Perinatal low-dose PBDE-47 exposure hampered thyroglobulin turnover and induced thyroid cell apoptosis by triggering ER stress and lysosomal destabilization contributing to thyroid toxicity in adult female rats.

• In utero and lactation exposure of rats to environmentally relevant doses of PBDE-47. • Perinatal PBDE-47 exposure decreases thyroid hormones levels in adult female rats. • PBDE-47 induces thyroid structural abnormality, most likely as a result of hypoplasia. • PBDE-47 causes thyroid apoptosis by triggering ER stress and lysosomal destabilization. • PBDE-47 hampers thyroglobulin turnover by disrupting ER and lysosomal function. Evidence demonstrates that 2,2′,4,4′-tetrabromodiphenyl ether (PBDE-47) is able to disturb thyroid hormones (THs) homeostasis, yet the mechanisms remain unknown. We sought to investigate the effects of PBDE-47 on endoplasmic reticulum (ER) and lysosomes in thyroids. Using female Sprague-Dawley rats orally administered PBDE-47 at environmentally relevant doses (0.1, 1.0, 10 mg/kg/day) beginning ten days before breeding and ending at weaning, we showed that perinatal PBDE-47 exposure resulted in a reduction in serum THs levels and relative thyroid weight in adult female rats. These were accompanied by thyroid structural abnormalities with cell apoptosis. Mechanistically, PBDE-47 caused ER stress and activation of unfolded protein response (UPR). Moreover, PBDE-47 elicited lysosomal membrane permeabilization and the release of cathepsin. Importantly, the apoptotic cells co-localized with IRE1α, a stress sensor protein of UPR branch that mediates ER stress-induced apoptosis, or cathepsin B, a lysosomal cysteine protease that is involved in thyroglobulin, the precursor of THs, degradation and apoptosis induction. Interestingly, thyroglobulin was accumulated and predominantly presented in cells harboring compromised ER or lysosomal activity. Collectively, our findings suggest that perinatal low-dose PBDE-47 exposure hampers thyroglobulin turnover and induces thyroid cell apoptosis by triggering ER stress and lysosomal destabilization contributing to thyroid toxicity in adult female rats. [ABSTRACT FROM AUTHOR]