Background/Purpose: Osteoarthritis (OA) affects over 590 million individuals globally. Epidemiological data suggest that exposure to environmental pollutants, particularly endocrine-disrupting chemicals (EDCs) such as phthalates, PFAS, and heavy metals, may contribute to increased OA risk and severity (1). Chronic exposure to these compounds begins as early as in utero and continues throughout life via environmental and household sources with at least 14 EDCs ubiquitously present in daily life (2). Several have also been identified in the synovial fluid of OA patients, indicating both systemic and local joint exposure. Yet, their functional role in pain modulation and joint inflammation remains insufficiently understood This study aimed to determine whether local and/or systemic low-dose exposure to a mixture of 14 EDCs modulates OA severity and pain, and to explore potential effects on sensory neuron.

Methods: Male and female 12-week-old C57BL/6 mice were exposed either locally by intra-articular (IA) injections of an EDCs mix (e.g., Perfluorooctanoic acid [PFOA]=10⁻⁷M) or vehicle, one week before and after OA induction by IA injection of monoiodoacetate. An additional cohort was systemically (via lifelong administration through drinking water) exposed to the EDCs mix from in utero through 15 weeks. Pain-related behaviour, locomotor activity, and body weight were monitored over 21 days. Histological and molecular analyses were performed on knee joints and dorsal root ganglia (DRG). In vitro, primary DRG neurons from male mice were treated with the EDCs mix (e.g., [PFOA]=10⁻⁸M or 10⁻⁹M), and calcium responses to capsaicin (TRPV1 agonist) were recorded.

Results: In male mice, local IA EDCs exposure significantly increase OA-related pain over the 21-day period (p< 0.001) and reduce the physical activity (day 21: mean [SEM] 13.2m [4.7] vs. 17.4m [2.3] in controls, p< 0.05). Histological analysis revealed more severe synovitis (Krenn score) (5.1 [1.55] vs. 4.3 [1.5], p< 0.05) and OARSI cartilage damage (3 [0.75] vs. 2.5 [2.94], p=0.03). Enhanced macrophage infiltration and elevated Bdnf gene expression in the DRG were also observed. In contrast, female mice with IA EDCs exposure did not display significant mechanical hypersensitivity, although they exhibited reduced physical activity (day 21: 13.5m [1.4] vs 19.5m [2.3] in controls, p< 0.05) along with upregulation of Bdnf expression in DRGs.Male mice exposed systemically to EDCs via drinking water developed persistent OA pain-related behaviours (p=0.001) and unexpectedly showed increased physical activity (16.9m [181.0] vs. 13.6m [127.8], p< 0.05), potentially reflecting EDCs-induced anxiety. No significant effects were observed in female mice. In vitro, EDCs-treated sensory neurons displayed altered calcium dynamics with prolonged depolarization following capsaicin stimulation.

Conclusion: This study reveals that low-dose exposure to EDCs can amplify OA-related pain and inflammatory responses in a sex-specific manner. This study supports the role of EDCs in modulating neuroimmune interactions and sensory neuron excitability in OA pathophysiology. < !(1) Deprouw C, RMD Open. 2022< !(2) Woodruff, Environmental health perspectives. 2011

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/endocrine-disruptors-exacerbates-osteoarthritis-pain-and-inflammation/