AHR signaling in prostate growth, morphogenesis, and disease

Abstract

Most evidence of aryl hydrocarbon receptor (AHR) signaling in prostate growth, morphogenesis, and disease stems from research using 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to pharmacologically activate the AHR at various stages of development. This review discusses effects of TCDD on prostate morphogenesis and highlights interactions between AHR and other signaling pathways during normal and aberrant prostate growth. Although AHR signaling modulates estrogen and androgen signaling in other tissues, crosstalk between these steroid hormone receptors and AHR signaling cannot account for actions of TCDD on prostate morphogenesis. Instead, the AHR appears to act within a cooperative framework of developmental signals to regulate timing and patterning of prostate growth. Inappropriate activation of AHR signaling as a result of early life TCDD exposure disrupts the balance of these signals, impairs prostate morphogenesis, and has an imprinting effect on the developing prostate that predisposes to prostate disease in adulthood. Mechanisms of AHR signaling in prostate growth and disease are only beginning to be unraveled and recent studies have revealed its interactions with WNT5A, retinoic acid, fibroblast growth factor 10, and vascular endothelial growth factor signaling pathways.

Figure 1. In utero and lactational TCDD exposure impairs mouse prostate development

C57BL/6J mice were exposed to a maternal dose of vehicle or TCDD (5 μg/kg) on embryonic day (E) 13.5. Prostates were removed on postnatal day 90, separated into anterior, dorsolateral, and ventral lobes, and digested briefly with collagenase to expose individual ducts [18]. TCDD significantly decreased the weight of all lobes but most dramatically the ventral lobe. TCDD eliminated all main ducts in the ventral prostate causing ventral prostate agenesis, reduced the number of main ducts in the dorsolateral prostate, and reduced branching complexity of the anterior prostate.

Figure 2. Activation of AHR signaling by in utero TCDD exposure interferes with normal prostatic bud patterning in the fetal male mouse

Wild type and Ahr null mice were exposed on E13.5 to vehicle (5 ml/kg corn oil, po) or TCDD (5 μg/kg, maternal dose). UGM was removed from male UGSs on E18.5 and the underlying UGE was visualized by scanning electron microscopy (SEM). Results shown are representative SEM images of the lateral UGS surface of wild type and Ahr null mice that were exposed in utero to vehicle or TCDD. TCDD completely inhibited ventral prostatic bud formation, reduced the number of dorsolateral buds and caused them to emerge inappropriately on the anterior budding surface. Ventral prostatic buds are pseudocolored blue, dorsolateral buds are green, and anterior buds are red. Abbreviations used are: BL, bladder; DD, ductus deferens; PU, pelvic urethra; SV, seminal vesicle.

Figure 3. Interactions between the AHR signaling and WNT5A, androgen, retinoid, and FGF10 signaling during mouse prostatic bud formation

Androgens (testosterone and 5α-dihydrotestosterone), retinoic acid (RA) and fibroblast growth factor 10 (FGF10) all increase prostatic bud formation in the mouse urogenital sinus (UGS) by activating downstream molecular targets that have not been identified (denoted by the square box). TCDD activates AHR/ARNT-mediated transcription by binding to AHR response elements (AHREs) located in the promoters of AHR-responsive genes. However, Cyp1a1 and Cyp1b1, classical AHR-responsive genes, are not involved in the mechanism of prostatic budding inhibition by TCDD. Instead, AHR/ARNT appears to trigger downstream events that lead to WNT5A signaling and repression of prostatic budding. Inhibition of WNT5A signaling with an inhibitory antibody against WNT5A (Anti-WNT5A-IgG) restores prostatic budding in the presence of TCDD.

Figure 4. Ahr signaling suppresses tumor formation in the TRAMP mouse model of prostate cancer

The percentage of mice with prostate tumors was determined at 35 days intervals in Ahr^+/+, Ahr^+/-, and Ahr^-/- C57BL/6J TRAMP mice 35–210 days of age [40]. Starting at 140 days of age, chi-square analysis revealed a significant increase in prostate tumor incidence in TRAMP mice deficient in one or both functional Ahr alleles. A single asterisk denotes a significant difference from Ahr^+/+ TRAMP mice and a double asterisk denotes a significant difference from both Ahr^+/+ and Ahr^+/- TRAMP mice (p < 0.05). The number of Ahr^+/+, Ahr^+/-, and Ahr^-/- mice, respectively in each age group were: 35 days (20, 32 and 22), 70 days (20, 49 and 22), 105 days (14, 45 and 20), 140 days (19, 55 and 21), 175 days (19, 46 and 18) and 210 days (24, 43 and 18).

Figure 5. Perinatal and adult exposure to AHR agonists differentially affects the risk of prostate disease

Sustained activation of AHR in the UGS by TCDD during fetal prostate development increases the risk of prostate cancer in adulthood, whereas activation of AHR signaling in the prostate during adulthood by TCDD, other full AHR agonists, and selective AHR modulators (SARHMs) are protective against prostate cancer and/or benign prostate hyperplasia.