Arsenic and fluoride frequently co-occur in groundwater, but the gut-associated metabolic changes accompanying male reproductive toxicity from their co-exposure remain unclear. We established a chronic developmental drinking water co-exposure model in Sprague–Dawley rats using 100 mg/L NaF and 75 mg/L NaAsO2. Reproductive outcomes were evaluated at postnatal day (PND) 60 and PND120, and reciprocal fecal transfer was performed between control and arsenic–fluoride (AsF) backgrounds. Developmental AsF exposure impaired sperm production and quality, disrupted reproductive hormone homeostasis, altered spermatogenic-stage markers, and induced testicular and epididymal injury. Repeated administration of AsF-donor fecal material to control recipients was accompanied by selected adverse reproductive changes, whereas control-donor material was accompanied by partial changes in the opposite direction in AsF-exposed recipients. Endpoint 16S rRNA sequencing demonstrated exposure-associated microbial community differences, and donor-material administration was accompanied by changes in selected host phenotypes. Untargeted serum metabolomics revealed prominent remodeling of bile acid- and lipid-related signals, including reciprocal Fecal microbiota transplantation-associated patterns and exploratory relationships between bile-acid-related features and reproductive hormones. These metabolic findings were accompanied by differences in colonic junction- and inflammation-related markers, intestinal–hepatic FXR–FGF15-related proteins, hepatic bile acid and lipid endpoints, and testicular autophagy-related markers. Collectively, the findings characterize reproductive hazards at the tested concentrations and support a nonexclusive gut–liver–testis framework in which donor-material-associated microbial and metabolic changes accompany partial modification of recipient phenotypes.
Background Pharmaceuticals and personal care products (PPCPs) are pseudo-persistent contaminants with potential exposure risks. Atherosclerosis (AS) and Alzheimer’s disease (AD) share neurovascular and myeloid-immune remodeling, but whether chemical-target networks associated with exposure to PPCPs converge on shared mechanisms linking AD and AS remains unclear. Purpose To explore how exposure to PPCPs may contribute to AD-AS comorbidity through shared immune-toxicology mechanisms, and to identify natural compounds as candidate interventions against prioritized disease-relevant targets. Methods We integrated AD and AS bulk transcriptomic cohorts with single-cell datasets to define shared disease targets and locate them within relevant immune-cell states. Chemical-gene interactions associated with exposure to PPCPs were then overlaid onto this AD-AS target network, and candidate natural compounds were prioritized by reverse network pharmacology, structure-based virtual screening, molecular docking, molecular dynamics and genetic evidence analyses. The prioritized targets and intervention hypotheses were further examined in APP/PS1 AD mice, ApoE-knockout high-fat-diet AS mice, RAW264.7 macrophage-like cells and HMC3 microglial cells. Results The integrated analyses identified TREM2, SPP1, TGFBI and MRGPRF as four AD-AS signature genes, with diagnostic discrimination in independent AD (AUC 0.783–0.996) and AS (AUC 0.892–0.924) cohorts. Among them, TREM2 and SPP1 emerged as the key signature genes, were highly expressed in disease-associated microglial and macrophage states, and formed an SPP1-linked myeloid communication axis with neighboring disease niches. Metabolic scoring and in silico TREM2 perturbation pointed to lipid-metabolic remodeling in AD microglia and macrophage metabolic, adhesive and inflammatory-migration programs in AS lesions. Bisphenol A, bisphenol F, estradiol and acetaminophen were identified as PPCPs related to signature-gene regulation. Salvianolic acid B, β-sitosterol, quercetin and tanshinone IIA were identified as potential phytochemical modulators of TREM2, SPP1, TGFBI and MRGPRF, respectively, with favorable structural-stability evidence. MR analyses supported genetic causal associations between the signature genes and AD/AS outcomes, while TREM2-centered SMR and GTEx v10 eQTL colocalization for TREM2, SPP1 and TGFBI provided locus-level support. In vivo, TREM2, OPN/SPP1, and TGFBI were upregulated in both AD and AS tissues, whereas MRGPRF showed disease-context-dependent regulation, with increased expression in AD tissues but decreased expression in AS tissues. In vitro, BPA decreased TREM2 and increased OPN/SPP1, accompanied by enhanced lipid deposition, CD86 activation, and inflammatory transcription, whereas salvianolic acid B increased TREM2, suppressed OPN/SPP1, and attenuated lipid deposition and inflammatory responses. Conclusions TREM2, SPP1, TGFBI, and MRGPRF constitute a recurrent but directionally heterogeneous molecular signature across AD and AS, with MRGPRF showing disease-context-dependent regulation. Within this signature, TREM2 and SPP1 showed the strongest mechanistic convergence in disease-associated myeloid states. BPA disrupted the TREM2/OPN-SPP1 axis in microglia and macrophages, whereas salvianolic acid B partially counter-regulated these changes and attenuated associated inflammatory and lipid-metabolic disturbances.
