title: Developmental immunotoxicity of methylmercury: the relative sensitivity of developmental and immune parameters.
abstract: 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, and 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 PNDs 21, 42, and 70. The T cell-dependent antibody response to keyhole limpet hemocyanin (KLH) was assessed following sc immunizations on PNDs 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.
authors.affiliation: Department of Health Risk Analysis and Toxicology, Maastricht University, 6200 MD Maastricht, The Netherlands. ilse.tonk@rivm.nl
authors.forename: Elisa C M
authors.initials: EC
authors.lastname: Tonk
authors.forename: Didima M G
authors.initials: DM
authors.lastname: de Groot
authors.forename: André H
authors.initials: AH
authors.lastname: Penninks
authors.forename: Ine D H
authors.initials: ID
authors.lastname: Waalkens-Berendsen
authors.forename: André P M
authors.initials: AP
authors.lastname: Wolterbeek
authors.forename: Wout
authors.initials: W
authors.lastname: Slob
authors.forename: Aldert H
authors.initials: AH
authors.lastname: Piersma
authors.forename: Henk
authors.initials: H
authors.lastname: van Loveren
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000833:Animals, Suckling; D004305:Dose-Response Relationship, Drug; D005260:Female; D005313:Fetal Death / Q000139:chemically induced; D007107:Immune System / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D007774:Lactation / Q000187:drug effects; D008098:Litter Size / Q000187:drug effects; D008136:Longevity / Q000187:drug effects; D008297:Male; D018811:Maternal Exposure; D008767:Methylmercury Compounds / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced*; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018675:Toxicity Tests; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D008767:Methylmercury Compounds; D014874:Water Pollutants, Chemical