Citation:

Arzuaga Andino, X., A. Hotchkiss, AND T. Walker. Mode of action and human relevance evaluation of Dibutyl Phthalate (DBP)-induced male reproductive system toxicity-Poster. US EPA Board of Scientific Counselors Chemical Safety Subcommittee Meeting, Research Triangle Park, North Carolina, April 10 - 11, 2019.

Impact/Purpose:

The objective of this poster is to present a case study for evaluation of mechanistic evidence to ascertain the biological plausibility and human relevance of dibutyl phthalate-induced effects in male reproductive effects.

Description:

In vivo studies using various rat strains have shown that dibutyl phthalate (DBP), a phthalate ester used as a plasticizer, alters normal development of the male reproductive system by disrupting androgen synthesis during the masculinization programming window. However, studies using human xenograft models (fetal testicular tissue implanted in rodent hosts) report that DBP exposure does not affect androgen synthesis in developing male human fetal tissue. These findings question the relevance of the rat model for assessment of potential DBP-induced male reproductive effects in humans. In the current work, a mode of action (MOA) framework was used to evaluate the available evidence from in-vivo, in-vitro, and xenograft studies on DBP-induced toxicity to the male reproductive system. The proposed framework relies on established biochemical, molecular, cellular, and endocrine mechanisms which control gestational and post-natal development of the male reproductive system. Experimental studies on DBP-induced male reproductive effects were evaluated for biological plausibility as well as consistency across different species and life stages. Three conclusions were identified: (1) rats appear to be more responsive than other rodent species to DBP-induced anti-androgenic effects during gestation; (2) androgen-independent adverse responses to fetal DBP exposure are conserved among different mammalian experimental models (including rats) and human xenografts; and (3) anti-androgenic effects induced by DBP are conserved in different rodent species and non-human primates when exposure occurs during post-natal life stages. This analysis also identified data gaps, such as additional information on the specific molecular targets for DBP which activate cellular responses and lead to adverse male reproductive outcomes. Considering the similarities in male reproductive effects caused by various phthalates, the resulting MOA analysis for DBP may be useful in the evaluation of toxicological and mechanistic data on other phthalates. The views expressed are those of the authors and do not necessarily represent the views or policies of the US EPA.

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