Rat strain response differences upon exposure to technical or alpha hexabromocyclododecane.

Hexabromocyclododecane (HBCD) is a brominated flame retardant which was recommended by a UN expert body under the Stockholm Convention to be eliminated from the global marketplace in 2011; however, due to its ability to persist in the environment, undergo long-range transport and bioaccumulate, it remains a concern for human health. The commercial mix of HBCD (T-HBCD) consists of α-HBCD, ß-HBCD and γ-HBCD. Although the γ-HBCD (79%) isomer is the predominant isomer of T-HBCD, the most bioaccumulative isomer detected in mammals is the α-HBCD isomer. This study was undertaken to investigate three rat strains treated with commercial grade (technical) HBCD or HBCD enriched with the α isomer (A-HBCD) and to examine strain- and sex-related differences in response to exposure. Female Sprague Dawley (SD), Wistar (WI) and Fischer F344 (FI) rats were exposed for 28 days to either T-HBCD or A-HBCD in feed, at doses of 0, 250, 1250 and 5000 mg/kg diet. The FI rodent strain was found to be the most sensitive to effects of HBCD based on the greatest number of significantly affected endpoints which indicated that T-HBCD primarily affected liver and thyroid, resulting in multiple health effects. Consequently, male FI were included in the study and exposed to T- and A-HBCD. Histopathological data supports previously reported effects of HBCD on the thyroid and endocrine system although the effects in FI rats are significantly elevated compared to other strains. As with T-HBCD, liver and thyroid were found to be target organs of A-HBCD. Sex differences, specifically in tissue concentration levels, immune response parameters and in number and severity of thyroid and liver lesions, following exposure to either T- or A-HBCD were apparent, with treatment eliciting a greater response in males. Residue analysis revealed that α-HBCD is more bioaccumulative than γ-HBCD in all rodent strains, with levels of HBCD in animals treated with A-HBCD several fold higher for all tissues tested (7-11 fold at the highest dose). Thus, residue data supports the selective uptake (implies there are differences in bioavailability and/or bioaccumulation; is this the case or do certain isomers simply have a longer half-life) of specific isomers, with α-HBCD > γ-HBCD. Taken together, our study highlights the importance of selecting the most appropriate strain and of including both sexes in studies to ensure that sex-related differences in response to test chemical is taken into consideration. Moreover, ours is the first study to show the effects of a sub-acute exposure to a diet containing only HBCD enriched for the α isomer, which better represents the isomer ratios present in the biota due to bioaccumulation.

An in vitro model of innate lymphoid cell function and differentiation.

Innate lymphoid cells (ILC) are RAG-independent lymphocytes with important roles in innate immunity, and include group-1 (natural killer (NK) cell, ILC1), group-2 (ILC2), and group-3 (lymphoid tissue inducer (LTi), NCR(+) ILC3) subsets. Group-3 ILC express Rorγt, produce interleukin (IL)-22, and are critically important in the normal function of mucosal tissues. Here, we describe a novel model cell line for the study of ILC function and differentiation. The parental MNK cell line, derived from NKR-P1B(+) fetal thymocytes, shows a capacity to differentiate in γc cytokines. One IL-7-responsive subline, designated MNK-3, expresses Rorγt and produces high levels of IL-22 in response to IL-23 and IL-1ß stimulation. MNK-3 cells display surface markers and transcript expression characteristic of group-3 ILC, including IL-7Rα (CD127), c-kit (CD117), CCR6, Thy1 (CD90), RANK, RANKL, and lymphotoxin (LTα1ß2). Using an in vitro assay of LTi cell activity, MNK-3 cells induce ICAM-1 and VCAM-1 expression on stromal cells in a manner dependent upon LTα1ß2 expression. A second IL-2-responsive subline, MNK-1, expresses several NK cell receptors, perforin and granzymes, and shows some cytotoxic activity. Thus, MNK-1 cells serve as a model of ILC1/NK development and differentiation, whereas MNK-3 cells provide an attractive in vitro system to study the function of ILC3/LTi cells.