A Maternal Ahr Null Genotype Sensitizes Embryos to Chemical Teratogenesis

Abstract

The aryl hydrocarbon receptor (encoded by the Ahr locus) is a ligand-activated transcription factor that mediates the toxicology and teratology of 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin). In an effort to understand the role of the maternal compartment in dioxin teratology, we designed a breeding strategy that allowed us to compare the teratogenic response in embryos from Ahr ؊/؊ (null) and Ahr ؉/؉ (wild-type) dams. Using this strategy, we demonstrate that embryos from the Ahr ؊/؊ dams are 5-fold more sensitive to dioxin-induced cleft palate and hydronephrosis as compared with embryos from an Ahr ؉/؉ dam. Moreover, this increased teratogenic sensitivity extends beyond dioxin, because embryos from Ahr ؊/؊ dams exhibited a 9-fold increase in their sensitivity to the fetotoxic effects of the glucocorticoid, dexamethasone. In searching for an explanation for this increased sensitivity, we found that more dioxin and dexamethasone reached the embryos from Ahr ؊/؊ dams as compared with embryos from Ahr ؉/؉ dams. We propose that increased deposition of teratogens/fetotoxicants to the embryonic compartment is the result of porto-systemic shunting and/or blocked P4501A induction in Ahr ؊/؊ dams. In addition to demonstrating the importance of maternal AHR in teratogenesis, these data may have implications that reach beyond the mechanism of action of dioxin. In this regard, the Ahr ؊/؊ mouse may provide a system that allows pharmacological agents and toxicants to be more easily studied in a model where first pass clearance is a significant obstacle.Chemical teratogens can perturb normal mammalian development through direct action on the embryo, indirectly through maternal toxicity, or as the result of a combination of both of these mechanisms. The maternal compartment can afford protection by functioning as a metabolic or physical barrier that reduces embryonic exposure to a given agent (1). The maternal compartment also holds the potential to serve as a site of teratogen bioactivation and may serve to increase the concentrations of active metabolites that directly perturb normal embryonic development (2, 3). Understanding the relative contributions of maternal and embryonic physiology for a given teratogen can be difficult, especially when chemical agents induce a variety of teratogenic end points or display remarkable pharmacological potency.One approach to understanding the relative contributions of the maternal and embryonic physiology is to define these two compartments via their respective genotypes. Such an approach is particularly powerful when working with null alleles that have been generated via gene targeting. In such cases, the dominance order is clear, as is the functional relationship between one or two copies of the wild-type allele. Through appropriate genetic crosses one can then generate informative combinations of maternal and embryonic genotypes that can help identify when maternally or embryonically expressed loci play a differential role in the teratogenic response to a specific chemical (4).Based...

The Teratogenic Sensitivity to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Is Modified by a Locus on Mouse Chromosome 3

“…Given that dioxin-induced hydronephrosis occurs at a dose approximately 10-fold lower than the dose that produces cleft palate, the screen was less sensitive for detecting loci influencing dioxin-induced hydronephrosis (Thomae et al, 2004). Although our linkage analysis suggested the potential for numerous modifiers of dioxininduced hydronephrosis, the relatively low LOD scores led us to focus on modifiers of dioxin-induced cleft palate where our screen was more sensitive.…”

Liver Deformation in Ahr-Null Mice: Evidence for Aberrant Hepatic Perfusion In Early Development

“…Fetal mice were obtained from timed breeding of Ahr ϩ/Ϫ female mice with Ahr Ϫ/Ϫ male mice as described previously (Thomae et al, 2004). In brief, the morning after mating was considered E0.5.…”

Review on genetic variants and maternal smoking in the etiology of oral clefts and other birth defects

“…Interestingly, and consistent with the hypothesis, Thomae et al (2005) reported that the addition of TGFβ3 to dioxin-exposed in vitro palatal culture restored palatal fusion. Mouse embryos from Ahr null mothers were reported to be five times more sensitive to dioxin-induced cleft palate, suggesting potential maternal effects of the AhR gene (Thomae et al, 2004).…”