Skip to main content

Advertisement

SpringerLink
Log in

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

  • Immunotoxicology
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Barron S, Kelly SJ, Riley EP (1991) Neonatal alcohol exposure alters suckling behavior in neonatal rat pups. Pharmacol Biochem Behav 39(2):423–427

    Article  PubMed  CAS  Google Scholar 

  • Basham KB, Whitmore SP, Adcock AF, Basta PV (1998) Chronic and acute prenatal and postnatal ethanol exposure on lymphocyte subsets from offspring thymic, splenic, and intestinal intraepithelial sources. Alcohol Clin Exp Res 22(7):1501–1508

    Article  PubMed  CAS  Google Scholar 

  • Burns-Naas LA, Hastings KL, Ladics GS, Makris SL, Parker GA, Holsapple MP (2008) What’s so special about the developing immune system? Int J Toxicol 27:223–254

    Article  PubMed  Google Scholar 

  • Chiappelli F, Taylor AN (1995) The fetal alcohol syndrome and fetal alcohol effects on immune competence. Alcohol 30(2):259–262

    CAS  Google Scholar 

  • Dietert RR (2009) Developmental immunotoxicology: focus on health risks. Chem Res Toxicol 22(1):17–23

    Article  PubMed  CAS  Google Scholar 

  • EFSA (2009) Guidance of the Scientific Committee on a request from EFSA on the use of the benchmark dose approach in risk assessment. EFSA J 1150:1–72

    Google Scholar 

  • Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 126(1):131–138

    Article  PubMed  CAS  Google Scholar 

  • Guerri C, Sanchis R (1985) Acetaldehyde and alcohol levels in pregnant rats and their fetuses. Alcohol 2(2):267–270

    Article  PubMed  CAS  Google Scholar 

  • Guerri C, Sanchis R (1986) Alcohol and acetaldehyde in rat’s milk following ethanol administration. Life Sci 38(17):1543–1556

    Article  PubMed  CAS  Google Scholar 

  • Holsapple MP, Burns-Naas LA, Hastings KL, Ladics GS, Lavin AL, Makris SL et al (2005) A proposed testing framework for developmental immunotoxicology (DIT). Toxicol Sci 83:18–24

    Article  PubMed  CAS  Google Scholar 

  • Jerrells TR, Weinberg J (1998) Influence of ethanol consumption on immune competence of adult animals exposed to ethanol in utero. Alcohol Clin Exp Res 22(2):391–400

    Article  PubMed  CAS  Google Scholar 

  • Johnson S, Knight R, Marmer DJ, Steele RW (1981) Immune deficiency in fetal alcohol syndrome. Pediatr Res 15(6):908–911

    Article  PubMed  CAS  Google Scholar 

  • Luebke RW, Chen DH, Dietert R, Yang Y, King M, Luster MI (2006) The comparative immunotoxicity of five selected compounds following developmental or adult exposure. J Toxicol Environ Health B Crit Rev 9(1):1–26

    Article  PubMed  CAS  Google Scholar 

  • McGill J, Meyerholz DK, Edsen-Moore M, Young B, Coleman RA, Schlueter AJ, Waldschmidt TJ, Cook RT, Legge KL (2009) Fetal exposure to ethanol has long-term effects on the severity of influenza virus infections. J Immunol 182(12):7803–7808

    Article  PubMed  CAS  Google Scholar 

  • Molina P, Happel KI, Zhang P, Kolls JK, Nelson S (2010) Focus on: alcohol and the immune system. Alcohol Res Health 33(1 & 2):97–108

    Google Scholar 

  • Murillo-Fuentes L, Artillo R, Carreras O, Murillo L (2001) Effects of maternal chronic alcohol administration in the rat: lactation performance and pup’s growth. Eur J Nutr 40(4):147–154

    Article  PubMed  CAS  Google Scholar 

  • Nagy LE (2004) Stabilization of tumor necrosis factor-alpha mRNA in macrophages in response to chronic ethanol exposure. Alcohol 33(3):229–233

    Article  PubMed  CAS  Google Scholar 

  • Norman DC, Chang MP, Wong CM, Branch BJ, Castle S, Taylor AN (1991) Changes with age in the proliferative response of splenic T cells from rats exposed to ethanol in utero. Alcohol Clin Exp Res 15(3):428–432

    Article  PubMed  CAS  Google Scholar 

  • OECD (2011) Test No. 443: extended one-generation reproductive toxicity study, OECD guidelines for the testing of chemicals, Section 4: health effects, OECD Publishing. doi:10.1787/9789264122550-en

  • Riley EP, Infante MA, Warren KR (2011) Fetal alcohol spectrum disorders: an overview. Neuropsychol Rev 21(2):73–80

    Article  PubMed  Google Scholar 

  • Seelig LL Jr, Steven WM, Stewart GL (1999) Second generation effects of maternal ethanol consumption on immunity to Trichinella spiralis in female rats. Alcohol Alcohol 34(4):520–528

    Article  PubMed  CAS  Google Scholar 

  • Selgrade MK (2007) Immunotoxicity: the risk is real. Toxicol Sci 100(2):328–332

