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DOI: 10.1055/s-0031-1275832
© Georg Thieme Verlag KG Stuttgart · New York
Endokrin aktive Substanzen in der Umwelt (Endocrine Disruptors): Gefahr für den Menschen?
Endocrine disruptors: hormone-active chemicals from the environment: a risk to humans?Publication History
eingereicht: 3.5.2010
akzeptiert: 27.1.2011
Publication Date:
27 April 2011 (online)

Zusammenfassung
Zahlreiche Substanzen aus der technischen und natürlichen Umwelt können Schädigungen des Endokriniums bewirken. Tierversuche belegen, dass sogenannte Endocrine Disruptors (ED), z. B. Pestizide, Fungizide, Weichmacher (Phthalate), Bisphenol A (BPA), zinnorganische Verbindungen, zu erheblichen Störungen führen können. Aus in vitro Untersuchungen an humanen Zellen und Geweben sowie aufgrund vieler klinischer Hinweise darf man schließen, dass auch der Mensch betroffen sein kann. Auch zeigen bestimmte medizinische Therapieverfahren, wie sehr empfindlich das endokrine System des Menschen ist. Angriffspunkte der ED sind vor allem die Schlüsselenzyme des Sexualhormon-Metabolismus und die hormonelle Signalübertragung in die und innerhalb der jeweiligen Zielzelle. Im Vordergrund stehen Störungen der Reproduktion wie Beeinträchtigung der Spermatogenese, verminderte Testosteronsynthese und Missbildungen der externen Genitalien sowie Tumoren wie z. B. das Mammakarzinom. Beim Menschen ist es jedoch schwierig, Störungen des Hormonsystems bzw. der Reproduktionsfunktion auf bestimmte ED zurückzuführen. Die Fülle der Befunde veranlassten die amerikanische FDA u. a. präventiv zu empfehlen, die Produktion BPA-haltiger Plastikflaschen und Babyfläschchen zu stoppen. Die EU fördert Verbundprojekte wie COMPRENDO, mit Studien über das Gefährdungspotential und die Risikoabschätzung bestimmter Chemikalien für die Gesundheit. Bemerkenswert ist, dass bei manchen EDs die Dosis-Wirkungsbeziehung nicht monoton sondern u-förmig verläuft und dass zahlreiche Chemikalien bei extrem niedrigen Konzentrationen stark schädigend wirken können (Low Dose Impact). Weitere Forschungen sind erforderlich, um zu klären, ob die beobachteten Befunde nur Assoziationen oder kausale Ergebnisse darstellen.
Abstract
Many substances from the technical and natural environment can cause damage to the endocrine system. Animal tests show that so-called endocrine disruptors (ED), such as pesticides, fungicides, plasticizers (phthalates), bisphenol A (BPA), and organotin compounds can interfere with the endocrine system. In humans, it is difficult to attribute such changes to specific ED. Nevertheless, in vitro studies with human cells and tissues clearly show that ED are able to interfere with endogenous hormones, i. e. affecting the steroid hormone metabolism and intracellular signaling. Several clinical studies show that humans are also affected, including reproductive disorders like reduction of spermatogenesis, decreased testosterone production or malformation of the genitals or induction of tumors like mammary carcinoma. Facing the body of reports documenting the effects of ED, the European Union supported – inter alia – COMPRENDO, a project addressing risk assessment of particular ED in human and wildlife species, while the FDA supports the industry’s actions to stop producing BPA-containing baby bottles and infant feeding cups. Some ED show an u-shaped dose response curve and specific ED have effects at levels dramatically lower than thought relevant to traditional toxicology, a phenomenon termed „Low Dose Impact”. Further research is needed to clarify whether the observed findings represent associations or causal results.
Schlüsselwörter
endokrine Disruptoren - Umweltchemikalien - Phthalate - Bisphenol A - Testicular Dysgenesis Syndrome
Keywords
endocrine disruptors - environmental chemicals - phthalates - bisphenol A - testicular dysgenesis syndrome
Literatur
- 1
Alléra A, Lo S, King I, Steglich F, Klingmuller D.
