Parental ochratoxin A exposure induces multigenerational and transgenerational neurotoxicity and visual impairment in...

Ochratoxin A (OTA), a ubiquitous mycotoxin detected in humans and animals, has attracted increasing concern owing to its potential health risks. However, its multigenerational and transgenerational neurotoxicity, visual impairment, and the underlying mechanisms remain largely unclear. In the present study, parental exposure to OTA (0, 10, and 100 ng/L) for 3 months induced developmental impairment in unexposed F1 larvae and provided evidence of parental OTA transfer. Whole-genome DNA methylation sequencing revealed that parental OTA exposure altered DNA methylation patterns in F1 larvae, characterized by disruptions in retinol metabolism, neurotransmitter homeostasis, and xenobiotic detoxification. Consistently, decreased dopamine, serotonin, and norepinephrine concentrations were observed in F1 larvae. Moreover, neurodevelopmental abnormalities, altered behaviors (increased swimming speed, anxiety-like behavior, social behavior deficits), and reduced lens size in F1 larvae indicated the multigenerational neurotoxicity and visual impairments of OTA. In F1 adults, 8-OHdG levels showed an upward trend, suggesting persistent multigenerational toxicity. Meanwhile, sex-dependent effects on thigmotaxis and social interaction were observed. Although the adverse effects on locomotor behavior and neurotransmitter levels were alleviated in F2 larvae, social behavior deficits and visual impairment were intensified, indicating the transgenerational toxicity of OTA. Overall, this study demonstrates, for the first time, the transgenerational neurotoxicity and visual impairment of OTA, and highlights the need for rigorous risk assessment of OTA exposure in unexposed offspring.