A recent study directed new focus on the fetal and neonatal environment as a risk factor for urinary dysfunction in aging males. Male mice were exposed in utero and via lactation (IUL) to the persistent environmental contaminant
2,3,7,8-tetrachlorodibenzo-p-dioxin (
TCDD) and then administered slow-release, subcutaneous implants of
testosterone and
estradiol (T+E2) as adults to mimic the hormonal environment of aging men. IUL
TCDD exposure worsened T+E2-induced voiding dysfunction. Mice in the previous study were genetically prone to prostatic
neoplasia and it was therefore unclear whether
TCDD exacerbates voiding dysfunction through a malignant or non-malignant mechanism. We demonstrate here that IUL
TCDD exposure acts via a non-malignant mechanism to exacerbate T+E2-mediated male mouse voiding dysfunction characterized by a progressive increase in spontaneous void
spotting. We deployed a proteomic approach to narrow the possible mechanisms. We specifically tested whether IUL
TCDD exacerbates urinary dysfunction by acting through the same prostatic signaling pathways as T+E2. The prostatic
protein signature of
TCDD/T+E2-exposed mice differed from that of mice exposed to T+E2 alone, indicating that the mechanism of action of
TCDD differs from that of T+E2. We identified 3641 prostatic
proteins in total and determined that IUL
TCDD exposure significantly changed the abundance of 102
proteins linked to diverse molecular and physiological processes. We shed new light on the mechanism of IUL
TCDD-mediated voiding dysfunction by demonstrating that the mechanism is independent of
tumorigenesis and involves molecular pathways distinct from those affected by T+E2.