Georg Aichinger

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Aichinger

First Name

Georg

ORCID

0000-0003-1691-7609

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03853 - Sturla, Shana / Sturla, Shana

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Publications 1 - 10 of 12

Physiologically-Based Pharmacokinetic Modeling of the Postbiotic Supplement Urolithin A Predicts its Bioavailability Is Orders of Magnitude Lower than Concentrations that Induce Toxicity, but also Neuroprotective Effects
Aichinger, Georg; Stevanoska, Maja; Beekmann, Karsten; et al. (2023)
Molecular Nutrition & Food Research
Scope: A range of health benefits are attributed to consuming urolithin A (UA), such as improved muscle health, anti-aging activity, and neuroprotection, whereas few studies raise possible adverse effects at high doses, including genotoxicity and estrogenic effects. Therefore, understanding UA bioactivity and safety depends on its pharmacokinetics. However, there is no physiologically-based pharmacokinetic (PBPK) model available for UA, thus limiting reliable assessment of effects observed from in vitro experimentation. Methods and results: We characterizes glucuronidation rates of UA by human S9 fractions. Partitioning and other physicochemical parameters are predicted using quantitative structure-activity relationship tools. Solubility and dissolution kinetics are determined experimentally. These parameters are used to construct a PBPK model, and results are compared with data from human intervention studies. We evaluates how different supplementation scenarios may influence UA plasma and tissue concentrations. Concentrations at which either toxic or beneficial effects are previously observed in vitro appear unlikely to be achieved in vivo. Conclusion: A first PBPK model for UA is established. It enables prediction of systemic UA concentrations and is critical for extrapolating in vitro results to in vivo uses. Results support the safety of UA, but also challenge the potential for readily achieving beneficial effects by postbiotic supplementation.
Natural Dibenzo-α-Pyrones: Friends or Foes?
Aichinger, Georg (2021)
International Journal of Molecular Sciences
Natural dibenzo-α-pyrones (DAPs) can be viewed from two opposite angles. From one angle, the gastrointestinal metabolites urolithins are regarded as beneficial, while from the other, the emerging mycotoxin alternariol and related fungal metabolites are evaluated critically with re-gards to potential hazardous effects. Thus, the important question is: can the structural characteris-tics of DAP subgroups be held responsible for distinct bioactivity patterns? If not, certain toxicolog-ical and/or pharmacological aspects of natural DAPs might yet await elucidation. Thus, this review focuses on comparing published data on the two groups of natural DAPs regarding both adverse and beneficial effects on human health. Literature on genotoxic, estrogenic, endocrine-disruptive effects, as well as on the induction of the cellular anti-oxidative defense system, anti-inflammatory properties, the inhibition of kinases, the activation of mitophagy and the induction of autophagy, is gathered and critically reviewed. Indeed, comparing published data suggests similar bioactivity profiles of alternariol and urolithin A. Thus, the current stratification into hazardous Alternaria toxins and healthy urolithins seems debatable. An extrapolation of bioactivities to the other DAP sub-class could serve as a promising base for further research. Conclusively, urolithins should be further evaluated toward high-dose toxicity, while alternariol derivatives could be promising chemicals for the development of therapeutics.
Predicting in vivo concentrations of dietary hop phytoestrogens by physiologically based kinetic modeling
Stevanoska, Maja; Beekmann, Karsten; Punt, Ans; et al. (2025)
Food and Chemical Toxicology
