POPs and Human Health

POPs AND MEN: RISK ASSESSMENT FOR REPRODUCTIVE HEALTH OF MEN IN THE REPUBLIC OF BASHKORTOSTAN

Assumption of higher sensitivity of women to impacts of adverse environmental factors is a deep-rooted stereotype, shared by the general public and even by many specialists. Indeed, in baseline, fixed, "standard" conditions, there are sustained differences between the two sexes in metabolism of alien compounds in the liver, and male liver neutralises these compounds more efficiently. However, in the case of many xenobiotics, it has beens proven that, under extreme circumstances, induced reactivity of enzymatic detoxification systems of men is substantially lower than induced reactivity of women. In other words, men have low adaptive capacity and their capacity might be easily exhausted, especially under impacts of long-term intake of eco-toxicants.

It is obvious, that it is sex-specific differentiation of metabolism of alien compounds, that defines different behaviour of POPs, including dioxins, in males and females. Let us describe the most illustrative examples.

Estimated net cumulative dose of dioxins for highly exposed men exceeds the dose for women in 34 times, while estimated half-time (Т1/2) for men reaches 286 months (comparatively to 146 moths for women) (Sibiryak et al., 1998). In the case of the same group of men, higher levels of cells, which expose specific protein CD95 (an apoptosis marker) were found. These data suggest the phenomenon of accelerating ageing.

Hypotesteronemia among man, who had occupational contacts with dioxins, induces changes in male/female ratios of their descendants - i.e. higher shares of female descendants (James, 1997). This means, that feminisation effects of dioxins manifest themselves at the level of population, in addition to their effects at the level of individuals, that segregation of sexes occurs at the stage of spermatozoa development.

Besides that, dioxins and dioxin-like organic compounds behave as inductors of cytochrome Р450. These cytochromes usually deactivate xenobiotics. Cunning nature of dioxins and some other POPs (e.g. PCBs) is associated with the fact that they stimulate (using specific arylhydrocarbon receptor - АhR) aggressive toxificating isomers of the cytochroms - CYP4501A1, which cause mutations, carcinogenic effects, alterations of metabolism of sex hormones, etc. In our current context it is important to note, that expression of Ah-receptor gene is observed in male reproductive organs, not in female ones (Yonemoto et al., 1998).

So, we are approaching one of the most relevant aspects of the problem in question - i.e. impacts of POPs on male reproductive health. In early 1990s, general problems of reproductive health of men attracted major attention, these developments were associated with research publications on reduction of sperm quantity and quality in 50 recent years. The most reliable evidence of actual reduction of spermatogenesis activity was provided by results of the analytic study of spermograms of about 15000 healthy men from different countries (based on results of 61 publications from 1938 to 1991). The study demonstrated reduction of ejaculate volumes from 3.4ml in 1940 to 2.75ml in 1990 and reduction of sperm count from 113 million/ml to 66 million/ml (Carlsen et al., 1992). The survey of sperm quality of 1351 healthy donors, carried out in France with application of the uniform technique, demonstrated steady reduction of sperm counts from 89 million/ml in 1973 to 60 million/ml in 1992, these data suggest annual reduction of 2% (Auger et al., 1995). Besides that, similar results were obtained by survey of men in UK, Greece, Italy, Germany, Belgium, Canada and other countries.

Two series of studies, that were carried out in Finland with use of autopsy materials of suddenly died middle-aged men, allowed to reveal direct evidence of spermatogenesis oppression in a comparatively short period of time: the ratio of cases of normal and abnormal spermatogenesis decreased from 56.4% in 1981 to 26.9% in 1991 (Payarinen et al., 1997). Spermatogenesis anomalies did not depend on smoking, alcohol consumption or use of medical preparations.

The second groups of facts is associated with higher incidence of male reproductive anomalies in recent years (cryptorchism and hypospadias) and malignant tumours of testicles. For example, incidence of testicle cancer increased world-wide more than in 3 - 4 times comparatively to 1940, and more than twice between 1960 and 1990. It is rather characteristic, that the highest rates of the pathology were observed in the same countries, where the highest reduction of sperm counts were observed - in UK, Denmark and Norway (Adami et al., 1994).

The hypothesis of environmental causes of so dramatic impairment of reproductive capacity of men seems to be the most soundly based (Bykov, 2000; Schuhler, 1997). Among different environmental factors, the large group of gonadothropic compounds plays a specific role. These compounds generate estrogenic or counter-androgenic effects, they affect foetuses or adults, disrupt spermatogenesis or androgenophoesis by interruption of regulatory mechanisms or by direct cytotoxic effects. For example, samples of common soot were found to have estrogenic activity of the range of estrogenic activity of blood serum of a pregnant woman (Rehmann et al., 1999). Samples of blood serum and ejaculate of men from Central Europe also were found to have elevated estrogenic and even dioxin-like activity (Machala et al., 1999).

