Estrogenic and growth inhibitory responses to organophosphorus flame retardant metabolites in zebrafish embryos.

Recent evidence has revealed that organophosphorus flame retardants (OPFRs) elicit a variety of toxic effects, including endocrine disruption. The present study examined estrogenic and growth inhibitory responses to OPFR metabolites in comparison to their parent compounds using zebrafish eleutheroembryos.1 Exposure to 4-hydroxylphenyl diphenyl phosphate (HO-p-TPHP) but not its parent compound triphenyl phosphate (TPHP) elicited upregulation of a marker gene of estrogenic responses, cytochrome P450 19A1b (CYP19A1b), and this upregulation was reversed by co-exposure to an estrogen receptor antagonist. Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), as well as 3-hydroxylphenyl diphenyl phosphate (HO-m-TPHP) and diphenyl phosphate (DPHP), did not elicit significant changes in the CYP19A1b expression. Reduction in body length was induced by TPHP and to a lesser extent by its hydroxylated metabolites. Altered expression of genes involved in the synthesis and action of thyroid hormones, including iodothyronine deiodinases 1 and 2, thyroid hormone receptor alpha, and transthyretin, were commonly observed for TPHP and its hydroxylated metabolites. Reduction in the body length was also seen in embryos exposed to TDCIPP but not BDCIPP. The transcriptional effect of TDCIPP was largely different from that of TPHP, with decreased expression of growth hormone and prolactin observed only in TDCIPP-exposed embryos. Considering the concentration-response relationships for the growth retardation and gene expression changes, together with existing evidence from other researchers, it is likely that prolactin is in part involved in the growth inhibition caused by TDCIPP. The present study showed similarities and differences in the endocrine disruptive effects of OPFRs and their metabolites.

Developmental circulatory failure caused by metabolites of organophosphorus flame retardants in zebrafish, Danio rerio.

Organophosphate triesters are used worldwide as additives in flame retardants and plasticizer as a replacement of polybrominated diphenyl ethers. Increasing evidence on human exposure to and environmental contamination with organophosphorus flame retardants (OPFRs) requires an adequate toxicity assessment for this class of chemicals. While developmental toxicity of several OPFRs has been reported, developmental effects of OPFR metabolites have still to be understood. The present study aimed at characterizing developmental effects of OPFR metabolites using zebrafish embryos (Danio rerio). Triphenyl phosphate (TPHP) and two of its metabolites, 3-hydroxylphenyl diphenyl phosphate and 4-hydroxylphenyl diphenyl phosphate, were most potent for inducing pericardial edema and reduction in blood flow in trunk vessels. Other TPHP metabolites, such as diphenyl phosphate and 4-hydroxylphenyl phenyl phosphate, showed no substantial increase in circulatory failure at concentrations up to 30 µM. Tris (1,3-dichloro-2-propyl) phosphate showed circulatory failure at 30 µM, but its metabolite bis(1,3-dichloro-2-propyl) phosphate did not. Neither tris(2-chloroethyl) phosphate nor its metabolite bis(2-chloroethyl) phosphate, induced circulatory failure. The circulatory failure appeared to be enhanced with the increase in the octanol-water partition coefficients of OPFRs and their metabolites, suggesting that developmental circulatory failure posed by these chemicals could be estimated by their bioaccumulative potential. The present study demonstrated developmental circulatory failure of hydroxylated TPHP metabolites, which was almost equipotent to TPHP. Diester OPFR metabolites showed no major developmental toxicity at the concentrations used in this study. The current results establish the foundation for further understanding the similarities and differences in the toxic mechanisms between OPFRs and their metabolites.

Protective Effects of Hydrolyzed Nucleoproteins from Salmon Milt against Ethanol-Induced Liver Injury in Rats.

Dietary nucleotides play a role in maintaining the immune responses of both animals and humans. Oral administration of nucleic acids from salmon milt have physiological functions in the cellular metabolism, proliferation, differentiation, and apoptosis of human small intestinal epithelial cells. In this study, we examined the effects of DNA-rich nucleic acids prepared from salmon milt (DNSM) on the development of liver fibrosis in an in vivo ethanol-carbon tetrachloride cirrhosis model. Plasma aspartate transaminase and alanine transaminase were significantly less active in the DNSM-treated group than in the ethanol plus carbon tetrachloride (CCl4)-treated group. Collagen accumulation in the liver and hepatic necrosis were observed histologically in ethanol plus CCl4-treated rats; however, DNSM-treatment fully protected rats against ethanol plus CCl4-induced liver fibrosis and necrosis. Furthermore, we examined whether DNSM had a preventive effect against alcohol-induced liver injury by regulating the cytochrome p450 2E1 (CYP2E1)-mediated oxidative stress pathway in an in vivo model. In this model, CYP2E1 activity in ethanol plus CCl4-treated rats increased significantly, but DNSM-treatment suppressed the enzyme's activity and reduced intracellular thiobarbituric acid reactive substances (TBARS) levels. Furthermore, the hepatocytes treated with 100 mM ethanol induced an increase in cell death and were not restored to the control levels when treated with DNSM, suggesting that digestive products of DNSM are effective for the prevention of alcohol-induced liver injury. Deoxyadenosine suppressed the ethanol-induced increase in cell death and increased the activity of alcohol dehydrogenase. These results suggest that DNSM treatment represents a novel tool for the prevention of alcohol-induced liver injury.