Orally administered cellulose nanofibrils impact cardiac performance, neurotransmitters, and metabolite profile in male and female rat pups in an age- and sex-related manner

Abstract

The potential applications of cellulose nanofibrils (CNFs) as food additives or in food packaging, present a possible source of human ingestion. Little is known about biological responses to CNFs exposure during infancy when both the intestinal tract and brain are still undergoing considerable development. In the study presented here male and female rat pups received four daily oral doses of 10 mg/kg CNFs between postnatal day (PND) 7-10 or 17-20 and were sacrificed at PND 21. Basic neurobehavioral (acoustic startle response, locomotor activity, and rotarod) and cardiac assessments were performed at PND 20. Six neurotransmitters/metabolites were quantified in brain by UPLC with electrochemical detection. Plasma metabolites (n = 186) were quantified using AbsoluteIDQ® p180Kits (Biocrates) analyzed by LC-MS. Pups dosed between PND 7-10 had significantly (P<0.05) increased neurotransmitters/metabolites in brain tissue (male: dopamine, norepinephrine, and serotonin, female: dopamine and serotonin). The plasma ratio serotonin/tryptophan was found to have a significantly increased fold change (FC, male: 1.29, female: 1.42), tryptophan is a biosynthetic precursor for serotonin. No changes in the neurobehavioral assessment were observed following dosing between PND 7-10. However, female pups dosed between PND 17-20 had a significantly increased response time in the acoustic startle test. While no significant changes in neurotransmitters/metabolites were found in the brain for female pups orally administered CNF between PND 17-20, 16 amino acids had a decreased FC in plasma, including glutamate (FC: 0.75) and aspartate (FC: 0.67). Also, the FC for the sums of essential, non-essential, branch-chain, and aromatic acids were decreased. Amino acids are important for proper neurotransmission, having specific, but interconnected, roles. Metabolomic analysis of plasma showed that 23-48 individual metabolites were important for discrimination of CNF dose groups from control, and that largest class of metabolites was amino acids for all dosing groups with between 7-16 individual amino acids. Our results show that the biological responses to orally dosed CNF in early life happen in an age- and sex-related manner. Our data suggests that CNF may impact neurobehavioral, neurotransmitter/metabolite concentrations in brain, as well as the metabolite profile in plasma.