Paternal Preconception Calcitriol Intervention Rescued DBDPE-Induced Transgenerational Developmental and Visual Toxicity in Zebrafish

Abstract

Growing evidence highlights the impact of preconception paternal environmental exposures on offspring health, yet the specific paternal contributions and transgenerational mechanisms of emerging contaminants remain poorly understood. Thus, we exposed male zebrafish to decabromodiphenyl ethane (DBDPE), a widely used replacement for legacy flame retardants, for 2 months to investigate its intergenerational (F1) and transgenerational (F2) effects. Paternal DBDPE exposure severely impaired sperm quality in F0 zebrafish, and induced transgenerational developmental toxicity with elevated malformations in F2 larvae. Moreover, significant eye malformations occurred even at low doses in F2 groups, revealing the visual system to be highly sensitive to transgenerational DBDPE toxicity. F1 and F2 larvae exhibited marked behavioral disorders, retinal thinning, and phototransduction gene dysregulation, indicating significant visual dysfunction. Notably, transcriptome analysis revealed that steroid biosynthesis (especially calcitriol synthesis) was consistently disrupted across dose levels and generations, with its enrichment factor progressively increasing from F1 to F2; this was accompanied by a pronounced deficiency of calcitriol in paternal F0 testes. Accordingly, paternal calcitriol supplementation during DBDPE exposure effectively restored F0 sperm quality and mitigated visual and developmental toxicity in offspring. These findings suggest that paternal exposure to emerging contaminants may induce intergenerational and transgenerational effects, and that targeted preconception nutritional intervention may reduce these risks.