The atrophy and changes in the cellular compositions of the thymus and spleen observed in mice subjected to short-term exposure to perfluorooctanesulfonate are high-dose phenomena mediated in part by peroxisome proliferator-activated receptor-alpha (PPARalpha).
We have previously shown that short-term, high-dose exposure of mice to the environmentally persistent perfluorooctanoate (PFOA) results in thymic and splenic atrophy and the attenuation of specific humoral immune responses. Here we characterize the effects of a 10-day treatment with different dietary doses (1-0.001%, w/w) of perfluorooctanesulfonate (PFOS), a similar fluorochemical, on the immune system of male C57BL/6 mice. At doses greater than 0.02%, PFOS induced clinical signs of toxicity in the animals, whereas at the concentration of 0.02%, this compound caused weight loss, hepatomegaly and atrophy of the thymus, spleen and adipose tissue without toxicity. With this latter dose, histopathological and flow-cytometric analysis revealed that (i) the thymic cortex was virtually depleted of cells; (ii) the total numbers of thymocytes and splenocytes were reduced by 84 and 43%, respectively; (iii) although all populations of thymocytes and splenocytes were smaller, the thymic CD4(+)CD8(+) cells and the splenic B-lymphocytes were most decreased. These alterations resembled those evoked by analogous exposure to PFOA, but were less pronounced. At lower doses (less than 0.02%), PFOS induced hepatomegaly without affecting the thymus or spleen. Finally, comparison of male wild-type 129/Sv mice and the corresponding knock-outs lacking peroxisome proliferator-activated receptor-alpha (PPARalpha) indicated that these effects of PFOS are not strain-dependent. More importantly, hepatomegaly is independent of PPARalpha, the thymic changes are partially dependent on this receptor, and splenic responses are largely eliminated in its absence. Thus, immunomodulation caused by PFOS is a high-dose phenomenon partially dependent on PPARalpha.
Qazi
Mousumi Rahman
MR
Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
Xia
Zhenlei
Z
Bogdanska
Jasna
J
Chang
Shu-Ching
SC
Ehresman
Dave J
DJ
Butenhoff
John L
JL
Nelson
B Dean
BD
DePierre
Joseph W
JW
Abedi-Valugerdi
Manuchehr
M
D017738:Alkanesulfonic Acids / Q000097:blood / Q000633:toxicity*; D000818:Animals; D001284:Atrophy / Q000139:chemically induced / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D001835:Body Weight / Q000187:drug effects; D002210:Caprylates / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D005434:Flow Cytometry; D005466:Fluorocarbons / Q000097:blood / Q000633:toxicity*; D016130:Immunophenotyping; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009929:Organ Size / Q000187:drug effects; D047493:PPAR alpha / Q000172:deficiency* / Q000276:immunology; D013154:Spleen / Q000033:anatomy & histology / Q000187:drug effects* / Q000276:immunology / Q000473:pathology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013950:Thymus Gland / Q000033:anatomy & histology / Q000187:drug effects* / Q000276:immunology / Q000473:pathology*
D017738:Alkanesulfonic Acids; D002210:Caprylates; D005466:Fluorocarbons; D047493:PPAR alpha; C023036:perfluorooctanoic acid; C076994:perfluorooctane sulfonic acid