Paternal exposure to decabromodiphenyl ethane (DBDPE) accelerates aging in offspring mice: Intergenerational effects and underlying mechanisms.

Abstract

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.