AREHNA (Awareness Raising about Environment and Health of Non Expert Advisors)

Workshop: Environmental impact on Congenital Diseases

Kos island in the Aegean sea from 2005 June, 9-11

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Environmental impact on congenital diseases:the case of cryptorchidism

where are we now, and where are we going?

Cryptorchidism is the most frequent abnormality of male sexual differentiation, and it is generally agreed that the incidence of this congenital disorder is increasing in many industrialized

countries (Toppari, 1996; Boisen, 2004).

As yet, there are no obvious reasons which could explain this phenomenon. Numerous

epidemiological studies have been conducted during recent decades to identify risk factors for

cryptorchidism (low birth weight, low parity, twinship, uteroplacental malfunction) and to explain

the rising incidence, but without any really convincing results (Huyghe, 2003).

Increasing evidence of a link between various male reproductive health

issues

Besides the rising incidence of cryptorchidism, we have also observed a recent marked increase in hypospadias and testicular germ cell cancer rates and a decline in semen

quality, with strong regional differences between industrialized countries (Carlsen, 1992).

The current hypothesis, mainly developed by Skakkebaek (Skakkebaek, 2003) and colleagues (Hoei-Hansen, 2003; Holm, 2003), is that all these male reproductive disorders

are interrelated, forming the testicular dysgenesis syndrome (TDS).

TDS may have different clinical or biological expressions (hypospadias, cryptorchidism, testis cancer, infertility), but all arise from the same syndrome which originates

during fetal development.

This being so, any type of endocrine disruptor which could lead to imbalance within the male endocrine system during the period of pregnancy will have potentially

damaging consequences on reproductive tract development.

Another question which remains to be solved is the relationship between use of potent estrogens, probable decrease

of androgen levels, and genital tract abnormalities.

II. Toxic effect of anti-androgenic compounds on male reproductive health

The evidence-based central role of Sertoli cells and androgen production in testis and male

reproductive tract development

• After activation of the sex-determining region of the Y chromosome, the differentiation of Sertoli cells constitutes the main signal, and these cells both drive and lead the orientation of testis development (Koopman, 1990, 2001; Capel, 2000). Regression of the Müllerian duct is mediated by Sertoli-cell secretion of anti-Müllerian hormone (AMH), and the Sertoli cell is certainly also responsible for the blockage of germ cells entering the oogenic pathway. The differentiation of Leydig cells is also induced by the Sertoli cell.

• Androgens play a key role in maintenance of the Wolffian duct which differentiates into the epididymis, vas deferens and seminal vesicles, with masculinization mediated by testosterone. Masculinization of the external genital organs and prostate is controlled by dihydrotestosterone (DHT), a testosterone metabolite produced by the action of the 5alpha-reductase enzyme.

A non-exhaustive list of environmental chemicals with anti-androgenic effects

• First of all, we must point out that the large majority of published works in this domain have been performed in pregnant rodents, and that human data, whether epidemiological investigations or in vivo studies, are very scarce.

• Nevertheless, the following environmental compounds, more and less widely used in industrialized countries, have demonstrated (in animals) their potential ability to inhibit the action of androgen receptors or testosterone synthesis: vinclozolin, a dicarboximide fungicide with anti-androgenic properties (Gray, 2001, Wolf, 2000); linuron, a herbicide and androgen receptor antagonist (McIntyre, 2002); p,p’DDE and methoxychlor (derivatives of the DDT pesticide), considered as androgen and/or estrogen receptor antagonists; phthalates (mainly used in the cosmetic and manufacturing industries), which have several major impacts on androgen regulation (Fisher, 2004; Mylchreest, 2002; Mylchreest, 2000).

• Two interesting studies on phthalate exposure and its consequences should be mentioned. Firstly, a study performed in the USA showed higher levels of phthalate metabolites in women of reproductive age compared with the rest of the population (Blount, 2000). Secondly, similar histological changes have been observed in testicular biopsies in patients with TDS and after in utero phthalate exposure (Skakkebaek, 2003; Hoei-Hansen, 2003).

Limited data on environmental impact of

cryptorchidism in humans

The story of DES

The best documented adverse effects of estrogens concern the use of DES, a nonsteroidal estrogenic substance, in

pregnant women to prevent abortion complications (Brackbill & Berendes, 1978; Stillman, 1982).

DES is associated with undescended testes in male offspring (Gill, 1979; Wilcox, 1995).

Epidemiological studies(occupational and environmental conditions)

In a spatial ecological study undertaken in the province of Granada, Spain, the authors observed that orchidopexy tended to be more frequent in districts where the family was involved in intensive farming and pesticide spraying (Garcia-Rodriguez, 1996).

In Denmark, in a register-based case-control study of parental occupation, the authors found that sons of women working in gardening had a significantly higher risk of cryptorchidism (Weidner, 1998).

In Hungary, higher frequency of undescended testes was reported in newborns of mothers living closest to a factory producing vinyl chloride monomer and acrylonitrile (manufacture of stiffened plastic tubes and cartons used for the packaging of margarine) (Czeizel, 1999).

• Where do we go from here, and how can we answer the question?

If we assume that the incidence of cryptorchidism is increasing in many industrialized countries (which is a

plausible hypothesis), and if we are also convinced that cryptorchidism, hypospadias, germ cell testicular cancer

and decreasing semen quality are on the same continuum of TDS, involving in utero exposure to

endocrine disruptors (which is not so evident for sperm decline), we must rapidly perform appropriately designed

studies to identify what kind of environmental components could be involved, how their properties or derivatives may interfere with male endocrine system

balance, and certainly also to define the exact exposure window during the pregnancy period (Sharpe, 2001).

Hopefully, cryptorchidism is quite a good model. The relatively high frequency of cryptorchidism and the short period between in utero exposure and endpoint are strong

arguments for pursuing research into this malformation.

Epidemiologically speaking, it is much more difficult and costly to undertake a prospective study and to enroll and follow

several hundred thousand pregnant women (to have enough cases of cryptorchidism) than to perform

appropriate case-control studies.

So far, we have several different and reasonable hypotheses concerning the potential impact of some environmental compounds (phthalates for example) on cryptorchidism

during pregnancy. So, the key questions are how to identify and assess maternal exposure to these compounds, and how to evaluate the anti-androgenic properties of these

compounds or of their derivatives.

Finally, if we want to be able to solve the question of a potential impact of our environment on

reproductive health, we definitely need close collaboration between scientists in fields as

different as chemistry, toxicology, endocrinology, andrology and epidemiology! Furthermore, the link

between in vitro and in vivo models must be developed, as well as collaboration with scientists

working with various animal species and those involved in human studies.

In conclusion, and taking all these factors into account, cryptorchidism is certainly an excellent

potential indicator and may potentially provide an answer to the key question of the impact of some

environmental pollutants on male reproductive health.

Welcome to the next EAA Congress in Toulouse in 2006