«L.I. Medved’s Research Center of Preventive Toxicology, Food and Chemical Safety, Ministry of Health, Ukraine (State Enterprise)», Kyiv, Ukraine
ABSTRACT. Objective of the study. Evaluation of prevalence of reproductive system problems in women living in the vicinity of a waste incineration plant and the possible involvement of manganese and nickel emissions in the occurrence of gynaecological disease.
Materials and Мethods. The author has reviewed statistical indicators of the prevalence of gynaecological disease in women over 18 years of age. These indicators of disease were estimated per 10,000 of the population. Prior studies have shown high levels of exposure of the population to manganese and nickel. The study was conducted among the residents of a 2-kilometre zone around a waste incineration plant (Group 1) and the residents of an environmentally pristine area (Group 2) in Kyiv. The first group enrolled 89.747 women and the second group enrolled 29.492 women. The comparison across the two groups was performed by assessment of the statistical significance of the differences for two relative quantities using Statistica 8.0 software.
Results. The findings of the study have shown that compared to Group 2, patients of Group 1 were more frequently found to have the following: uterine leiomyoma (by 80.32 %, p — 0.0000), endometriosis (by 17.31 %, p — 0.027), endometrial hyperplasia (by 67.46 %, p — 0.001), cervical dysplasia (by 93.46 %, p — 0.0000), abnormal menopause (by 123.63 %, p — 0.0000), benign lesions of the mammary gland (by 371.20 %, p = 0.0000). There were approximately identical levels of prevalence of polyps, cervical cancer and menstrual disorders. The article discusses possible pathogenetic mechanisms associated with the role of increased exposure to manganese and nickel in the occurrence of gynaecological disease.
Key Words: gynecological pathology, prevalence, ecology, manganese, nickel.
The ecological environment plays a great role in shaping the health of the population. The female reproductive system is characterized by special vulnerability to environmental factors. In their previous research, the author studied the prevalence of female reproductive disease depending on the place of residence. The findings obtained by the author have shown the structure of this morbidity in women may be related to how far they live from a waste incineration plant [1]. When waste is incinerated, large amounts of organic and inorganic substances are released into the air. At high temperatures, much of the organic matter disintegrates. Metals form compounds that are exhausted into the air.
During further research in women with polycystic ovaries (PCO) residing in Kyiv, the author has detected increased serum levels of manganese and nickel [2]. In this connection, a question arose on the possible involvement of increased exposure to manganese and nickel in the occurrence of another reproductive disease.
Exposure to manganese and nickel may occur chiefly via alimentary route and by inhalation of polluted air. Waste incineration plants are major sources of environmental pollution with manganese and nickel [3, 4]. It has been demonstrated that 12 % of manmade nickel pollution is associated with municipal waste incineration [3]. In the author’s opinion, these microelements may cause not only polycystic ovary but also other diseases of the reproductive system.
Objective of the study. Evaluation of prevalence of reproductive system problems in women living near a waste incineration plant and the possible involvement of manganese and nickel emissions in the occurrence of gynaecological disease.
Materials and methods. A powerful source of environmental pollution in large cities, including Kyiv, is waste incineration plants (WIPs). In order to study the indices of reproductive disease prevalence, a two-kilometre zone around a WIP was chosen (Group І). As a reference area, the author has chosen Vynogradar residential area located at a distance of 20 km from the WIP, close to a recreation zone with no major air-polluting manufacturing facilities (Group II).
Statistical data was provided by Centres for Medical Statistics at Central District Polyclinic of Darnytskyi district (Group 1) and Polyclinic No. 2 of Podilskyi district (Group 2). At the time of the study, the first group enrolled 89,747 women over 18 years of age and the second group enrolled 29,492 women.
The indicators of prevalence of disease were estimated per 10,000 of the population. The comparison across the two groups was conducted by assessment of the statistical significance of the differences for two relative quantities (p) using Statistica 8.0 software.
Results and discussion . In large cities, there are infinite sources of exposure to various substances. These may include industrial enterprises, thermal power plants, motor vehicles, etc. In addition to that, there are hazardous employments where people are in contact with toxic substances. It is not implausible that the statistical pool of this study included the data from people with workplace exposure to toxic chemicals. However, the percentage of these workers was quite small compared to our overall statistical pool; in addition, there are hygienic regulations in place concerning hazardous occupations, which minimize the risk of occupational disease.
People usually spend more of their time where they live; this is why the assessment of population health is performed mostly in their communities.
Women living in the vicinity of a waste incineration plant were found to have significantly higher (compared to Group 1) rates of uterine leiomyoma (by 80.32 %), endometriosis (by 17.31 %), endometrial hyperplasia (by 67.46 %), cervical dysplasia (by 93.46 %), abnormal menopause (by 123.63 %) and benign lesions of the mammary gland (by 371.20 %) (see Table). Both groups had approximately identical levels of prevalence of polyps, cervical cancer and menstrual disorders.
