US EPA

2718039 

Journal Article 

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, S; McKinnell, C; Calarrão, A; Kennedy, L; Hutchison, GR; Hrabalkova, L; Jobling, MS; Macpherson, S; Anderson, RA; Sharpe, RM; Mitchell, RT 

2015 

Yes 

Environmental Health Perspectives
ISSN: 0091-6765
EISSN: 1552-9924 

123 

3 

223-230 

English 

25514601 

10.1289/ehp.1408248 

WOS:000352167900012 

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.