If we agree with the majority of experts and assume (as a working hypothesis) that aggressive environmental factors play the decisive role in higher incidence of male reproductive pathologies, it would be fairly natural to ask about specific molecular and cellular mechanisms, that form the base of these negative phenomena. First and foremost, we should consider three interrelated processes. Here we consider them separately, just to simplify the picture.

Hormonal chaos. Many POPs, including dioxins and PCBs, may act as hormone disrupting substances. In the case of the male reproductive system, this means interruption of fine regulatory mechanisms of hypothalamus - hypophysis - testicles axis, androgen deficiency, excessive levels of estrogens and prolactin, etc.

POPs may directly induce free radical processes in reproductive organs. Several studies demonstrated activation of free radical oxidation in spermatozoa, this mechanism is considered as the most probable cause in the course of analysis of causes of spermatogenesis oppression among modern men.

Activation of apoptosis or "pre-programmed cell death". Apoptosis is a normal physiological process, which regulates inter alia spermatogenesis intensity. In testicles, apoptosis is particularly intensive - this mechanism destroys a large part of spermatozoa at different stages of spermatogenesis. It is worth to note, that in 24 hours an average man produces about 200000000 spermatozoa (or 15000 gametes at the time of one heartbeat!). As it was already noted, apoptosis processes are induced by POPs, first of all by dioxins.

It is necessary to emphasise, that the hypothesis on decisive role of environmental factors in decline of male reproductive health does not contradict to major concepts of Hill's environmental epidemiology (biological, geographic, temporal credibility, specificity, etc.).

In particular, relevance of the principle of geographic credibility to the problem in question may be illustrated by such problem-prone territories as Chapaievsk and Bashkiria. The latter region is of higher interest to us, therefore we will discuss the problem of assessment of reproductive health risks in the Republic of Bashkortostan (RB) more closely.

Results of long-term studies demonstrate that the Republic of Bashkortostan is prone to long-term "dioxin" pollution of environmental media and food. The acute nature of the problem is associated with the fact that 2 largest facilities of Russia, that produce organochlorine herbicides, are located at the territory of the Republic - State plant "Khimprom" (Ufa) "Kaustik" Co. (Sterlitamak). Emissions of these facilities have resulted in contamination of air and surface water bodies. For example, in 1990, net dioxin emissions of "Khimprom" plant reached about 900g. Now, the plant utilises only some part of its production capacity, as a result, its annual dioxin emissions do not exceed 50g.

According to the latest (1998) recommendations of the European WHO Centre for Environment and Health (WHO-ECEH), tolerable human daily dose of dioxins is set as 1 - 4 picograms/kg of body weight. In the Republic of Bashkortostan, an average industrial city resident intakes daily about 140 picograms of dioxins and similar compounds. It is absolutely clear, that this figure falls into the range of critical doses. In this context, "dioxin" threat for residents of Ufa and Sterlitamak seems to be fairly real.

In several recent years, our research team focused on study of some parameters of the male reproductive system in adverse environmental conditions. We think, that wider application of biologic markers represent a promising option for improvement of techniques for assessment of reproductive risks (biological markers characterise responses of the reproductive system to impacts of potentially harmful agents). Traditional techniques, which are based on comparative analysis of air pollution levels at a given territory and incidence of particular disfunctions of the reproductive function (infertility) in some cases produce contradictory and hardly interpretable results, that do not meet the study objectives adequately.

We have developed the technique for assessment of risks of reproductive system's impairments for men, staying in regions with different industrial loads. Accounting for the need of more comprehensive assessment of the male reproductive system, our modification of the technique stipulates application of additional criteria of the system's status. We used the following indices: androgen deficiency (based on testosterone in blood serum), a degree of spermatogenesis deficiency (based on ejaculate parameters), a degree of activation of free radical processes in sperm samples (based on intensity of spontaneous and induced chemiluminiscence), morbidity rates of men of a region under study (infertility, cryptorchism, hypospadias, malignant tumours of testicles and prostate gland) and male/female ratio of children, born within a given area. The first three parameters are measured in biological liquids (sperm and blood serum) with application of automatic analysers. 4th and 5th parameters are calculated, based on data of official statistical reporting. Then we estimate indices, based on the above parameters. These indices are compared with net contamination levels of the area under study (if the necessary data are available, the indices may be assessed vs. pollution levels of priority eco-toxicants - dioxins, PCBs, etc. or, alternatively, vs. their blood levels). Final factors are directly proportional to a degree of reproductive risk.

Pilot implementation of the technique in some cities of the Republic of Bashkortostan, notwithstanding its complexity and labour intensity, has demonstrated informative and universal nature of the approaches proposed and allows us to recommend them for more broad testing.