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The constitutively active Ah receptor (CA-AhR) mouse as a model for dioxin exposure - effects in reproductive organs
Sara Brunnberg1, Patrik Andersson, Lorenz Poellinger
1Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden. Sara.Brunnberg@ki.se
Abstract:
The dioxin/aryl hydrocarbon receptor (AhR) mediates most toxic effects of dioxins. In utero/lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) impairs fetal/neonatal development and the developing male reproductive tract are among the most sensitive tissues. TCDD causes antiestrogenic responses in rodent mammary gland and uterus and in human breast cancer cell lines in the presence of estrogen. Also, more recently an estrogen-like effect of TCDD/AhR has been suggested in the absence of estrogen. A transgenic mouse expressing a constitutively active AhR (CA-AhR) was developed as a model mimicking a situation of constant exposure to AhR agonists. Male and female reproductive tissues of CA-AhR mice were characterized for some of the effects commonly seen after dioxin exposure. Sexually mature CA-AhR female mice showed decreased uterus weight, while an uterotrophic assay in immature CA-AhR mice resulted in increased uterus weight. In immature mice, both TCDD-exposure and CA-AhR increased the expression of the estrogen receptor target gene Cathepsin D. When co-treated with 17β-estradiol no increase in Cathepsin D levels occurred in either TCDD-exposed or CA-AhR mice. In sexually mature male CA-AhR mice the weights of testis and ventral prostate were decreased and the epididymal sperm reserve was reduced. The results of the present study are in accordance with previous studies on dioxin-exposed rodents in that an activated AhR (here CA-AhR) leads to antiestrogenic effects in the presence of estrogen, but to estrogenic effects in the absence of estrogen. These results suggest the CA-AhR mouse model as a useful tool for studies of continuous low activity of the AhR from early development, resembling the human exposure situation.
Insights
A constitutively active aryl hydrocarbon receptor (AhR) mouse model reveals dioxin-like compounds exert anti-estrogenic effects with estrogen but estrogenic effects without estrogen, impacting reproductive development.
Area of Science:
- Toxicology and Environmental Health
- Endocrinology and Reproductive Biology
- Molecular Biology
Background:
- The aryl hydrocarbon receptor (AhR) mediates dioxin toxicity, with developmental exposure impacting reproductive systems.
- Dioxins like TCDD exhibit anti-estrogenic effects in some contexts but potentially estrogenic effects in others.
- A constitutively active AhR (CA-AhR) mouse model was created to study constant AhR agonist exposure.
Purpose of the Study:
- To characterize the effects of a constitutively active AhR (CA-AhR) on male and female reproductive tissues.
- To investigate the dual estrogenic/anti-estrogenic potential of AhR activation in different hormonal environments.
- To validate the CA-AhR mouse as a model for continuous, low-level AhR activation relevant to human exposure.
Main Methods:
- Development and characterization of a transgenic mouse model with a constitutively active aryl hydrocarbon receptor (CA-AhR).
- Assessment of reproductive organ weights (uterus, testis, prostate) and sperm reserve in mature and immature CA-AhR mice.
- Analysis of estrogen receptor target gene expression (Cathepsin D) in immature mice, with and without 17β-estradiol co-treatment.
Main Results:
- CA-AhR female mice exhibited decreased uterine weight in mature animals but increased uterine weight in immature animals during uterotrophic assays.
- Both TCDD exposure and CA-AhR activation increased Cathepsin D expression in immature mice, an effect abolished by co-administration of 17β-estradiol.
- Mature male CA-AhR mice showed reduced testis and ventral prostate weights, along with decreased epididymal sperm reserve.
Conclusions:
- Activated AhR elicits anti-estrogenic effects in the presence of estrogen and estrogenic effects in its absence, consistent with prior dioxin studies.
- The CA-AhR mouse model effectively mimics continuous AhR activation, offering a valuable tool for studying developmental exposure effects.
- Findings highlight the complex interplay between AhR and estrogen signaling pathways in reproductive health.