Impact of androgenic/antiandrogenic compounds (AAC)
on human sex steroid metabolizing key enzymes.
Toxicology.
2004;
205
75-85
MissingFormLabel
- 2
Andrade A J, Grande S W, Talsness C E, Grote K, Chahoud I.
A dose-response study following in utero
and lactational exposure to di-(2-ethylhexyl)-phthalate (DEHP).
Toxicology.
2006;
227
185-192
MissingFormLabel
- 3
Bhasin S.
Secular decline in male reproductive function: Is manliness threatened?.
J Clin Endocrinol Metab.
2007;
92
44-45
MissingFormLabel
- 4 Bigsby R M, Mercado-Feliciano M, Mubiru J. Molecular mechanisms of endocrine disruption in estrogen dependent
processes. In: Naz RK Endocrine Disruptors. Boca
Raton: CRC Press; 2005: 217-247
MissingFormLabel
- 5
Bliesener N, Albrecht S, Schwager A, Weckbecker K, Lichtermann D, Klingmüller D.
Plasma
testosterone and sexual function in men receiving buprenorphine
maintenance for opioid dependence.
J Clin Endocrinol Metab.
2005;
90
203-206
MissingFormLabel
- 6
Boisen K A, Main K M, De Rajpert-Meyts E, Skakkebaek N E.
Are male reproductive disorders a common entity?.
Ann
N Y Acad Sci.
2001;
948
90-99
MissingFormLabel
- 7
Braun J M, Yolton K, Dietrich K N. et al .
Prenatal bisphenol A exposure and early
childhood behavior.
Environ Health Perspect.
2009;
117
1945-1952
MissingFormLabel
- 8
Brennemann W, Stoffel-Wagner B, Helmers A, Mezger J, Jager N, Klingmuller D.
Gonadal function of
patients treated with cisplatin based chemotherapy for germ cell
cancer.
J Urol.
1997;
158
844-850
MissingFormLabel
- 9 Daufeldt S, Alléra A. SteroCheck.
A bioassay for the determination of agonistic and antagonistic steroid
hormone activities. In: Schänzer W, Geyer H,
Gotzmann A, Maeck U Recent Advances in Doping Analysis. Köln: Sport & Buch Strauß; 2004: 159-167
MissingFormLabel
- 10
Damgaard I N, Jensen T K, Petersen J H, Skakkebaek N E, Toppari J, Main K M.
Maternal
alcohol consumption during pregnancy increases risk for cryptorchidism.
Environ Health Perspect.
2007;
115
272-277
MissingFormLabel
- 11
Doering D, Steckelbroeck S, Doering T, Klingmuller D.
Effects of butyltins
on human 5a-reductase type 1 and type 2 activity.
Steroids.
2002;
67
859-867
MissingFormLabel
- 12 FDA .Update
on Bisphenol A for Use in Food Contact Applications, U.S. Food and
Drug Administration, January 2010. http://www.fda.gov/downloads/NewsEvents/PublicHealthFocus/UCM197778.pdf letzter Zugriff 18.4.2011
MissingFormLabel
- 13
Gies C, Gottschalk P, Greiner W. et al .
Nachhaltigkeit und Vorsorge bei der Risikobewertung
und beim Risikomanagement von Chemikalien, Teil II: Umweltchemikalien,
die auf das Hormonsystem wirken – Belastungen, Auswirkungen,
Minderungsstrategien.
Umweltbundesamt.
2003
Texte 30/01;
MissingFormLabel
- 14
Heidrich D, Steckelbroeck S, Klingmüller D.
Inhibition of human cytochrome P450 aromatase
activity by butyltins.
Steroids.
2001;
66
763-769
MissingFormLabel
- 15
Hiroi H, Tsutsumi O, Takeuchi T. et al .
Differences in serum bisphenol A concentrations
in premenopausal normal women and women with endometrial hyperplasia.
Endocr J.
2004;
51
595-600
MissingFormLabel
- 16
Howdeshell K L, Hotchkiss A K, Thayer K A, Vandenbergh J G, vom Saal F S.
Environmental
toxins: Exposure to bisphenol A advances puberty.
Nature.
