title: Role of p53-dependent placental apoptosis in the reproductive and developmental toxicities of caffeine in rodents.
abstract: The aim of the present study was to evaluate the role of placental apoptosis in mediating the reproductive and developmental toxicity of caffeine in rodents. Female Kunming mice were treated with caffeine (60, 120 and 240 mg/kg per day) before and during pregnancy. The conception rate, maternal bodyweight gain, placental weight and indices of fetal developmental, including the rate of intrauterine growth retardation (IUGR; i.e. the actual number of fetuses exhibiting IUGR as a percentage of the total number of fetuses), were determined on gestational day (GD) 18. Female Wistar rats were treated with caffeine (20, 60 and 180 mg/kg per day) from GD11 to GD20. The IUGR rate, maternal plasma angiotensin (Ang) II and prolactin concentrations, placental pathology, expression of angiotensin AT(1)  and AT(2)  receptors and apoptosis-related proteins were measured on GD20. In mice, caffeine treatment dose-dependently reduced the total conception rate, delayed conception and decreased maternal bodyweight gain, placental weight, fetal bodyweight and fetal body and tail lengths, whereas the IUGR rate was increased. In rats, caffeine treatment dose-dependently decreased placental weight and fetal bodyweight and increased the IUGR rate. Abnormal placental structures and decreased maternal plasma prolactin concentrations were observed following 180 mg/kg per day caffeine treatment, which resulted in increases in renin-angiotensin system (RAS) activity, including maternal plasma AngII concentrations and placental AT(1B)  and AT(2)  receptor expression, and Bax and p53 expression, but decreases in placental Bcl-2 expression. On the basis of the results of the present study, it appears that caffeine ingestion has detrimental effects on the reproductive system and fetal development in rodents that are associated with chronic activation of the maternal and placental RAS, and induction of p53-dependent placental apoptosis.
authors.affiliation: Department of Pharmacology, Basic Medical School of Wuhan University, 185 Donghu Road, Wuhan 430071, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Shu
authors.initials: S
authors.lastname: Zhou
authors.forename: Jie
authors.initials: J
authors.lastname: Ping
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Pan
authors.forename: Gai
authors.initials: G
authors.lastname: Liang
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.forename: Hao
authors.initials: H
authors.lastname: Kou
authors.forename: Chong
authors.initials: C
authors.lastname: Bao
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002110:Caffeine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005306:Fertilization / Q000187:drug effects / Q000502:physiology; D047109:Fetal Development / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D010920:Placenta / Q000187:drug effects* / Q000502:physiology; D011247:Pregnancy; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012098:Reproduction / Q000187:drug effects* / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D016159:Tumor Suppressor Protein p53; D002110:Caffeine