Advanced

Amniotic fluid INSL3 measured during the critical time window in human pregnancy relates to cryptorchidism, hypospadias, and phthalate load : A large case-control study

Anand-Ivell, Ravinder; Cohen, Arieh LU ; Nørgaard-Pedersen, Bent; Jönsson, Bo A.G. LU ; Bonde, Jens Peter; Hougaard, David M.; Lindh, Christian H. LU ; Toft, Gunnar; Lindhard, Morten S. and Ivell, Richard (2018) In Frontiers in Physiology 9(APR).
Abstract

The period of the first to second trimester transition in human pregnancy represents a sensitive window for fetal organogenesis, particularly in regard to the development of the male reproductive system. This is a time of relative analytical inaccessibility. We have used a large national biobank of amniotic fluid samples collected at routine amniocentesis to determine the impacts of exogenous endocrine disruptor load on specific fetal biomarkers at this critical time. While adrenal and testicular steroids are highly correlated, they are also mostly positively influenced by increasing phthalate load, represented by the metabolites 7cx-MMeHP and 5cx-MEPP, by perfluorooctane sulfonate (PFOS) exposure, and by smoking, suggesting an adrenal... (More)

The period of the first to second trimester transition in human pregnancy represents a sensitive window for fetal organogenesis, particularly in regard to the development of the male reproductive system. This is a time of relative analytical inaccessibility. We have used a large national biobank of amniotic fluid samples collected at routine amniocentesis to determine the impacts of exogenous endocrine disruptor load on specific fetal biomarkers at this critical time. While adrenal and testicular steroids are highly correlated, they are also mostly positively influenced by increasing phthalate load, represented by the metabolites 7cx-MMeHP and 5cx-MEPP, by perfluorooctane sulfonate (PFOS) exposure, and by smoking, suggesting an adrenal stress response. In contrast, the testis specific biomarkers insulin-like peptide 3 (INSL3) and androstenedione are negatively impacted by the phthalate endocrine disruptors. Using a case-control design, we show that cryptorchidism and hypospadias are both significantly associated with increased amniotic concentration of INSL3 during gestational weeks 13-16, and some, though not all steroid biomarkers. Cases are also linked to a specifically increased variance in the Leydig cell biomarker INSL3 compared to controls, an effect exacerbated by maternal smoking. No influence of phthalate metabolites or PFOS was evident on the distribution of cases and controls. Considering that several animal and human studies have shown a negative impact of phthalate load on fetal and cord blood INSL3, respectively, the present results suggest that such endocrine disruptors may rather be altering the relative dynamics of testicular development and consequent hormone production, leading to a desynchronization of tissue organization during fetal development. Being born small for gestational age appears not to impact on the testicular biomarker INSL3 in second trimester amniotic fluid.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Amniotic fluid, Cryptorchidism, Fetal steroids, Hypospadias, INSL3, PFOS, Phthalate, Testicular dysgenesis syndrome
in
Frontiers in Physiology
volume
9
issue
APR
publisher
Frontiers
external identifiers
  • scopus:85045916527
ISSN
1664-042X
DOI
10.3389/fphys.2018.00406
language
English
LU publication?
yes
id
51d8aa95-cd71-419c-8cfa-bc36a4d09dbc
date added to LUP
2018-05-04 08:58:49
date last changed
2019-01-06 13:53:22
@article{51d8aa95-cd71-419c-8cfa-bc36a4d09dbc,
  abstract     = {<p>The period of the first to second trimester transition in human pregnancy represents a sensitive window for fetal organogenesis, particularly in regard to the development of the male reproductive system. This is a time of relative analytical inaccessibility. We have used a large national biobank of amniotic fluid samples collected at routine amniocentesis to determine the impacts of exogenous endocrine disruptor load on specific fetal biomarkers at this critical time. While adrenal and testicular steroids are highly correlated, they are also mostly positively influenced by increasing phthalate load, represented by the metabolites 7cx-MMeHP and 5cx-MEPP, by perfluorooctane sulfonate (PFOS) exposure, and by smoking, suggesting an adrenal stress response. In contrast, the testis specific biomarkers insulin-like peptide 3 (INSL3) and androstenedione are negatively impacted by the phthalate endocrine disruptors. Using a case-control design, we show that cryptorchidism and hypospadias are both significantly associated with increased amniotic concentration of INSL3 during gestational weeks 13-16, and some, though not all steroid biomarkers. Cases are also linked to a specifically increased variance in the Leydig cell biomarker INSL3 compared to controls, an effect exacerbated by maternal smoking. No influence of phthalate metabolites or PFOS was evident on the distribution of cases and controls. Considering that several animal and human studies have shown a negative impact of phthalate load on fetal and cord blood INSL3, respectively, the present results suggest that such endocrine disruptors may rather be altering the relative dynamics of testicular development and consequent hormone production, leading to a desynchronization of tissue organization during fetal development. Being born small for gestational age appears not to impact on the testicular biomarker INSL3 in second trimester amniotic fluid.</p>},
  articleno    = {406},
  author       = {Anand-Ivell, Ravinder and Cohen, Arieh and Nørgaard-Pedersen, Bent and Jönsson, Bo A.G. and Bonde, Jens Peter and Hougaard, David M. and Lindh, Christian H. and Toft, Gunnar and Lindhard, Morten S. and Ivell, Richard},
  issn         = {1664-042X},
  keyword      = {Amniotic fluid,Cryptorchidism,Fetal steroids,Hypospadias,INSL3,PFOS,Phthalate,Testicular dysgenesis syndrome},
  language     = {eng},
  month        = {04},
  number       = {APR},
  publisher    = {Frontiers},
  series       = {Frontiers in Physiology},
  title        = {Amniotic fluid INSL3 measured during the critical time window in human pregnancy relates to cryptorchidism, hypospadias, and phthalate load : A large case-control study},
  url          = {http://dx.doi.org/10.3389/fphys.2018.00406},
  volume       = {9},
  year         = {2018},
}