    Article  PubMed  CAS  Google Scholar 

  • Slob W (2002) Dose-response modeling of continuous endpoints. Toxicol Sci 66(2):298–312

    Article  PubMed  CAS  Google Scholar 

  • Szabo G, Mandrekar P (2009) A recent perspective on alcohol, immunity, and host defense. Alcohol Clin Exp Res 33(2):220–232

    Article  PubMed  CAS  Google Scholar 

  • Tavares do Carmo MG, Oller do Nascimento CM, Martin A, Herrera E (1999) Ethanol intake during lactation impairs milk production in rats and affects growth and metabolism of suckling pups. Alcohol 18(1):71–76

    Article  PubMed  CAS  Google Scholar 

  • Taylor AN, Tio DL, Chiappelli F (1999) Thymocyte development in male fetal alcohol-exposed rats. Alcohol Clin Exp Res 23(3):465–470

    Article  PubMed  CAS  Google Scholar 

  • Tonk EC, de Groot DM, Penninks AH, Waalkens-Berendsen ID, Wolterbeek AP, Slob W, Piersma AH, van Loveren H (2010) Developmental immunotoxicity of methylmercury: the relative sensitivity of developmental and immune parameters. Toxicol Sci 117(2):325–335

    Article  PubMed  CAS  Google Scholar 

  • Tonk EC, Verhoef A, de la Fonteyne LJ, Waalkens-Berendsen ID, Wolterbeek AP, van Loveren H, Piersma AH (2011a) Developmental immunotoxicity in male rats after juvenile exposure to di-n-octyltin dichloride (DOTC). Reprod Toxicol 32(3):341–348

    Article  PubMed  CAS  Google Scholar 

  • Tonk ECM, de Groot DMG, Penninks AH, Waalkens-Berendsen IDH, Wolterbeek APM, Piersma AH, van Loveren H (2011b) Developmental immunotoxicity of di-n-octyltin dichloride (DOTC) in an extended one-generation reproductive toxicity study. Toxicol Lett 204(2–3):156–163

    Article  PubMed  CAS  Google Scholar 

  • Van Loveren H, Vos J, Putman E, Piersma A (2003) Immunotoxicological consequences of perinatal chemical exposures: a plea for inclusion of immune parameters in reproduction studies. Toxicology 185(3):185–191

    Article  PubMed  Google Scholar 

  • Waltenbaugh C, Vasquez K, Peterson JD (1998) Alcohol consumption alters antigen-specific Th1 responses: mechanisms of deficit and repair. Alcohol Clin Exp Res 22(5 Suppl):220S–223S

    Article  PubMed  CAS  Google Scholar 

  • Weinberg J, Jerrells TR (1991) Suppression of immune responsiveness: sex differences in prenatal ethanol effects. Alcohol Clin Exp Res 15(3):525–531

    Article  PubMed  CAS  Google Scholar 

  • Zajac CS, Abel EL (1992) Animal models of prenatal alcohol exposure. Int J Epidemiol 21(Suppl 1):S24–S32

    Article  PubMed  Google Scholar 

  • Zhang X, Sliwowska JH, Weinberg J (2005) Prenatal alcohol exposure and fetal programming: effects on neuroendocrine and immune function. Exp Biol Med (Maywood) 230(6):376–388

    CAS  Google Scholar 

  • Zisman DA, Strieter RM, Kunkel SL, Tsai WC, Wilkowski JM, Bucknell KA, Standiford TJ (1998) Ethanol feeding impairs innate immunity and alters the expression of Th1- and Th2-phenotype cytokines in murine Klebsiella pneumonia. Alcohol Clin Exp Res 22(3):621–627

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge the excellent technical assistance of Gerard van Beek and Lidy van Oostrum (and colleagues) and Aart Verhoef for animal handling and necropsy skills, Anja Dijkstra for help with the planning and logistics involved in this study and Eric Gremmer, Liset de la Fonteyne, Jolanda Vermeulen, Arja de Klerk, Bert Verlaan and Henny Verharen for immunologic evaluations.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands

    Elisa C. M. Tonk & Henk van Loveren

  2. Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands

    Elisa C. M. Tonk, Aldert H. Piersma & Henk van Loveren

  3. TNO, Zeist, The Netherlands

    Elisa C. M. Tonk, Didima M. G. de Groot & André P. M. Wolterbeek

  4. TNO Triskelion BV, Zeist, The Netherlands

    André H. Penninks & Ine D. H. Waalkens-Berendsen

  5. Veterinary Faculty, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands

    Aldert H. Piersma

Authors
  1. Elisa C. M. Tonk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Didima M. G. de Groot
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. André P. M. Wolterbeek
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. André H. Penninks
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ine D. H. Waalkens-Berendsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aldert H. Piersma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Henk van Loveren
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elisa C. M. Tonk.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tonk, E.C.M., de Groot, D.M.G., Wolterbeek, A.P.M. et al. Developmental immunotoxicity of ethanol in an extended one-generation reproductive toxicity study. Arch Toxicol 87, 323–335 (2013). https://doi.org/10.1007/s00204-012-0940-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-012-0940-1

Keywords

Search

Navigation