Introduction Few studies have examined prenatal co-exposure to organophosphate esters (OPEs) and phthalic acid esters (PAEs) in relation to childhood autism spectrum disorder (ASD) symptoms, and whether vitamin D modifies these associations. Methods Included 2400 mother–child dyads from the Ma’anshan Birth Cohort and examined levels of maternal OPEs, PAEs, and vitamin D across the three trimesters. Used the Clancy Autism Behavior Scale to assess preschoolers’ ASD symptoms at ages 3, 5, and 6, then used group-based trajectory modeling to fit ASD symptom trajectories. Results ASD symptom scores fit 3 trajectories: low, moderate, and high. Average-MEOHP, average-ΣHMWP, first-trimester-ΣHMWP, third-trimester-DPHP, and third-trimester-BCIPP were associated with increased risk in the moderate group (p < 0.05). Average-MMP, average-ΣHMWP, second-trimester-BEHP, and third-trimester-ΣHMWP were associated with increased risk in the high-score group (p < 0.05). By contrast, first-trimester-BCIPP was negatively correlated with the moderate group. DPHP, DBP, and Σdi-OPEs showed sex-specific effects (psex-int < 0.05). Maternal vitamin D levels modified these associations, with women with vitamin D deficiency showing significantly higher risks. OPEs and PAEs showed mixed effects. Conclusion Prenatal exposure to OPEs/PAEs exhibited heterogeneous associations with preschoolers’ ASD symptom trajectories, and maternal vitamin D deficiency exacerbates the effects of OPEs/PAEs individual exposure on symptom trajectories.
Background Neonicotinoid insecticides are widely used globally, raising concerns about their impact on human health, particularly during the vulnerable prenatal period. However, long-term epidemiological evidence regarding their role in childhood allergic disease development remains unclear. This study evaluated the association between prenatal neonicotinoid exposure and longitudinal trajectories of atopic dermatitis (AD) and wheeze in early childhood to provide data for environmental risk assessment. Methods Using data from the Japan Environment and Children’s Study (JECS), we analyzed a nationwide sub-cohort of approximately 8,900 mother–child pairs. Neonicotinoid concentrations were measured in maternal urine during early and mid-pregnancy. Disease trajectories (1–6 years) for AD and wheeze were identified using Latent Class Growth Analysis (LCGA). Multivariable logistic regression was used to estimate the association between exposure levels and trajectory phenotypes, focusing on the impact of background environmental exposure. Results Four distinct trajectories were identified for both AD and wheeze. In the multivariable analyses, several nominal associations were observed (e.g., ACE and late-onset AD: aOR 1.67, 95 % CI 1.09–2.54); however, none remained statistically significant after Benjamini–Hochberg correction. Overall, prenatal exposure to neonicotinoids at current environmental levels in Japan was not consistently associated with any specific trajectory of AD or wheeze. Conclusion We found no robust and consistent evidence of an association between prenatal neonicotinoid exposure and childhood atopic dermatitis or wheeze trajectories in this Japanese cohort under relatively low background exposure conditions. Further studies in populations with different exposure profiles are warranted.
