- J.P.F.G. Helsper (1)
- D. Jennen (1)
- M.J.A. Jetten (1)
- J.C.S. Kleinjans (1)
- J.C. Kleinjans (1)
- T.M. Kok de (2)
- A. Lommen (1)
- A.A.C.M. Peijnenburg (1)
- A. Ruiz Aracama (1)
- E.P. Someren van (1)
- R. Stierum (1)
- L.C. Wilms (1)
Can transcriptomics provide insight into the underlying chemopreventive mechanisms of complex mixtures of phytochemicals in humans?
Breda, S.G. van; Wilms, L.C. ; Gaj, S. ; Briedé, J.J. ; Helsper, J.P.F.G. ; Kleinjans, J.C. ; Kok, T.M. de - \ 2014
Antioxidants and redox signaling 20 (2014)14. - ISSN 1523-0864 - p. 2107 - 2113.
Blueberries contain relatively large amounts of different phytochemicals which are suggested to have chemopreventive properties, but little information is available on the underlying molecular modes of action. This study investigates whole genome gene expression changes in lymphocytes of 143 humans after a four-week blueberry-apple juice dietary intervention. Differentially expressed genes and genes correlating with the extent of antioxidant protection were identified in 4 subgroups. The magnitude of the preventive effect after the intervention differed between these four subgroups. Furthermore, subjects in two groups carried genetic polymorphisms that were previously found to influence the chemopreventive response. Pathway analysis of the identified genes showed strong but complex gene expression changes in pathways signaling for apoptosis, immune response, cell adhesion, and lipid metabolism. These pathways indicate increased apoptosis, upgraded growth control, induced immunity, reduced platelet aggregation and activation, blood glucose homeostasis, and regulation of fatty acid metabolism. Based on these observations, we hypothesize that combining transcriptomic data with phenotypic markers of oxidative stress may provide insight into the relevant cellular processes and genetic pathways which contribute to the antioxidant response of complex mixtures of phytochemicals, such as found in blueberry-apple juice
'Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans
Jetten, M.J.A. ; Gaj, S. ; Ruiz Aracama, A. ; Kok, T.M. de; Delft, J.H.M. van; Lommen, A. ; Someren, E.P. van; Jennen, D. ; Claessen, S.M. ; Peijnenburg, A.A.C.M. ; Stierum, R. ; Kleinjans, J.C.S. - \ 2012
Toxicology and Applied Pharmacology 259 (2012)3. - ISSN 0041-008X - p. 320 - 328.
induced liver-injury - gene-expression - induced hepatotoxicity - circulating micrornas - liquid-chromatography - potential biomarkers - toxicity - metabolomics - metabolites - paracetamol
Acetaminophen is the primary cause of acute liver toxicity in Europe/USA, which led the FDA to reconsider recommendations concerning safe acetaminophen dosage/use. Unfortunately, the current tests for liver toxicity are no ideal predictive markers for liver injury, i.e. they only measure acetaminophen exposure after profound liver toxicity has already occurred. Furthermore, these tests do not provide mechanistic information. Here, 'omics techniques (global analysis of metabolomic/gene-expression responses) may provide additional insight. To better understand acetaminophen-induced responses at low doses, we evaluated the effects of (sub-)therapeutic acetaminophen doses on metabolite formation and global gene-expression changes (including, for the first time, full-genome human miRNA expression changes) in blood/urine samples from healthy human volunteers. Many known and several new acetaminophen-metabolites were detected, in particular in relation to hepatotoxicity-linked, oxidative metabolism of acetaminophen. Transcriptomic changes indicated immune-modulating effects (2 g dose) and oxidative stress responses (4 g dose). For the first time, effects of acetaminophen on full-genome human miRNA expression have been considered and confirmed the findings on mRNA level. 'Omics techniques outperformed clinical chemistry tests and revealed novel response pathways to acetaminophen in humans. Although no definitive conclusion about potential immunotoxic effects of acetaminophen can be drawn from this study, there are clear indications that the immune system is triggered even after intake of low doses of acetaminophen. Also, oxidative stress-related gene responses, similar to those seen after high dose acetaminophen exposure, suggest the occurrence of possible pre-toxic effects of therapeutic acetaminophen doses. Possibly, these effects are related to dose-dependent increases in levels of hepatotoxicity-related metabolites.