Zhipeng Cheng

Quaternary ammonium disinfectants (QACs) are being increasingly used since the COVID-19 pandemic, however, their potential impacts on sensitive populations (e.g., pregnant populations and developing fetuses) remain largely unexplored. In this study, we combined human biomonitoring with in vivo models (including rat uterine perfusion and oral administration in mice) and an in vitro model (human placental trophoblast BeWo cell line) to evaluate gestational exposure, the transplacental transport, and the toxic effects of QACs on placenta function. QACs are frequently detected in human maternal and cord blood/serum, revealing widespread gestational exposure and potential health effects. The molecular structure and lipid solubility affect the transplacental transfer of QACs. Using RT–qPCR, Western blotting, immunofluorescence staining of rat placenta, siRNA-mediated knockdown in BeWo cells, and molecular docking analysis, we demonstrated that organic cation/carnitine transporters (OCTN1/2) are involved in the transplacental transfer of QACs. QACs exhibit stronger acute cytotoxicity (e.g., 3.75 μM for C10DDAC) than well-recognized reproductive toxicants (e.g., TCS, PFOS, PFOA and MEHP). Exposure to nonlethal concentrations of QACs disrupts the expression of genes involved in cell differentiation and placental vascular development and dysregulates progesterone release in BeWo cells. Together, these findings suggest a mechanistic pathway through which ubiquitous disinfectants reach the fetus and impair placental function, highlighting the urgent need to re-evaluate their use during pregnancy to prevent exposure and health risks to the developing fetus.

Evidence linking quaternary ammonium compounds (QACs) to cardiac function changes remains limited, particularly at the population level, and mechanistic insights are largely unexplored. To address this critical knowledge gap, we conducted a five-month longitudinal panel study that integrated epidemiological assessments with mechanistic multiomics analyses, involving 76 healthy elderly participants in Jinan, Shandong Province, China. Across five repeated measurement visits, participants underwent structured, face-to-face questionnaires, standardized physical examinations, and systematic biosample collection. Data on demographic characteristics, urinary QAC concentrations, and electrocardiogram (ECG) parameters were comprehensively gathered. Correlations between 9 QACs and 5 ECG parameters were assessed using a linear mixed-effects model (LMM), while interaction and stratified analyses examined body fat-related modulation of QAC-induced ECG disturbances. To elucidate the underlying biomolecular perturbations, multiomics analyses were further performed. Our results revealed that benzyltrimethylammonium bromide (BTMAC), dimethyldioctylammonium bromide (C8-DDAC), and diallyldimethylammonium chloride (DAD) were significantly associated with ECG alterations, suggesting potential cardiotoxicity in human populations. Specifically, both BTMAC and DAD were associated with prolonged QRS time, whereas C8-DDAC was related to increased QT interval, QTc interval, and RV5/SV1 amplitude, as well as a reduced QRS time. Interestingly, higher body fat content attenuated the adverse cardiac effects induced by QAC exposures, indicating a possible protective buffering mechanism. Moreover, the causal inference test (CIT) and ingenuity pathway analysis (IPA) collectively indicated that QAC-induced cardiac electrophysiological dysfunction may be associated with certain critical signaling pathways, particularly those involving tumor protein p53 (TP53), nucleosome assembly protein 1 like 1 (NAP1L1), dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), and peroxisome proliferator activated receptor alpha (PPARα) signaling. Taken together, this study provides the first population-based evidence of QAC-associated cardiotoxicity and proposes the underlying biomolecular alternations. These insights offer a scientific foundation for developing targeted strategies to prevent and mitigate environmentally induced cardiovascular risks in susceptible populations.

