Alterations in the balance between cell proliferation and death during spermatogenesis, which may contribute to infertility, are influenced by several factors, including exposure to environmental mycotoxins. Among these, zearalenone (ZEN) impairs spermatogenesis through poorly understood mechanisms. Here, we investigated the toxic effects of ZEN in GC-2 mouse spermatocyte-derived cells. ZEN significantly inhibited cell growth and caused metabolic dysfunction. Bioenergetic profiling by Seahorse XF analysis revealed a marked decline in mitochondrial respiration and glycolytic reserve, reflecting impaired metabolic flexibility. Consistent with these findings, ZEN-mediated reductions in PPARγ and GLUT1 protein expression further supported dysregulation of mitochondrial metabolism and glucose homeostasis. These metabolic alterations disrupted cellular redox balance, resulting in increased oxidative stress. Indeed, ZEN enhanced reactive oxygen species production and upregulated HO-1 mRNA and protein expression. NAC treatment attenuated these effects and restored TOMM20 expression, as assessed by immunofluorescence analysis, suggesting a role for oxidative stress in mitochondrial structural alterations. Furthermore, ZEN induced ferroptosis-associated features, including membrane lipid peroxidation and intracellular Fe²⁺ accumulation. Nevertheless, ferroptosis inhibitors failed to restore cell viability, indicating that ferroptosis is not the primary mechanism of cell death. Conversely, ZEN upregulated both Slc7a11 and Slc3a2 expression and promoted disulfide stress, as evidenced by reduced free protein thiol content, associated with altered F-actin organization. Importantly, NAC restored intracellular thiol pools, mitigated actin disorganization, and rescued cell viability. Collectively, these findings support the involvement of a disulfidptosis-like phenotype in ZEN-treated GC-2 cells, providing new insights into the metabolic and redox dysregulation underlying ZEN-mediated germ cell toxicity.
Lead (Pb) is one of the oldest recognized environmental neurotoxicants with its toxic potential especially pronounced in early-life stages, where even very low exposures can result in long-lasting adverse effects. The glutamatergic system important for cognitive function and closely associated with memory impairment and various neurological disorders is one target of Pb. In this study, glutamatergic mechanisms underlying low-concentration Pb exposure during neurodevelopment were evaluated in F0 and F1 generation of zebrafish. For the F0, wild-type embryos (5D strain) were exposed to 0, 0.01, 0.1, or 1 part per billion (ppb, µg/L) Pb from 1 to 72 h post fertilization (hpf). Following exposure, fish were rinsed and either grown to 120 hpf for neurological assessments or raised to 4 months and bred to generate the F1 (exposed as germ cells). Levels of glutamate, glutamine, glutathione, and NMDAR were measured. Biochemical activity of enzymes involved in glutamatergic metabolism were also evaluated alongside targeted lipidomic profiling. Non-associative learning was assessed using the acoustic startle response (ASR) test. Data suggest Pb developmental neurotoxicity is driven by a combination of glutamate accumulation and upregulation of NMDAR, which coupled contribute to excitotoxicity and impaired learning. These impacts were most significant in the group exposed to 1 ppb in the F0 generation. The findings of this study demonstrate Pb exerts its neurotoxic effects through multi-target mechanisms involving metabolic, enzymatic, and lipid-mediated disruption of the glutamatergic pathway with these effects being restricted to the embryonic exposed generation with limited evidence of multigenerational transmission.
