Aroclor 1254 and BDE-47 inhibit dopaminergic function manifesting as changes in locomotion behaviors in zebrafish embryos.

Contamination with polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in the environment is a major concern due to their persistent bioaccumulative toxicity that can disturb neurobehavioral functions including movements. Recently, it was reported that some PBDE including BDE-47 stimulates locomotor activities of zebrafish embryos by unknown mechanism. In this study, motor movements of the zebrafish embryo were used as a model system to evaluate the neuronal toxicity of a non-coplanar PCB-dominant mixture (Aroclor 1254) and BDE-47. Both organohalogens increased tail shaking and rotation of embryos in a concentration-dependent manner. Chemical inhibition and gene knock-down of tyrosine hydroxylase and vesicular monoamine transporter 2 (VMAT2) also induced hyperactivities. Hyperactivities induced by these treatments were all inhibited by supplementation of l-tyrosine and l-dopa, precursors of dopamine synthesis. Both organohalogens reduced dopamine contents and increased the 3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine ratio in whole embryos. The results suggest that functional inhibition of dopaminergic neurons is involved in hyperactivities of zebrafish embryos caused by Aroclor 1254 and BDE-47.

Cyclic versus hemi-bastadins. pleiotropic anti-cancer effects: from apoptosis to anti-angiogenic and anti-migratory effects.

Bastadins-6, -9 and -16 isolated from the marine sponge Ianthella basta displayed in vitro cytostatic and/or cytotoxic effects in six human and mouse cancer cell lines. The in vitro growth inhibitory effects of these bastadins were similar in cancer cell lines sensitive to pro-apoptotic stimuli versus cancer cell lines displaying various levels of resistance to pro-apoptotic stimuli. While about ten times less toxic than the natural cyclic bastadins, the synthetically derived 5,5'-dibromohemibastadin-1 (DBHB) displayed not only in vitro growth inhibitory activity in cancer cells but also anti-angiogenic properties. At a concentration of one tenth of its in vitro growth inhibitory concentration, DBHB displayed actual antimigratory effects in mouse B16F10 melanoma cells without any sign of cytotoxicity and/or growth inhibition. The serum concentration used in the cell culture media markedly influenced the DBHB-induced antimigratory effects in the B16F10 melanoma cell population. We are currently developing a specific inhalation formulation for DBHB enabling this compound to avoid plasmatic albumin binding through its direct delivery to the lungs to combat primary as well as secondary (metastases) tumors.

Assessment of possible carcinogenicity of oxyfluorfen to humans using mode of action analysis of rodent liver effects.

Oxyfluorfen is a herbicide that is not genotoxic and produces liver toxicity in rodents, following repeated administration at high dose levels. Lifetime rodent feeding studies reported in 1977 with low-purity oxyfluorfen (85%) showed no increase in any tumor type in rats (800 ppm, high dose) and only a marginally increased incidence of hepatocellular tumors in male CD-1 mice at the highest dose (200 ppm). To evaluate the potential carcinogenicity of the currently registered oxyfluorfen (> 98% purity), we conducted a series of short-term liver mode of action (MOA) toxicology studies in male CD-1 mice administered dietary doses of 0, 40, 200, 800, and 1600 ppm for durations of 3, 7, 10, or 28 days. MOA endpoints examined included liver weight, histopathology, cell proliferation, nuclear receptor-mediated gene expression, and other peroxisome proliferator-specific endpoints and their reversibility. Minimal liver effects were observed in mice administered doses at or below 200 ppm for up to 28 days. Increased liver weight, single-cell necrosis, cell proliferation, and peroxisomal acyl-CoA oxidase (ACO) were observed at 800 ppm after 28 days, but there was no increase in peroxisomes. Expression of Cyp2b10 and Cyp4a10 transcripts, markers of constitutive androstane receptor and peroxisome proliferator activated receptor α nuclear receptor activation, respectively, were increased at 800 and 1600 ppm after 3 or 10 days. Collectively, these data along with the negative genotoxicity demonstrate that oxyfluorfen (> 98% purity) has the potential to induce mouse liver tumors through a nongenotoxic, mitogenic MOA with a clear threshold and is not predicted to be carcinogenic in humans at relevant exposure levels.