Qian S. Liu

Airborne particulate matter (PM) is a major environmental contributor to allergic disease prevalence, yet the skin-sensitizing potency of PM from different emission sources and its active components remain unclear. We adopted the human cell line activation test (h-CLAT) and keratinocyte–dendritic cell (KC–DC) co-culture activation test (COCAT) to evaluate three standard reference materials (SRMs): urban PM (UPM) 1648a, coal fly ash (CFA) 2693, and diesel exhaust particles (DEP) 2975. Distinct source-dependent sensitization profiles were observed. In THP-1 monocultures, 1648a upregulated CD54 expression by stimulating TNF-α and IL-1β secretion. Co-culture with KCs potentiated DC activation against all three SRMs, elevating CD86 and CD54 levels via increased IL-1β and extracellular ATP release. Mechanistically, aryl hydrocarbon receptor (AhR) signaling in HaCaT cells was critical for THP-1 activation. Functional component analysis uncovered that amorphous silica drove 1648a-triggered CD54 upregulation in monocultures, while soot and magnetite, common to all SRMs, along with amorphous and crystalline silica in 1648a, collectively elevated CD86 levels under co-culture. AhR-agonistic soluble components, such as polycyclic aromatic hydrocarbons (PAHs), acted as synergistic regulators. This study presents the first comprehensive evidence that PM of disparate origins induces cutaneous sensitization via differential modulation of KC–DC crosstalk, offering a basis for reducing PM-related allergic risks.

Per- and polyfluoroalkyl substances (PFAS) can persist in human blood and may perturb hematological homeostasis by interacting with coagulation factor XII (FXII), the initiator of the contact system. This study combined in vitro, ex vivo, and in vivo experiments with computational modeling to evaluate the effects of legacy PFAS (PFOS and PFOA) and their alternatives (6:2 Cl-PFESA, HFPO-DA, HFPO-TA, and HFPO-TeA) on FXII and downstream contact activation. In vitro and ex vivo screening showed that 6:2 Cl-PFESA had a greater capacity to activate FXII than PFOS, whereas HFPO-TA induced more pronounced FXII cleavage and a larger, albeit modest, increase in activated FXII (FXIIa) activity relative to PFOA. Both alternatives also triggered plasma prekallikrein activation. Intravenous exposure to 6:2 Cl-PFESA significantly increased plasma FXIIa activity in mice, suggesting that this PFAS alternative may perturb the contact system in vivo. Structure-activity analysis showed that, unlike linear PFAS, FXII activation induced by HFPO alternatives did not follow a simple carbon chain-length dependence. Molecular dynamics simulations and virtual alanine scanning analysis using FXII crystal and AlphaFold structures suggested a domain-selective mechanism, with the carboxylic PFAS favoring the fibronectin type-II domain (Fib-II) and the sulfonic PFAS favoring both the Fib-II and the proline-rich (PR) domain. These findings uncover new activators of the contact system, informing the potential hematological effects of PFAS alternatives, and provide computational support for a possible domain-selective mechanism for PFAS–FXII interactions.

4-Alkylphenols (APs), as typical endocrine-disrupting chemicals (EDCs) widely present in the environment and the human body, have been implicated in the disruption of lipid metabolism. However, the structure-activity relationships (SARs) and underlying mechanisms of their hepatic lipotoxicity remain unclear. This study systematically evaluated the effects of nine 4-AP isomers with linear (4-n-APs) and branched (4-t-APs) para-alkyl substituents on hepatic lipid metabolism in HepG2 cells. The results showed that all 4-n-APs significantly promoted intracellular triglyceride (TG) accumulation in a dose-dependent manner, whereas 4-t-APs exerted no such effects. The lipogenic potency of 4-n-APs followed an inverted U-shaped curve with increasing linear alkyl chain length. Either ER antagonism or ROS inhibition effectively mitigated 4-n-AP-induced hepatic lipogenesis, demonstrating the coordinated actions of ER signaling and oxidative stress underlying the lipotoxic phenotype. Collectively, linear 4-n-APs induce hepatic lipid accumulation through the combined contributions of ER agonism and excessive ROS production, while branched 4-t-APs lack such activity due to structural differences. These findings clarify the SAR framework for hepatic lipogenesis triggered by 4-AP congeners and the underlying dual ER-ROS mechanism, providing a scientific basis for assessing their environmental health risks.

