Allosteric Activation of GDP-Bound Ras Isoforms by Bisphenol Derivative Plasticisers

Schöpel, Miriam; Shkura, Oleksandr; Seidel, Jana; Kock, Klaus; Zhong, Xueyin; Löffek, Stefanie; Helfrich, Iris; Bachmann, Hagen S.; Scherkenbeck, Jürgen; Herrmann, Christian; Stoll, Raphael

doi:10.3390/ijms19041133

Cited by 11 publications

(13 citation statements)

References 30 publications

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“…Indeed, in HEK293T cells, both bisphenols can associate with a Ras protein, K-Ras4B; the affinity of BPA is much higher compared to BPS (Schopel et al 2016). Ras functions as a molecular switch that leads to the activation of signalling cascade, such as MAPK3/1 or AKT phosphorylation (Schopel et al 2018). Differences between the BPA and BPS affinity towards Ras protein may help explain the difference in signalling pathway activation observed in the present study.…”

Section: Bpa and Bps Effects May Be Mediated Through Different Mechanisms Of Actionmentioning

confidence: 58%

Bisphenol A and S impaired ovine granulosa cell steroidogenesis

et al. 2020

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Bisphenols, plasticisers used in food containers, can transfer to food. Bisphenol A (BPA) has been described as an endocrine disruptor and consequently banned from the food industry in several countries. It was replaced by a structural analogue, Bisphenol S (BPS). BPA action on the steroidogenesis is one of the mechanisms underlying its adverse effects on the efficiency of female reproduction. This study aimed to determine whether BPS is a safe alternative to BPA regarding GC functions. Antral follicles (2–6 mm), of approximatively 1000 adult ewe ovaries, were aspired and GC purified. For 48 h, ovine GC were treated with BPA or BPS (from 1 nM to 200 µM) and the effects on cell viability, proliferation, steroid production, steroidogenic enzyme expression and signalling pathways were investigated. Dosages at and greater than 100 μM BPA and 10 µM BPS decreased progesterone secretion by 39% (P < 0.001) and 22% (P = 0.040), respectively. BPA and BPS 10 μM and previously mentioned concentrations increased oestradiol secretion two-fold (P < 0.001 and P = 0.082, respectively). Only 100 µM BPA induced a decrease (P < 0.001) in gene expression of the enzymes of steroidogenesis involved in the production of progesterone. BPA reduced MAPK3/1 phosphorylation and ESR1 and ESR2 gene expression, effects that were not observed with BPS. BPA and BPS altered steroidogenesis of ovine GC. Thus, BPS does not appear to be a safe alternative for BPA. Further investigations are required to elucidate BPA and BPS mechanisms of action.

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Section: Bpa and Bps Effects May Be Mediated Through Different Mechanisms Of Actionmentioning

confidence: 58%

Bisphenol A and S impaired ovine granulosa cell steroidogenesis

et al. 2020

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“…For instance, binding energies measured for all 34 candidate targets are considerably lower than the typical accepted threshold value for stable protein-ligand associations (−6.0 kcal/mol) (Shityakov and Förster 2014) (Table 3); best binding poses calculated for many of these enzymes (14/34) are within conserved cofactor or coenzyme binding sites (Figure S1 and Table 4); and also, several likely affected pathways or biological functions (Table 3) have already been reported for other biological systems. On the other hand, whether such associations will cause enzyme activation, as described for small GTPase Ras proteins, after the binding of BPA to their GTP site (Schöpel et al 2018; Schöpel et al 2013) or inactivation, such for thyroid receptors, which occurs through the displacement of T3 hormone from the receptor (Moriyama et al 2002), cannot be clearly accessed through bioinformatics and would require further investigations through biochemical approaches.…”

Section: Discussionmentioning

confidence: 99%

Toxicological impacts and likely protein targets of bisphenol A in Paramecium caudatum

Senra

2021

Preprint

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Bisphenol A (BPA) is a chemical agent widely used in plastic production and a well-known ubiquitous endocrine disruptor, frequently associated with a series of reproductive, developmental, and transgenerational impacts over wildlife, livestocks, and humans. Although widely studied, toxicological data on the effects of BPA are mostly restricted to mammalian models, remaining largely underexplored for other groups of organisms such as protists, which represents a considerable proportion of eukaryotic diversity. Here, we used acute end-point toxicological assay to evaluate the impacts of BPA over the survival of the cosmopolitan Paramecium caudatum; and a proteome-wide inverted virtual-screening (IVS) to predict the most likely P. caudatum proteins and pathways affected by BPA. This xenobiotic exerts a time-dependent effect over P. caudatum survival, which may be a consequence of impairments to multiple core cellular functions. We discuss the potential use of this ciliate as a biosensor for environmental BPA and as a new model organism to study the general impacts of this plasticizer agent over Eukaryotes. Finally, our data stress the relevance of bioinformatic methods to leverage the current knowledge on the molecular impacts of environmental contaminants over a diversity of biological systems.

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“…For example, fluoxetine (FLX) that is the SSRI (selective serotonin reuptake inhibitor) active substance in the Prozac™ antidepressant has been shown to modify a number of intracellular signaling pathways in various cell types [14,15,16]. Several bisphenols have been shown to interact with Ras small G proteins (particularly K-Ras4B) leading to the activation of the Ras signaling cascade, as shown by raised pERK and pAKT levels [17].…”

Section: Edcs Interacting With Hormone Signaling Pathways (Mechanimentioning

confidence: 99%

Comparative Overview of the Mechanisms of Action of Hormones and Endocrine Disruptor Compounds

Combarnous

Nguyen

2019

Toxics

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Endocrine Disruptor Compounds (EDCs) are synthetic or natural molecules in the environment that promote adverse modifications of endogenous hormone regulation in humans and/or in wildlife animals. In the present paper, we review the potential mechanisms of EDCs and point out the similarities and differences between EDCs and hormones. There was only one mechanism, out of nine identified, in which EDCs acted like hormones (i.e. binding and stimulated hormone receptor activity). In the other eight identified mechanisms of action, EDCs exerted their effects either by affecting endogenous hormone concentration, or its availability, or by modifying hormone receptor turn over. This overview is intended to classify the various EDC mechanisms of action in order to better appreciate when in vitro tests would be valid to assess their risks towards humans and wildlife.

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Allosteric Activation of GDP-Bound Ras Isoforms by Bisphenol Derivative Plasticisers

Cited by 11 publications

References 30 publications

Bisphenol A and S impaired ovine granulosa cell steroidogenesis

Bisphenol A and S impaired ovine granulosa cell steroidogenesis

Toxicological impacts and likely protein targets of bisphenol A in Paramecium caudatum

Comparative Overview of the Mechanisms of Action of Hormones and Endocrine Disruptor Compounds

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