Comparative Effects of Di(n-Butyl) Phthalate Exposure on Fetal Germ Cell Development in the Rat and in Human Fetal Testis Xenografts

van den Driesche, Sander; McKinnell, Chris; Calarr�o, Ana; Kennedy, Laura; Hutchison, Gary R.; Hrabalkova, Lenka; Jobling, Matthew S.; Macpherson, Sheila; Anderson, Richard A.; Sharpe, Richard M.; Mitchell, Rod T.

Abstract

Background: Phthalate exposure induces germ cell effects in the fetal rat testis. Although experimental models have shown that the human fetal testis is insensitive to the steroidogenic effects of phthalates, the effects on germ cells have been less explored.
Objectives: We sought to identify the effects of phthalate exposur on human fetal germ cellsin a dynamic model and to establish whether the rat is an appropriate model for investigatingsuch effects.
Methods: We used immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction to examine Sertoli and germ cell markers on rat testes and human fetal testis xenografts after exposure to vehicle or di(n‑butyl) phthalate (DBP). Our study included analysis of germ cell differentiation markers, proliferation markers, and cell adhesion proteins.
Results: In both rat and human fetal testes, DBP exposure induced similar germ cell effects, namely, germ cell loss (predominantly undifferentiated), induction of multinucleated gonocytes
(MNGs), and aggregation of differentiated germ cells, although the latter occurred rarely in the human testes. The mechanism for germ cell aggregation and MNG induction appears to be loss of Sertoli cell–germ cell membrane adhesion, probably due to Sertoli cell microfilament redistribution.
Conclusions: Our findings provide the first comparison of DBP effects on germ cell number, differentiation, and aggregation in human testis xenografts and in vivo in rats. We observed comparable effects on germ cells in both species, but the effects in the human were muted compared with those in the rat. Nevertheless, phthalate effects on germ cells have potential implications for the next generation, which merits further study. Our results indicate that the rat is a human-relevant model in which to explore the mechanisms for germ cell effects.

• Journal Article Type: Article
• Acceptance Date: Dec 12, 2014
• Online Publication Date: Dec 16, 2014
• Publication Date: May 1, 2015
• Deposit Date: May 1, 2019
• Publicly Available Date: May 29, 2019
• Journal: Environmental Health Perspectives
• Print ISSN: 0091-6765
• Electronic ISSN: 1552-9924
• Publisher: National Institute of Environmental Health Sciences
• Peer Reviewed: Peer Reviewed
• Volume: 123
• Issue: 3
• Pages: 223-230
• DOI: https://doi.org/10.1289/ehp.1408248
• Keywords: Phthalate exposure, fetus, testis, embryology.
• Public URL: http://researchrepository.napier.ac.uk/Output/1749485
• Contract Date: May 29, 2019