In utero exposure to di(n-butyl) phthalate and testicular dysgenesis: comparison of fetal and adult end points and their dose sensitivity.
BACKGROUND
Fetal exposure of male rats to di(n-butyl) phthalate (DBP) induces reproductive disorders similar to those in human testicular dysgenesis syndrome (TDS), including infertility, cryptorchidism, focal "dysgenetic areas," and Sertoli cell-only tubules in the adult testis. Humans are widely exposed to DBP, but at much lower levels than those causing adverse effects in rats.


OBJECTIVE
The objective of this study was to evaluate end points affected by DBP action in rats in fetal and adult life that are relevant to human TDS, and to compare their dose sensitivity.


METHODS
Pregnant rats were gavaged daily with corn oil (control) or with 4, 20, 100, or 500 mg/kg DBP. We examined adult end points of TDS (infertility, cryptorchidism) and indicators within the fetal testis of dysgenesis [abnormal Leydig cell (LC) aggregation, multinucleated gonocytes (MNGs)], as well as conditions that may result from these indicators in adulthood (occurrence of focal dysgenetic areas). Fetal testis weight and testicular testosterone levels were also evaluated.


RESULTS
The fetal end points analyzed (testicular testosterone levels, abnormal LC aggregation, occurrence of MNGs) were most sensitive to disruption by DBP, as all were significantly affected at a dose of 100 mg/kg/day DBP, with a trend toward effects occurring at 20 mg/kg/day DBP; adult end points were affected consistently only by 500 mg/kg/day DBP.


CONCLUSIONS
The fetal end points we evaluated can be objectively quantified and may prove helpful in evaluating the health risk of exposure to DBP and other phthalates, as well as identifying DBP-sensitive fetal events that have adult consequences/end points that are identifiable in human TDS.
Mahood
I Kim
IK
MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen's Medical Research Institute, Edinburgh, United Kingdom.
Scott
Hayley M
HM
Brown
Richard
R
Hallmark
Nina
N
Walker
Marion
M
Sharpe
Richard M
RM
D000818:Animals; D002449:Cell Aggregation / Q000187:drug effects; D003993:Dibutyl Phthalate / Q000008:administration & dosage / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D023381:Endpoint Determination; D005260:Female; D005854:Germ Cells / Q000187:drug effects / Q000378:metabolism; D006059:Gonadal Dysgenesis / Q000139:chemically induced*; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D013737:Testis / Q000187:drug effects* / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism
D003993:Dibutyl Phthalate; D013739:Testosterone