Comparison of the methylglyoxal scavenging effects of kaempferol and glutathione and the consequences for the toxicity of methylglyoxal in SH-SY5Y cells.

This study aimed to characterize the methylglyoxal (MGO) scavenging capacity of glutathione (GSH) and kaempferol in more detail with special emphasis on the possible reversible nature of the adduct formation and their competition for MGO, and the safety consequences of their MGO-scavenging effects. GSH showed immediate and concentration-dependent MGO-scavenging effects, while the scavenging effects by kaempferol appeared concentration- but also time-dependent, with stable adducts formed over time. The GSH adduct gradually disappeared in a competition reaction with kaempferol, and kaempferol became the preferred scavenger over time. Furthermore, the scavenging of MGO by kaempferol provided better protection than GSH against extracellular MGO in SH-SY5Y cells. It is concluded that flavonoids like kaempferol provide better scavengers for food-borne MGO than thiol-based scavengers such as GSH, while, given the endogenous concentrations of both scavengers and the detoxification of the GSH-MGO adduct by the glyoxalase system, GSH will be dominant for intracellular MGO protection.

Contrasting dose response relationships of neuroactive antidepressants on the behavior of C. elegans.

Antidepressant prescriptions are on a rise worldwide and this increases the concerns for the impacts of these pharmaceuticals on nontarget organisms. Antidepressants are neuroactive compounds that can affect organism's behavior. Behavior is a sensitive endpoint that may also propagate effects at a population level. Another interesting aspect of antidepressants is that they have shown to induce non-monotonic dose-response (NMDR) curves. While such NMDR relationships may have clear implications for the environmental risk, the resolution of current studies is often too coarse to be able to detect relevant NMDR. Therefore, the current study was performed into the behavioral effects (activity, feeding and chemotaxis) in Caenorhabditis elegans as the model organism of the selective serotonin reuptake inhibitors fluoxetine and sertraline and the acetylcholinesterase inhibiting pesticide chlorpyrifos, using a wide range of concentrations (ng/l to mg/l). In order to statistically examine the non-monotonicity, nonlinear regression models were applied to the results. The results showed a triphasic dose-response relationship for activity and chemotaxis after exposure to fluoxetine, but not to sertraline or chlorpyrifos. Effects of fluoxetine already occurred at low concentrations in the range of ng/l while sertraline only showed effects at concentrations in the µg/l range, similar to chlorpyrifos. The different responses between fluoxetine and sertraline, both SSRIs, indicate that response patterns may not always be extrapolated from chemicals with the same primary mode of action. The effects of fluoxetine at low concentrations, in a non-monotonic manner, confirm the relevance of examining such responses at low concentrations.

Estrogen receptor alpha (ERα)-mediated coregulator binding and gene expression discriminates the toxic ERα agonist diethylstilbestrol (DES) from the endogenous ERα agonist 17ß-estradiol (E2).

Diethylstilbestrol (DES) is a synthetic estrogen and proven human teratogen and carcinogen reported to act via the estrogen receptor α (ERα). Since the endogenous ERα ligand 17ß-estradiol (E2) does not show these adverse effects to a similar extent, we hypothesized that DES' interaction with the ERα differs from that of E2. The current study aimed to investigate possible differences between DES and E2 using in vitro assays that detect ERα-mediated effects, including ERα-mediated reporter gene expression, ERα-mediated breast cancer cell (T47D) proliferation and ERα-coregulator interactions and gene expression in T47D cells. Results obtained indicate that DES and E2 activate ERα-mediated reporter gene transcription and T47D cell proliferation in a similar way. However, significant differences between DES- and E2-induced binding of the ERα to 15 coregulator motifs and in transcriptomic signatures obtained in the T47D cells were observed. It is concluded that differences observed in binding of the ERα with several co-repressor motifs, in downregulation of genes involved in histone deacetylation and DNA methylation and in upregulation of CYP26A1 and CYP26B1 contribute to the differential effects reported for DES and E2.