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Submitted on April 25, 2006
Accepted on August 9, 2006
MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
* To whom correspondence should be addressed. E-mail: r.sharpe{at}hrsu.mrc.ac.uk.
This study investigated effects of in utero exposure (e13.5-e21.5) to di(n-butyl) phthalate (DBP) on fetal gonocytes and postnatal germ cell (GC) development in rats and focused on changes (delayed development) relevant to the postulated origins of human carcinoma-in situ (CIS) cells. DBP treatment resulted in both early (e15.5-e17.5) and late (e19.5-e21.5) effects on gonocytes. The former involved delayed entry of proliferating gonocytes into quiescence, as indicated by prolongation/overexpression of OCT3/4, retinoblastoma protein (Rb) phosphorylated at Ser 807/811 and Ki67, plus a 2- to 4-fold increase in gonocyte apoptosis. The late effect of DBP was to induce a >10-fold increase in occurrence of multinucleated gonocytes (MNG). GC numbers in DBP-exposed males were reduced (P < 0.01) by 37%, 53%, 79% and 80% at e21.5 and postnatal d4, d8 and d15 respectively, with recovery to normal in scrotal testes between d25 and d90. The DBP-induced decrease in GC numbers at d4-8 was associated with delayed exit from quiescence, as indicated by Rb expression and by a 28% reduction (P < 0.001) in GC proliferation index at d6, though the latter was increased by 84% at d25. The postnatal GC changes were associated with the early, but not the late, effects of DBP on gonocytes as ‘short-term’ DBP treatment from e19.5-e20.5, induced MNG as effectively as did treatment from e13.5-e20.5, but did not reduce GC numbers on d4. In conclusion, fetal DBP exposure delays normal GC development in both fetal (as early as e15.5) and postnatal life with the possibility of consequences for fertility.
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