The Toxicologist - Society of Toxicology

transport (72% of control). MRP2 transport was only inhibited by genistein (75%
of control). None of the chemicals tested altered MRP5-mediated transport.
Additional studies demonstrated that metabolites of methoxychlor (including
HPTE and mono OH-methoxychlor) inhibited BCRP transport in membrane
vesicles. Preliminary cytotoxicity studies suggested that BCRP mediates direct
transport of genistein and zearalonone in BCRP-expressing HEK293 cells as evidenced
by increased cytotoxicity of both chemicals in the presence of the BCRP inhibitor,
Ko143. Inhibition of BCRP function in the placenta by endocrine disrupting
chemicals may increase exposure of the fetus to environmental contaminants
and pharmaceuticals and enhance susceptibility to developmental adverse events.
Ongoing studies are investigating the ability of BCRP in placenta cells to transport
endocrine disrupting chemicals at environmentally-relevant concentrations
(Supported by ES-005022).
1048 THE EFFECTS OF TRIS (2-ETHYLHEXYL)
TRIMELLITATE (TOTM) ON GENE EXPRESSION
ASSOCIATED WITH TESTICULAR MAL-
DEVELOPMENT (TMD) IN RAT FETAL TESTES.
C. R. Elcombe 1 , D. Dan 1 , D. G. Farrar 2 and S. M. Plummer 1 . 1 CXR Biosciences,
Dundee, United Kingdom and 2 INEOS Chlor Limited, Runcorn, United Kingdom.
To assess the potential of tris (2-ethylhexyl) trimellitate (TOTM) to induce testicular
mal-development (TMD) in the rat we studied its effects on expression of genes
in steroidogenesis/testes development pathways, thought to be involved in TMD
induction by certain phthalates. The effects of TOTM were compared with those of
di(2-ethylhexyl phthalate (DEHP), mono-(2-ethylhexyl) phthalate (MEHP), an
active metabolite of DEHP, and with 2-ethyl hexanol (EHO), considered to be an
‘inactive’ DEHP metabolite. Wistar rats were exposed to TOTM, MEHP, DEHP,
EHO (500 mg/Kg) or corn oil (vehicle) in utero by oral gavage to pregnant dams on
gestational days (GD) 12-19. A low-dose DEHP (0.25mg/Kg) treatment group was
also included as DEHP can be a minor contaminant of the technical grade of
TOTM. Whole Rat Genome Microarrays were used to screen for gene expression
changes in TMD pathways using RNA isolated from GD19 fetal testes. MEHP &
DEHP (500 mg/Kg) caused a repression of genes in TMD pathways involved in
cholesterol synthesis and transport (HMGCS, HMGCR, StAR, SCARB1, FDFT1,
FDPS), steroidogenesis (Cyp11a, Cyp17a, 3βHSD1, SC4MOL) and testes positioning/function
(INSL3, INHA). EHO, induced weak repression StAR,
HMGCS, INHA and SCARB1, but did not repress Cyp 11a, Cyp17a, 3βHSD1,
SC4MOL or INSL3. By contrast TOTM or DEHP (0.25mg/Kg) did not cause a
significant repression of TMD-pathway genes. We conclude that TOTM, and its
technical grade, would be unlikely to cause testicular dysgenesis in foetal rats under
these treatment conditions. The effects of EHO can be partly rationalised on the
basis of it being a weak PPARα agonist. Our recent work on mechanisms of phthalate-induced
TMD suggests that the ability of certain phthalates to repress steroidogenic
genes, including StAR, is mediated by direct binding of PPARα to the promoter
regions of steroidogenic genes (Plummer et al (2010) The Toxicologist CD,
114:1488). This work was supported by INEOS Enterprises Limited, Polynt SpA,
Oxea Deutschland GmBh and Novasol N.V/S.A.
1049 EPIVAGINAL TISSUE MODEL FOR PRECLINICAL
SCREENING OF SINGLE OR REPEAT EXPOSURE TO
VAGINALLY APPLIED CHEMICALS/FORMULATIONS.
C. Cannon, M. Klausner, S. Ayehunie, A. Wang, K. LaRosa and T. Landry.
MatTek Corp, Ashland, MA. Sponsor: P. J.
A predictive test system for assessing the vaginal irritation potential of chemicals
and formulations will have far reaching application in the testing of feminine care
products. The vaginal mucosa is commonly exposed to chemicals and therapeutic
agents that may result in irritation/inflammation which can make women susceptible
to infections such as HIV-1 and HSV-2. Hence, chemical or therapeutic agent
induced vaginal irritation is a public health concern. In the current study, we investigated
whether the highly differentiated EpiVaginal TM tissue of normal human
vaginal/ectocervical cells could be used as a non-animal alternative for the FDA approved
rabbit vaginal irritation (RVI) assay. The tissue was exposed to 1X (24 hr) or
5X (1 hr/day for 5 days) to 6 test articles (TA). Tissue viability (MTT assay), barrier
disruption (measured by trans-epithelial electrical resistance, TEER and sodium
fluorescein (FL) leakage), and inflammatory cytokine release (IL-1α, IL-1β, IL-6,
and IL-8) were examined. Two irritating TA, benzalkonium chloride (BC) and
nonoxynol 9 (N9), reduced tissue viability to