Exposure to the environmentally relevant fungicide Maneb: Studying toxicity in the soil nematode Caenorhabditis elegans

Maneb is a manganese-containing ethylene bisdithiocarbamate fungicide and is still commonly used as no cases of resistance have been documented. However, studies have shown that Maneb exposure has neurodegenerative potential in mammals, resulting in symptoms affecting the motor system. Despite its extensive use, structural elucidation of Maneb has only recently been accomplished by our group. This study aimed to examine the bioavailability of Maneb, the quantification of oxidative stress-related endpoints and neurotransmitters employing pure Maneb, its metabolites and structural analogues, in the model organism Caenorhabditis elegans. Exposure to Maneb did not increase the bioavailability of Mn compared to manganese chloride, although Maneb was about 8 times more toxic with regard to lethality. Maneb generated not significantly reactive oxygen and nitrogen species (RONS) but decreased the ATP level while increasing the amount of glutathione and its oxidized form in a dose-dependent manner. Nevertheless, an alteration in the neurotransmitter homeostasis of dopamine, acetylcholine, and gamma-butyric acid (GABA) was observed as well as morphological changes in the dopaminergic neurons upon Maneb exposure, which underlines the assumption of the neurotoxic potential of Maneb. This study showed that Maneb exhibits effects based on a combined interaction of the ligand and manganese

Nutritive Manganese and Zinc Overdosing in Aging C. elegans Result in a Metallothionein‐Mediated Alteration in Metal Homeostasis

Scope Manganese (Mn) and zinc (Zn) are not only essential trace elements, but also potential exogenous risk factors for various diseases. Since the disturbed homeostasis of single metals can result in detrimental health effects, concerns have emerged regarding the consequences of excessive exposures to multiple metals, either via nutritional supplementation or parenteral nutrition. This study focuses on Mn‐Zn‐interactions in the nematode Caenorhabditis elegans (C. elegans) model, taking into account aspects related to aging and age‐dependent neurodegeneration. Methods and Results Chronic co‐exposure of C. elegans to Mn and Zn increases metal uptake, exceeding levels of single metal exposures. Supplementation with Mn and/or Zn also leads to an age‐dependent increase in metal content, a decline in overall mRNA expression, and metal co‐supplementation induced expression of target genes involved in Mn and Zn homeostasis, in particular metallothionein 1 (mtl‐1). Studies in transgenic worms reveal that mtl‐1 played a prominent role in mediating age‐ and diet‐dependent alterations in metal homeostasis. Metal dyshomeostasis is further induced in parkin‐deficient nematodes (Parkinson's disease (PD) model), but this did not accelerate the age‐dependent dopaminergic neurodegeneration. Conclusions A nutritive overdose of Mn and Zn can alter interactions between essential metals in an aging organism, and metallothionein 1 acts as a potential protective modulator in regulating homeostasis.DFG, 316442145, FOR 2558: Interaktionen von essenziellen Spurenelementen in gesunden und erkrankten älteren Menschen(TraceAge

Differences and Interactions in Placental Manganese and Iron Transfer across an In Vitro Model of Human Villous Trophoblasts

Manganese (Mn) as well as iron (Fe) are essential trace elements (TE) important for the maintenance of physiological functions including fetal development. However, in the case of Mn, evidence suggests that excess levels of intrauterine Mn are associated with adverse pregnancy outcomes. Although Mn is known to cross the placenta, the fundamentals of Mn transfer kinetics and mechanisms are largely unknown. Moreover, exposure to combinations of TEs should be considered in mechanistic transfer studies, in particular for TEs expected to share similar transfer pathways. Here, we performed a mechanistic in vitro study on the placental transfer of Mn across a BeWo b30 trophoblast layer. Our data revealed distinct differences in the placental transfer of Mn and Fe. While placental permeability to Fe showed a clear inverse dose-dependency, Mn transfer was largely independent of the applied doses. Concurrent exposure of Mn and Fe revealed transfer interactions of Fe and Mn, indicating that they share common transfer mechanisms. In general, mRNA and protein expression of discussed transporters like DMT1, TfR, or FPN were only marginally altered in BeWo cells despite the different exposure scenarios highlighting that Mn transfer across the trophoblast layer likely involves a combination of active and passive transport processes