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Abstract
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 ([18F]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.
Acknowledgements
The authors like to thank Marijana Radonjic and Rob Stierum for assistance in the analysis and interpretation of the genomics data, and helpful discussions; Gerard van Beek and Lidy van Oostrum for technical support on animal care and necropsy; Linda van der Horst-Groeneveld and Marlies Otto for behavioral testing and histotechnical support; Anja Dijkstra for study assistance and archiving; Jurgen Sijbesma for his support in the PET imaging studies. Special thanks go to postgraduate, graduate and undergraduate students participating on different aspects of the study: Anke Wesselius (neurodevelopment study and PET), Jasper Swierstra, Luc Blaauw, Lianne Damptsteeg, Lotte Houtepen and Martje de Groot (neurodevelopment study); Nadine Jetten and Maria Berk (MRI); Bart Voet and Mark Boogaard (PET); Fariza Boualala (graphics). The fruitful discussions with our partners from the National Institute for Public Health and the Environment (RIVM, Bilthoven, The Netherlands) Elisa C.M. Tonk, Aldert H. Piersma and Henk van Loveren, are gratefully acknowledged.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The data that support the findings of this study are available from the corresponding author, DMGdG, upon reasonable request.