Cord blood insulin-like peptide 3 is reduced in idiopathic cryptorchidism: the missing link between fetal exposure to endocrine disruptors like bisphenol A and undescended testis?

Presentation Number: OR22-2
Date of Presentation: June 16th, 2013

Patrick Fenichel*1, Najiba Lahlou2, Patrick Coquillard3, Michel Marie Pugeat4, Patricia Pacini5, Patricia Ferrari6, Kathy Wagner7 and Francoise S Brucker-Davis8
1Universitary Hospital of Nice, Nice Cedex, France, 2Hopital Cochin, Paris, France, 3INRA-CNRS-Université de Nice, Sophia Antipolis, France, 4Hospices Civils de Lyon, Bron, France, 5Observatoire du développement durable de la ville de Nice, Nice, France, 6Universitary Hospital of Nice, Nice, France, 7GCSpediatrie cHU-Lenval, Nice, France, 8Hopital L'Archet 2, Nice, France

Abstract

Background Undescended testis (UDT), or cryptorchidism, is the most frequent congenital malformation in full-term male newborns and it carries an increased risk of hypofertility and testicular cancer. In most cases, UDT remains idiopathic but epidemiological and experimental studies have suggested the role of genetic and environmental factors. Fetal testicular descent is controlled by INSL3 and testosterone. In rodents, fetal exposure to estrogenic or antiandrogenic endocrine disrupting chemicals induces cryptorchidism. However, such environmental factors have never been demonstrated in humans. 

Methods In a prospective case control study from 2002 to 2005 at the Nice University Hospital, cord blood INSL3 (assessed by EIA) and testosterone (assessed by RIA) were measured and correlations with cord blood bisphenol A (assessed by RIA) and breast milk DDE, PCB 153, and mono- and dibutyl phthalates were calculated. These last were measured by gas chromatography coupled to mass spectrometry in 180  boys (52 cryptorchidic boys born after 34 weeks gestation: 26 transient and 26 persistent, as well as 128 controls matched for term, weight and time of birth

Findings INSL3 was decreased in the cryptorchidic boys (p=0.03), especially transient UDT (p=0.002), while testosterone was unchanged and LH was increased (p<0.056). In the whole population, LH correlated negatively with INSL3 (p=0.002). None of the Environmental Endocine Disrupors (EEDs) was significantly increased in the UDT group. However, in the whole population (n=180), BPA was inversely correlated with INSL3 (p=0.003). 

Interpretation INSL3 is a major actor in testicular descent. It is decreased in the cord blood of cryptorchidic newborns and is a specific marker of impaired Leydig cell function associated with fetal exposure to EEDs. As a xenoestrogen, BPA can repress INSL3 gene expression. This is the first time that a direct link between fetal exposure to EEDs, decreased INSL3, and cryptorchidism has been established in humans. Fetal exposure to a cocktail of EEDs with estrogenic and antiandrogenic effects should be considered as one of the cofactors, associated with genetic susceptibility, contributing to this frequent, complex and multifactorial disease.

 

Nothing to Disclose: PF, NL, PC, MMP, PP, PF, KW, FSB