The Journal of Steroid Biochemistry and Molecular Biology
Dithioerythritol (DTE) prevents inhibitory effects of triphenyltin (TPT) on the key enzymes of the human sex steroid hormone metabolism
Introduction
Organotin compounds are widely used as unselective biocides for pest control. Applications include a variety of industrial products like preservatives, antifouling paints and stabilisers but also everyday materials like sports wear, plastic gloves and silicon baking parchment [1], [2], [3]. Tributyltin (TBT) and triphenyltin (TPT) additives in coatings for marine vessels prevent sessile animals, which need to adhere to a substrate during their life cycle, to settle down. These substances are permanently leaching into the aquatic environment [4]. Photochemical and biochemical influences lead to successive degradation of organotins and TPT disintegrates into diphenyltin, monophenyltin and inorganic tin [4]. However, organotins stored in sediments are stable up to several years. This is a potential threat to aquatic life as a consequence of natural resuspension and particulate consumption by benthic organisms which live in seabeds and riverbeds [5], [6]. TPT compounds are rather selective in their action against fungal species, demonstrating a low risk for fungal resistance, a low volatility and a relatively rapid disintegration to “non-toxic” compounds by sunlight. Consequently, they were utilised for pest and fungal plant pathogen control [4]. Since August 2002, the use of TPT acetate and TPT hydroxide has been banned within the European Union.
The extensive use of organotins as biocides leads to an ongoing contamination of aquatic and terrestic environment. In the aquatic environment, a strong food chain accumulation of organotins has been noticed [7]. Examination of marine vertebrates showed considerable concentrations in liver and kidney, as well as in hair, nails and feathers [8]. Terrestic animals and humans incorporate organotins by consumption of contaminated food and surface water, or by direct contact with contaminated products. In previous studies, reasonable butyltin concentrations were detected in all of the human liver and blood samples investigated [9].
Both TBT and TPT are reported to affect the immune system, the nervous system and the hormone system as well as embryogenesis [10], [11], [12]. TBT is known to act as an endocrine disruptor causing imposex in various female prosobranch snails. Investigations showed that incorporated TBT induced an increased testosterone/estradiol ratio in the snails suggesting that TBT inhibits cytochrome P450 aromatase (P450arom) [1]. Previously, TBT and TPT were shown to act as inhibitors of human P450arom activity [13], [14]. As a consequence, most developed nations have imposed a ban on TBT-based antifouling paints for vessels under 25 m in length since the late 1980s [15]. Other triorganic tin compounds, such as TPT, have recently been found to likewise cause imposex [16]. Hence, TPT should similarly be considered as an endocrine disruptor. The release of environmental chemicals, such as pesticides, detergents and plasticizers, are suggested to play a role in the observed increased incidence of male reproductive disorders.
The enzymes examined in the present study maintain the proper balance of androgens and estrogens in the human body. 3β-HSD converts Δ5-3β-hydroxysteroids into the corresponding Δ4-3-ketosteroids [17]. 17β-HSD 3 catalyses the testicular conversion of the weak androgen Δ4-androstendione into the strong androgen testosterone. Testosterone is the most abundant androgen in the male sex steroid hormone system [18]. Dihydrotestosterone is synthesized from testosterone via 5α-Re 2 activity [18]. It represents the most potent androgen naturally occurring [18] and is indispensable for the normal virilization of the male external genitalia and prostate [19]. P450arom is responsible for the conversion of C19 androgens into the corresponding C18 estrogens in a variety of tissues, including the ovary, testis, placenta, brain and adipose tissue [20], [21]. 17β-HSD 1 predominantly catalyses the conversion of the weak estrogen estrone into the strong estrogen 17β-estradiol [22].
Organotins possess both lipophilic and ionic properties. The former encourages their accumulation in lipids and their membrane toxicity, while the latter enables their binding to macromolecules [8], [23]. The biochemical effects of organotins on human sex steroid hormone metabolism remain to be elucidated. Therefore, we studied the inhibitory effects of TPT on the in vitro activity of the key enzymes of human sex steroid hormone metabolism using human tissue samples. In several experiments, it was demonstrated that sulfhydryl compounds antagonise the harmful effects of organotins [24], [25], [26], [27]. It is suggested that organotins interact with any thiol residues accessible, thus, the sulfhydryl antagonist prevents modification of the tertiary structure of the proteins [24], [25], [26], [27]. Therefore, we also investigated the in vitro effects of the reducing agent dithioerythritol (DTE) on TPT inhibited enzyme activities. To elucidate the potential risk of TPT evoked endocrine disruption in man, the content of a variety of organotin compounds was determined in blood samples of eight healthy adult human volunteers.
Section snippets
Steroids and other chemicals
[1β-]-androstenedione (25.9 Ci/mmol), [4-]-estrone (51.3 mCi/mmol) and [4-]-dehydroepiandrosterone (53.8 mCi/mmol) were obtained from New England Nuclear Co. (Dreieich, Germany) and purified by thin layer chromatography (TLC) prior to use. Non-radioactive reference steroids (5α-androstane-3,17-dione (androstanedione), androst-4-ene-3,17-dione (androstenedione), 5α-androstane-17β-ol-3-one (dihydrotestosterone), 5α-androstane-3α-ol-17-one (androsterone), androst-4-ene-17β-ol-3-one
Determination of different organotin species in human blood
The blood of eight healthy human volunteers was analysed for the presence of different organotin compounds. As shown in Table 1, TPT is the major organotin compound found in human blood (0.17–0.67 μg organotin cation/l, i.e. 0.49–1.92 nmol cation/l). Furthermore, we were able to demonstrate the presence of minor concentrations of TBT in human blood, whereas the concentrations of monobutyltin, dibutyltin, tetrabutyltin, monooctyltin as well as dioctyltin were below the detection limit of 0.02 μg
Discussion
In the present study, investigations regarding the organotin blood load demonstrated the presence of significant amounts of TPT in the human blood, while the other organotin compounds were close to the detection limit (Table 1). Women showed a slightly higher average blood concentration of TPT and TBT. This possibly reflects the higher percentages of body fat in women [33] and the accumulation of tinorganic compounds in lipids [8].
One might suggest that humans incorporate organotins mainly by
Acknowledgements
This work was generously supported by a grant from the Deutsche Forschungsgemeinschaft (KL 524/6-1). We are grateful to Merck, Sharp, and Dohme, who kindly provided us with MK906 and to Schering AG for placing atamestane at our disposal. Also, we would like to express our gratitude to Westdeutscher Rundfunk who financed the survey of organotin compounds in blood samples. Many thanks to Mrs. S. Dentler who kindly edited the English version of the manuscript.
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