| In Utero Exposure to Di(n-butyl) Phthalate and Testicular Dysgenesis: Comparison of Fetal and Adult End Points and Their Dose Sensitivity
and Adult Endpoints and their Dose-Sensitivity I. Kim Mahood, Hayley M. Scott, Richard
Brown, Nina Hallmark, Marion Walker, and Richard M. Sharpe MRC Human Reproductive Sciences Unit,
Centre for Reproductive Biology, The Queen's Medical
Research Institute, Edinburgh,
United Kingdom Abstract
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. Objectives: 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. Key words: cryptorchidism, di(n-butyl) phthalate, dose response, dose sensitivity, dysgenetic areas, infertility, Leydig cell aggregation, male reproductive development, multinucleated gonocytes, testicular dysgenesis syndrome. Environ Health Perspect 115(suppl 1) :55–61 (2007) . doi:10.1289/ehp.9366 available via http://dx.doi.org/ [Online 8 June 2007]
Address correspondence to R.M. Sharpe, MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK. Telephone: 44 (0) 131 2426387. Fax: 44 (0) 131 242 6231. E-mail: r.sharpe@hrsu.mrc.ac.uk We thank M. Fisken for expert animal husbandry. This work was supported in part by grants QLK4-199-01422 and QLK4-CT-200-00603 from the European Union. The authors declare they have no competing financial interests. Received 22 May 2006 ; accepted 8 February 2007.
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