title: Developmental immunotoxicity in male rats after juvenile exposure to ethanol.
abstract: The aim of the present study was to determine the sensitivity of the developing immune system to ethanol (EtOH) after exposure from postnatal day (PND) 10 onward. Adult Wistar dams and litters were exposed to EtOH via drinking water (0, 0.25, 1.5, 2.75, 4, 5.25, or 6.5% (w/v) EtOH ad libitum) and drinking water exposure of the F1 was continued from weaning until sacrifice. Immune assessments were performed at postnatal days (PNDs) 21, 42, and 70. Furthermore, Keyhole Limpet Hemocyanin (KLH) specific immune responses were evaluated following subcutaneous immunizations on PNDs 21 and 35. EtOH exposure affected innate immune responses, such as LPS-induced NO-production by adherent splenocytes, as well as adaptive immune responses as represented by KLH-specific parameters. The most sensitive developmental parameters included effects on maternal and pup bodyweight with calculated BMDs of 4.0% and 4.3% EtOH, respectively. The most sensitive immune parameters were affected at dose levels lower than those affecting developmental parameters and included KLH-specific immune responses, LPS-induced NO production by adherent splenocytes, and IL-10 production by ConA stimulated splenocytes. Calculated BMDs for these parameters were between 0.01% and 0.1% EtOH. A comparison of the results of this juvenile study with an extended one-generation reproductive toxicity study revealed that the juvenile study design may result in a higher sensitivity related to differences in the exposure design. These findings demonstrate the relative sensitivity of the developing immune system for EtOH exposure, the additional value of assessing functional immune parameters, and the importance of the juvenile window in developmental immunotoxicity testing.
authors.affiliation: Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands. ilse.tonk@rivm.nl
authors.forename: Elisa C M
authors.initials: EC
authors.lastname: Tonk
authors.forename: Aart
authors.initials: A
authors.lastname: Verhoef
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gremmer
authors.forename: Henk
authors.initials: H
authors.lastname: van Loveren
authors.forename: Aldert H
authors.initials: AH
authors.lastname: Piersma
mesh_terms: D000367:Age Factors; D000818:Animals; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D007111:Immunity, Cellular / Q000187:drug effects* / Q000276:immunology*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D009929:Organ Size / Q000187:drug effects / Q000276:immunology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors
chemical_list: D000431:Ethanol