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Temporal Decline of Sperm Concentration: Role of Endocrine Disruptors - Beyond the Abstract

Over the past half-century, there has been an adverse affect on male reproductive and sexual health, most evidenced by a decline in sperm concentration and total sperm count, as well as a rise in testicular dysgenesis syndrome manifested by an increase in testicular tumors and structural anomalies such as cryptorchidism and hypospadias.1-3 A recent study by Levine and colleagues has demonstrated that this decline in male fertility potential is a world wide phenomenon and is occurring at an accelerated rate.3

This study has highlighted the urgency to identify potential causes so that responsible factors can be reversed. There is a growing body of evidence that environmental conditions and exposure to endocrine disrupting chemicals (EDCs) may be responsible at least in some capacity. EDCs are thought to exert their deleterious effects by binding to hormone receptors, dysregulating the expression of receptors, disrupting steroidogenesis and hormonal metabolism, and altering epigenetic mechanisms.4-7 Population-based studies have found EDCs associated with poor semen quality, increased sperm DNA fragmentation, elevated gonadotropin levels, and testicular dysgenesis syndrome.2,8 The risk of adverse effects from exposure to EDCs appears to have a temporal manifestation starting with prenatal exposure and sustaining a cumulative effect throughout one's lifetime. Several EDCs have been implicated, namely bisphenol A, phthalates, polychlorinated biphenyls, polybrominated diphenyl esters, dichlorodiphenyldichloroethylene, pesticides, herbicides, organophosphates, and heavy metals.

Despite the evidence, it is difficult to make a definitive association in humans. Research on the impacts of EDCs has been impeded by the difficulty of evaluating exposure and the fact that the consequences of exposure manifest only after a lengthy latency period, making it challenging to demonstrate causation. Through the examination of a large number of previously published studies, our team was able to highlight the numerous difficulties associated with decoding the intricate connections between exposure to EDCs and the development of disease and disability across the lifetime. Many studies have limitations, such as their cross-sectional designs and the inaccuracy of their exposure assessment methods, which is especially true for chemicals with short half-lives and for which there is limited data. Confounding and complex mixtures of exposures and their inter-relationships are also other disputes. Further complicating issue in human research is our continuing ignorance of how chemicals are distributed and mobilized in response to physiological processes, as well as our inability to take precise measurements in specific target organs (such as the testis). Besides, in published papers, many studies focus solely on one type of chemical exposure or its metabolites. Despite advances in biostatistics, there is still no foolproof way to control for any potential vulnerabilities to which humans may be exposed. Differences in mixture composition and the high cost of analytical technology has prevented the comprehensive and simultaneous investigation of the thousands of natural and synthetic substances with endocrine effects.

New approaches to research design may help overcome some of these obstacles. What is missing to understand is if the increase in EDCs environmental concentration over time has a role in the temporal decline of sperm concentration and count occurring in the last decades and to assess if EDCs are able to affect the proliferation of pre-pubertal Sertoli cells. Ideally, this could be achieved using porcine pre-pubertal Sertoli cells, as experimental models have already been developed. The role of Sertoli cells in sustaining germ cell proliferation and differentiation has already been acknowledged. However, before puberty, these cells are immature and while, on the one hand, they have the ability to proliferate, on the other hand, they cannot support spermatogenesis. When puberty starts, they switch from an immature to a mature state; thus, they lose the capability to proliferate but acquire the capacity to sustain spermatogenesis. Factors limiting Sertoli cell proliferation during pre-puberty can potentially limit the subject's fertility capacity since the final number of Sertoli cells at puberty will be low. Therefore, a low number of germ cells will be supported. Thus, the patient will likely experience a condition of oligozoospermia. If EDCs decrease the proliferation of pre-pubertal porcine Sertoli cells, then a cause-effect relationship between EDCs exposure and the decline of sperm concentration over time can be supposed. Experimental models such as this will be the key to fully understanding the relationship between EDCs and male reproductive and sexual health.

Written by: Amarnath Rambhatla,1 Murat Gül,2 Rossella Cannarella,3,4 Ashok Agarwal5

  1. Vattikuti Urology Institute, Henry Ford Health, Detroit, MI, USA
  2. Department of Urology, Selcuk University School of Medicine, Konya, Turkey
  3. Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, OH, USA
  4. Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
  5. Global Andrology Forum, Cleveland, OH, USA

Reference:

  1. H. Levine, N. Jørgensen, A. Martino-Andrade, J. Mendiola, D. Weksler-Derri, I. Mindlis, R. Pinotti, S.H. Swan, Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum. Reprod. Update 23(6), 646–659 (2017)
  2. Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod. 2001 May;16(5):972-8.
  3. Levine H, Jørgensen N, Martino-Andrade A, Mendiola J, Weksler-Derri D, Jolles M, Pinotti R, Swan SH. Temporal trends in sperm count: a systematic review and meta-regression analysis of samples collected globally in the 20th and 21st centuries. Hum Reprod Update. 2022 Nov 15:dmac035.
  4. B.N. Karman, M.S. Basavarajappa, Z.R. Craig, J.A. Flaws, 2,3,7,8-Tetrachlorodibenzo-p-dioxin activates the aryl hydrocarbon receptor and alters sex steroid hormone secretion without affecting growth of mouse antral follicles in vitro. Toxicol. Appl. Pharmacol. 261(1), 88–96 (2012)
  5. W.R. Kelce, C.R. Stone, S.C. Laws, L.E. Gray, J.A. Kemppainen, E.M. Wilson, Persistent DDT metabolite p,p’-DDE is a potent androgen receptor antagonist. Nature 375(6532), 581–585 (1995)
  6. D.B. Martinez-Arguelles, M. Culty, B.R. Zirkin, V. Papadopoulos, In utero exposure to di-(2-ethylhexyl) phthalate decreases mineralocorticoid receptor expression in the adult testis. Endocrinology 150(12), 5575–5585 (2009)
  7. D. Gunnarsson, P. Leffler, E. Ekwurtzel, G. Martinsson, K. Liu, G. Selstam, Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes. Reprod. (Camb., Engl.) 135(5), 693–703 (2008)
  8. P.P. Chen, C. Liu, M. Zhang, Y. Miao, F.P. Cui, Y.L. Deng et al. Associations between urinary bisphenol A and its analogues and semen quality: A cross-sectional study among Chinese men from an infertility clinic. Environ. Int. 161, 107132 (2022)
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