Oxidative Stress-Mediated DNA Damage and Macrophage Polarization Microenvironment: A Novel Mechanism of DCHP-Induced Male Reproductive System Impairment.
The findings reveal close associations between DCHP exposure and testicular injury, proposing a working model involving oxidative stress and inflammation; however, further functional studies are required to establish definitive causal relationships.
Abstract
The global decline in male fertility has emerged as a major public health challenge, with mounting evidence pointing to a close association between endocrine-disrupting chemicals (EDCs) and reproductive dysfunction. As a representative member of this class, dicyclohexyl phthalate (DCHP) exhibits strong environmental persistence and bioaccumulation potential within the mammalian reproductive system. In the present study, male ICR mice were orally administered DCHP at 10, 100, or 300mg/kg/day for six consecutive weeks, and GC‑2 mouse spermatocyte cells were exposed to 5, 20, or 50μM DCHP for 24h. Long‑term, high‑dose DCHP exposure (300mg/kg/day) was associated with significant testicular histopathological alterations and impaired epididymal sperm parameters in mice. Both the in vivo and in vitro models revealed that DCHP treatment correlated with cell cycle disruption and proliferative arrest. Western blotting and TUNEL assays further indicated that DCHP could triggered apoptosis. As an exploratory acute ex vivo assessment, 35 human semen samples were exposed to DCHP (5, 20 and 50μM) for 12h, which revealed a dose-dependent reduction in sperm quality. At the mechanistic level, our data suggest a potential cascade wherein DCHP exposure is linked to oxidative stress, concomitant DNA damage, and mitochondrial dysfunction. RNA‑seq analysis further highlighted the enrichment of inflammatory responses and related signaling pathways. Subsequent validation experiments showed that DCHP exposure was accompanied by an increased testicular M1 macrophage population, elevated secretion of pro‑inflammatory cytokines (IL‑6, TNF‑α), and activation of the NF‑κB pathway-changes that may collectively contribute to an unfavorable testicular microenvironment and impaired sperm quality. Overall, our findings reveal close associations between DCHP exposure and testicular injury, proposing a working model involving oxidative stress and inflammation; however, further functional studies are required to establish definitive causal relationships.
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Dicyclohexyl phthalate (DCHP) is a widely detected environmental endocrine-disrupting chemical found in various consumer products. Maternal exposure to DCHP may adversely affect offspring health. However, its effects on early embryonic development and female offspring, and the underlying mechanisms affecting offspring reproductive function remain unclear. In this study, using an in vitro mouse embryo culture system and a maternal gestational exposure model, we found that DCHP exposure induced DNA damage, disrupted spindle morphology and chromosome alignment during the first cleavage of early mouse embryos, accompanied by reduced blastocyst formation. Transcriptomic analysis of ovarian tissues from high-dose DCHP-exposed offspring revealed enrichment of pathways related to mitochondrial dysfunction and apoptosis. Functional validation showed that DCHP exposure was associated with oxidative stress and mitochondrial dysfunction, characterized by increased reactive oxygen species levels and reduced mitochondrial membrane potential, along with increased autophagy and apoptosis. Rescue assays using Mito-TEMPO and Mdivi-1 alleviated DCHP-induced mitochondrial damage and restored blastocyst developmental competence, suggesting that mitochondrial dysfunction and subsequent mitophagy activation act as key upstream events in DCHP-induced embryonic damage. Moreover, gestational exposure to the highest dose of DCHP significantly increased ovarian apoptosis and reduced oocyte maturation in female offspring. Collectively, these findings suggest that gestational high-dose DCHP exposure is linked to reduced reproductive potential and ovarian dysfunction in female offspring through oxidative stress-mediated mitophagy, providing new insights into female reproductive dysfunction associated with environmental phthalates.
Initial evidence that formaldehyde triggers DAMP-associated sterile inflammation with disruption of metabolism and reproduction is provided and the potential benefit of quercetin treatment as a nutraceutical against environmental aldehydes by suppressing multitarget pathways is demonstrated.
Chronic exposure to the widely used organophosphate pesticide chlorpyrifos has been associated with reproductive dysfunction; however, the early subclinical events preceding overt reproductive dysfunction remain poorly understood due to cell-specific and non-monotonic responses to the toxicant. The present study investigated the effect of chronic CPF exposure on the spermatogenic niche and sperm epigenome in a mouse model. Despite the absence of detectable oxidative stress or reproductive toxicity, chronic CPF exposure induced significant changes in the testicular microenvironment. Testicular proteomic analysis revealed dysregulated expression of proteins involved in extracellular matrix remodeling in CPF-exposed mice. These changes were associated with increased expression of Ctnnb1 and Axin1 indicating modulation of β-catenin-associated signaling in the testis. Furthermore, CPF exposure was associated with dysregulation of Sertoli cell function characterized by a significant reduction in Kitlg expression, increased c-kit levels, and reduced expression of the gap junction protein Connexin 43. CPF exposure also led to a significant dose-dependent increase in the expression of Tet1 suggesting altered epigenetic regulation in the testis. Interestingly, there was a trend toward increased sperm DNA methylation in CPF-exposed mice. Overall, these findings reveal that chronic CPF exposure induces early remodeling of the spermatogenic niche and alters testicular epigenetic regulation prior to overt reproductive dysfunction, identifying the Sertoli cell-extracellular matrix axis as a potential early target underlying CPF-induced testicular toxicity.
