23/11/2014 Endocrine disruption in the human fetal testis: use of a xenograft system to assess effects of exposure to environmental agents

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The Lancet, Volume 381, Page S77, 27 February 2013

doi:10.1016/S0140‐6736(13)60517‐6

Copyright © 2013 Elsevier Ltd All rights reserved.

Endocrine disruption in the human fetal testis: use of a xenograft

system to assess effects of exposure to environmental agents and
pharmaceutical drugs
Dr RT Mitchell a , RA Anderson a, CJH Kelnar b, WHB Wallace b, C McKinnell a, RM Sharpe a

Abstract
Background
Many environmental chemicals have been proposed as endocrine disruptors in the fetal testis. Studies in rats have
demonstrated reproductive abnormalities after in‐utero exposure to environmental chemicals (eg, phthalates) or
pharmaceutical drugs such as paracetamol. Whether such effects also occur in the human fetal testis has been difficult to
determine. We have recently demonstrated that xenografting of human fetal testis tissue results in normal seminiferous
cord formation and cellular development/function. We aimed to determine the effects of proposed endocrine disruptors
(eg, phthalates, paracetamol) on the human fetal testis using a xenograft approach.

Methods
Human fetal testes (14—20 weeks’ gestation, n=17) obtained from elective terminations were xenografted into nude mice.
Host mice received di‐n‐butyl phthalate (500 mg/kg/day), paracetamol (350 mg/kg/day), or vehicle during the grafting
period. Testosterone production was determined by measurement of host animal seminal vesicle weight. Morphological and
immunohistochemical analysis with a range of markers was performed to investigate seminiferous cord structure,
steroidogenesis, and cellular development.

Findings
Exposure to paracetamol resulted in a significant reduction in seminal vesicle weight (mean 13·6 mg [SD 8·5] vs 10·0 [5·4],
p<0·01). Expression of 3β hydroxysteroid dehydrogenase (3β‐HSD) was also decreased in paracetamol compared with vehicle
treated grafts. Exposure to di‐n‐butyl phthalate did not result in a reduction in testosterone or 3β‐HSD expression in human
xenografts (in contrast to rats); however, testosterone independent germ cell effects were demonstrated with a reduction
in gonocytes in di‐n‐butyl phthalate exposed grafts compared with vehicle (mean 13% [SD 11·6] vs 23 [11·3], p<0·05).

Interpretation
These results suggest that paracetamol may impair testosterone production in the human fetal testis, whereas phthalates
do not. This highlights important differences between rat and man in terms of the effects of chemical exposure on the
developing testis.

Funding
Wellcome Trust and British Society for Paediatric Endocrinology and Diabetes.

a Edinburgh University/MRC Centre for Reproductive Health, Edinburgh, UK

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23/11/2014 Endocrine disruption in the human fetal testis: use of a xenograft system to assess effects of exposure to environmental agents and pharmaceutical drugs …
b Edinburgh University, Department of Child Life and Health, Edinburgh, UK
Correspondence to: Dr Rod Mitchell, Centre for Reproductive Health, Queens Medical Research Institute, 47 Little France Crescent,
Edinburgh EH16 4TJ, UK

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