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Published on: August 28, 2019
Elucidation of endocrine-disrupting polychlorinated biphenyls binding potency with steroidogenic genes: Integration
K Kranthi Kumar1, B Uma Devi1, P Neeraja1
1Department of Zoology, Sri Venkateswara University, Tirupati, 517502 A.P., India.
Abstract:
A myriad of polychlorinated biphenyls (PCBs) may have potential to reproductive axis and endocrine disruptions. PCBs mostly breach the cholesterol biotransformation in mitochondria through interfering with steroidogenic genes and lead to adverse consequences in steroidogenesis; however, studies are scanty. In this examination, the combinations of quantitative structure-activity relationship (QSAR) modeling and ensemble docking approaches was performed to envisage structural properties of PCBs that influence the developmental toxicity, estrogen receptor-mediated impacts, and to provide a better comprehension of binding levels between PCBs, steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (CYP11A1). Prognostic QSAR models were illustrated with good robustness and predictive ability. Models provide extensive data on applicability domain and similarities between PCBs and training set compounds was used to implement for clustering and classification of toxic PCBs by employing Self-Organizing Maps. Docking and interaction profiles interpretations provided various insights into the structural features of PCBs that influence the cholesterol binding to StAR and CYP11A1 domains. The non-polar, atomic π - stacking and halogen bonds of PCBs with novel hotspots residues of StAR and CYP11A1 was indicated subtle conformational changes that barrier to cholesterol binding and/or locks to cholesterol ejection from Ω1-loop of StAR, and inhibits cholesterol to pregnenolone biosynthesis by CYP11A1; thus, these are probably revealed as block-cluster mechanisms. These outcomes are potential to be useful to predict developmental toxicity, endocrine disruption potencies and anti-steroidogenic activities of other environmental pollutants and provided sorted pinpoints for further evaluation of interaction mechanisms of PCBs with other sterodogenic genes.
Insights
Polychlorinated biphenyls (PCBs) disrupt endocrine function by interfering with cholesterol metabolism in mitochondria. This study reveals how PCB structures impact steroidogenesis, offering insights into developmental toxicity and endocrine disruption.
Area of Science:
- Environmental Toxicology
- Molecular Endocrinology
- Computational Chemistry
Background:
- Polychlorinated biphenyls (PCBs) are environmental pollutants linked to endocrine disruption and reproductive toxicity.
- PCBs interfere with cholesterol biotransformation and steroidogenesis, but the precise mechanisms remain unclear.
- Existing research on PCB-induced steroidogenic disruption is limited, necessitating further investigation.
Purpose of the Study:
- To elucidate the structural properties of PCBs that contribute to developmental toxicity and endocrine disruption.
- To understand the binding interactions between PCBs, the steroidogenic acute regulatory protein (StAR), and cholesterol side-chain cleavage enzyme (CYP11A1).
- To develop predictive models for PCB toxicity and anti-steroidogenic activities.
Main Methods:
- Quantitative Structure-Activity Relationship (QSAR) modeling to predict toxicity and estrogen receptor impacts.
- Ensemble docking simulations to analyze binding affinities and interactions with StAR and CYP11A1.
- Self-Organizing Maps (SOM) for clustering and classifying toxic PCBs based on structural similarities.
Main Results:
- Developed robust QSAR models with good predictive capabilities for PCB toxicity.
- Identified key structural features of PCBs, including non-polar interactions, π-stacking, and halogen bonds, that affect binding to StAR and CYP11A1.
- Revealed that PCBs induce conformational changes, hindering cholesterol binding and inhibiting pregnenolone biosynthesis via a 'block-cluster' mechanism.
Conclusions:
- The study provides a mechanistic understanding of how PCBs disrupt steroidogenesis at the molecular level.
- Findings offer valuable insights for predicting the developmental toxicity and endocrine-disrupting potential of other environmental pollutants.
- The identified 'block-cluster' mechanism highlights specific structural interactions crucial for anti-steroidogenic activity evaluation.
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