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Developmental immunotoxicity of ethanol in an extended one-generation reproductive toxicity study

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Author: Tonk, E.C.M. · Groot, D.M.G. de · Wolterbeek, A.P.M. · Penninks, A.H. · Waalkens-Berendsen, I.D.H. · Piersma, A.H. · Loveren, H. van
Type:article
Date:2013
Source:Archives of Toxicology, 2, 87, 323-335
Identifier: 471493
doi: doi:10.1007/s00204-012-0940-1
Keywords: Biology · Benchmark dose approach · Developmental immunotoxicity · Ethanol · Extended one-generation reproductive toxicity study · Alcohol · Concanavalin A · Drinking water · Keyhole limpet hemocyanin · Lipopolysaccharide · Nitric oxide · Tumor necrosis factor alpha · Adaptive immunity · Adult animal · Animal experiment · Animal model · blood cell · Cell adhesion · Cell proliferation · Cell stimulation · Cell subpopulation · Chemical parameters · Controlled study · Cytokine production · Developmental parameters · Developmental toxicity · Female · Immune response · Immunization · Immunological parameters · Immunomodulation · Immunotoxicity · Innate immunity · Lactation · Male · Mating · Medical parameters · Perinatal period · Priority journal · Rat · Reproductive toxicity · Spleen cell · Toxicity testing · Wistar rat · Rattus norvegicus · Biomedical Innovation · Healthy Living · Life Triskelion BV · QS - Quality & Safety TARA - Toxicology and Risk Assessment RAPID - Risk Analysis for Products in Development · EELS - Earth, Environmental and Life Sciences TNO Bedrijven

Abstract

The susceptibility of developing immune system to chemical disruption warrants the assessment of immune parameters in reproductive and developmental testing protocols. In this study, a wide range of immune endpoints was included in an extended one-generation reproduction toxicity study (EOGRTS) design to determine the relative sensitivity of immune and developmental parameters to ethanol (EtOH), a well-known developmental toxicant with immunomodulatory properties. Adult Wistar rats were exposed to EtOH via drinking water (0, 1.5, 4, 6.5, 9, 11.5 and 14 % (w/v EtOH)) during premating, mating, gestation and lactation and continuation of exposure of the F1 from weaning until killed. Immune assessments were performed at postnatal days (PNDs) 21, 42 and 70. Keyhole limpet hemocyanin (KLH)-specific immune responses were evaluated following subcutaneous immunizations on PNDs 21 and 35. EtOH exposure affected innate as well as adaptive immune responses. The most sensitive immune parameters included white blood cell subpopulations, ConA-stimulated splenocyte proliferation, LPS-induced NO and TNF-α production by adherent splenocytes and KLH-specific immune responses. Most parameters showed recovery after cessation of EtOH exposure after weaning in the 14 % exposure group. However, effects on LPS-induced NO and TNF-α production by adherent splenocytes and KLH-specific parameters persisted until PND 70. The results demonstrate the relative sensitivity to EtOH of especially functional immune parameters and confirm the added value of immune parameters in the EOGRTS. Furthermore, this study identified an expanded KLH-specific parameter set and LPS-induced NO and TNF-α production by adherent splenocytes as valuable parameters that can provide additional information on functional immune effects. © 2012 Springer-Verlag.