1999;
401
763-764
MissingFormLabel
- 17
Jensen T K, Jorgensen N, Punab M, Haugen T B, Suominen J, Zilaitiene B.
Association of in
utero exposure to maternal smoking with reduced semen quality and
testis size in adulthood.
Am J Epidemiol.
2004;
159
49-58
MissingFormLabel
- 18
Kangasniemi M, Wilson G, Huhtaniemi I, Meistrich M L.
Protection
against procarbazine-induced testicular damage by GnRH-agonist and
antiandrogen treatment in the rat.
Endocrinology.
1995;
136
3677-3680
MissingFormLabel
- 19
Lang I A, Galloway T S, Scarlett A. et al .
Association of urinary bisphenol A concentration
with medical disorders and laboratory abnormalities in adults.
JAMA.
2008;
300
1303-1310
MissingFormLabel
- 20
Li D, Zhou Z, Qing D. et
al .
Occupational exposure to bisphenol-A (BPA) and the
risk of Self-Reported Male Sexual Dysfunction.
Hum Reprod.
2010;
25
519-527
MissingFormLabel
- 21
Lo S, Alléra A, Albers P, Heimbrecht J, Jantzen E, Klingmüller D, Steckelbroeck S.
Dithioerythritol (DTE) prevents inhibitory
effects of triphenyltin (TPT) on the key enzymes of the human sex
steroid hormone metabolism.
J Steroid Biochem Mol Biol.
2003;
84
569-576
MissingFormLabel
- 22
Lo S, King I, Alléra A, Klingmuller D.
Effects of various
pesticides on human 5alpha-reductase activity in prostate and LNCaP
cells.
Toxicol In Vitro.
2007;
21
502-508
MissingFormLabel
- 23
Lottrup G, Andersson A M, Leffers H. et al .
Possible impact of phthalates on infant
reproductive health.
Int J Androl.
2006;
29
172-180
MissingFormLabel
- 24
Lovekamp-Swan T, Jetten A M, Davis B J.
Dual activation of PPARalpha and PPARgamma
by mono-(2-ethylhexyl) phthalate in rat ovarian granulosa cells.
Mol Cell Endocrinol.
2003;
201
133-141
MissingFormLabel
- 25
Main K M, Toppari J, Suomi A M. et al .
Larger testes and higher inhibin B levels
in Finnish than in Danish newborn boys.
J Clin Endocrinol
Metab.
2006;
91
2732-2737
MissingFormLabel
- 26
McKee R H, Pavkov K L, Trimmer G W, Keller L H, Stump D G.
An assessment of the potential
developmental and reproductive toxicity of di-isoheptyl phthalate
in rodents.
Reprod Toxicol.
2006;
21
241-245
MissingFormLabel
- 27
McLachlan J A.
Environmental signaling: what embryos and evolution teach us
about endocrine disrupting chemicals.
Endocr Rev.
2001;
22
319-341
MissingFormLabel
- 28
Myrup C, Westergaard T, Schnack T. et al .
Testicular cancer risk in first- and second-generation
immigrants to Denmark.
J Natl Cancer Inst.
2008;
100
41-47
MissingFormLabel
- 29
Oehlmann J, Markert B, Stroben E, Schulte-Oehlmann U, Bauer B, Fioroni P.
Tributyltin biomonitoring
using prosobranchs as sentinel organisms.
Anal Bioanal
Chem.
1996;
354
540-545
MissingFormLabel
- 30
Rajapakse N, Silva E, Kortenkamp A.
Combining xenoestrogens at levels below individual no-observed-effect
concentrations dramatically enhances steroid hormone action.
Environ
Health Perspect.
2002;
110
917-921
MissingFormLabel
- 31
Reinsberg J, Wegener-Toper P, van der Ven K, van der Ven H, Klingmüller D.
Effect of mono-(2-ethylhexyl) phthalate
on steroid production of human granulosa cells.
Toxicol
Appl Pharmacol.
2009;
239
116-123
MissingFormLabel
- 32
Richter-Kuhlmann E A.
Umweltschadstoffe: Niedrige Dosierungen.
Dtsch Ärztebl.
