Although animal studies have raised concern that the influence of endocrine-disrupting compounds would obstruct the development of the male reproductive system, in general, exposure levels far above those found in humans have been needed to induce reproductive toxicity in animal models. Human data are inconclusive and have evoked the question whether endocrine-disrupting compounds can have any impact on hormonal function and thus health consequences when natural hormones are present. Indeed, many contaminants with hormone-like activity are much less potent than endogenous hormones themselves: 17β-oestradiol was, for instance, estimated to be 17,000 times more potent than o,p′-DDT. However, humans are exposed to a multitude of agents, and when present in sufficient number and concentration, they might in principle act collected on the actions of endogenous hormones. Whether such effects will be physiologically relevant is still not known. Nevertheless, in the worst-case scenario, there are no threshold levels below which there are no effects at all, and one target molecule is the androgen receptor. This mini review focuses on the androgen receptor gene, its link with classical endocrine disruptors and smoking, and how common genetic variants in the androgen receptor gene may influence physiological outcomes.

1.
Bergman Å, Heindel J, Jobling S, Kidd K, Zoeller R (eds): WHO (World Health Organization)/UNEP (United Nations Environment Programme): State of the science of endocrine disrupting chemicals - 2012. Geneva, UNEP/WHO, 2013, p 296.
2.
Schell LM, Burnitz KK, Lathrop PW: Pollution and human biology. Ann Hum Biol 2010;37:347-366.
3.
Welsh M, Saunders PT, Fisken M, Scott HM, Hutchison GR, Smith LB, et al: Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest 2008;118:1479-1490.
4.
Mazaud-Guittot S, Nicolas Nicolaz C, Desdoits-Lethimonier C, Coiffec I, Ben Maamar M, Balaguer P, et al: Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent. J Clin Endocrinol Metab 2013;98:E1757-E1767.
5.
Kristensen DM, Hass U, Lesne L, Lottrup G, Jacobsen PR, Desdoits-Lethimonier C, et al: Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat. Hum Reprod 2011;26:235-244.
6.
Fenichel P, Brucker-Davis F, Chevalier N: The history of Distilbène® (Diethylstilbestrol) told to grandchildren - the transgenerational effect. Ann Endocrinol (Paris) 2015;76:253-259.
7.
Titus-Ernstoff L, Troisi R, Hatch EE, Palmer JR, Hyer M, Kaufman R, et al: Birth defects in the sons and daughters of women who were exposed in utero to diethylstilbestrol (DES). Int J Androl 2010;33:377-384.
8.
Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, et al: Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev 2009;30:293-342.
9.
Kelce WR, Monosson E, Gray LE Jr: An environmental antiandrogen. Recent Prog Horm Res 1995;50:449-453.
10.
Wilson VS, Blystone CR, Hotchkiss AK, Rider CV, Gray LE Jr: Diverse mechanisms of anti-androgen action: impact on male rat reproductive tract development. Int J Androl 2008;31:178-187.
11.
Aneck-Hahn NH, Schulenburg GW, Bornman MS, Farias P, de Jager C: Impaired semen quality associated with environmental DDT exposure in young men living in a malaria area in the Limpopo Province, South Africa. J Androl 2007;28:423-434.
12.
De Jager C, Farias P, Barraza-Villarreal A, Avila MH, Ayotte P, Dewailly E, et al: Reduced seminal parameters associated with environmental DDT exposure and p,p'-DDE concentrations in men in Chiapas, Mexico: a cross-sectional study. J Androl 2006;27:16-27.
13.
Llobet JM, Domingo JL, Bocio A, Casas C, Teixido A, Muller L: Human exposure to dioxins through the diet in Catalonia, Spain: carcinogenic and non-carcinogenic risk. Chemosphere 2003;50:1193-1200.
14.
Sorg O, Zennegg M, Schmid P, Fedosyuk R, Valikhnovskyi R, Gaide O, et al: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: identification and measurement of TCDD metabolites. Lancet 2009;374:1179-1185.
15.
Schecter A, Birnbaum L, Ryan JJ, Constable JD: Dioxins: an overview. Environ Res 2006;101:419-428.
16.
Chamie K, DeVere White RW, Lee D, Ok JH, Ellison LM: Agent Orange exposure, Vietnam War veterans, and the risk of prostate cancer. Cancer 2008;113:2464-2470.
17.
Chang ET, Boffetta P, Adami HO, Cole P, Mandel JS: A critical review of the epidemiology of Agent Orange/TCDD and prostate cancer. Eur J Epidemiol 2014;29:667-723.
18.
