Predisposal of Interferon Regulatory Factor 1 Deficiency to Accumulate DNA Damage and Promote Osteoarthritis Development in Cartilage.

OBJECTIVE: Interferon regulatory factor 1 (IRF1) is a transcriptional regulator conventionally associated with immunomodulation. Recent molecular analyses mapping DNA binding sites of IRF1 have suggested its potential function in DNA repair. However, the physiologic significance of this noncanonical function remains unexplored. Here, we investigated the role of IRF1 in osteoarthritis (OA), a condition marked by senescence and chronic joint inflammation. METHODS: OA progression was examined in wild-type and Irf1-/- mice using histologic assessments and microcomputed tomography analysis of whole-joint OA manifestations and behavioral assessments of joint pain. An integrated analysis of assay for transposase-accessible chromatin with sequencing and whole transcriptome data was conducted for the functional assessment of IRF1 in chondrocytes. The role of IRF1 in DNA repair and senescence was investigated by assaying γ-H2AX foci and senescence-associated beta-galactosidase activity. RESULTS: Our genome-wide investigation of IRF1 footprinting in chondrocytes revealed its primary occupancies in the promoters of DNA repair genes without noticeable footprint patterns in those of interferon-responsive genes. Chondrocytes lacking IRF1 accumulated irreversible DNA damage under oxidative stress, facilitating their entry into cellular senescence. IRF1 was down-regulated in the cartilage of human and mouse OA. Although IRF1 overexpression did not elicit an inflammatory response in joints or affect OA development, genetic deletion of Irf1 caused enhanced chondrocyte senescence and exacerbated post-traumatic OA in mice. CONCLUSION: IRF1 offers DNA damage surveillance in chondrocytes, protecting them from oxidative stress associated with OA risk factors. Our study provides a crucial and cautionary perspective that compromising IRF1 activity renders chondrocytes vulnerable to cellular senescence and promotes OA development.

Severe contamination and time trend of legacy and alternative plasticizers in a highly industrialized lake associated with regulations and coastal development.

Few studies have been conducted on aquatic contamination by alternative plasticizers. Phthalates and novel plasticizers were measured in sediments from a highly industrialized lake to assess occurrence, sources, time trends, and ecological risks. Legacy and alternative plasticizers were detected in all sediments. Di(2-ethylhexyl) phthalate (DEHP) was a predominant plasticizer, indicating its popular industrial consumption for the last two decades. Predominant novel plasticizers were changed over time. The highest sedimentary DEHP level was recorded on the global scale. Legacy and alternative plasticizers in creek sediments significantly increased from 2008 to 2016, while those from inshore and offshore regions of the lake significantly decreased in association with a dilution effect caused by the operation of a tidal power plant. Concentration ratios of alternative plasticizers to DEHP increased for the last decade, implying a shift in consumption of plasticizers. Sedimentary DEHP concentrations in creeks exceeded almost all threshold values associated with ecological risks.

Contamination and historical trends of legacy and emerging plasticizers in sediment from highly industrialized bays of Korea.

Domestic and global regulations on phthalates have led to the introduction of non-phthalate plasticizers (NPPs) in industrial markets as alternative plasticizers. In this study, phthalates and NPPs from surface and core sediment samples taken from industrialized bays in Korea were measured to determine their distribution, contamination sources, historical records, and the ecological risks they posed. Phthalates and alternative plasticizers were detected in all surface samples and sediment cores, indicating ubiquitous contamination. Predominant phthalates were di(2-ethylhexyl)phthalate (DEHP), diisononyl phthalate (DiNP), and diisodecyl phthalate (DiDP) and di(2-ethylhexyl)terephthalate (DEHT) and tris(2-ethylhexyl)trimellitate (TOTM) were the most common NPPs. The total concentrations of phthalates and NPPs ranged from 76.3 to 59,400 ng/g dry weight and <0.02 to 35,300 ng/g dry weight, respectively. The highest concentrations of phthalates and NPPs were observed in sediment from rivers, streams, and inner parts of bays, with the levels decreasing gradually toward the outer parts of the bays. Our findings suggest that proximity to industrial complexes is crucial for sedimentary distribution for plasticizers. Historical records in a sediment core show clearly increasing trends in phthalate and NPP levels from the 1970s to the 2010s, consistent with their production history. In particular, TOTM has rapidly increased over the last decade, presenting an emerging concern of contaminant in the coastal environment. Industrialization and population growth were suggested as major factors affecting plasticizer contamination. Almost all sediment (>95%) exceeded quality guidelines for DEHP, implying a potential risk for benthic organisms. This is the first report on historical trends of phthalates and alternative plasticizers.

Occurrence, distribution, and sources of phthalates and non-phthalate plasticizers in sediment from semi-enclosed bays of Korea.

Due to strong regulation of phthalates, non-phthalate plasticizers (NPPs) have been introduced to the industrial market. In this study, concentrations of 16 phthalates and five NPPs in sediment were measured to investigate the occurrence, potential source, and ecotoxicological implications of these contaminants. Phthalates and NPPs were detected in all sediment samples, indicating ubiquitous contaminants. Di(2-ethylhexyl)phthalate (DEHP) and trioctyl trimellitate (TOTM) were the dominant for phthalates and NPPs, respectively, implying emerging contamination by TOTM. Spatial distribution of these contaminants showed decreasing gradients from inner to outer bays. Clear declining trends in phthalate and NPP concentrations were found in sediment near a wastewater treatment plant outfall, suggesting a potential source of contamination. Approximately 95% of sediment samples exceeded sediment quality guidelines for DEHP suggested by previous studies, implying that benthic organisms are suffering from adverse biological effects. This is the first report on the occurrence of NPPs in the coastal environment.