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A Short-term In vivo Screen using Fetal Testosterone Production, a Key Event in the Phthalate Adverse Outcome Pathway, to Predict Disruption of Sexual Differentiation.
Furr, J., C. Lambright, V. Wilson, P. Foster, AND E. Gray. A Short-term In vivo Screen using Fetal Testosterone Production, a Key Event in the Phthalate Adverse Outcome Pathway, to Predict Disruption of Sexual Differentiation. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 140(2):403-424, (2014).
Phthalate esters (PEs) are a family of compounds used in a wide array of products including medical tubing, toys for children and adults, pharmaceuticals, personal care products, flooring and cables, for example. There are concerns about the potential effects of PEs on human health due to widespread indirect and direct exposures (Adibi et al 2003; Adibi et al 2008; Blount et al 2000; Silva et al 2004; Silva et al 2011) and the adverse developmental and reproductive effects seen in laboratory animal studies (Gray et al. 2000; Mylchreest et al 1998; Saillenfait et al. 2009b). Recent trends in PE indicate that while some human PE exposures are declining, others are increasing. For example, from 2001 to 2010 exposures to DEP’, DBP, BBP and DEHP have declined whereas DiBP, a reproductive toxicant in rats (Saillenfait et al 2008b), has increased by 260% (Zota et al. 2014). One would hope that as new PEs or alternatives replace older PEs in consumer products that well-studied, relatively nontoxic PEs are not• replaced by ones that are less well studied, and may be more toxic.
This study was designed to develop and validate a short-term in vivo protocol termed the Fetal Phthalate Screen (FPS) to detect phthalate esters (PEs) and other chemicals that disrupt fetal testosterone synthesis and testis gene expression in rats. We propose that the FPS can be used to screen chemicals that produce adverse developmental outcomes via disruption of the androgen synthesis pathway more rapidly and efficiently, and with fewer animals than a postnatal one-generation study. Pregnant rats were dosed from gestational day (GO) 14 to 18 at one dose level with one of 27 chemicals including PEs, PE alternatives,pesticides known to inhibit stero~ogenesis, an estrogen and a potent PPARa agonist and ex vivo testis testosterone production (T Prod) was measured on GO 18. We also included some chemicals with "unknown" activity including DMEP, DHeP, DHEH, DPHCH, DAP, TOTM, tetrabromo-diethyl hexyl phthalate (BrDEHP), and a relatively potent environmental estrogen BPAF. Dose response studies also were conducted with this protocol with 11 of the above chemicals to determine their relative potencies. CD-1 mice also were exposed to varying dose levels of DPeP from GO 13 to 17 to determine if OPeP reduced T Prod in this species since there is a discrepancy among the results of in utero studies of PEs in mice. Compared to the known male reproductive effects of the PEs in rats the FPS correctly identified all known "positives" and "negatives" tested. Seven of eight "unknowns" tested were "negatives", they did not reduce T Prod, whereas DAP produced an "equivocal" response. Finally, a dose-response study with DPeP in CD-1 mice revealed that fetal T Prod can be inhibited by exposure to aPE in utero in this species, but at a higher dose level than required in rats. Key words. Phthalate Syndrome, Fetal endocrine biomarkers, Phthalate adverse outcome pathway, testosterone production, fetal rat testis.