Per- and polyfluoroalkyl substances (PFAS) have triggered a global crisis due to their severe toxicities and widespread occurrence in human populations. Notably, PFAS is frequently detected in maternal blood, placental tissue, and umbilical cord blood, indicating direct fetal exposure to PFAS through the maternal–fetal interface. As the central organ regulating nutrient exchange, endocrine signaling, and immune balance, the placenta is particularly vulnerable to PFAS exposure, and its dysfunction is linked with various adverse pregnancy outcomes, including fetal growth restriction, low birth weight, preterm birth, preeclampsia, etc. However, existing knowledge on PFAS-induced placental dysfunction remains fragmented, typically addressing their occurrence, transplacental transfer, specific mechanistic targets, or epidemiological evidence in isolation. This review synthesizes evidence tracing the entire trajectory of PFAS exposure─from maternal uptake and distribution in the bloodstream to placental accumulation, transplacental passage, and fetal exposure. It further highlights how PFAS may interfere with key processes of placental development, including angiogenesis and vascular remodeling, trophoblast migration and invasion, lipid metabolism, hormone production, and establishment of the maternal–fetal immune microenvironment, which provides mechanistic explanations linking PFAS exposure to adverse pregnancy outcomes. By integrating transplacental behaviors, mechanistic insights, epidemiological findings, and methodological advances, this review offers a comprehensive perspective on PFAS-induced placental toxicity and presents new directions for assessing maternal–fetal health risks.

The nonmonotonic dose–response curve (NMDRC) is a prevalent characteristic of endocrine-disrupting chemicals (EDCs) in activating nuclear receptors (NRs), implicating intricate regulatory mechanisms. In this study, the agonistic and antagonistic activities of 11 bisphenols on the estrogen receptor (ER) were screened using MVLN cells. Three distinct dose–response patterns were observed, namely, S-shaped, inverted S-shaped, and bell-shaped profiles, corresponding to the agonistic, antagonistic, and nonmonotonic effects on ERs, respectively. To further explore NMDRC, bisphenol B (BPB) and bisphenol AF (BPAF), as representative compounds, were specifically investigated for their antagonistic effects on ER under high exposure concentrations (10–50 μmol/L). Notably, the successive decline in cell viability suggested a subhealthy cell state upon high-dose chemical treatments, compromising cell response in ER transactivation. Unlike the specific effect induced by an ERα antagonist (4-hydroxytamoxifen, 4OHT), the nonspecific inhibitory effects of BPB and BPAF on ER transactivation were further confirmed with their identical antagonistic curves, with or without E2 cotreatment, due to hydrophobicity-related cellular baseline toxicity. Accordingly, the inhibitory effects on NR transactivation might not necessarily be considered as a specific antagonistic activity. Thus, a more cautious inspection is highly encouraged in screening NR antagonism-centered endocrine-disrupting effects of emerging chemicals by carefully reviewing the specificity of signal reduction or inhibition.

Atmospheric fine particulate matter (PM_2.5) poses threats to the cardiovascular system. Red blood cells (RBCs) are the most abundant cells in blood, which are actively involved in multiple hematological diseases, such as blood clot formation and thrombosis. Exploring how PM_2.5 with spatiotemporal heterogeneity influences the hematological system by targeting RBCs would help gain insights into the deleterious effects of PM_2.5 and provide clues for finding the causative components therein. Herein, the PM_2.5 samples collected from 3 urban sites in Beijing (i.e., Chaoyang, Shunyi, and Yanqing districts) during 4 seasons of 2022 were studied for their toxicities to mouse RBCs, and the main contributing components were further explored through chemical analysis and correlation measure. The results showed that exposure to PM_2.5 samples decreased adenosine triphosphate (ATP) levels and increased phosphatidylserine (PS) externalization of RBCs, causing cell morphological deformity. The Pearson correlation analysis showed that the aromaticity of the dissolved organic matter (DOM) in PM_2.5 samples was positively correlated with PS exposure of RBCs, showing that the lignin-like compounds were the potential contributors. The negative correlation of zeta potentials of PM_2.5 samples with PS exposure of RBCs showed the particle-derived bioactivities of this airborne pollutant. The simulative test based on artificial nanomaterials of carbon black (CB) and oxidized CB (OCB) confirmed the crucial role of particulate carbon in PM_2.5-induced effects on RBCs, and soot with a certain oxidation degree was, thus, recognized as another contributor, given its ubiquitous existence in PM_2.5 samples. This study, for the first time, revealed PM_2.5-induced PS exposure of RBCs, and the causative components of DOM and soot were unraveled. Considering the inevitable contact of airborne PM_2.5 with RBCs in the blood circulatory system, the findings obtained herein would help bridge the gap between PM_2.5 exposure and the risk of cardiovascular diseases, like thrombogenesis.