**Environmental Toxicants Induced Male Reproductive Disorders: Identification and Mechanism of Action**

Kuladip Jana and Parimal C. Sen *Division of Molecular Medicine, Bose Institute, Kolkata, India* 

*"Several observations on poor trends in Male Reproductive Health have been reported during the last Decades. These difficult trends include the increasing prevalence of Testicular Cancer, Low and possibly declining Semen Quality, high and possibly rising frequencies of Cryptorchidism (Undescended Testis) and malformation of the Penis (Hypospadias) as well as a increasing demand for Assisted Reproduction".* 

### **1. Introduction**

472 Toxicity and Drug Testing

Kenny, J.R., Maggs, J.L., Tettey, J.N., Harrell, A.W., Parker, S.G., Clarke, S.E., & Park, B.K.

Kusuhara, H., & Sugiyama, Y. (2010). Pharmacokinetic modeling of the hepatobiliary

MacGregor, J.T., Collins, J.M., Sugiyama, Y., Tyson, C.A., Dean, J., Smith, L., Andersen, M.,

*Dispos,* Vol.33, No.2, pp. 271-281, ISSN 0090-9556

*Rev,* Vol.42, No.3, pp. 539-550, ISSN 1097-9883

1096-6080

1409-1417, ISSN 0090-9556

(2005). Formation and protein binding of the acyl glucuronide of a leukotriene B4 antagonist (SB-209247): relation to species differences in hepatotoxicity. *Drug Metab* 

transport mediated by cooperation of uptake and efflux transporters. *Drug Metab* 

Curren, R.D., Houston, J.B., Kadlubar, F.F., Kedderis, G.L., Krishnan, K., Li, A.P., Parchment, R.E., Thummel, K., Tomaszewski, J.E., Ulrich, R., Vickers, A.E., & Wrighton, S.A. (2001). In vitro human tissue models in risk assessment: report of a consensus-building workshop. *Toxicol Sci,* Vol.59, No.1, pp. 17-36, ISSN 1096-6080 MacIntyre, A.C., & Cutler, D.J. (1988). The potential role of lysosomes in tissue distribution of weak bases. *Biopharm Drug Dispos,* Vol.9, No.6, pp. 513-526, ISSN 0142-2782 Okumura, H., Katoh, M., Sawada, T., Nakajima, M., Soeno, Y., Yabuuchi, H., Ikeda, T.,

Tateno, C., Yoshizato, K., & Yokoi, T. (2007). Humanization of excretory pathway in chimeric mice with humanized liver. *Toxicol Sci,* Vol.97, No.2, pp. 533-538, ISSN

Commentary on metabolites in safety testing. *Drug Metab Dispos,* Vol.33, No.10, pp.

Physiologically Based Pharmacokinetic Models in Risk Assessment, In: *Toxicokinetics and Risk Assessment*, Lipscomb, J.C., & Ohanian, E.V. (Ed.), pp. 123-

Smith, D.A., & Obach, R.S. (2005). Seeing through the mist: abundance versus percentage.

Thompson, C., Sonawane, B., Nong, A., & Krishnan, K. (2007). Considerations for Applying

140, Informa Healthcare USA Inc., ISBN 978-0-8493-3722-2, New York, NY Ward, P. (2008). Importance of drug transporters in pharmacokinetics and drug safety.

*Toxicol Mech Methods,* Vol.18, No.1, pp. 1-10, ISSN 1537-6524

The phrase 'endocrine disruption' has seemingly become inextricably linked with terms like 'environmental oestrogens' and 'falling sperm counts'. While these connections aid understanding about these issues, they represent a simplified view of the field of endocrine disruption. There is currently no strong data to suggest that environmental endocrine disrupters (EDCs) are responsible for the observed disintegration in human male reproductive health, but there are secular trends to suggest that it is declining. There is, however, very good evidence that lifestyle factors (e.g. smoking, alcohol consumption and/or use of cosmetics) can have an impact on fertility (Sharpe & Franks 2002; Sharpe & Irvine, 2004). Similarly, the notion that all EDCs act by mimicking oestrogen (environmental oestrogens) is too simplistic. The current literature illustrates that EDCs can act as oestrogens, anti-oestrogens, anti-androgens, steroidogenic enzyme inhibitors and can also act via interaction with the thyroid hormones and their receptors, or within the brain and the hypothalamo–pituitary axis, as well as the immune system (Fisher, 2004; Jana et al., 2006; 2010a). Reports of declining sperm counts over the past 50 years and other disturbing trends alerted scientists to the possibility that exposure to chemicals in the environment may damage male reproductive health (Carlsen et al., 1992). Testicular cancer, the most common malignancy in men 15-44 years of age, has increased markedly in incidence in this century in virtually all countries studied. The incidence of hypospadias, a developmental malformation of the male urethra, appears to be increasing worldwide. Cryptorchidism (undescended testicle), another developmental defect, may have increased in some human populations and appears to be increasing in wildlife (Toppari et al., 1996; Fisher, 2004, Sharpe, 2010). The causes of these trends have not been identified and relevant toxicological data about male reproductive effects of environmental toxicants are limited. Recent research efforts have

Environmental Toxicants Induced

from Sharpe & Irvine, BMJ, 2004).

Male Reproductive Disorders: Identification and Mechanism of Action 475

Fig. 1. Routes of human exposure to some common environmental chemicals. DDE= 1, 1 dichloro-2, 2-bis (p- chlorophenyl) ethylene; DDT= dichlorodiphenyltrichloroethane; PAHs= polycyclic aromatic hydrocarbons; PCBs= polychlorinated biphenyls. (Modified

blood–testis barrier (BTB; Walker & Cheng, 2005). There are three major phases of spermatogenesis: (1) spermatogonial phase, (2) spermatocyte phase, and (3) spermatid phase (**Figure 2**). In the first phase the diploid spermatogonia undergo mitosis and create stem cells and diploid primary spermatocytes. During the second phase the primary spermatocytes undergo two rounds of meiosis, producing haploid spermatids. Finally, the spermatids begin a differentiation phase, sometimes referred to as spermiogenesis, during which the immature gametes develop into mature spermatozoa (O'Donnell et al., 2001). Spermatids continue their differentiation (spermiogenesis) while physically associated with the Sertoli cells. Spermiogenesis includes polarization of the spermatid, formation of the acrosome cap and flagellum, condensation, elongation of the nucleus, and cytoplasmic remodelling to produce the characteristic appearance of the mature spermatozoa. Spermatozoa are morphologically mature but immotile and are then released into the lumen of the seminiferous tubules (spermiation). At this stage these immotile testicular spermatozoa are not yet capable of fertilization (O'Donnell et al., 2001). The BTB between Sertoli cells comprises a co-existing tight junction (TJ), desmosome, gap junction and a testisspecific adherens junction (AJ) called the basal ectoplasmic specialization (ES). The basal ES is typified by the presence of actin filament bundles 'sandwiched' between the plasma membrane and the cisternae of endoplasmic reticulum in two neighbouring Sertoli cells.

focused on the possibility that exposures to hormonally active compounds, particularly during childhood and *in utero*, are to blame, at least in part, for changes in semen quality, increasing rates of testicular cancer, and malformations of the male urogenital tract (Sharpe, 2010). The ability to investigate environmental determinants of these indicators of male reproductive health is currently limited by available methodologies and data.