Hop extracts containing prenylated polyphenols such as 8-prenylnaringenin (8-PN) and its precursor isoxanthohumol (iXN) are popular among women seeking natural alternatives to hormone therapy for postmenopausal symptoms. Due to structural similarities with estrogens, these compounds act as estrogen receptor agonists. Especially 8-PN, described as the most potent phytoestrogen known to date, poses a potential risk for endocrine disruption. Therefore, its use as a hormone replacement raises concerns for human health. However, a significant challenge in assessing the potential endocrine-disruptive effects of hop polyphenols is the lack of data on their toxicokinetics. Particularly, information on in vivo concentrations in target tissues is lacking. To address this gap, we developed a physiologically based kinetic (PBK) model tailored to female physiology. The model was used to predict the levels of hop polyphenols in human blood and target tissues under realistic exposure scenarios. The predictions suggest that iXN and 8-PN concentrations in target tissues reach the low nanomolar range after dietary supplementation. This study enhances our understanding of internal concentrations of iXN and 8-PN after dietary consumption and is of direct applicability for respective risk assessment.
Markers for DNA damage are induced in the rat colon by the Alternaria toxin altertoxin-II, but not a complex extract of cultured Alternaria alternata
Aichinger, Georg; Pahlke, Gudrun; Puntscher, Hannes; et al. (2022)
Frontiers in Toxicology
Mycotoxins produced by Alternaria spp. act genotoxic in cell-based studies, but data on their toxicity in vivo is scarce and urgently required for risk assessment. Thus, male Sprague-Dawley rats received single doses of a complex Alternaria toxin extract (CE; 50 mg/kg bw), altertoxin II (ATX-II; 0.21 mg/kg bw) or vehicle by gavage, one of the most genotoxic metabolites in vitro and were sacrificed after 3 or 24 h, respectively. Using SDS-PAGE/Western Blot, a significant increase of histone 2a.X phosphorylation and depletion of the native protein was observed for rats that were exposed to ATX-II for 24 h. Applying RT-PCR array technology we identified genes of interest for qRT-PCR testing, which in turn confirmed an induction of Rnf8 transcription in the colon of rats treated with ATX-II for 3 h and CE for 24 h. A decrease of Cdkn1a transcription was observed in rats exposed to ATX-II for 24 h, possibly indicating tissue repair after chemical injury. In contrast to the observed response in the colon, no markers for genotoxicity were induced in the liver of treated animals. We hereby provide the first report of ATX-II as a genotoxicant in vivo. Deviating results for similar concentrations of ATX-II in a natural Alternaria toxin mixture argue for substantial mixture effects.
Physiologically based kinetic (PBK) modeling as a new approach methodology (NAM) for predicting systemic levels of gut microbial metabolites
Stevanoska, Maja; Folz, Jacob; Beekmann, Karsten; et al. (2024)
Toxicology Letters
There is a clear need to develop new approach methodologies (NAMs) that combine in vitro and in silico testing to reduce and replace animal use in chemical risk assessment. Physiologically based kinetic (PBK) models are gaining popularity as NAMs in toxico/pharmacokinetics, but their coverage of complex metabolic pathways occurring in the gut are incomplete. Chemical modification of xenobiotics by the gut microbiome plays a critical role in the host response, for example, by prolonging exposure to harmful metabolites, but there is not a comprehensive approach to quantify this impact on human health. There are examples of PBK models that have implemented gut microbial biotransformation of xenobiotics with the gut as a dedicated metabolic compartment. However, the integration of microbial metabolism and parameterization of PBK models is not standardized and has only been applied to a few chemical transformations. A challenge in this area is the measurement of microbial metabolic kinetics, for which different fermentation approaches are used. Without a standardized method to measure gut microbial metabolism ex vivo/in vitro, the kinetic constants obtained will lead to conflicting conclusions drawn from model predictions. Nevertheless, there are specific cases where PBK models accurately predict systemic concentrations of gut microbial metabolites, offering potential solutions to the challenges outlined above. This review focuses on models that integrate gut microbial bioconversions and use ex vivo/in vitro methods to quantify metabolic constants that accurately represent in vivo conditions.
N-acetyl cysteine alters the genotoxic and estrogenic properties of Alternaria toxins in naturally occurring mixtures
Aichinger, Georg; Grgic, Dino; Beisl, Julia; et al. (2022)
Emerging Contaminants
