Skip to main content
SpringerLink
Log in

Environmental Impact on the Hypothalamus-Pituitary-Testis Axis

  • Living reference work entry
  • First Online:
Environmental Endocrinology and Endocrine Disruptors

Part of the book series: Endocrinology ((ENDOCR))

  • 22 Accesses

Abstract

Many andrological pathologies seen in adults, including infertility, actually arose in younger age, due to the strong susceptibility and vulnerability of male gonad to external insults, starting from gestation age and during all growth phases. Three main phases are particularly susceptible for subsequent normal testis development and function: the intrauterine phase, the neonatal phase comprising the so called minipuberty, and puberty. However, even during infancy, when the testes are apparently “sleeping,” damaging causes with permanent effects on testicular function can occur. Among risk factors for alterations of sexual and reproductive organs and function, endocrine-disrupting chemicals (EDCs) have gained particular attention in last decades, given their ability to disrupt them at different levels and at different ages, with long-term consequences and possibly also transgenerational effects. Bisphenol, phthalates, perfluoroalkyl substances, heavy metals, and dioxins are particularly intriguing, given the strong experimental evidence of effects on hormone nuclear receptors, hypothalamus-pituitary-testis axis, and direct action on spermatogenesis and steroidogenesis. Although epidemiological studies in humans have shown controversial and inconsistent results, the overall conclusion points toward a positive association between exposure to EDCs and alteration of the reproductive system.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Similar content being viewed by others

References

  • Abreu AP, Kaiser UB. Pubertal development and regulation. Lancet Diabetes Endocrinol. 2016;4:254–64.

    Article  Google Scholar 

  • Aggerholm AS, Thulstrup AM, Toft G, Ramlau-Hansen CH, Bonde JP. Is overweight a risk factor for reduced semen quality and altered serum sex hormone profile? Fertil Steril. 2008;90(3):619–26.

    Article  CAS  Google Scholar 

  • Bach CC, Vested A, Jørgensen KT, Bonde JP, Henriksen TB, Toft G. Perfluoroalkyl and polyfluoroalkyl substances and measures of human fertility: a systematic review. Crit Rev Toxicol. 2016;46(9):735–55. https://doi.org/10.1080/10408444.2016.1182117.

    Article  CAS  Google Scholar 

  • Barr DB, Silva MJ, Kato K, Reidy JA, Malek NA, Hurtz D, et al. Assessing human exposure to phthalates using monoesters and their oxidized metabolites as biomarkers. Environ Health Perspect. 2003;111:1148–51.

    Article  Google Scholar 

  • Biegel LB, Liu RCM, Hurtt ME, Cook JC. Effects of ammonium perfluorooctanoate on Leydig-cell function: in vitro, in vivo, and ex vivo studies. Toxicol Appl Pharmacol. 1995;134:18–25.

    Article  CAS  Google Scholar 

  • Bonde JP, Flachs EM, Rimborg S, Glazer CH, Giwercman A, Ramlau-Hansen CH, Hougaard KS, Høyer BB, Hærvig KK, Petersen SB, Rylander L, Specht IO, Toft G, Bräuner EV. The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis. Hum Reprod Update. 2016;23(1):104–25.

    Article  Google Scholar 

  • Cargnelutti F, Di Nisio A, Pallotti F, Sabovic I, Spaziani M, Tarsitano MG, Paoli D, Foresta C. Effects of endocrine disruptors on fetal testis development, male puberty, and transition age. Endocrine. 2020. https://doi.org/10.1007/s12020-020-02436-9.

  • Chen X, Liu YN, Zhou QH, Leng L, Chang Y, Tang NJ. Effects of low concentrations of Di-(2-ethylhexyl) and mono-(2-ethylhexyl) phthalate on steroidogenesis pathways and apoptosis in the murine Leydig tumor cell line MLTC-1. Biomed Environ Sci. 2013;26:986–9.

    CAS  Google Scholar 

  • Conder JM, Hoke RA, De Wolf W, Russell MH, Buck RC. Are PFCAs bioaccumulative? A critical review and comparison with regulatory criteria and persistent lipophilic compounds. Environ Sci Technol. 2008;42:995–1003.

    Article  CAS  Google Scholar 

  • Corona G, Sansone A, Pallotti F, et al. People smoke for nicotine, but lose sexual and reproductive health for tar: a narrative review on the effect of cigarette smoking on male sexuality and reproduction [published online ahead of print, 2020 Apr 22]. J Endocrinol Investig. 2020;43:1391. https://doi.org/10.1007/s40618-020-01257-x.

