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REPRODUCTIVE AND DEVELOPMENTAL PHARMACOKINETIC AND MECHANISTIC RESEARCH
Impact/Purpose:
This effort provides data regarding the mode, or mechanism, of action for priority DBPs that perturb reproduction (e.g. pregnancy maintenance, fertility) and embryonic/fetal development. Additionally, considerable effort is underway to provide structure-activity relationships, particularly with regard to developmental effects. The overriding goal is to provide toxicological data which will either support or refute various associations between DBPs and the reproductive/developmental effects reported in epidemiologic studies recently.
Description:
In 1993, an expert panel convened by the EPA and the International Life Sciences Institute (ILSI) decided that: 1) screening studies should be implemented to fill critical data gaps; 2) fertility assessments should be enhanced; and 3) biomarkers of effect should be developed. More recently at a workshop convened by OW and NCEA it was decided that additional issues such as route of exposure, relevant animal models, mixtures of drinking water chemicals, and critical periods of reproductive development be addressed in future reproductive studies. On the epidemiologic front, two recent studies associated DBP exposures to spontaneous abortions (see Waller et al.) and still births (see Dodd et al.). Reproductive toxicology studies indicate that many DBPs, particularly the haloacids, alter spermatogenesis, fertility, and pubertal development in rats and rabbits. For dibromoacetic acid (DBA), dichloroacetic acid (DCA), and bromochloroacetic acid (BCA), similar alterations in spermatogenesis have been observed. Moreover, this was associated with reduced fertility and compromised expression of a novel sperm biomarker protein (SP22).
To determine whether haloacids that compromise spermatogenesis, SP22, and fertility in an additive fashion, we conducted an intensive binary mixture study using DBA and BCA. Effects were observed at the lowest doses (2 mg/kg DBA, 1.6 mg/kg BCA), and these effects were indeed additive. This study also compared SP22 quantitation by 2D-SDSPAGE and ELISA. That ELISA results were found to be comparable enables us to now use ELISA to assay SP22 levels in sperm extracts of men recruited in the UNC epidemiology study. This study will allow us to determine if semen quality is compromised in men exposed to varying levels of DBPs.