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

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

Research output: Contribution to journalArticlepeer-review


BACKGROUND: Phthalate exposure induces germ cell effects in the rat fetal testis. Whilst experimental models have shown that the human fetal testis is insensitive to the steroidogenic effects of phthalates, the effects on germ cells are less explored.

OBJECTIVES: To identify the effects of phthalate exposure on human fetal germ cells in a dynamic model and to establish if the rat is an appropriate model for investigating such effects.

METHODS: Immunohistochemistry, immunofluorescence and quantitative real-time PCR for Sertoli and germ cell markers on vehicle/di(n-butyl) phthalate (DBP)-exposed rat testes and human fetal testis xenografts. This 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. The mechanism for germ cell aggregation/MNG induction appears to be loss of Sertoli-germ cell membrane adhesion, probably due to Sertoli cell microfilament redistribution.

CONCLUSIONS: Our findings provide the first comparison of DBP effects in vivo on germ cell number, differentiation and aggregation in human and rat. They show comparable effects on germ cells in both species, but the effects in the human were muted compared with the rat. Nevertheless, phthalate effects on germ cells have potential implications for the next generation, which merits further study. Our results show that the rat is a human-relevant model in which to explore the mechanisms for germ cell effects.

Original languageEnglish
JournalEnvironmental Health Perspectives
Early online date16 Dec 2014
Publication statusPublished - 1 Mar 2015


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