It is unclear if complex mycotoxin mixtures produced by Alternaria spp. act estrogenic and/or genotoxic under physiological conditions, particularly considering the co-occurrence with antioxidants in food. Thus, this study focused on enlightening the impact of N-acetyl cysteine (NAC), as a representative anti-oxidative SH-donor, on the mentioned toxicological endpoints of the signature Alternaria toxins alternariol (AOH), altertoxin-II (ATX-II) and a complex extract (CE) of an Alternaria alternata culture. Using Ishikawa cells as an in vitro model, we monitored alterations in toxin concentrations by LC-MS/MS, estrogenicity by alkaline phosphatase assays, cytotoxicity by sulforhodamine B assays, genotoxicity by single-cell gel electrophoresis and the transcription of selected genes of interest by quantitative real-time PCR. The results indicate that the strong genotoxic effects of epoxide-carrying perylene quinones such as ATX-II are erased in the presence of NAC. The cellular effects of ATX-II/AOH mixtures are dominated by the genotoxicity of the perylene chinone. In this mixture, AOH regained its estrogenicity when co-incubated with NAC. In contrast, NAC treatment of an AOH/CE mixture did not result in a recovery of estrogenicity, but in potentiated anti-estrogenic effects. These findings were in line with gene transcription data, that indicated the aryl hydrocarbon receptor (AhR) to be a prime mediator of Alternaria toxin – induced antagonistic effects towards estrogen receptor signaling. Taken together, further studies on potential endocrine-disruptive properties of non-genotoxic perylene quinones should be a future research priority in the field of these emerging contaminants.
Baricitinib and tofacitinib off-target profile, with a focus on Alzheimer's disease
Faquetti, Maria L.; Slappendel, Laura; Bigonne, Hélène; et al. (2024)
Alzheimer's & Dementia: Translational Research & Clinical Interventions
Introduction: Janus kinase (JAK) inhibitors were recently identified as promising drug candidates for repurposing in Alzheimer's disease (AD) due to their capacity to suppress inflammation via modulation of JAK/STAT signaling pathways. Besides interaction with primary therapeutic targets, JAK inhibitor drugs frequently interact with unintended, often unknown, biological off-targets, leading to associated effects. Nevertheless, the relevance of JAK inhibitors’ off-target interactions in the context of AD remains unclear. Methods: Putative off-targets of baricitinib and tofacitinib were predicted using a machine learning (ML) approach. After screening scientific literature, off-targets were filtered based on their relevance to AD. Targets that had not been previously identified as off-targets of baricitinib or tofacitinib were subsequently tested using biochemical or cell-based assays. From those, active concentrations were compared to bioavailable concentrations in the brain predicted by physiologically based pharmacokinetic (PBPK) modeling. Results: With the aid of ML and in vitro activity assays, we identified two enzymes previously unknown to be inhibited by baricitinib, namely casein kinase 2 subunit alpha 2 (CK2-α2) and dual leucine zipper kinase (MAP3K12), both with binding constant (K_d) values of 5.8 μM. Predicted maximum concentrations of baricitinib in brain tissue using PBPK modeling range from 1.3 to 23 nM, which is two to three orders of magnitude below the corresponding binding constant. Conclusion: In this study, we extended the list of baricitinib off-targets that are potentially relevant for AD progression and predicted drug distribution in the brain. The results suggest a low likelihood of successful repurposing in AD due to low brain permeability, even at the maximum recommended daily dose. While additional research is needed to evaluate the potential impact of the off-target interaction on AD, the combined approach of ML-based target prediction, in vitro confirmation, and PBPK modeling may help prioritize drugs with a high likelihood of being effectively repurposed for AD.
Human Internal Exposures of Bisphenol A and Six Data-Poor Analogs Predicted by Physiologically Based Kinetic Models with Multimodal Parametrization
Bigonne, Hélène; Rolof, Amrei; Potapova, Inga; et al. (2025)
Environmental Science & Technology
