Identification of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-inducible and -suppressive Genes in the Rat Placenta: Induction of Interferon-regulated Genes with Possible Inhibitory Roles for Angiogenesis in the Placenta

Abstract

Abstract. Exposure to a low dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in a variety of toxic manifestations, including fetal death. In order to evaluate the effects of low dose TCDD on placental function, pregnant Holtzman rats were given a single oral dose of 1600 ng TCDD/kg body wt or an equivalent volume of vehicle (control) on gestation day 15 (GD15), and changes in the gene expression in the placenta on GD20 were analyzed by two comprehensive methods, representational difference analysis (RDA) and DNA microarray technology. Candidates of TCDD-inducible and -suppressive genes were selected. Quantitative real-time PCR analysis was then performed to verify the induction or suppression levels of the candidate genes. Finally, we identified 81 TCDD-inducible and 21 TCDD-suppressive genes from the placenta of TCDD-treated Holtzman rats on GD20. One of the remarkable profiles of the gene expression was that glucose transporters were strongly up-regulated by the TCDD treatment. Furthermore, many interferon-inducible genes were also up-regulated by the treatment. They included several cytokines such as IP-10 known as a potent angiogenesis inhibitor. In addition, interferon molecules are known to suppress angiogenesis. The above observations suggest that activation of the interferon signaling pathway and the induction of anti-angiogenic factors by TCDD might have a role in causing the inhibition of neovascularization, resulting in the hypoxic state of placenta and increased incidence of fetal death.Key words: TCDD, Placenta, Gene expression, Real-time PCR, DNA microarray (Endocrine Journal 51: 569-577, 2004) 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to be the most toxic congener among the dioxin and related compounds found in the environment. Exposure to TCDD causes a diverse spectrum of toxicities in humans and laboratory animals [1][2][3][4]. The fetus is one of the most sensitive targets of TCDD and exhibits a wide range of biological responses at low TCDD levels that have no detectable effects on maternal side (usually the levels were ten to hundred times lower than those of LD50). One of the most severe adverse effects of TCDD is intrauterine fetal death [1,[5][6][7]. The incidence has been shown in all species studied to date, including the monkey, hamster, rat, and mouse. Although fetal death is an important aspect of TCDD toxicity, its precise mechanism is not well understood. Placenta plays a crucial role in maintaining normal fetal growth such as exchange of oxygen and carbohydrate nutrients. In previous studies Ishimura et al.

The Effect of Gestational Age on Angiogenic Gene Expression in the Rat Placenta

“…This finding is consistent with current literature. Furthermore, the data for Ptgs2 are consistent with the literature where expression is known to increase prior to the onset of labour [10], [12], [13]). Phospholipases hydrolyze phospholipids into fatty acids.…”

“…The molecular and cellular mechanisms that regulate vascularisation and angiogenesis within the placental villous tree during pregnancy remain to be fully elucidated. Previous studies have established the utility of rat and mouse models to eluciate the molecular and cellular mechanisms involved in placentation and placental development since it is more difficult to obtain human placenta at various gestational stages [8]–[10]. Genome-wide gene expression in rat placenta has been studied in late pregnancy [11] [12].…”

Aryl Hydrocarbon Receptor Activation by TCDD Modulates Expression of Extracellular Matrix Remodeling Genes during Experimental Liver Fibrosis

“…Thus, it is possible that the expression of TIMPs in CCl 4 /TCDD-treated mice was not sufficient to counteract MMP activity. Other studies have reported that TIMP expression is modulated by in vitro and in vivo TCDD exposure as well [ 10 , 79 – 81 ].…”

ITE and TCDD Differentially Regulate the Vascular Remodeling of Rat Placenta via the Activation of AhR

“…Because of its resistance to metabolic breakdown and accumulation in biologic chain, TCDD can cause many toxic effects on human and animal health, including teratogenicity, immunotoxicity and various metabolic dysfunctions [14], [16], [17]. Among all the adverse events of TCDD, intrauterine fetal death is the most common in mammals as the fetus is much more sensitive to TCDD when compared with the mother [7], [18], [19]. Convincing evidence from laboratory animal studies has shown that TCDD affects placental angiogenesis and vascular remodeling during embryo and fetal development by reducing blood flow and circulatory function [7], [19]–[21].…”