Differential susceptibilities of Holtzman and Sprague-Dawley rats to fetal death and placental dysfunction induced by 2,3,7,8-teterachlorodibenzo-p-dioxin (TCDD) despite the identical primary structure of the aryl hydrocarbon receptor.
A single oral dose of 2,3,7,8-tetrachlorodibenzo-p-dioin (TCDD) administered to pregnant Holtzman (HLZ) rats on gestational days 15 (GD15) caused placental dysfunction, resulting in fetal death (Ishimura, R., Ohsako, S., Miyabara, Y., Sakaue, M., Kawakami, T., Aoki, Y., Yonemoto, J., Tohyama, C., 2002a. Increased glycogen content and glucose transporter 3 mRNA level in the placenta of Holtzman rats after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Appl. Pharmacol. 178, 161-171; Ishimura, R., Ohsako, S., Kawakami, T., Sakaue, M., Aoki, Y., Tohyama, C., 2002b. Altered protein profile and possible hypoxia in the placenta of 2,3,7,8-tetrachlorodibenzo-p-dioxin-exposed rats. Toxicol. Appl. Pharmacol. 185, 197-206). In order to investigate the mechanism underlying the TCDD-induced fetal death, we compared two outbred strains of rats, namely, the HLZ and the Sprague-Dawley International Genetic Standard rats (SD-IGS), a strain with characteristics resembling those of the HLZ rats. Pregnant HLZ and SD-IGS rats were administered TCDD as a single dose by gavage on GD15, as described within the parentheses (HLZ, 0, 1.6 mug TCDD/kg; SD-IGS, 0, 2, 5, 10 microg TCDD/kg). Whereas a high incidence (14%) of fetal death was observed on GD20 in the HLZ rats, no fetal deaths occurred in the SD-IGS rats, even at the highest dose of TCDD. A histological marker of cellular abnormality at the placental junctional zone, i.e., delay in the disappearance of the glycogen cells and cysts filled with an eosinophilic material (GC-EM), which normally disappear by GD20, was observed in the HLZ rats after exposure to the lowest dose of TCDD (1.6 microg TCDD/kg), but not in the SD-IGS rats even after exposure to the highest dose of TCDD. Furthermore, maternal blood sinusoids in the labyrinth zone were constricted following exposure to TCDD in the HLZ, but not SD-IGS rats. These observations indicate that HLZ rats are more susceptible to the adverse effects of TCDD on fetal growth and placental function, than SD-IGS rats. Direct sequencing analysis of the aryl hydrocarbon receptor (AhR) gene revealed no difference in the primary structure of the receptor between the HLZ and SD-IGS rats. In addition, no significant differences were observed between the two strains of rats in the levels of induction of placental cytochrome P450 1A1, 1B1, AhR, and AhRR mRNAs following administration of serially increasing doses of TCDD (0.0125, 0.05, 0.2, 0.8, and 1.6 microg TCDD/kg), indicating that the activity of TCDD-AhR complex in the placenta is similar between the HLZ and SD-IGS rats. Taken together, the above-described findings indicate that the higher susceptibility of HLZ rats to TCDD-induced placental dysfunction and fetal death may be modulated by other factor(s) in the genetic background of HLZ rats than the AhR.
Kawakami
Takashige
T
Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba 305-8506, Japan.
Ishimura
Ryuta
R
Nohara
Keiko
K
Takeda
Ken
K
Tohyama
Chiharu
C
Ohsako
Seiichiroh
S
D000284:Administration, Oral; D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005313:Fetal Death / Q000139:chemically induced* / Q000235:genetics; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D008297:Male; D008969:Molecular Sequence Data; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis* / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D013723:Teratogens / Q000633:toxicity*
D051792:Basic Helix-Loop-Helix Proteins; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D012097:Repressor Proteins; D013723:Teratogens; C492161:Ahrr protein, rat