Sensitization to inorganic mercury could be a risk factor for infertility
Neuroendocrinology Letters 2005
Heavy metals can negatively influence the reproduction due to the fact that they are able to impair the immune reactions including autoantibody production in susceptible individuals. In such a way the infertility could be also caused by altered pathologic immune reaction.
AIM OF THE STUDY:
To investigate the in vitro lymphocyte reaction after stimulation with metals and production of gamma interferon and antisperm antibodies in supernatants after lymphocyte stimulation in patients with infertility and with proven antisperm antibodies in their serum. The cause of antisperm antibodies presence was not determined.
The diagnosis of metal allergy was performed by the lymphocyte proliferation method modified for metals (MELISA®). In supernatants of tissue cultures of lymphocytes without the antigen stimulation and after stimulation with mercury chloride, the in vitro production of gamma interferon and antisperm antibodies was studied by ELISA.
More than 50% of patients were reacting to mercury, iron, aluminium and silver as mean by lymphocyte reactivity. When compared the lymphocyte reaction in patients with and without mercury allergy we found that the lymphocytes of patients with mercury intolerance produced less gamma interferon and more antisperm antibodies in supernatants after mercury stimulation of their lymphocytes.
In patients with metal intolerance diagnosed by the MELISA® test the release of metal ions from dental materials can be one of the stimulating factors which may adversely affect fertility.
Infertility is currently a growing problem. The reasons for infertility may be due to endocrine, genetic, anatomical, immunological or psychogenic problem. It is well known that one of the immunological infertility may be caused by decreased mobility of spermatozoa induced by various physical and biochemical factors. The external sperm membrane consists of soluble antigenic components and in some cases can induce the production of auto–(iso–)antibodies .
Heavy metals are biologically active substances and may in susceptible individuals affect the immune system and cause health disturbances. Heavy metals are known to induce so called cellular hypersensitivity (delayed type or type 4 reaction) but humoral responses may be affected as well. An association between undesirable reaction to metals and presence of autoantibodies has been suggested by several authors [2,3,4]. Changes in cytokine production were reported by others [5,6,7,8,9].
Since metals such as mercury, cadmium and lead are toxic in relatively low concentrations , undesirable reactions caused by metal antigens may further complicate the health status of the patient. Patients with autoimmune and allergic diseases may be particularly vulnerable . Metal-induced reactions are influenced by genetic background in experimental animals  and associated with certain HLA antigens in man . Association between the exposure to organic and inorganic mercury and male infertility has been described by Choy and Hanf with coworkers [14,15].
The exposition to lead and cadmium resulted in the decrease of fertility and in lower quality of sperm as described by several authors [16–20].
Dental amalgam, the most frequently used dental alloy worldwide, is considered as risk factor of pregnancy by Pleva .
The aim of this study was to examine the in vitro lymphocyte reactivity to wide range of metals in infertile men and women with anti-sperm antibodies. A modified lymphocyte stimulation test, so called MELISA®, was used and the production of interferon γ (IFN-γ) and anti-sperm antibodies in lymphocyte cultures was also determined.
In this study, infertile patients frequently showed increased lymphocyte stimulation in vitro to inorganic mercury and other metals ubiquitous in the environment. Compared to fertile group the results in infertile patients were significantly higher for all metals tested.
The highest reactivity was detected to inorganic mercury, followed by iron and aluminium. Mercury is main component of dental amalgam, a frequently used dental material in restorative dentistry. Increased in vitro lymphocyte stimulation triggered by mercury may indicate the possibility of mercuryinduced inflammation in vivo. It is generally accepted that some metals, such as nickel, chromium, cobalt, mercury and gold are highly allergenic as demonstrated by standard patch testing and often cause oral lichen planus [26,27,28], contact allergy [29,30,31,32] or fatigue and autoimmunity .
During the last years there has been an increase in diseases characterized by hyporeactivity or hyperreactivity of the immune system. In young generation, infertility is now affecting one couple in six [34,35]. This may be due to the decrease in sperm quality as described previously [36,37,38].
Various other factors such as exposure to heavy metals [15,16,18,20,21,39], diet , smoking [17,19,35,40] and diverse environmental factors [37,38,41] were implicated to explain infertility in men and women. The most frequent factors implicated in male infertility are occupational exposure to heavy metals, such as Cd, Pb, Mn and Hg, to pesticides and solvents, smoking (exposure to Cd, Pb, Hg, Ni, Ar, Mn) and diet rich in sea food (exposure to methylmercury).
In women, diet rich in sea food (exposure to methylmercury), delayed childbearing, changes in sexual behavior, smoking and long-term use of contraceptives are most often implicated. Contraceptives such as vaginal gels may contain mercury preservatives.
In the context of autoimmune etiology we postulate that metals might participate in autoantibodies formation and inflammation reactions that may have negative impact on the outcome of pregnancy. Infertile men have high levels of anti-sperm antibodies in the blood and the ejaculate, which implies clinical relevance of antisperm antibodies . In genetically susceptible animals, mercury and gold induce local and systemic autoimmunity [42–46]. Since our patients were exposed to amalgam, the negative effect of inorganic mercury leaking from amalgam restorations and affecting the outcome of pregnancy cannot be excluded.
The group from Heidelberg (Germany) reported that removal of mercury and other metals by chelation with DMPS (2,3–dimercaptopropan–1–sulfonic acid, sodium salt) improved the spontaneous conception chances of infertile women . The study of cytokine pattern in responders and non responders showed that IFN-γ production in mercury treated cultures in both groups increased as comparedto IFN-γ production in control cultures. Increase in IFN-γ production was higher in non responder group as in responders. This could possible be due to different kinetics in the production of cytokine where responder cultures produced IFN-γ during 24 to 48 hours.
Since cytokine measurement was performed at the end of the culture, the cytokine synthesis could have been downregulated in responder cultures.
Regarding the titers of anti-sperm antibodies, the responder group had at least three times higher levels of anti-sperm antibodies in the culture supernatant as did the non responder group. The presence of mercury in the cultures did not affect the levels of anti-sperm antibodies. The low presence of anti-sperm antibodies in control group might be due to its low content in patient’s sera used for lymphocyte culture cultivation. We can speculate that mercury-sensitive individuals (responders) may have activated B lymphoblasts in the blood which may secrete anti-sperm antibodies during the cultivation in vitro. The clinical relevance of antisperm antibodies for infertility has been described in workers occupationally exposed to mercury .
Some authors reviewed that existing scientific evidence does not demonstrate that mercury from dental amalgam poses a public health hazard . Although there exists a controversy regarding the effects of dental amalgam on health [48,49], there is accumulating evidence of pathological effect of mercury on susceptible individuals [7,11,12,13,21,33,50] and on susceptible groups such as fetuses and young children [51–4].
In conclusion, results of this study indicate that mercury from amalgam fillings could be a risk factor which could negatively influence fertility in metal-sensitive patients.