2003;
100
A 3201
MissingFormLabel
- 33
Saal F S, Akingbemi B T, Belcher S M. et al .
Chapel Hill bisphenol A
expert panel consensus statement: integration of mechanisms, effects
in animals and potential to impact human health at current levels
of exposure.
Reprod Toxicol.
2007;
24
131-138
MissingFormLabel
- 34
Saal F S, Meyers J P.
Bisphenol A
and risk of metabolic disorders.
JAMA.
2008;
300
1353-1355
MissingFormLabel
- 35
Schulte-Oehlmann U, Albanis T, Alléra A. et al .
COMPRENDO. Focus and approach.
Environ
Health Perspect.
2006;
Suppl 1, 114
98-100
MissingFormLabel
- 36
Sharpe R M, Drake A J.
Bisphenol A
and metabolic syndrome.
Endocrinology.
2010;
151
2404-2407
MissingFormLabel
- 37
Stahlhut R W, van Wijngaarden E, Dye T D, Cook S, Swan S H.
Concentrations of urinary phthalate metabolites
are associated with increased waist circumference and insulin resistance
in adult U.S. males.
Environ Health Perspect.
2007;
115
876-882
MissingFormLabel
- 38
Sugiura-Ogasawara M, Ozaki Y, Sonta S, Makino T, Suzumori K.
Exposure to bisphenol A is associated with recurrent miscarriage.
Hum Reprod.
2005;
20
2325-2329
MissingFormLabel
- 39
Swan S H, Main K M, Liu F. et al .
Decrease in anogenital distance among male
infants with prenatal phthalate exposure.
Environ Health
Perspect.
2005;
113
1056-1061
MissingFormLabel
- 40
Swan S H, Liu F, Hines M. et
al .
Prenatal phthalate exposure and reduced masculine
play in boys.
Int J Androl.
2009; Nov 16. [Epub
ahead of print];
MissingFormLabel
- 41
Takeuchi T, Tsutsumi O, Ikezuki Y, Takai Y, Taketani Y.
Positive relationship between androgen and the endocrine disruptor,
bisphenol A, in normal women and women with ovarian dysfunction.
Endocr J.
2004;
51
165-169
MissingFormLabel
- 42
Travison T G, Araujo A B, O’Donnell A B, Kupelian V, McKinlay J B.
A Population-level decline in
serum testosterone levels in American men.
J Clin Endocrinol
Metab.
2007;
92
196-202
MissingFormLabel
- 43 WHO .Endocrinology
and Endocrine toxicology. In: Global assessment of the state-of-the-science
of endocrine disruptors; WHO/PCS/EDC/02.2 WHO
2002; S. 23. www.who.int/ipcs/publications/new_issues/endocrine_disruptors/en/
MissingFormLabel
- 44
Wichers M, Benz E, Palmedo H, Biersack H J, Grunwald F, Klingmuller D.
Testicular function
after radioiodine therapy for thyroid carcinoma.
Eur J Nucl
Med.
2000;
27
503-507
MissingFormLabel
- 45
Wozniak A L, Bulayeva N N, Watson C S.
Xenoestrogens at picomolar to nanomolar
concentrations trigger membrane estrogen receptor-α-mediated
Ca2+ fuxes and prolactin release in GH3/B6 pituitary
tumor cells.
Environ Health Perspect.
2005;
113
431-439
MissingFormLabel
- 46
Zsarnovszky A, Le H H, Wang H S, Belcher S M.
Ontogeny of
rapid estrogen-mediated extracellular signal-regulated kinase signaling
in the rat cerebellar cortex: potent nongenomic agonist and endocrine
disrupting activity of the xenoestrogen bisphenol A.
Endocrinology.
2005;
146
5388-5
MissingFormLabel
Prof. Dr. Dietrich Klingmüller
Arzt für Innere Medizin – Endokrinologie
Institut
für Klinische Chemie und Pharmakologie
Universitätsklinikum
Bonn
Sigmund-Freud-Str. 25
53105 Bonn
Phone: 0228/2871-6513
Fax: 0228/2871-5028
Email: d.klingmueller@uni-bonn.de