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


1
  • 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
  • -------------------------------------------
  • Environmental impact on congenital diseases
  • the case of cryptorchidism
  • where are we now, and where are we going?

2
  • 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).

3
  • 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).

4
  • 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.

5
  • Another question which remains to be solved is
    the relationship between use of potent estrogens,
    probable decrease of androgen levels, and genital
    tract abnormalities.

6
  • II. Toxic effect of anti-androgenic compounds on
    male reproductive health

7
  • 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.

8
  • 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,pDDE 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).

9
  • 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).

10
  • 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).

11
  • 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).

12
  • 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.

13
  • 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.

14
Welcome to the next EAA Congress in Toulouse in
2006
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