Bioaccumulation and Potential Endocrine Disruption Risk of Legacy and Emerging Organophosphate Esters in Cetaceans from the Northern South China Sea

Despite the increasing health risks shown by the continuous detection of organophosphate esters (OPEs) in biota in recent years, information on the occurrence and potential risks of OPEs in marine mammals remains limited. This study conducted the first investigation into the body burdens and potential risks of 10 traditional OPEs (tOPEs) and five emerging OPEs (eOPEs) in 10 cetacean species (n = 84) from the northern South China Sea (NSCS) during 2005–2021. All OPEs, except for 2-ethylhexyl diphenyl phosphate (EHDPHP), were detected in these cetaceans, indicating their widespread occurrence in the NSCS. Although the levels of the ∑10tOPEs in humpback dolphins remained stable from 2005 to 2021, the concentrations of the ∑5eOPEs showed a significant increase, suggesting a growing demand for these new-generation OPEs in South China. Dolphins in proximity to urban regions generally exhibited higher OPE concentrations than those from rural areas, mirroring the environmental trends of OPEs occurring in this area. All OPE congeners, except for EHDPHP, in humpback dolphins exhibited a maternal transfer ratio >1, indicating that the dolphin placenta may not be an efficient barrier for OPEs. The observed significant correlations between levels of OPEs and hormones (triiodothyronine, thyroxine, and testosterone) in humpback dolphins indicated that OPE exposures might have endocrine disruption effects on the dolphin population

ARRDC3 regulates the targeted therapy sensitivity of clear cell renal cell carcinoma by promoting AXL degradation

AXL plays crucial roles in the tumorigenesis, progression, and drug resistance of neoplasms; however, the mechanisms associated with AXL overexpression in tumors remain largely unknown. In this study, to investigate these molecular mechanisms, wildtype and mutant proteins of arrestin domain-containing protein 3 (ARRDC3) and AXL were expressed, and co-immunoprecipitation analyses were performed. ARRDC3-deficient cells generated using the CRISPR-Cas9 system were treated with different concentrations of the tyrosine kinase inhibitor sunitinib and subjected to cell biological, molecular, and pharmacological experiments. Furthermore, immunohistochemistry was used to analyze the correlation between ARRDC3 and AXL protein expressions in renal cancer tissue specimens. The experimental results demonstrated that ARRDC3 interacts with AXL to promote AXL ubiquitination and degradation, followed by the negative regulation of downstream signaling mechanisms, including the phosphorylation of protein kinase B and extracellular signal-regulated kinase. Notably, ARRDC3 deficiency decreased the sunitinib sensitivity of clear cell renal cell carcinoma (ccRCC) cells in a manner dependent on the regulation of AXL stability. Overall, our results suggest that ARRDC3 is a negative regulator of AXL and can serve as a novel predictor of sunitinib therapeutic response in patients with ccRCC.</p