Dietary exposure of juvenile female mice to polyhalogenated seafood contaminants (HBCD, BDE-47, PCB-153, TCDD): Comparative assessment of effects in potential target tissues F. Maranghi a,⇑ , R. Tassinari a,1 , G. Moracci a,2 , I. Altieri b,3 , J.D. Rasinger c , T.S. Carroll d , C. Hogstrand d , A.-K. Lundebye c , A. Mantovani a,4 a Food and Veterinary Toxicology Unit, Veterinary Public Health and Food Safety Dept., Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy b Food Chemical Safety and Human Health Unit, Veterinary Public Health and Food Safety Dept., Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy c National Institute of Nutrition and Seafood Research (NIFES), Bergen, Norway, PO Box 2029, Nordnes, 5817 Bergen, Norway d Diabetes and Nutritional Sciences Division, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK article info Article history: Received 13 September 2012 Accepted 28 February 2013 Available online 14 March 2013 Keywords: Thyroid Thymus Feed Steroid hormones Liver abstract Fish represents source of nutrients and major dietary vehicle of lipophilic persistent contaminants. The study compared the effects of two legacy and two emerging fish pollutants (Hexabromocyclododecane HBCD; 2,2 0 ,4,4 0 -Tetrabromodiphenyl ether BDE-47; 2,2 0 ,4,4 0 ,5,5 0 -Hexachlorobiphenyl PCB-153; 2,3,7,8- Tetrachlorodibenzo-p-doxin TCDD) in juvenile female mice exposed through a salmon based rodent diet for 28 days (dietary doses: HBCD 199 mg/kg bw/day; BDE-47 450 lg/kg bw/day; PCB-153 195 lg/kg bw/ day; TCDD 90 ng/kg bw/day). Dose levels were comparable to previously reported developmental Lowest Observed Adverse Effect Levels. None of the treatments elicited signs of overt toxicity, but HBCD increased relative liver weight. All compounds caused changes in liver, thymus and thyroid; spleen was affected by BDE-47 and PCB-153; no effects were seen in uterus and adrenals. Strongest effects in thyroid follicles were elicited by PCB-153, in thymus and liver by BDE-47. HBCD and BDE-47 induced liver fatty changes, but appeared to be less potent in the other tissues. HBCD, BDE-47 and TCDD increased serum testosterone levels and the testosterone/estradiol ratio, suggesting a potential involvement of pathways related to sex steroid biosynthesis and/or metabolism. The results support the role of toxicological studies on juvenile rodents in the hazard characterization of chemicals, due to endocrine and/or immune effects. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction In many countries fish represents an important source of nutri- ents (FAO/WHO, 2011; EFSA, 2005). Due to the high lipid content in comparison to other species, both wild and farmed oily fish (e.g. herring, mackerel, tuna and salmon) are – at the same time – a die- tary source of long chain n-3 polyunsaturated fatty acids and tend also to accumulate lipophilic contaminants such as persistent or- ganic pollutants (POPs); therefore they represent a significant source of human exposure (EFSA, 2012). POPs include compounds regularly monitored in feeds and foods, such as dioxins and poly- chlorinated biphenyls (PCBs) as well as compounds that have still to be included in routine food control programmes, such as some brominated flame retardants (BFRs). BFR include hexabromocyclododecane (HBCD) (EFSA, 2011a) and polybrominated diphenyl ethers (PBDEs) (EFSA, 2011b). The 2,2 0 ,4,4 0 Tetrabromodiphenyl ether (BDE-47) congener is a major contributor to dietary intake and human body burden (EPA, 2008); main targets of PBDE and HBCD toxicity are the liver (e.g. hepatic enzyme induction), thyroid (reduced hormone levels and gland hyperplasia) as well as the reproductive, nervous and im- mune system (EFSA, 2011b). Dioxins, including 2,3,7,8 Tetrachlorodibenzo-p-doxin (TCDD) and dioxin-like PCBs are thoroughly investigated POPs, due to their widespread distribution and high toxicity; main targets are the 0278-6915/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.fct.2013.02.056 Abbreviations: BDE-47, 2,2 0 4,4 0 Tetrabromodiphenyl ether; BFR, brominated flame retardants; Bw, body weight; DMSO, dimethylsulfoxide; E2, 17-beta estra- diol; EU, European Union; HBCD, hexabromocyclododecane; LOAEL, Lowest Observed Adverse Effect Level; NDL, non dioxin-like; PBDEs, polybrominated diphenyl ethers; PCBs, polychlorinated biphenyls; PCB-153, 2,2 0 4,4 0 5,5 0 Hexachlo- robiphenyl; PM, post-mortem; POPs, persistent organic pollutants; SD, Standard Deviation; T, testosterone; TCDD, 2,3,7,8 Tetrachlorodibenzo-p-doxin. ⇑ Corresponding author. Tel.: +39 06 49902527; fax: +39 06 49902658. E-mail addresses: francesca.maranghi@iss.it (F. Maranghi), roberta.tassinari@iss. it (R. Tassinari), gabriele.moracci@iss.it (G. Moracci), ilaria.altieri@iss.it (I. Altieri), jra@nifes.no (J.D. Rasinger), thomas.carroll@kcl.ac.uk (T.S. Carroll), christer. hogstrand@kcl.ac.uk (C. Hogstrand), aha@nifes.no (A.-K. Lundebye), alberto. mantovani@iss.it (A. Mantovani). 1 Tel.: +39 06 49902528; fax: +30 06 49387099. 2 Tel.: +39 06 49902540; fax: +30 06 49387099. 3 Tel.: +39 06 49902650; fax: +39 06 49903686. 4 Tel.: +39 06 49902815; fax: +39 06 49902658. Food and Chemical Toxicology 56 (2013) 443–449 Contents lists available at SciVerse ScienceDirect Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtox