2019;172:373-9.

29. Mahmoodi Y, Mehrnejad F, Khalifeh K. Understanding the interactions of human follicle stimulating hormone with single-walled carbon nanotubes by molecular dynamics simulation and free energy analysis. European Biophysics Journal. 2017;47(1):49-57.

30. Qu Y, Yang B, Jiang X, Ma X, Lu C, Chen C. Multiwalled Carbon Nanotubes Inhibit Steroidogenesis by Disrupting Steroidogenic Acute Regulatory Protein Expression and Redox Status. Journal of Nanoscience and Nanotechnology. 2017;17(2):914-25.

31. Chooi YC, Ding C, Magkos F. The epidemiology of obesity. Metabolism. 2019;92:6-10.

32. Ye Q, Zou B, Yeo YH, Li J, Huang DQ, Wu Y, et al. Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis. The Lancet Gastroenterology & Hepatology. 2020;5(8):739-52.

33. Ansarimoghaddam A, Adineh HA, Zareban I, Iranpour S, HosseinZadeh A, Kh F. Prevalence of metabolic syndrome in Middle-East countries: Meta-analysis of cross-sectional studies. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2018;12(2):195-201.

34. Poulsen SS, Saber AT, Mortensen A, Szarek J, Wu D, Williams A, et al. Changes in cholesterol homeostasis and acute phase response link pulmonary exposure to multi-walled carbon nanotubes to risk of cardiovascular disease. Toxicology and Applied Pharmacology. 2015;283(3):210-22.

35. Kim J-E, Lee S, Lee AY, Seo HW, Chae C, Cho M-H. Intratracheal exposure to multi-walled carbon nanotubes induces a nonalcoholic steatohepatitis-like phenotype in C57BL/6J mice. Nanotoxicology. 2014;9(5):613-23.

36. Xu Y-Y, Ge J, Zhang M-H, Sun W-J, Zhang J, Yu P-L, et al. Intravenous Administration of Multiwalled Carbon Nanotubes Aggravates High-Fat Diet-Induced Nonalcoholic Steatohepatitis in Sprague Dawley Rats. International Journal of Toxicology. 2016;35(6):634-43.

37. Priyam A, Singh PP, Gehlout S. Role of Endocrine-Disrupting Engineered Nanomaterials in the Pathogenesis of Type 2 Diabetes Mellitus. Frontiers in Endocrinology. 2018;9.

38. M. D. M. L. B. T. M. G. G. A. B. A. Fufă MO, “In vivo biodistribution of CNTs using a BALB/c mouse experimental model.,” Rom J Morphol Embryol., vol. 56, no. 4, pp. 1481-93., 2015.

39. Ahangarpour A, Alboghobeish S, Oroojan AA, Dehghani MA. Mice pancreatic islets protection from oxidative stress induced by single-walled carbon nanotubes through naringin. Human & Experimental Toxicology. 2018;37(12):1268-81.

40. Stapleton PA. Gestational nanomaterial exposures: microvascular implications during pregnancy, fetal development and adulthood. The Journal of Physiology. 2015;594(8):2161-73.

41. Ema M, Gamo M, Honda K. A review of toxicity studies of single-walled carbon nanotubes in laboratory animals. Regulatory Toxicology and Pharmacology. 2016;74:42-63.

42. Cheng W-W, Lin Z-Q, Ceng Q, Wei B-F, Fan X-J, Zhang H-S, et al. Single-wall carbon nanotubes induce oxidative stress in rat aortic endothelial cells. Toxicology Mechanisms and Methods. 2012;22(4):268-76.

43. Pacurari M, Qian Y, Fu W, Schwegler-Berry D, Ding M, Castranova V, et al. Cell Permeability, Migration, and Reactive Oxygen Species Induced by Multiwalled Carbon Nanotubes in Human Microvascular Endothelial Cells. Journal of Toxicology and Environmental Health, Part A. 2011;75(2):112-28.

44. Urankar RN, Lust RM, Mann E, Katwa P, Wang X, Podila R, et al. Expansion of cardiac ischemia/reperfusion injury after instillation of three forms of multi-walled carbon nanotubes. Particle and Fibre Toxicology. 2012;9(1):38.

45. Thompson LC, Frasier CR, Sloan RC, Mann EE, Harrison BS, Brown JM, et al. Pulmonary instillation of multi-walled carbon nanotubes promotes coronary vasoconstriction and exacerbates injury in isolated hearts. Nanotoxicology. 2012;8(1):38-49.

