Toxic effects on immune system development may seriously impair human health, but immunotoxicity is rarely considered in risk assessment of environmental chemicals. A main problem is the absence of systematic epidemiological evidence. We have successfully established birth cohorts for prospective studies in a unique fishing population exposed to marine contaminants - the Faroe Islands - and we have demonstrated that vaccine responses in children can be applied as a model of immunotoxicity associated with polychlorinated biphenyl (PCB) exposure. This competitive renewal application extends the follow-up of the same birth cohort of >600 children for sustained serum concentrations of antibodies against vaccines and in regard to allergic disease up to adolescence. In a second birth cohort of 500 children recently established, we will test whether the immunotoxicant exposure at age 18 months represents a main window of vulnerability in regard to the subsequent serum antibody concentrations. Further, we will explore the impact of past and cumulated exposure levels on responses to a vaccine booster, as reflected by specific antibody concentrations and by changes in lymphocyte populations and cytokine production. Likewise, clinical evidence of allergy development, including serum concentrations of total and specific IgEs against common antigens, will be evaluated in regard to exposures during prenatal and postnatal time windows. In addition to already confirmed immunotoxicants PCBs and methylmercury, the study will examine the possible immunotoxicity of the total AhR (dioxin-related) activity in serum and of perfluorinated compounds and butyltins. Vaccine antibody assays for tetanus and diphtheria toxoids will be expanded to include Pneumococcus polysaccharide antigens. Because this study relies on two existing birth cohorts with banked blood samples and background information already collected - in part financed by other sources - the proposed research will cover a time span of 14 years to allow consideration of exposures incurred prenatally and outcomes followed until adolescence. The cumulated evidence will therefore likely be of substantial importance for the understanding of developmental immunotoxicity in humans and for risk assessment of immunotoxic agents.

Public Health Relevance

Due to the lack of systematic data, immunotoxicity is rarely taken into account in risk assessment. This systematic study aims at providing a stronger basis for prevention of immune system dysfunctions related to environmental chemicals. It will examine antibody concentrations and cellular responses to routine childhood immunizations as well as the occurrence of allergic disease up to adolescence in regard to exposures to environmental chemicals prenatally and at different ages after birth.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Innate Immunity and Inflammation Study Section (III)
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Gray, Kimberly A
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Harvard University
Public Health & Prev Medicine
Schools of Public Health
United States
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Budtz-Jørgensen, Esben; Grandjean, Philippe (2018) Application of benchmark analysis for mixed contaminant exposures: Mutual adjustment of perfluoroalkylate substances associated with immunotoxicity. PLoS One 13:e0205388
Hu, Xindi C; Dassuncao, Clifton; Zhang, Xianming et al. (2018) Can profiles of poly- and Perfluoroalkyl substances (PFASs) in human serum provide information on major exposure sources? Environ Health 17:11
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Grandjean, Philippe; Heilmann, Carsten; Weihe, Pal et al. (2017) Estimated exposures to perfluorinated compounds in infancy predict attenuated vaccine antibody concentrations at age 5-years. J Immunotoxicol 14:188-195
Valvi, Damaskini; Oulhote, Youssef; Weihe, Pal et al. (2017) Gestational diabetes and offspring birth size at elevated environmental pollutant exposures. Environ Int 107:205-215
Timmermann, Clara Amalie Gade; Choi, Anna L; Petersen, Maria Skaalum et al. (2017) Secondary sex ratio in relation to exposures to polychlorinated biphenyls, dichlorodiphenyl dichloroethylene and methylmercury. Int J Circumpolar Health 76:1406234
Grandjean, Philippe; Heilmann, Carsten; Weihe, Pal et al. (2017) Serum Vaccine Antibody Concentrations in Adolescents Exposed to Perfluorinated Compounds. Environ Health Perspect 125:077018
Timmermann, Clara Amalie Gade; Budtz-Jørgensen, Esben; Petersen, Maria Skaalum et al. (2017) Shorter duration of breastfeeding at elevated exposures to perfluoroalkyl substances. Reprod Toxicol 68:164-170

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