| Autor: |
de Groot DMG; Department of Toxicology and Applied Pharmacology, TNO Nutrition and Food Research (as part of TNO Quality of Life), Zeist, the Netherlands., Linders L; Department of Toxicology and Applied Pharmacology, TNO Nutrition and Food Research (as part of TNO Quality of Life), Zeist, the Netherlands., Kayser R; Department of Toxicology and Applied Pharmacology, TNO Nutrition and Food Research (as part of TNO Quality of Life), Zeist, the Netherlands., Nederlof R; Department of Toxicology and Applied Pharmacology, TNO Nutrition and Food Research (as part of TNO Quality of Life), Zeist, the Netherlands., de Esch C; Department of Toxicology and Applied Pharmacology, TNO Nutrition and Food Research (as part of TNO Quality of Life), Zeist, the Netherlands., Slieker RC; Department of Toxicology and Applied Pharmacology, TNO Nutrition and Food Research (as part of TNO Quality of Life), Zeist, the Netherlands., Kuper CF; Department of Toxicology and Applied Pharmacology, TNO Nutrition and Food Research (as part of TNO Quality of Life), Zeist, the Netherlands., Wolterbeek A; Department of Toxicology and Applied Pharmacology, TNO Nutrition and Food Research (as part of TNO Quality of Life), Zeist, the Netherlands., de Groot VJ; Department of Toxicology and Applied Pharmacology, TNO Nutrition and Food Research (as part of TNO Quality of Life), Zeist, the Netherlands., Veltien A; Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, the Netherlands., Heerschap A; Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, the Netherlands., van Waarde A; Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands., Dierckx RAJO; Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands., de Vries EFJ; Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. |
| Abstrakt: |
Disruption of the immune system during embryonic brain development by environmental chemicals was proposed as a possible cause of neurodevelopmental disorders. We previously found adverse effects of di-n-octyltin dichloride (DOTC) on maternal and developing immune systems of rats in an extended one-generation reproductive toxicity study according to the OECD 443 test guideline. We hypothesize that the DOTC-induced changes in the immune system can affect neurodevelopment. Therefore, we used in-vivo MRI and PET imaging and genomics, in addition to behavioral testing and neuropathology as proposed in OECD test guideline 443, to investigate the effect of DOTC on structural and functional brain development. Male rats were exposed to DOTC (0, 3, 10, or 30 mg/kg of diet) from 2 weeks prior to mating of the F0-generation until sacrifice of F1-animals. The brains of rats, exposed to DOTC showed a transiently enlarged volume of specific brain regions (MRI), altered specific gravity, and transient hyper-metabolism ([ 18 F]FDG PET). The alterations in brain development concurred with hyper-responsiveness in auditory startle response and slight hyperactivity in young adult animals. Genomics identified altered transcription of key regulators involved in neurodevelopment and neural function (e.g. Nrgrn , Shank3 , Igf1r , Cck , Apba2 , Foxp2 ); and regulators involved in cell size, cell proliferation, and organ development, especially immune system development and functioning (e.g. LOC679869 , Itga11 , Arhgap5 , Cd47 , Dlg1 , Gas6 , Cml5 , Mef2c ). The results suggest the involvement of immunotoxicity in the impairment of the nervous system by DOTC and support the hypothesis of a close connection between the immune and nervous systems in brain development. |