46. Cao Y, Jacobsen NR, Danielsen PH, Lenz AG, Stoeger T, Loft S, et al. Vascular Effects of Multiwalled Carbon Nanotubes in Dyslipidemic ApoE−/− Mice and Cultured Endothelial Cells. Toxicological Sciences. 2014;138(1):104-16.

47. Chen R, Zhang L, Ge C, Tseng MT, Bai R, Qu Y, et al. Subchronic Toxicity and Cardiovascular Responses in Spontaneously Hypertensive Rats after Exposure to Multiwalled Carbon Nanotubes by Intratracheal Instillation. Chemical Research in Toxicology. 2015;28(3):440-50.

48. Han SG, Howatt D, Daugherty A, Gairola G. Pulmonary and Atherogenic Effects of Multi-Walled Carbon Nanotubes (MWCNT) in Apolipoprotein-E-Deficient Mice. Journal of Toxicology and Environmental Health, Part A. 2015;78(4):244-53.

49. Boivin A, Poulsen V. Environmental risk assessment of pesticides: state of the art and prospective improvement from science. Environmental Science and Pollution Research. 2016;24(8):6889-94.

50. Kumar V, Sachdev D, Pasricha R, Maheshwari PH, Taneja NK. Zinc-Supported Multiwalled Carbon Nanotube Nanocomposite: A Synergism to Micronutrient Release and a Smart Distributor To Promote the Growth of Onion Seeds in Arid Conditions. ACS Applied Materials & Interfaces. 2018;10(43):36733-45.

51. Hao Y, Yu F, Lv R, Ma C, Zhang Z, Rui Y, et al. Carbon Nanotubes Filled with Different Ferromagnetic Alloys Affect the Growth and Development of Rice Seedlings by Changing the C:N Ratio and Plant Hormones Concentrations. PLOS ONE. 2016;11(6):e0157264.

52. Vithanage M, Herath I, Almaroai YA, Rajapaksha AU, Huang L, Sung J-K, et al. Effects of carbon nanotube and biochar on bioavailability of Pb, Cu and Sb in multi-metal contaminated soil. Environmental Geochemistry and Health. 2017;39(6):1409-20.

53. Zhang Y, Yang J, Zhong L, Liu L. Effect of multi-wall carbon nanotubes on Cr(VI) reduction by citric acid: Implications for their use in soil remediation. Environmental Science and Pollution Research. 2018;25(24):23791-8.

54. Song B, Zeng G, Gong J, Zhang P, Deng J, Deng C, et al. Effect of multi-walled carbon nanotubes on phytotoxicity of sediments contaminated by phenanthrene and cadmium. Chemosphere. 2017;172:449-58.

55. Hua S, Gong J-L, Zeng G-M, Yao F-B, Guo M, Ou X-M. Remediation of organochlorine pesticides contaminated lake sediment using activated carbon and carbon nanotubes. Chemosphere. 2017;177:65-76.

56. Lico D, Vuono D, Siciliano C, B.Nagy J, De Luca P. Removal of unleaded gasoline from water by multi-walled carbon nanotubes. Journal of Environmental Management. 2019;237:636-43.

57. Qu Y, Wang J, Zhou H, Ma Q, Zhang Z, Li D, et al. Concentration-dependent effects of carbon nanotubes on growth and biphenyl degradation of Dyella ginsengisoli LA-4. Environmental Science and Pollution Research. 2015;23(3):2864-72.

58. Sarlak N, Taherifar A, Salehi F. Synthesis of Nanopesticides by Encapsulating Pesticide Nanoparticles Using Functionalized Carbon Nanotubes and Application of New Nanocomposite for Plant Disease Treatment. Journal of Agricultural and Food Chemistry. 2014;62(21):4833-8.

59. Fujitani T, Ohyama K-i, Hirose A, Nishimura T, Nakae D, Ogata A. Teratogenicity of multi-wall carbon nanotube (MWCNT) in ICR mice. The Journal of Toxicological Sciences. 2012;37(1):81-9.

60. Campagnolo L, Massimiani M, Palmieri G, Bernardini R, Sacchetti C, Bergamaschi A, et al. Biodistribution and toxicity of pegylated single wall carbon nanotubes in pregnant mice. Particle and Fibre Toxicology. 2013;10(1):21.

61. Philbrook NA, Walker VK, Afrooz ARMN, Saleh NB, Winn LM. Investigating the effects of functionalized carbon nanotubes on reproduction and development in Drosophila melanogaster and CD-1 mice. Reproductive Toxicology. 2011;32(4):442-8.

62. Icoglu Aksakal F, Ciltas A, Simsek Ozek N. A holistic study on potential toxic effects of carboxylated multi-walled carbon nanotubes (MWCNTs-COOH) on zebrafish (Danio rerio) embryos/larvae. Chemosphere. 2019;225:820-8.

