title: Modulation of acute steroidogenesis, peroxisome proliferator-activated receptors and CYP3A/PXR in salmon interrenal tissues by tributyltin and the second messenger activator, forskolin.
abstract: There are uncertainties regarding the role of sex steroids in sexual development and reproduction of gastropods, leading to the recent doubts as to whether organotin compounds do inhibit steroidogenic enzymes in these species. These doubts have led us to suspect that organotin compounds may affect other target molecules, particularly signal transduction molecules or secondary mediators of steroid hormone and lipid synthesis/metabolism. Therefore, we have studied the effects of TBT exposure through food on acute steroidogenesis, PPARs and CYP3A responses in the presence and absence of a cyclic AMP (cAMP) activator, forskolin. Two experiments were performed. Firstly, juvenile salmon were force-fed once with diet containing TBT doses (0.1, 1 and 10mg/kg fish) dissolved in ethanol and sampled after 72h. Secondly, fish exposed to solvent control and 10mg/kg TBT for 72h were transferred to new tanks and exposed to waterborne forskolin (200microg/L) for 2 and 4h. Our data show that juvenile salmon force-fed TBT showed modulations of multiple biological responses in interrenal tissues that include, steroidogenesis (cAMP/PKA activities; StAR and P450scc mRNA, and plasma cortisol), and mRNA for peroxisome proliferator-activated receptor (PPAR) isoforms (alpha, beta, gamma), acyl-CoA oxidase-1 (ACOX1) and CYP3A/PXR (pregnan X receptor). In addition, forskolin produced differential effects on these responses both singly and also in combination with TBT. Overall, combined forskolin and TBT exposure produced higher effects compared with TBT exposure alone, for most of the responses (cortisol, PPARbeta, ACOX1 and CYP3A). Interestingly, forskolin produced PPAR isoform-specific effects when given singly or in combination with TBT. Several TBT mediated toxicity in fish that includes thymus reduction, decrease in numbers of lymphocytes, inhibition of gonad development and masculinization, including the imposex phenomenon have been reported. When these effects are considered with the present findings, it suggests that studies on mechanisms of action or field studies may reveal endocrine, reproductive or other effects of TBT at lower concentrations than those reported to date from subchronic tests of fishes. Since the metabolic fate of organotin compounds may contribute to the toxicity of these chemicals, the present findings may represent some new aspects of TBT toxicity not previously reported.
authors.affiliation: Department of Biology, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Nela
authors.initials: N
authors.lastname: Pavlikova
authors.forename: Trond M
authors.initials: TM
authors.lastname: Kortner
authors.forename: Augustine
authors.initials: A
authors.lastname: Arukwe
mesh_terms: D042962:Acyl-CoA Oxidase; D000818:Animals; D001483:Base Sequence; D005576:Colforsin / Q000633:toxicity*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism*; D000077297:Pregnane X Receptor; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D020317:Salmo salar / Q000235:genetics / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D013256:Steroids / Q000096:biosynthesis*; D013997:Time Factors; D014220:Trialkyltin Compounds / Q000008:administration & dosage / Q000633:toxicity*; D014874:Water Pollutants, Chemical / Q000633:toxicity
chemical_list: D047492:Peroxisome Proliferator-Activated Receptors; D000077297:Pregnane X Receptor; D020033:Protein Isoforms; D012333:RNA, Messenger; D011987:Receptors, Steroid; D013256:Steroids; D014220:Trialkyltin Compounds; D014874:Water Pollutants, Chemical; D005576:Colforsin; C011559:tributyltin; D010088:Oxidoreductases; D051544:Cytochrome P-450 CYP3A; C107176:peroxisomal acyl-CoA oxidase; D042962:Acyl-CoA Oxidase; D017868:Cyclic AMP-Dependent Protein Kinases; D006854:Hydrocortisone