Relative sensitivity of developmental and immune parameters in juvenile versus adult male rats after exposure to di(2-ethylhexyl) phthalate.
The developing immune system displays a relatively high sensitivity as compared to both general toxicity parameters and to the adult immune system. In this study we have performed such comparisons using di(2-ethylhexyl) phthalate (DEHP) as a model compound. DEHP is the most abundant phthalate in the environment and perinatal exposure to DEHP has been shown to disrupt male sexual differentiation. In addition, phthalate exposure has been associated with immune dysfunction as evidenced by effects on the expression of allergy. Male wistar rats were dosed with corn oil or DEHP by gavage from postnatal day (PND) 10-50 or PND 50-90 at doses between 1 and 1000 mg/kg/day. Androgen-dependent organ weights showed effects at lower dose levels in juvenile versus adult animals. Immune parameters affected included TDAR parameters in both age groups, NK activity in juvenile animals and TNF-α production by adherent splenocytes in adult animals. Immune parameters were affected at lower dose levels compared to developmental parameters. Overall, more immune parameters were affected in juvenile animals compared to adult animals and effects were observed at lower dose levels. The results of this study show a relatively higher sensitivity of juvenile versus adult rats. Furthermore, they illustrate the relative sensitivity of the developing immune system in juvenile animals as compared to general toxicity and developmental parameters. This study therefore provides further argumentation for performing dedicated developmental immune toxicity testing as a default in regulatory toxicology.
Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands. ilse.tonk@rivm.nl
Elisa C M
EC
Tonk
Aart
A
Verhoef
Eric R
ER
Gremmer
Henk
H
van Loveren
Aldert H
AH
Piersma
D000367:Age Factors; D000728:Androgens / Q000378:metabolism; D000818:Animals; D004051:Diethylhexyl Phthalate / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007107:Immune System / Q000187:drug effects*; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010968:Plasticizers / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology*
D000728:Androgens; D010968:Plasticizers; D014409:Tumor Necrosis Factor-alpha; D004051:Diethylhexyl Phthalate