63. Asharani PV, Serina NGB, Nurmawati MH, Wu YL, Gong Z, Valiyaveettil S. Impact of Multi-Walled Carbon Nanotubes on Aquatic Species. Journal of Nanoscience and Nanotechnology. 2008;8(7):3603-9.

64. De Marchi L, Neto V, Pretti C, Figueira E, Chiellini F, Morelli A, et al. Toxic effects of multi-walled carbon nanotubes on bivalves: Comparison between functionalized and nonfunctionalized nanoparticles. Science of The Total Environment. 2018;622-623:1532-42.

65. M. X. W. X. M. L. G. W. M. Y. S. H. W. C. L. X. Liu XT, “Toxicity of Multi-Walled Carbon Nanotubes, Graphene Oxide, and Reduced Graphene Oxide to Zebrafish Embryos,” Biomed Environ Sci. , vol. 27, no. 9, pp. 676-83. , 2014.

66. Cheng J, Chan CM, Veca LM, Poon WL, Chan PK, Qu L, et al. Acute and long-term effects after single loading of functionalized multi-walled carbon nanotubes into zebrafish (Danio rerio). Toxicology and Applied Pharmacology. 2009;235(2):216-25.

67. Cordeiro MF, Girardi FA, Gonçalves COF, Peixoto CS, Dal Bosco L, Sahoo SK, et al. Toxicological assessment of PEGylated single-walled carbon nanotubes in early developing zebrafish. Toxicology and Applied Pharmacology. 2018;347:54-9.

68. “Nanotechnology-based recent approaches for sensing and remediation of pesticides,” Journal of Environmental Management, vol. 206, no. 15, pp. 749-762, 2018.

69. Wang X, Liu X, Chen J, Han H, Yuan Z. Evaluation and mechanism of antifungal effects of carbon nanomaterials in controlling plant fungal pathogen. Carbon. 2014;68:798-806.

70. Zaytseva O, Neumann G. Carbon nanomaterials: production, impact on plant development, agricultural and environmental applications. Chemical and Biological Technologies in Agriculture. 2016;3(1).

71. Suarez-Diez M, Porras S, Laguna-Teno F, Schaap PJ, Tamayo-Ramos JA. Toxicological response of the model fungus Saccharomyces cerevisiae to different concentrations of commercial graphene nanoplatelets. Scientific Reports. 2020;10(1).

72. Fang H, Cui Y, Wang Z, Wang S. Toxicological assessment of multi-walled carbon nanotubes combined with nonylphenol in male mice. PLOS ONE. 2018;13(7):e0200238.

73. Wang W, Jiang C, Zhu L, Liang N, Liu X, Jia J, et al. Adsorption of Bisphenol A to a Carbon Nanotube Reduced Its Endocrine Disrupting Effect in Mice Male Offspring. International Journal of Molecular Sciences. 2014;15(9):15981-93.

74. Raja IS, Song S-J, Kang MS, Lee YB, Kim B, Hong SW, et al. Toxicity of Zero- and One-Dimensional Carbon Nanomaterials. Nanomaterials. 2019;9(9):1214.

75. Kah M, Machinski P, Koerner P, Tiede K, Grillo R, Fraceto LF, et al. Analysing the fate of nanopesticides in soil and the applicability of regulatory protocols using a polymer-based nanoformulation of atrazine. Environmental Science and Pollution Research. 2014;21(20):11699-707.

76. Chen H. Metal based nanoparticles in agricultural system: behavior, transport, and interaction with plants. Chemical Speciation & Bioavailability. 2018;30(1):123-34.

77. Rastogi A, Tripathi DK, Yadav S, Chauhan DK, Živčák M, Ghorbanpour M, et al. Application of silicon nanoparticles in agriculture. 3 Biotech. 2019;9(3).

78. Arumugam G, Velayutham V, Shanmugavel S, Sundaram J. Efficacy of nanostructured silica as a stored pulse protector against the infestation of bruchid beetle, Callosobruchus maculatus (Coleoptera: Bruchidae). Applied Nanoscience. 2015;6(3):445-50.

79. Ziaee M, Ganji Z. Insecticidal efficacy of silica nanoparticles against Rhyzopertha dominica F. and Tribolium confusum Jacquelin du Val. Journal of Plant Protection Research. 2016;56(3):250-6.

80. H. M. Magda S, “Determinations of the effect of using silica gel and nano-silica gel against Tutaabsoluta (Lepidoptera:Gelechiidae) in tomato fields.,” J Chem Pharm Res , vol. 8, no. 4, p. 506–512, 2016.