Primary aromatic amines (PAAs) are carcinogenic chemicals that are ubiquitous in indoor environments. However, little is known about their placental transfer and associated toxicity. Herein, we developed an approach integrating human biomonitoring, uterine perfusion experiments in pregnant rats, computational modeling, and in vitro placental cell bioassays. Nine of 30 PAAs including 8 PAAs with a monobenzene ring (e.g., aniline, ANI; ortho-toluidine, o-TD; para-toluidine, p-TD; ortho-anisidine, o-ANSD; 4-ethylaniline, 4-EA; 4-chloroaniline, 4-CA; and 3-chloroaniline, 3-CA) and 1 PAA with bis-benzene ring (2-naphthylamine, 2-NA), were widely detected (detection rate >50%) in 47 paired maternal and cord serum samples with median Σ₉PAAs concentrations of 11.2 and 11.7 ng/mL, respectively. Transplacental transfer efficiencies (TTEs) of PAAs were notably high, with median values ranging from 0.91 (p-CD) to 1.60 (2-NA), indicating efficient placental transfer. Excluding 2-NA, both biomonitoring data and rat uterine perfusion experiments revealed a significant negative correlation between log K_ow and TTEs (or PAA concentrations in fetal rat), supporting passive diffusion as a mechanism involved in placental transfer of monoaromatic PAAs. Crucially, molecular docking and molecular dynamics simulations indicated that 2-NA forms dynamically stable complexes with specific solute carrier (SLC) and ATP-binding cassette (ABC) transporters, suggesting a transporter-mediated active transport process. Cytotoxicity assays further indicated that 2-NA exhibited the highest toxicity among all PAAs. Moreover, in syncytialized BeWo cells, 2-NA exposure significantly compromised placental barrier integrity and function. The widespread presence of PAAs in maternal and fetal serum underscores the need for regulatory measures to reduce exposure, particularly among pregnant women and fetuses.

Melamine (MEL) and its derivatives are known for acute nephrotoxicity, but the risks from chronic exposure and underlying mechanisms of toxicity are unclear. We integrated environmental monitoring (356 pairs of house dust and urine samples collected across mainland China) with cell-based bioassays to investigate MEL exposure sources and toxic effects. MEL-related chemicals were frequently detected in dust (median: 10.3 μg/g) and urine (22.3 ng/mL) samples, indicating their widespread presence in indoor environments and chronic exposure among the Chinese population. Significant positive correlations were observed between MEL-related chemicals and neutrophil gelatinase-associated lipocalin (NGAL), a urinary biomarker of nephrotoxicity. RNA-sequencing of MEL-exposed human kidney-2 (HK-2) cells revealed significant enrichment of the ferroptosis signaling pathway. Further bioassays demonstrated that MEL exposure induces iron-driven mitochondrial lipid peroxidation in HK-2 cells. The system X_c^-/GPX4, ACSL4, and TFR1/DMT1 pathways identified as potential targets in ferroptosis-mediated early renal injury in both acute toxicity experiments and chronic exposure to environmentally relevant concentrations. This finding was further supported by urinary malondialdehyde and Fe²⁺ levels that mediated 13-31% of the effect of MEL-related chemicals on NGAL in humans. Our study provides valuable insights into the role of ferroptosis in chronic kidney injury associated with environmental exposure to MEL and its derivatives.

Humans are frequently exposed to quaternary ammonium compounds (QACs) via direct dermal contact with disinfectants and personal care products. However, the dermal exposure, skin penetration, and tissue distribution behavior of QACs remain unclear. Herein, we used human skin wipe samples and an in vivo rat model to explore the dermal absorption, percutaneous penetration, and exposure behaviors of 19 QACs with different physicochemical properties. QACs were frequently detected in hand wipe samples (n = 99), with a median total concentration of 17,200 ng/m². Females had significantly higher (p < 0.05) skin exposure levels to QACs than males. The application of skin care products could contribute to the dermal exposure of QACs. The skin-permeable fraction of QACs in Sprague-Dawley rats ranged from 9.09% ± 0.97% to 25.2% ± 3.89% and from 9.53% ± 0.83% to 20.5% ± 1.44% in low- (1.7 μg/cm²) and high-dose (4.2 μg/cm²) groups, respectively. The skin accumulation and penetration behaviors of QACs were associated with their log K_ow values, molecular weights, and chain lengths, with varied correlations among different QAC categories. Fecal excretion was identified as the main elimination route for dermally adsorbed QACs. Exposure assessment emphasized the significance of dermal exposure to QACs.