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

• Published in: Toxicology and applied pharmacology 2006-05, Vol.212 (3), p.224-236
• Main Authors: Kawakami, Takashige, Ishimura, Ryuta, Nohara, Keiko, Takeda, Ken, Tohyama, Chiharu, Ohsako, Seiichiroh
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Administration, Oral; Animals; ANOXIA; AUDITORY ORGANS; Base Sequence; Basic Helix-Loop-Helix Transcription Factors; Biological and medical sciences; BLOOD; CYSTS; Cytochrome P-450 CYP1A1 - biosynthesis; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1A2 - biosynthesis; Cytochrome P-450 CYP1A2 - genetics; DEATH; DIOXIN; Diseases of mother, fetus and pregnancy; Dose-Response Relationship, Drug; Female; Fetal death; Fetal Death - chemically induced; Fetal Death - genetics; Gene Expression Profiling; Genetic Predisposition to Disease; GLUCOSE; GLYCOGEN; Gynecology. Andrology. Obstetrics; HYDROCARBONS; Male; Medical sciences; Molecular Sequence Data; PLACENTA; Placenta - drug effects; Placenta - metabolism; Polychlorinated Dibenzodioxins - toxicity; Pregnancy; Pregnancy. Fetus. Placenta; RATS; Rats, Sprague-Dawley; RECEPTORS; Receptors, Aryl Hydrocarbon - biosynthesis; Receptors, Aryl Hydrocarbon - genetics; Repressor Proteins - biosynthesis; Repressor Proteins - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Species Specificity; STRUCTURAL CHEMICAL ANALYSIS; Susceptibility; TCDD; Teratogens - toxicity; Toxicology; VESTIBULAR APPARATUS
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2005.08.007

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 μg TCDD/kg; SD-IGS, 0, 2, 5, 10 μg 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 μg 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 μg TCDD/kg), indicating that the ac