81. Rastogi A, Tripathi DK, Yadav S, Chauhan DK, Živčák M, Ghorbanpour M, et al. Application of silicon nanoparticles in agriculture. 3 Biotech. 2019;9(3).

82. Liang Y, Sun W, Zhu Y-G, Christie P. Mechanisms of silicon-mediated alleviation of abiotic stresses in higher plants: A review. Environmental Pollution. 2007;147(2):422-8.

83. Bai Y, Zhang Y, Zhang J, Mu Q, Zhang W, Butch ER, et al. Repeated administrations of carbon nanotubes in male mice cause reversible testis damage without affecting fertility. Nature Nanotechnology. 2010;5(9):683-9.

84. K. Y. Y. H. K. M. K. M. Y. Yamashita, “Silica and titanium dioxide nanoparticles cause pregnancy complications in mice.,” Nat. Nanotechnol. , vol. 6, p. 321–328., 2011.

85. Ahangarpour A, Alboghobeish S, Oroojan AA, Dehghani MA. Mice pancreatic islets protection from oxidative stress induced by single-walled carbon nanotubes through naringin. Human & Experimental Toxicology. 2018;37(12):1268-81.

86. Davis G, Lucero J, Fellers C, McDonald JD, Lund AK. The effects of subacute inhaled multi-walled carbon nanotube exposure on signaling pathways associated with cholesterol transport and inflammatory markers in the vasculature of wild-type mice. Toxicology Letters. 2018;296:48-62.

87. Bisesi J, Ngo T, Ponnavolu S, Liu K, Lavelle C, Afrooz ARM, et al. Examination of Single-Walled Carbon Nanotubes Uptake and Toxicity from Dietary Exposure: Tracking Movement and Impacts in the Gastrointestinal System. Nanomaterials. 2015;5(2):1066-86.

88. K. G. D. D. A.-M. F. A.-T. R. A. A. A. A. B. W. B. D. B. G. C. A. C. T. C. A. D. F. F. S. G. L. H. R. K. L. L. L. L. d. C. S. A. M. L. M. Langie SA, “Causes of Genome Instability: The Effect of Low Dose Chemical Exposures in Modern Society,” Carcinogenesis. , vol. 36, no. Suppl , pp. S61-88., 2015.

89. Z. Q. W. Z. Y. B. Sun J, “Carboxyl-functionalized MWCNTs caused mortality and alter gene expression in zebrafish embryos.,” Int J Mol Sci. , vol. 14, no. 5, p. 9319–9337., 2013.

90. Sarlak N, Taherifar A, Salehi F. Synthesis of Nanopesticides by Encapsulating Pesticide Nanoparticles Using Functionalized Carbon Nanotubes and Application of New Nanocomposite for Plant Disease Treatment. Journal of Agricultural and Food Chemistry. 2014;62(21):4833-8.

91. Veiga-Lopez A, Pu Y, Gingrich J, Padmanabhan V. Obesogenic Endocrine Disrupting Chemicals: Identifying Knowledge Gaps. Trends in Endocrinology & Metabolism. 2018;29(9):607-25.

92. Z. J. L. R. G. J. L. J. L. W. Zhang J, “Endocrine-Disrupting Effects of Pesticides Through Interference With Human Glucocorticoid Receptor,” Environ Sci Technol. , vol. 50, no. 1, pp. 435-43., 2016.

93. Zhang J, Yang Y, Liu W, Liu J. Potential endocrine-disrupting effects of metals via interference with glucocorticoid and mineralocorticoid receptors. Environmental Pollution. 2018;242:12-8.

94. Sifakis S, Androutsopoulos VP, Tsatsakis AM, Spandidos DA. Human exposure to endocrine disrupting chemicals: effects on the male and female reproductive systems. Environmental Toxicology and Pharmacology. 2017;51:56-70.

95. Schug TT, Janesick A, Blumberg B, Heindel JJ. Endocrine disrupting chemicals and disease susceptibility. The Journal of Steroid Biochemistry and Molecular Biology. 2011;127(3-5):204-15.

96. Khodakovskaya MV, Kim B-S, Kim JN, Alimohammadi M, Dervishi E, Mustafa T, et al. Carbon Nanotubes as Plant Growth Regulators: Effects on Tomato Growth, Reproductive System, and Soil Microbial Community. Small. 2012;9(1):115-23.

97. B. A. R. P. A. R. B. S. C. Q. C. G. F. T. Kookana RS, “Nanopesticides: guiding principles for regulatory evaluation of environmental risks.,” J. Agric. Food Chem , vol. 62, p. 4227–4240., 2014.