    Article  CAS  Google Scholar 

  • de Angelis C, Galdiero M, Pivonello C, et al. The environment and male reproduction: the effect of cadmium exposure on reproductive function and its implication in fertility. Reprod Toxicol. 2017;73:105–27. https://doi.org/10.1016/j.reprotox.2017.07.021.

    Article  CAS  Google Scholar 

  • De Toni L, De Rocco PM, Petre GC, Rtibi K, Di Nisio A, Foresta C. Bisphenols and male reproductive health: from toxicological models to therapeutic hypotheses. Front Endocrinol (Lausanne). 2020;11:301. Published 2020 Jun 4. https://doi.org/10.3389/fendo.2020.00301.

    Article  Google Scholar 

  • Desdoits-Lethimonier C, Albert O, Le Bizec B, Perdu E, Zalko D, Courant F, et al. Human testis steroidogenesis is inhibited by phthalates. Hum Reprod. 2012;27:1451–9.

    Article  CAS  Google Scholar 

  • Di Nisio A, Foresta C. Water and soil pollution as determinant of water and food quality/contamination and its impact on male fertility. Reprod Biol Endocrinol. 2019;17(1):4.

    Article  Google Scholar 

  • Di Nisio A, Sabovic I, Valente U, Tescari S, Rocca MS, Guidolin D, Dall’Acqua S, Acquasaliente L, Pozzi N, Plebani M, Garolla A, Foresta C. Endocrine disruption of androgenic activity by perfluoroalkyl substances: clinical and experimental evidence. J Clin Endocrinol Metab. 2019;104(4):1259–71.

    Article  Google Scholar 

  • Fan J, Traore K, Li W, Amri H, Huang H, Wu C, et al. Molecular mechanisms mediating the effect of mono-(2-Ethylhexyl) phthalate on hormone-stimulated steroidogenesis in MA-10 mouse tumor Leydig cells. Endocrinology. 2010;151:3348–62.

    Article  CAS  Google Scholar 

  • Foresta C, Tescari S, Di Nisio A. Impact of perfluorochemicals on human health and reproduction: a male’s perspective. J Endocrinol Investig. 2018;41(6):639–45.

    Article  CAS  Google Scholar 

  • Formosa R, Vassallo J. The complex biology of the aryl hydrocarbon receptor and its role in the pituitary gland. Horm Cancer. 2017;8(4):197–210. https://doi.org/10.1007/s12672-017-0300-y.

    Article  CAS  Google Scholar 

  • Galloway T, Cipelli R, Guralnik J, Ferrucci L, Bandinelli S, Corsi AM, Money C, McCormak P, Merlzer D. Daily bisphenol A excretion and associations with sex hormone concentrations: results from the InCHIANTI adult population study. Environ Health Perspect. 2010;118:1603–8.

    Article  CAS  Google Scholar 

  • Garolla A, Torino M, Miola P, Caretta N, Pizzol D, Menegazzo M, Bertoldo A, Foresta C. Twenty-four-hour monitoring of scrotal temperature in obese men and men with a varicocele as a mirror of spermatogenic function. Hum Reprod. 2015;30(5):1006–13.

    Article  CAS  Google Scholar 

  • Gore AC, Chappell VA, Fenton SE, Flaws JA, Nadal A, Prins GS, Toppari J, Zoeller RT. EDC-2: the Endocrine Society’s second scientific statement on endocrine-disrupting chemicals. Endocr Rev. 2015;36(6):E1–E150.

    Article  CAS  Google Scholar 

  • Gould JC, Leonard LS, Maness SC, Wagner BL, Conner K, Zacharewski T, Safe S, McDonnell DP, Gaido KW. Bisphenol A interacts with the estrogen receptor alpha in a distinct manner from estradiol. Mol Cell Endocrinol. 1998;142:203–14.

    Article  CAS  Google Scholar 

  • Gunnarsson D, Leffler P, Ekwurtzel E, Martinsson G, Liu K, Selstam G. Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes. Reproduction. 2008;135:693–703.

    Article  CAS  Google Scholar 

  • Gurmeet K, Rosnah I, Normadiah MK, Das S, Mustafa AM. Detrimentaleffects of bisphenol A on development and functions of the male reproductive system in experimental rats. EXCLI J. 2014;13:151–60.

    Google Scholar 

  • Hanaoka T, Kawamura N, Hara K, Tsugane S. Urinary bisphenol A and plasma hormone concentrations in male workers exposed to bisphenol A diglycidyl ether and mixed organic solvents. Occup Environ Med. 2002;59:625–8.

