Di-(2-ethylhexyl) phthalate induces testicular endoplasmic reticulum stress and germ cell apoptosis in adolescent mice.

Abstract

Di-(2-ethylhexyl) phthalate (DEHP) is a male reproductive toxicant. This research is aimed at investigating the effect of pubertal DEHP exposure on testicular endoplasmic reticulum (ER) stress and germ cell apoptosis. Five-week-old male mice were orally administered with DEHP (0, 0.5, 50, or 500mg/kg/day) for 35 days. Testis weight and sperm count were reduced in mice exposed to 500mg/kg/day DEHP. The number of seminiferous tubules in stages VII-VIII, mature seminiferous tubules, was reduced and the number of seminiferous tubules in stages IX-XII, immature seminiferous tubules, was elevated in mice treated with 500mg/kg/day DEHP. Numerous apoptotic germ cells were observed in mouse seminiferous tubules exposed to 50 and 500mg/kg/day DEHP. Moreover, cleaved caspase-3 was elevated in mouse testes exposed to 500mg/kg/day DEHP. In addition, Bcl-2 was reduced and Bax/Bcl-2 was elevated in mouse testes exposed to 500mg/kg/day DEHP. Additional experiment showed that GRP78, an ER molecular chaperone, was downregulated in mouse testes exposed to 500mg/kg/day DEHP. Testicular p-IRE-1α, p-JNK, and CHOP, three markers of ER stress, were upregulated in mice exposed to 500mg/kg/day DEHP. These results suggest that pubertal exposure to high doses of DEHP induces germ cell apoptosis partially through initiating ER stress in testes.