Table
Prevalence (Pr.) of female reproductive disease in Kyiv
* the level of statistical significance of the differences for two relative values
In previous research, the author has found high levels of manganese and nickel in women with PCO [2]. Based on a review of literature data, the author concluded that the population of Ukraine is subject to increased exposure to manganese and nickel [5, 6]. This means that at least a part of the above disease may be attributable to high levels of exposure to the aforementioned elements. With this in mind, the author undertook to review potential mechanisms explaining how increased exposure to manganese and nickel could increase the occurrence of reproductive system disorders.
Manganese is known to be one of the endocrine disruptors [7]. It has been demonstrated to disrupt dopaminergic pathways by causing degenerative changes in the neurons responsible for the synthesis of dopamine [8], the latter inhibiting secretion of prolactin. Subsequently, the synthesis of prolactin is increased. Hyperprolactinaemia underlies many types of female reproductive disease. The effects of manganese also extend to changes in the GABA-ergic system [9]. These mediator systems are playing an important role in the regulation of gonadotropin secretion. Dysfunction of these systems is associated with abnormal functions of the pituitary.
Nickel is also capable of disrupting the function of the gonadotropic system. It has been demonstrated to form a complex compound with gonadotropin-releasing hormone (gonadoliberin); this compound stimulates the secretion of follicle stimulating hormone and luteinizing hormone more actively than the naturally occurring gonadotropin-releasing hormone [10]. In addition to that, nickel is capable of causing degenerative changes in the granulosa of ovarian cells, leading to impaired steroid synthesis. Experimental studies have shown nickel nanoparticles to cause impaired circulation in the ovaries, leukocyte infiltration and ovarian inflammation [11].
High levels of both manganese and nickel trigger oxidative stress in the body. According to the WHO, uterine leiomyoma, endometriosis, endometrial disease, mammary gland disease, abnormal menopause and endocrine disorders are attributable to the impact of endocrine disruptors [7]. The author’s hypothesis of the involvement of manganese in gynaecological disease seems to have credible support since levels of manganese and some other heavy metals were found to be increased in women with uterine leiomyoma [12].
Manganese-induced increase in prolactin levels could be one of the factors to stimulate proliferation in the body. Prolactin may have tissue effects by exhibiting the properties of a cytokine due to its involvement in the mechanisms of paracrine and autocrine regulation. Prolactin is viewed as a factor of tumorigenesis; it is believed to play an important role in the pathogenesis of uterine leiomyoma [13]. There is an active ongoing discussion concerning the role of prolactin in the pathogenesis of endometriosis and endometrial hyperplasia, etc. [14] It helps to develop and regulate the function of mammary glands. Increased levels of prolactin are believed to be associated with dishormonal, benign and malignant lesions of the mammary gland [15].
Manganese toxicity may also manifest through other mechanisms. For example, such mechanisms may involve hypoxia-induced factor (HIF) and vascular endothelial growth factor (VEGF), inflammation and induction of apoptosis [9]. VEGF is one of the angiogenic peptides; it stimulates proliferative processes in tumours. It is believed that VEGF is involved in the pathogenesis of such diseases as uterine leiomyoma, endometrial hyperplasia, endometriosis, endometrial polyps, mammary gland disease and cervical dysplasia [16, 17, 18, 19, 20].
Oestrogens are known to stimulate proliferative processes in a female body. Nickel is one of the metal-oestrogens. In the tissues, it binds with oestrogen receptors and imitates the effects of these hormones. The research of recent years has shown that nickel plays a role in diseases of the mammary gland. In addition to that, it cannot be excluded that exposure to nickel may play a role in endometriosis [21].
Therefore, the statistical data from this study suggests that the prevalence of reproductive system disease may largely depend on the ecological situation in a given region. Increased levels of exposure to manganese and nickel are pathogenetically capable of disrupting hormonal homeostasis in the body, triggering oxidative stress, inflammation and stimulation of apoptosis. In a setting of such changes, activation of proliferative transformation may take place, the latter being a potential cause of hyperplasia in the organs of the reproductive system. All of these data provide evidence that increased levels of exposure to manganese and nickel may serve as a factor or a cofactor for the occurrence of reproductive disease.
Conclusions
1. The female reproductive disease was substantially more frequent among the population residing near a waste incineration plant.
2. Increased levels of exposure to manganese and nickel may be the cause of reproductive disease in women.
REFERENCES
1. Prodančuk N.G. Rol' organohlorinov v formirovanii patologii moločnoj železy /N.G. Prodančuk, R.A. Moiseenko, S.V. Gun'kov. // Sovremennye problemy toksikologii: naučno-praktičeskij žurnal. — 2010. —№1. — S. 7–16.
2. Doslidzhennia balansu essencialnykh makro- ta mikroelementiv u zhinok z polikistozom yaiechnykiv / S.V. Hunkov, T.F. Tatarchuk, V.O. Vykhor [ta in.]//Suchasni problemy toksykolohii kharchovoi ta khimichnoi bezpeky. — 2015. —№1. — S.51–53.
3. ATSDR (Agency for Toxic Substances and Disease Registry). 2005. Toxicological profile for nickel. Atlanta, Georgia: [Elektron. resurs]. — Rezhym dostupu: https://www.atsdr.cdc.gov/toxprofiles/tp15.pdf [accessed 18 July 2018].