    Article  CAS  Google Scholar 

  • Hu Y, Dong C, Chen M, Lu J, Han X, Qiu L, et al. Low-dose monobutyl phthalate stimulates steroidogenesis through steroidogenic acute regulatory protein regulated by SF-1, GATA-4 and C/EBP-beta in mouse Leydig tumor cells. Reprod Biol Endocrinol. 2013;11:72.

    Article  CAS  Google Scholar 

  • La Rocca C, Alessi E, Bergamasco B, Caserta D, Ciardo F, Fanello E, et al. Exposure and effective dose biomarkers for perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in infertile subjects: preliminary results of the PREVIENI project. Int J Hyg Environ Health. 2012;215:206–11.

    Article  Google Scholar 

  • La Rocca C, Tait S, Guerranti C, Busani L, Ciardo F, Bergamasco B, et al. Exposure to endocrine disruptors and nuclear receptors gene expression in infertile and fertile men from Italian areas with different environmental features. Int J Environ Res Public Health. 2015;12:12426–45.

    Article  Google Scholar 

  • La Vignera S, Condorelli RA, Vicari E, D’Agata R, Calogero AE. Effects of the exposure to mobile phones on male reproduction: a review of the literature. J Androl. 2012;33(3):350–6. https://doi.org/10.2164/jandrol.111.014373.

    Article  Google Scholar 

  • Lan HC, Wu KY, Lin IW, Yang ZJ, Chang AA, Hu MC. Bisphenol A disrupts steroidogenesis and induces a sex hormone imbalance through c-Jun phosphorylation in Leydig cells. Chemosphere. 2017;185:237–46.

    Article  CAS  Google Scholar 

  • López-Doval S, Salgado R, Pereiro N, Moyano R, Lafuente A. Perfluorooctane sulfonate effects on the reproductive axis in adult male rats. Environ Res. 2014;134:158–68.

    Article  Google Scholar 

  • López-Doval S, Salgado R, Lafuente A. The expression of several reproductive hormone receptors can be modified by perfluorooctane sulfonate (PFOS) in adult male rats. Chemosphere. 2016;155:488–97.

    Article  Google Scholar 

  • Martinez-Arguelles DB, Campioli E, Culty M, Zirkin BR, Papadopoulos V. Fetal origin of endocrine dysfunction in the adult: the phthalate model. J Steroid Biochem Mol Biol. 2013 Sep;137:5–17. https://doi.org/10.1016/j.jsbmb.2013.01.007. Epub 2013 Jan 17. PMID: 23333934.

  • Martinez-Arguelles DB, Papadopoulos V. Prenatal phthalate exposure: epigenetic changes leading to lifelong impact on steroid formation. Andrology. 2016;4(4):573–84. https://doi.org/10.1111/andr.12175.

    Article  CAS  Google Scholar 

  • Meeker JD, Ferguson KK. Urinary phthalate metabolites are associated with decreased serum testosterone in men, women, and children from NHANES 2011-2012. J Clin Endocrinol Metab. 2014;99:4346–52.

    Article  CAS  Google Scholar 

  • Meeker JD, Calafat AM, Hauser R. Urinary metabolites of Di(2-ethylhexyl) phthalate are associated with decreased steroid hormone levels in adult men. J Androl. 2009 May-Jun;30(3):287–97. https://doi.org/10.2164/jandrol.108.006403

  • Mehrpour O, Karrari P, Zamani N, Tsatsakis AM, Abdollahi M. Occupational exposure to pesticides and consequences on male semen and fertility: a review. Toxicol Lett. 2014;230(2):146–56. https://doi.org/10.1016/j.toxlet.2014.01.029.

    Article  CAS  Google Scholar 

  • Murata M, Kang JH. Bisphenol A and all cell signaling pathways. Biotechnol Adv. 2017;36:311–27.

    Article  Google Scholar 

  • Pallotti F, Pelloni M, Gianfrilli D, Lenzi A, Lombardo F, Paoli D. Mechanisms of testicular disruption from exposure to bisphenol A and Phtalates. J Clin Med. 2020;9(2) pii: E471

    Google Scholar 

  • Pereiro N, Moyano R, Blanco A, Lafuente A. Regulation of corticosterone secretion is modified by PFOS exposure at different levels of the hypothalamic–pituitary–adrenal axis in adult male rats. Toxicol Lett. 2014;230:252–62.

    Article  CAS  Google Scholar 

  • Peretz J, Vrooman L, Ricke WA, Hunt PA, Ehrlich S, Hauser R, Padmanabhan V, Taylor HS, Swan SH, VandeVoort CA, Flaws JA. Bisphenol a and reproductive health: update of experimental and human evidence, 2007–2013. Environ Health Perspect. 2014;122:775–86.

