Developmental immunotoxicity of methylmercury: the relative sensitivity of developmental and immune parameters.

E.C. Tonk*, D.M. de Groot, A.H. Penninks, I.D. Waalkens Berendsen, A.P. Wolterbeek, W. Slob, A.H. Piersma, H. van Loveren

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review


    Current developmental and reproductive toxicity protocols include only a limited set of parameters for effects on the developing immune system. In this study a wide range of immunological parameters were included in a pre- and postnatal developmental toxicity study. Dose-response data were compared to determine the relative sensitivity of different immune and developmental parameters. Mated female Wistar rats were dosed daily by gavage with methylmercury (0, 0.1, 0.4, 0.7, 1.0, 1.5, 2.0 mg/kg bw/day) from gestational day 6 to postnatal day (PND) 10. In addition to general, reproductive and developmental parameters, a wide range of immunological parameters were assessed in male offspring at PND 21, 42 and 70. The T cell-dependent antibody response to keyhole limpet hemocyanin (KLH) was assessed following subcutaneous immunizations on PND 21 and 35. Dose-response data were analyzed using the benchmark dose (BMD) approach by fitting dose-response models to the various endpoints. Methylmercury induced effects on developmental parameters such as growth parameters and pup mortality. Effects on the immune system were found at doses without observed developmental toxicity. Immune effects differed at the three time points and consisted mainly of effects on functional parameters. The parameter with the lowest 5% lower confidence bound of the BMD (BMDL) was the primary KLH-specific IgG antibody response, which showed a dose-dependent decrease with a BMD of 0.039 mg/kg bw/day (CI 0.010-0.12). These data show the relatively high sensitivity of the developing immune system and thereby illustrate the relevance of testing immune parameters in reproductive and developmental toxicity testing protocols.
    Original languageEnglish
    Pages (from-to)325-335
    Number of pages11
    JournalToxicological Sciences
    Issue number2
    Publication statusPublished - Oct 2010


    • dose-response modeling
    • benchmark dose
    • Methylmercury
    • perinatal exposure
    • developmental toxicity
    • developmental immunotoxicity
    • rat
    • RATS
    • TESTS
    • MICE

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