Mocarelli P, Gerthoux PM, Needham LL, Patterson DG Jr, Limonta G, Falbo R, et al: Perinatal exposure to low doses of dioxin can permanently impair human semen quality. Environ Health Perspect 2011;119:713-718.
19.
Guo YL, Hsu PC, Hsu CC, Lambert GH: Semen quality after prenatal exposure to polychlorinated biphenyls and dibenzofurans. Lancet 2000;356:1240-1241.
20.
Miller KP, Ramos KS: Impact of cellular metabolism on the biological effects of benzo[a]pyrene and related hydrocarbons. Drug Metab Rev 2001;33:1-35.
21.
Agency for Toxic Substances and Disease Registry: Toxicological profile for Polycyclic Aromatic Hydrocarbons. Atlanta, US Department of Health and Human Services, 1990.
22.
Sharpe RM: Environmental/lifestyle effects on spermatogenesis. Philos Trans R Soc Lond B Biol Sci 2010;365:1697-1712.
23.
Inyang F, Ramesh A, Kopsombut P, Niaz MS, Hood DB, Nyanda AM, et al: Disruption of testicular steroidogenesis and epididymal function by inhaled benzo(a)pyrene. Reprod Toxicol 2003;17:527-537.
24.
Zenzes MT, Bielecki R, Reed TE: Detection of benzo(a)pyrene diol epoxide-DNA adducts in sperm of men exposed to cigarette smoke. Fertil Steril 1999;72:330-335.
25.
Kennedy WR, Alter M, Sung JH: Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology 1968;18:671-680.
26.
La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH: Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991;352:77-79.
27.
La Spada AR, Roling DB, Harding AE, Warner CL, Spiegel R, Hausmanowa-Petrusewicz I, et al: Meiotic stability and genotype-phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy. Nat Genet 1992;2:301-304.
28.
Schmidt BJ, Greenberg CR, Allingham-Hawkins DJ, Spriggs EL: Expression of X-linked bulbospinal muscular atrophy (Kennedy disease) in two homozygous women. Neurology 2002;59:770-772.
29.
Lund A, Udd B, Juvonen V, Andersen PM, Cederquist K, Ronnevi LO, et al: Founder effect in spinal and bulbar muscular atrophy (SBMA) in Scandinavia. Eur J Hum Genet 2000;8:631-636.
30.
Chamberlain NL, Driver ED, Miesfeld RL: The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 1994;22:3181-3186.
31.
Beilin J, Ball EM, Favaloro JM, Zajac JD: Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell lines. J Mol Endocrinol 2000;25:85-96.
32.
Nenonen H, Bjork C, Skjaerpe PA, Giwercman A, Rylander L, Svartberg J, et al: CAG repeat number is not inversely associated with androgen receptor activity in vitro. Mol Hum Reprod 2010;16:153-157.
33.
Nenonen HA, Giwercman A, Hallengren E, Giwercman YL: Non-linear association between androgen receptor CAG repeat length and risk of male subfertility - a meta-analysis. Int J Androl 2011;34:327-332.
34.
Mouritsen A, Hagen CP, Sorensen K, Aksglaede L, Mieritz MG, Main KM, et al: Androgen receptor CAG repeat length is associated with body fat and serum SHBG in boys: a prospective cohort study. J Clin Endocrinol Metab 2013;98:E605-E609.
35.
Davis-Dao C, Koh CJ, Hardy BE, Chang A, Kim SS, De Filippo R, et al: Shorter androgen receptor CAG repeat lengths associated with cryptorchidism risk among Hispanic white boys. J Clin Endocrinol Metab 2012;97:E393-E399.
36.
Gao T, Marcelli M, McPhaul MJ: Transcriptional activation and transient expression of the human androgen receptor. J Steroid Biochem Mol Biol 1996;59:9-20.
37.
Lundin KB, Giwercman A, Richthoff J, Abrahamsson PA, Giwercman YL: No association between mutations in the human androgen receptor GGN repeat and inter-sex conditions. Mol Hum Reprod 2003;9:375-379.
38.
Lundin KB, Giwercman A, Dizeyi N, Giwercman YL: Functional in vitro characterisation of the androgen receptor GGN polymorphism. Mol Cell Endocrinol 2007;264:184-187.
39.
Aschim EL, Nordenskjold A, Giwercman A, Lundin KB, Ruhayel Y, Haugen TB, et al: Linkage between cryptorchidism, hypospadias, and GGN repeat length in the androgen receptor gene. J Clin Endocrinol Metab 2004;89:5105-5109.
40.