4. ATSDR (Agency for Toxic Substances and Disease Registry). 2012. Toxicological Profile for Manganese. U.S. Department of Health and Human Services, Public Health Service. September, 2012. : [Elektron. resurs]. — Rezhym dostupu: https://www.atsdr.cdc.gov/toxprofiles/tp151.pdf
5. Vyvchennia rivnia eksponuvannia naselennia Ukrainy nikelem / S.V. Hunkov, O.O. Makarov, V.O. Vykhor, S.V. Babych //Suchasni problemy toksykolohii, kharchovoi ta khimichnoi bezpeky. — 2016. — № 2. — C. 62–65.
6. Hunkov S.V. Doslidzhennia rivnia eksponuvannia naselennia Ukrainy marhancem / S.V. Hunkov, O.O. Makarov // Klinichna ta eksperymentalna patolohiia. — 2016. —T. 15. — № 1. — S. 47–50.
7. Possible developmental early effects of endocrine disrupters on child health. — Geneva, Switzerland: World Health Organization, 2012. — 83 p.
8. p73 gene in dopaminergic neurons is highly susceptible to manganese neurotoxicity/ D.S. Kim, H. Jin, V. Anan-tharam, R Gordon [et al.] //Neurotoxicology. — 2017. —№59. — P. 231–239.
9. Costa L.G. Manganese in Health and Disease / L.G.Costa, M. Aschner; Royal Society of Chemistry — 2015. — 654 p. http://dx.doi.org/10.1039/9781782622383
10. Reproductive toxicology of nickel — review/ Z. Forgacs, P. Massanyi, N. Lukac [et al.] //J. Environ. Sci. Health. A. Tox. Hazard. Subst. Environ. Eng. — 2012. — № 9. —P.1249–1260. doi: 10.1080/10934529.2012.672114
11. Nickel nanoparticles exposure and reproductive toxicity in healthy adult rats / L.Kong, M. Tang, T. Zhang [et al.]//Int. J. Mol. Sci. — 2014. — V.15, № 11. — P. 21253–21269.
12. Increased trace metals in blood and urine are associated with uterine leiomyomata/ E. Johnstone, J. Dorais, P. Parsons [et al.] //Fertility and Sterility. — 2013. — №3. — P. S422–S423. DOI: https:// doi .org/ 10.1016/j.fertnstert.2013.07.601
13. Kosej N.V. Giperprolaktinemiâ v mehanizme razvitiâ lejomiomy matki / N.V. Kosej, L.A. Vasil'čenko, V.A. Džupin // Reproduktivna endokrinologiâ. — 2013. —№5. — C. 99 – 112.
14. Tatarčuk T.F. Rol' giperprolaktinemii v patogeneze giperplazii èndometriâ. Nužna li korrekciâ?/ T.F. Tatarčuk, T.N. Tutčenko, O.A. Efimenko. — Zdorov'e ženŝiny. — 2013. — №9. — C.30–35.
15. Tatarčuk T.F. Giperprolaktinemiâ kak pričina dobrokačestvennyh zabolevanij moločnoj železy / T.F. Tatarčuk, O.A. Efimenko // Medicinskie aspekty zdorov'â ženŝiny. — 2015. — № 5. — C. 2–7.
16. Tal R. The role of angiogenic factors in fibroid pathogenesis: potential implications for future therapy/ R. Tal, J.H. Segars// Hum. Reprod. Update. — 2014. — № 2. — C. 194–216. doi: 10.1093/humupd/dmt042. Epub 2013 Sep 29.
17. Lu Y. Study on the validity of serum VEGF-A for diagnosis of endometriosis/ Y. Lu, X. Yi, L.Chen// Am. J. Clin. Exp. Obstet. Gynecol. — 2017. — № 1. — P.20–25. www.ajceog.us/ISSN:23301899/ AJCEOG0030027
18. Enhanced expression of vascular endothelial growth factor and increased microvascular density in women with endometrial hyperplasia: a possible relationship with uterine natural killer cells/A.K. Elfayomy, S.M. Almasry, G.M. Attia, [et al.] //Rom. J. Morphol. Embryol. — 2015. — № 56 (2 Suppl). — P.725–734.
19. Erinanc H. Increased expression of nestin and VEGF in endometrial polyps: an immunhistochemical study/ H.Erinanc, E.Toprak // Int. J. Clin. Exp. Pathol. — 2016. — № 7. — P. 7458–7463. www.ijcep.com / ISSN:1936–2625/IJCEP0028990
20. VEGFR–2 expression in malignant tumours of the canine mammary gland: a prospective survival study/ A.Santos, C. Lopes, F.Gartner [et al.] //Vet. Comp. Oncol. — 2016 . —№ 3. — e83–92. doi: 10.1m/vco.12107. Epub 2014 Jun 27.
21. The role of cadmium and nickel in estrogen receptor signaling and breast cancer: Metalloestrogens or not?/Aquino, N.B.; Sevigny, M.B.; Sabangan, J. [et al.] // J. Environ. Sci. Health Part C. — 2012. — № 30. — P. 189–224.
Надійшла до редакції 11.04.2019 р.