Bisphenols (BP) AF, B, E, F, M, and S are increasingly used as bisphenol A (BPA) substitutes. Despite widespread exposure and potential adverse health outcomes, they are poorly understood in terms of toxicokinetics, i.e., their absorption, distribution, metabolism, and excretion. We thus developed physiologically based kinetic models for different human physiological standards to predict internal concentrations of prevalent bisphenols following oral exposure. To address the imbalances in available human data among these chemicals, we used multimodal parametrization methods, including in vitro measurements of metabolism, computational prediction of gastrointestinal absorption, and rat–human extrapolation of enterohepatic circulation. Then, the models were evaluated against available human toxicokinetic data for BPA and BPS, revealing that 66% of predicted C_max, t_max, and AUC values fell within a 2-fold difference from in vivo measures. Using environmentally relevant exposure levels to compare internal levels of all tested bisphenols, we observed significant differences in the toxicokinetic profiles. Concerning tissues of toxicological concern, BPS had the highest concentration in blood and testes, while BPM accumulated in the thyroid and BPAF in the breasts. The present models are expected to facilitate a more precise evaluation of health risks induced by BPA analogs, guiding their safer use.
Systemically Achievable Doses of Beer Flavonoids Induce Estrogenicity in Human Endometrial Cells and Cause Synergistic Effects With Selected Pesticides
Aichinger, Georg; Bliem, Gloria; Marko, Doris (2021)
Frontiers in Nutrition
Some prenylated polyphenols originating from hops, which are thus natural constituents of beer, have been discussed critically for their agonistic potential toward estrogen receptors. So far, little attention has been attributed to the fact that humans are typically not exposed to isolated compounds, but to mixtures which for example might comprise in addition to hop flavonoids further xenoestrogens, e.g., certain pesticides used for plant protection of hops and barley. Thus, we used the alkaline phosphatase assay to assess combinatory estrogenic effects of three signature compounds – xanthohumol, 8-prenylnaringenin and iso-xanthohumol–on Ishikawa cells in a combination that resembled the concentration ratios observable in beer. Moreover, we added this natural flavonoid pattern to a mixture of representative estrogenic pesticides to assess their combined effects. Using state-of-the-art statistical tools, we observed cumulative to slightly synergistic effects between isolated flavonoids as well as the flavonoid and the pesticide mixture. Of potential importance, these effects were found at low nanomolar hop polyphenol concentrations that one can reasonably expect to occur in vivo after the consumption of strongly hopped beer. Taken together, our results imply that cumulative/synergistic estrogenicity should be explored in detail and urgently be incorporated into risk assessment of prenylated chalcones.
Persistence of the antagonistic effects of a natural mixture of Alternaria mycotoxins on the estrogen-like activity of human feces after anaerobic incubation
Crudo, Francesco; Aichinger, Georg; Dellafiora, Luca; et al. (2022)
Toxicology Letters
Several Alternaria mycotoxins are believed to act as endocrine disruptive chemicals (EDCs), since they are reported to bind estrogen receptors in several experimental models. After ingestion of contaminated food commodities, the mycotoxins reach the intestine, where they come into direct contact with food constituents as well as the gut microbiota. Thus, the aim of the present work was to evaluate the modulatory potential of a complex extract of cultured Alternaria fungi (CE; containing eleven chemically characterized compounds) on the estrogenic signaling cascade of mammalian cells before and after anaerobic incubation with fecal slurries, in order to simulate an in vivo-like condition in the gut. Assessing alkaline phosphatase expression in Ishikawa cells as a measure for estrogenicity, we found the CE to partially quench the intrinsic estrogenic properties of fecal slurries and fecal waters, even after 3 h of fecal incubation. Investigation of the mechanisms underlying the effects observed carried out through an in vitro/in silico approach revealed the ability of the extract to decrease the ERα/ERβ nuclear ratio, while a possible action of the mycotoxins as ER-antagonists was excluded. Our results suggest that Alternaria mycotoxins might act as EDCs in vivo, and warrant further investigation in animal models.

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Georg Aichinger

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