Giwercman YL, Kleist KE, Giwercman A, Giwercman C, Toft G, Bonde JP, et al: Remarkably low incidence of hypospadias in Greenland despite high exposure to endocrine disrupters; possible protective effect of androgen receptor genotype. Pharmacogenet Genomics 2006;16:375-377.
41.
Friborg JT, Melbye M: Cancer patterns in Inuit populations. Lancet Oncol 2008;9:892-900.
42.
Giwercman C, Giwercman A, Pedersen HS, Toft G, Lundin K, Bonde JP, et al: Polymorphisms in genes regulating androgen activity among prostate cancer low-risk Inuit men and high-risk Scandinavians. Int J Androl 2008;31:25-30.
43.
Giwercman A, Rylander L, Rignell-Hydbom A, Jonsson BA, Pedersen HS, Ludwicki JK, et al: Androgen receptor gene CAG repeat length as a modifier of the association between persistent organohalogen pollutant exposure markers and semen characteristics. Pharmacogenet Genomics 2007;17:391-401.
44.
Bjork C, Giwercman YL: Androgen receptor CAG repeat length modifies the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on receptor activity in human prostate cells. Reprod Toxicol 2013;35:144-149.
45.
Jeng HA, Chen YL, Kantaria KN: Association of cigarette smoking with reproductive hormone levels and semen quality in healthy adult men in Taiwan. J Environ Sci Health A Tox Hazard Subst Environ Eng 2014;49:262-268.
46.
Richthoff J, Elzanaty S, Rylander L, Hagmar L, Giwercman A: Association between tobacco exposure and reproductive parameters in adolescent males. Int J Androl 2008;31:31-39.
47.
Shi Z, Araujo AB, Martin S, O'Loughlin P, Wittert GA: Longitudinal changes in testosterone over five years in community-dwelling men. J Clin Endocrinol Metab 2013;98:3289-3297.
48.
Travison TG, Araujo AB, Kupelian V, O'Donnell AB, McKinlay JB: The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men. J Clin Endocrinol Metab 2007;92:549-555.
49.
Caserta D, Bordi G, Di Segni N, D'Ambrosio A, Mallozzi M, Moscarini M: The influence of cigarette smoking on a population of infertile men and women. Arch Gynecol Obstet 2013;287:813-818.
50.
Richthoff J, Elzanaty S, Rylander L, Hagmar L, Giwercman A: Association between tobacco exposure and reproductive parameters in adolescent males. Int J Androl 2008;31:31-39.
51.
Fariello RM, Pariz JR, Spaine DM, Gozzo FC, Pilau EJ, Fraietta R, et al: Effect of smoking on the functional aspects of sperm and seminal plasma protein profiles in patients with varicocele. Hum Reprod 2012;27:3140-3149.
52.
Ramlau-Hansen CH, Thulstrup AM, Aggerholm AS, Jensen MS, Toft G, Bonde JP: Is smoking a risk factor for decreased semen quality? A cross-sectional analysis. Hum Reprod 2007;22:188-196.
53.
Vine MF, Tse CK, Hu P, Truong KY: Cigarette smoking and semen quality. Fertil Steril 1996;65:835-842.
54.
Pasqualotto FF, Sobreiro BP, Hallak J, Pasqualotto EB, Lucon AM: Cigarette smoking is related to a decrease in semen volume in a population of fertile men. BJU Int 2006;97:324-326.
55.
de Jong AM, Menkveld R, Lens JW, Nienhuis SE, Rhemrev JP: Effect of alcohol intake and cigarette smoking on sperm parameters and pregnancy. Andrologia 2014;46:112-117.
56.
Sepaniak S, Forges T, Gerard H, Foliguet B, Bene MC, Monnier-Barbarino P: The influence of cigarette smoking on human sperm quality and DNA fragmentation. Toxicology 2006;223:54-60.
57.
Vinggaard AM, Hnida C, Larsen JC: Environmental polycyclic aromatic hydrocarbons affect androgen receptor activation in vitro. Toxicology 2000;145:173-183.
58.
Kizu R, Okamura K, Toriba A, Kakishima H, Mizokami A, Burnstein KL, et al: A role of aryl hydrocarbon receptor in the antiandrogenic effects of polycyclic aromatic hydrocarbons in LNCaP human prostate carcinoma cells. Arch Toxicol 2003;77:335-343.
59.
Andreucci A, Mocevic E, Jonsson BA, Giwercman A, Giwercman YL, Toft G, et al: Cadmium may impair prostate function as measured by prostate specific antigen in semen: a cross-sectional study among European and Inuit men. Reprod Toxicol 2015;53:33-38.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.