Elucidating Cd release and fate in karst areas with high geological background is critical for constraining source-to-sink dynamics and underpinning geogenic risk management. This study integrated dissolution experiments, compositional analysis, mineral characterization, and monitoring of natural waters (drip water, pool water, and spring water) to systematically elucidate the source-to-sink migration and partitioning mechanisms of Cd. The results demonstrate that: (1) differential dissolution of bedrock released 65–82% of Cd into the solution phase, representing an upper-bound estimate of the mobilizable Cd inventory, while the remaining 18–35% was retained in insoluble residues that evolved in situ via weathering into Cd-enriched soil parent materials; (2) Cd2+ released from parent rock dissolution is partly retained by soil parent materials, exhibiting stable occurrence with high content and low activity, while another fraction is incorporated into the lattice of secondary carbonates (stalagmites and stalactites), forming metastable Cd-bearing calcite whose stability is governed by the susceptibility of the carbonate host to dissolution rather than by the bonding form of Cd; (3) hydrological export is not a dominant pathway for net Cd loss, and Cd in karst systems follows an internal cycling path of “lattice fixation, differential dissolution, resorption by the soil parent material, and secondary calcite” with the initial weathering stage as the critical ecological risk period. Accordingly, the management strategy should focus on preserving natural buffering capacity and preventing acidification disturbance.
Decabromodiphenyl ethane (DBDPE), an emerging brominated flame retardant widely used as a replacement for legacy flame retardants, is persistent in the environment and increasingly detected in humans. However, whether long-term DBDPE exposure impairs male reproductive function and consequently affects offspring health remains largely unknown. Here, male mice were orally exposed to DBDPE (0, 0.01, 0.1, 1, and 10 mg/kg body weight/day) for 6 months. Chronic DBDPE exposure resulted in dose-dependent testicular accumulation, impaired sperm quality, and reduced fertilization capacity. Paternal DBDPE exposure also induced aging-like pathological alterations and shortened lifespan in F1 offspring. Sperm small non-coding RNA sequencing identified marked alterations in the sperm PIWI-interacting RNA (piRNA) profile, including increased abundance of the database-annotated piRNA piR-001169. Mechanistically, piR-001169 suppressed ten-eleven translocation 3 (Tet3) expression during early embryonic development, leading to increased methylation of the heat shock protein family A member 1 A (Hspa1a) and Hspa1b promoters and reduced heat shock protein 70 (Hsp70) expression in multiple offspring tissues. This dysregulation of the Hsp70/proteostasis axis was accompanied by increased protein aggregation and aging-related tissue injury. Restoration of Hsp70 expression partially ameliorated proteostasis disruption and aging-related pathological changes, supporting a functional role of impaired Hsp70-dependent proteostasis in the offspring phenotype. Notably, the aging-related phenotypes observed in F1 offspring were not detectable in F2 offspring. Collectively, these findings demonstrate that chronic paternal DBDPE exposure impairs male reproductive function and induces aging-like phenotypes in F1 offspring, with sperm piR-001169-Tet3 regulation and subsequent disruption of Hsp70-dependent proteostasis representing a potential paternal epigenetic mechanism.
To avoid detrimental effects on non-target organisms and plants, pesticide use is restricted, including requirements for sufficient time between treatments to prevent cumulative or carry-over effects. Such intervals are usually derived from chemical-based persistence metrics (e.g., DT50), while organism recovery is rarely considered explicitly. With the increasing acceptance of toxicokinetic-toxicodynamic (TKTD) models for interpreting survival data, recovery-related parameters are becoming available for a growing range of taxa and compounds. In the TKTD framework, recovery is characterised by the elimination rate constant or the dominant rate constant. The time to reach 95% depuration/recovery (DRT95) can be calculated (provided that the external exposure has been eliminated, i.e. the exposure went to 0). Here we propose DRT95 as an effect-based “DT50 for organisms”, conceptually distinct from conventional DT50, and use it as an operational estimate of the minimum interval required between pesticide pulses for exposures to be treated as approximately independent. We conducted a targeted literature search and compiled published TKTD parameter estimates into a database. In total, 379 entries were extracted, spanning 75 species, 36 chemicals, and 134 unique species–chemical combinations; insecticides contributed the most data. The median DRT95 was approximately 10 days, implying that a new exposure can be treated as independent from the first exposure after 10 days. DRT95 varied systematically with taxonomic order and mode of action; Ephemeroptera generally showed longer DRT95 values, whereas Hymenoptera showed shorter values. In paired comparisons, IT yielded longer DRT95 than SD; under regulatory uncertainty, using the longer (typically IT-based) recovery time may provide a more precautionary estimate of the time required for damage dissipation.