    Article  Google Scholar 

  • Sansone A, Di Dato C, de Angelis C, et al. Smoke, alcohol and drug addiction and male fertility. Reprod Biol Endocrinol. 2018;16(1):3. Published 2018 Jan 15. https://doi.org/10.1186/s12958-018-0320-7.

    Article  CAS  Google Scholar 

  • Savchuk I, Söder O, Svechnikov K. Mono-2-Ethylhexyl phthalate stimulates androgen production but suppresses mitochondrial function in mouse Leydig cells with different steroidogenic potential. Toxicol Sci. 2015;145:149–56.

    Article  CAS  Google Scholar 

  • Sharpe RM. Environmental/lifestyle effects on spermatogenesis. Philos Trans R Soc Lond B Biol Sci. 2010;365:1697–712.

    Article  CAS  Google Scholar 

  • Shi Z, Zhang H, Liu Y, Xu M, Dai J. Alterations in gene expression and testosterone synthesis in the testes of male rats exposed to perfluorododecanoic acid. Toxicol Sci. 2007;98:206–15.

    Article  CAS  Google Scholar 

  • Sifakis S, Mparmpas M, Soldin OP, Tsatsakis A. Pesticide exposure and health related issues in male and female reproductive system. In: Stoytcheva M, editor. Pesticides—formulations, effects, fate. Rijeka, Croatia: InTech; 2011. p. 495–526.

    Google Scholar 

  • Sikka SC, Wang R. Endocrine disruptors and estrogenic effects on male reproductive axis. Asian J Androl. 2008a;10(1):134–45. https://doi.org/10.1111/j.1745-7262.2008.00370.x.

    Article  CAS  Google Scholar 

  • Sikka SC, Wang R. Endocrine disruptors and estrogenic effects on male reproductive axis. Asian J Androl. 2008b;10(1):134–45. https://doi.org/10.1111/j.1745-7262.2008.00370.x.

    Article  CAS  Google Scholar 

  • Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod. 2001;16:972–8.

    Article  CAS  Google Scholar 

  • Skakkebaek NE, Rajpert-De Meyts E, Buck Louis GM, Toppari J, Andersson AM, Eisenberg ML, Jensen TK, Jørgensen N, Swan SH, Sapra KJ, Ziebe S, Priskorn L, Juul A. Male reproductive disorders and fertility trends: influences of environment and genetic susceptibility. Physiol Rev. 2016;96:55–97.

    Article  CAS  Google Scholar 

  • Vandenberg LN, Hunt PA, Myers JP, vomSaal FS. Human exposures to bisphenol A: mismatches between data and assumptions. Rev Environ Health. 2013;28:37–58.

    Article  CAS  Google Scholar 

  • Wan HT, Zhao YG, Wong MH, Lee KF, Yeung WSB, Giesy JP, et al. Testicular signaling is the potential target of perfluorooctanesulfonate-mediated subfertility in male Mice1. Biol Reprod. 2011;84:1016–23.

    Article  CAS  Google Scholar 

  • Wolff MS, Engel SM, Berkowitz GS, Ye X, Silva MJ, Zhu C, et al. Prenatal phenol and phthalate exposures and birth outcomes. Environ Health Perspect. 2008;116:1092–7.

    Article  CAS  Google Scholar 

  • Zhang T, Sun H, Kannan K. Blood and urinary bisphenol A concentrations in children, adults, and pregnant women from China: partitioning between blood and urine and maternal and fetal cord blood. Environ Sci Technol. 2013;47:4686–94.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, Italy

    Andrea Di Nisio, Christian Corsini & Carlo Foresta

Authors
  1. Andrea Di Nisio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christian Corsini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carlo Foresta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carlo Foresta .

Editor information

Editors and Affiliations

  1. Endocrinology and Metabolism Dept., University of Naples Federico II, NAPOLI, Napoli, Italy

    Rosario Pivonello

  2. Endocrinology and Diabetes Department, National and Kapodistrian University of, Athens, Greece

    Evanthia Diamanti-Kandarakis

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Nature Switzerland AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Di Nisio, A., Corsini, C., Foresta, C. (2022). Environmental Impact on the Hypothalamus-Pituitary-Testis Axis. In: Pivonello, R., Diamanti-Kandarakis, E. (eds) Environmental Endocrinology and Endocrine Disruptors. Endocrinology. Springer, Cham. https://doi.org/10.1007/978-3-030-38366-4_8-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-38366-4_8-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-38366-4

  • Online ISBN: 978-3-030-38366-4

  • eBook Packages: Springer Reference MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation