'Idiopathic' partial androgen insensitivity syndrome in 28 newborn and infant males: impact of prenatal exposure to environmental endocrine disruptor chemicals?

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Abstract

46,XY disorders of sex differentiation (46,XY DSD) can be due to a testis determination defect, an androgen biosynthesis defect, or androgen resistance (complete or partial androgen insensitivity syndrome (PAIS), or 5α reductase deficiency). We aimed to evaluate the impact of a prenatal contamination by environmental xenoestrogens in 'idiopathic' PAIS-like phenotype.

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Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism.

Michael Hutchison, M Fisken, Richard Sharpe … (2008)

Becoming a phenotypic male is ultimately determined by androgen-induced masculinization. Disorders of fetal masculinization, resulting in hypospadias or cryptorchidism, are common, but their cause remains unclear. Together with the adult-onset disorders low sperm count and testicular cancer, they can constitute a testicular dysgenesis syndrome (TDS). Although masculinization is well studied, no unifying concept explains normal male reproductive development and its abnormalities, including TDS. We exposed rat fetuses to either anti-androgens or androgens and showed that masculinization of all reproductive tract tissues was programmed by androgen action during a common fetal programming window. This preceded morphological differentiation, when androgen action was, surprisingly, unnecessary. Only within the programming window did blocking androgen action induce hypospadias and cryptorchidism and altered penile length in male rats, all of which correlated with anogenital distance (AGD). Androgen-driven masculinization of females was also confined to the same programming window. This work has identified in rats a common programming window in which androgen action is essential for normal reproductive tract masculinization and has highlighted that measuring AGD in neonatal humans could provide a noninvasive method to predict neonatal and adult reproductive disorders. Based on the timings in rats, we believe the programming window in humans is likely to be 8-14 weeks of gestation.

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Hermaphroditic, demasculinized frogs after exposure to the herbicide atrazine at low ecologically relevant doses.

T. Hayes, A. Collins, M. Lee … (2002)

Atrazine is the most commonly used herbicide in the U.S. and probably the world. It can be present at several parts per million in agricultural runoff and can reach 40 parts per billion (ppb) in precipitation. We examined the effects of atrazine on sexual development in African clawed frogs (Xenopus laevis). Larvae were exposed to atrazine (0.01-200 ppb) by immersion throughout larval development, and we examined gonadal histology and laryngeal size at metamorphosis. Atrazine (> or =0.1 ppb) induced hermaphroditism and demasculinized the larynges of exposed males (> or =1.0 ppb). In addition, we examined plasma testosterone levels in sexually mature males. Male X. laevis suffered a 10-fold decrease in testosterone levels when exposed to 25 ppb atrazine. We hypothesize that atrazine induces aromatase and promotes the conversion of testosterone to estrogen. This disruption in steroidogenesis likely explains the demasculinization of the male larynx and the production of hermaphrodites. The effective levels reported in the current study are realistic exposures that suggest that other amphibian species exposed to atrazine in the wild could be at risk of impaired sexual development. This widespread compound and other environmental endocrine disruptors may be a factor in global amphibian declines.

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Increasing incidence of testicular cancer worldwide: a review.

Eric Huyghe, Tomohiro Matsuda, Patrick F Thonneau (2003)

Testicular cancer (TC) is the most common malignancy in 20 to 34-year-old men. Numerous publications have shown an increase in the incidence of testis cancer in the last 40 years with substantial differences among countries. We evaluated worldwide variations in testicular cancer incidence and compared trends in different regions in the world. We reviewed 441 studies provided by a MEDLINE search using the key words testis/testicular, cancer/tumor and incidence that were published between 1980 and 2002. From these articles we selected only those devoted to testis cancer incidence and of them only the most recent studies from each country or region. Nevertheless, articles using the same data base but providing new and additional information, for example differences among ethnic groups or controversial explanations for trends, were also retained. We selected 30 articles and analyzed their methodological approach and main results. Worldwide we observed a clear trend toward an increased TC incidence in the last 30 years in the majority of industrialized countries in North America, Europe and Oceania. Nevertheless, surprising differences in incidence rates were seen between neighboring countries (Finland 2.5/100,000 cases versus Denmark 9.2/100,000) as well as among regions of the same country (2.8 to 7.9/100,000 according to various regional French registers). In addition, substantial differences in the TC incidence and trends were observed among ethnic groups. The increase in the TC incidence was significantly associated with a birth cohort effect in the United States and in European countries. To date except for cryptorchidism no evident TC risk factor has been clearly demonstrated, although the environmental hypothesis with a key role of endocrine disrupters has been put forward by several groups. Such a recent increase in the TC rate in most industrialized countries should lead urologists and andrologists to give more attention to testicular cancer symptoms in adolescents and young adults. In a public health perspective further research using cases collected through national and regional population based registers and case-control studies must be strongly encouraged if we wish to be able to assess future trends in TC incidence rates and also identify risk factors.