Icomucret

Micro- and nanoplastics (MNPs) can enhance the toxicity of co-occurring chemicals via a proposed "Trojan horse" effect, yet the underlying mechanisms remain unclear. Here, we investigated the estrogenic effects of coexposure of ultraviolet filter homosalate (HMS) and polystyrene nanosphere (PNS) using ovariectomized mice (HMS: 0.1 and 1 mg/kg; PNS: 2.5 mg/kg) and human cell models (HMS: 0.01 - 1 μM; PNS: 1 mg/L). In mice, HMS-PNS coexposure significantly increased uterine weight, promoted mammary gland proliferation, and upregulated estrogen receptor 1 and its downstream targets amphiregulin and progesterone receptor. Integrated metabolomic and transcriptomic analyses identified endogenous 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) as a key mediator of these effects in mammary glands. In MCF-7 cells, HMS-PNS coexposure elevated 15(S)-HETE levels, promoting cell proliferation via the estrogen receptor alpha-arachidonate 15-lipoxygenase (ERα-ALOX15) axis. At a concentration of 100 nM 15(S)-HETE, pharmacological inhibition of phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) abrogated cell proliferation and serum and glucocorticoid-regulated kinase 1 (SGK1) activation. Moreover, immunoprecipitation and docking analyses suggested a direct interaction between 15(S)-HETE and SGK1. Knockdown of ALOX15, or PI3K/AKT inhibition, suppressed HMS-PNS-induced cell proliferation. Taken together, these results demonstrated that HMS-PNS coexposure amplifies estrogenic responses through ERα-ALOX15-dependent 15(S)-HETE production and PI3K/AKT/SGK1 signaling. Our findings uncover a mechanistic pathway beyond the canonical "Trojan horse" effect, providing new insight into how MNPs modulate endocrine-disrupting activity of co-occurring contaminants and informing future risk assessment of combined environmental exposures.

The pathogenesis of atopic dermatitis (AD) involves a complex immune regulatory network between dendritic cells (DCs) and keratinocytes (KCs). Recent studies have found that N6-methyladenosine (m⁶A) RNA modification modulates immune regulation and skin barrier homeostasis, but it is unclear whether it participates in AD through the DCs-KCs interaction crosstalk. This study aimed to investigate whether m⁶A modification contributes to the pathological features of atopic dermatitis by regulating ALOX15 expression in dendritic cells.

We integrated bioinformatics analysis with clinical sample validation to examine ALOX15 expression in AD skin lesions. Methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) was performed to quantify changes in the m⁶A methylation of ALOX15. Three co-culture systems using primary mouse bone marrow-derived DCs (BMDCs), DC 2.4 cells, and primary mouse KCs were established to investigate how ALOX15 mediates DC activation and influences the biological behavior of KCs.

ALOX15 expression was significantly upregulated in DCs from AD lesions. Mechanistically, WTAP-mediated m⁶A modification enhanced ALOX15 expression, prompting DCs activation and inflammatory factor secretion. Co-culture experiments demonstrated that ALOX15-overexpressing DCs secreted elevated levels of inflammatory factors and arachidonic acid metabolites (LTB4, 12-HETE, and 15-HETE), leading to abnormal KCs' differentiation, proliferation disorders, and lipid metabolism disorders, which are characteristic phenotypic changes of AD.

Our findings underscore the critical role of the WTAP-m⁶A-ALOX15 axis in regulating DCs-KCs interactions in AD, providing new theoretical foundations and potential intervention targets for future interventions.