Structure-based discovery of the endocrine disrupting effects of hydraulic fracturing chemicals as novel androgen receptor antagonists

Tachachartvanich, Phum; Singam, Ettayapuram Ramaprasad Azhagiya; Durkin, Kathleen A.; Smith, Martyn T.; Merrill, Michele A. La

doi:10.1016/j.chemosphere.2020.127178

Cited by 6 publications

(10 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…LNCaP cells form an androgen-dependent cell line with androgen binding in the AR and express androgen-responsive genes. Therefore, LNCaP cells have frequently been used for the screening of environmental AR antagonists . To investigate the AR antagonistic activity of BP-1, P1, and P2 in LNCaP cells, we detected their regulation on the expression of AR target genes kallikrein related peptidase 3 ( KLK3 ) and NK3 homeobox 1 ( NKX3.1 ).…”

Section: Resultsmentioning

confidence: 99%

“…To investigate the AR antagonistic activity of BP-1, P1, and P2 in LNCaP cells, we detected their regulation on the expression of AR target genes kallikrein related peptidase 3 ( KLK3 ) and NK3 homeobox 1 ( NKX3.1 ). Testosterone at a concentration of 2.5 × 10 3 nM was used as a positive control to avoid underestimating antiandrogenic activity upon exposure to test chemicals . The relative mRNA expression of KLK3 and NKX3.1 in LNCaP cells was determined after coexposure to BP-1, P1, or P2 with testosterone for 24 h. No cytotoxicity was observed in LNCaP cells after exposure to BP-1, P1, and P2 at concentrations ranging from 1 nM to 10 4 nM (Figure S11).…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, LNCaP cells have frequently been used for the screening of environmental AR antagonists. 57 To investigate the AR antagonistic activity of BP-1, P1, and P2 in LNCaP cells, we detected their regulation on the expression of AR target genes kallikrein related peptidase 3 (KLK3) and NK3 homeobox 1 (NKX3.1). Testosterone at a concentration of 2.5 × 10 3 nM was used as a positive control to avoid underestimating antiandrogenic activity upon exposure to test chemicals.…”

Section: Resultsmentioning

confidence: 99%

“…Testosterone at a concentration of 2.5 × 10 3 nM was used as a positive control to avoid underestimating antiandrogenic activity upon exposure to test chemicals. 57 The relative mRNA expression of KLK3 and NKX3.1 in LNCaP cells was determined after coexposure to BP-1, P1, or P2 with testosterone for 24 h. No cytotoxicity was observed in LNCaP cells after exposure to BP-1, P1, and P2 at concentrations ranging from 1 nM to 10 4 nM (Figure S11). Testosterone increased the relative mRNA expression of NKX3.1 and KLK3 to 12.87 ± 0.48 and 40.76 ± 7.31, respectively (Figure 4A,B).…”

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

Enhanced Disrupting Effect of Benzophenone-1 Chlorination Byproducts to the Androgen Receptor: Cell-Based Assays and Gaussian Accelerated Molecular Dynamics Simulations

Zhan

Cui

Liu

et al. 2021

Chem. Res. Toxicol.

View full text Add to dashboard Cite

Benzophenone-1 (BP-1), one of the commonly used ultraviolet filters, has caused increasing public concern due to frequently detected residues in environmental and recreational waters. Its susceptibility to residual chlorine and the potential to subsequently trigger endocrine disruption remain unknown. We herein investigated the chlorination of BP-1 in swimming pool water and evaluated the endocrine disruption toward the human androgen receptor (AR). The structures of monochlorinated (P1) and dichlorinated (P2) products were separated and characterized by mass spectrometry and 1H–1H NMR correlation spectroscopy. P1 and P2 exhibited significantly higher antiandrogenic activity in yeast two-hybrid assays (EC50, 6.13 μM and 9.30 μM) than did BP-1 (12.89 μM). Our 350 ns Gaussian accelerated molecular dynamics simulations showed the protein dynamics in a long-time scale equilibrium, and further energy calculations revealed that although increased hydrophobic interactions are primarily responsible for enhanced binding affinities between chlorinated products and the AR ligand binding domain, the second chloride in P2 still hinders the complex motion because of the solvation penalty. The mixture of BP-1–P1–P2 elicited additive antiandrogenic activity, well fitted by the concentration addition model. P1 and P2 at 1 μM consequently downregulated the mRNA expression of AR-regulated genes, NKX3.1 and KLK3, by 1.7–9.1-fold in androgen-activated LNCaP cells. Because chlorination of BP-1 occurs naturally by residual chlorine in aquatic environments, our results regarding enhanced antiandrogenic activity and disturbed AR signaling provided evidence linking the use of personal care products with potential health risks.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Enhanced Disrupting Effect of Benzophenone-1 Chlorination Byproducts to the Androgen Receptor: Cell-Based Assays and Gaussian Accelerated Molecular Dynamics Simulations

Zhan

Cui

Liu

et al. 2021

Chem. Res. Toxicol.

View full text Add to dashboard Cite

show abstract

“…Water quality is very important for water resource usage, agricultural activities, industrial production, aquaculture, and regional safety [2][3][4][5][6]. However, water has been frequently contaminated by diverse pollutants such as heavy metals [7], endocrine disrupting chemicals [8], antibiotic resistance genes [9], microplastics [9], and other emerging chemicals in recent decades. ese pollutants have occurred in seawater, groundwater, lakes, and rivers to possibly exert the potential risks to humans [7,9,10].…”

Section: Introductionmentioning

confidence: 99%

Variation of Water Quality in Ningxia Section of the Yellow River in Recent 5 Years

Jin

Wang

Dong³

2022

Journal of Chemistry

View full text Add to dashboard Cite

The Yellow River is very important for human health and social development in China to require good water quality. This study selected the Ningxia section of the Yellow River as the study area to investigate the water quality variation in 2016–2020. A total of 9 water quality parameters were monitored, and 8 parameters including pH, dissolved oxygen, biological oxygen demand, chemical oxygen demand, total phosphate, fluoride, ammonia-nitrogen, and permanganate index were in the range of Class II standard requirement. Dissolved oxygen concentrations ranged from 7.5 to 9.4 mg/L. However, total nitrogen concentrations in 2018–2020 ranged from 1.87 to 2.8 mg/L to cause the pollution. Both the Nemerow index method and the contamination degree method showed that total nitrogen with high concentration exerted the water pollution. Principal component analysis also proved this. Stricter environmental management strategies for controlling total nitrogen should be taken in the future. The findings provided some useful information for water pollution of the Ningxia section of the Yellow River.

show abstract

New approach methods for assessing indoor air toxicity

Mannerström

Dvořáková

Svobodová

et al. 2022

Current Research in Toxicology

View full text Add to dashboard Cite

Structure-based discovery of the endocrine disrupting effects of hydraulic fracturing chemicals as novel androgen receptor antagonists

Cited by 6 publications

References 30 publications

Enhanced Disrupting Effect of Benzophenone-1 Chlorination Byproducts to the Androgen Receptor: Cell-Based Assays and Gaussian Accelerated Molecular Dynamics Simulations

Enhanced Disrupting Effect of Benzophenone-1 Chlorination Byproducts to the Androgen Receptor: Cell-Based Assays and Gaussian Accelerated Molecular Dynamics Simulations

Variation of Water Quality in Ningxia Section of the Yellow River in Recent 5 Years

New approach methods for assessing indoor air toxicity

Contact Info

Product

Resources

About