A mechanism linking perinatal 2,3,7,8 tetrachlorodibenzo-p-dioxin exposure to lower urinary tract dysfunction in adulthood

Abstract

Benign Prostatic Hyperplasia / Lower Urinary Tract Dysfunction (BPH/LUTD) is a classic disease of aging which affects nearly all men. Symptoms typically present in the fifth or sixth decade and progressively worsen over the remainder of life. Here, we identify a surprising origin of this disease that traces back to the intrauterine environment of the developing male, challenging existing paradigms about when this disease process begins. We delivered a single bolus dose of a widespread environmental contaminant, present in the serum of most Americans (2,3,7,8 tetrachlorodibenzo-p-dioxin, TCDD, 1 µg/kg), and representative of a broader class of environmental contaminants, to pregnant mice and observed an increase in the abundance of a neurotrophic factor, artemin, in the developing mouse prostate. Artemin is required for noradrenergic axon recruitment across multiple tissues and TCDD rapidly increases prostatic noradrenergic axon density in the male fetus. The hyperinnervation does not resolve, but rather persists into adulthood, when it is coupled to autonomic hyperactivity of prostatic smooth muscle and abnormal urinary function, including increased urinary frequency, a bothersome symptom in men. We offer new evidence that prostate neuroanatomical development is malleable and that intrauterine chemical exposures can permanently reprogram prostate neuromuscular function to cause male LUTD in adulthood.

The Bladder Is a Novel Target of Developmental Polychlorinated Biphenyl Exposure Linked to Increased Inflammatory Cells in the Bladder of Young Mice

“…Increasing evidence suggests that exposure to environmental toxicants can contribute to lower urinary tract function in adulthood. Developmental exposure to environmental toxicant, dioxin (TCDD) via the dam, has been shown to decrease void intervals in adult male mouse offspring [ 63 ] and further exacerbates voiding dysfunction in susceptible mice [ 64 , 65 ]. There is also evidence that remodeling of collagen is one pathway by which environmental chemicals can impact the lower urinary tract.…”

Male Lower Urinary Tract Dysfunction: An Underrepresented Endpoint in Toxicology Research

“…Factors responsible for severe drug-refractory disease are not understood. Recent studies reveal potential roles for environmental chemical exposures, during the fetal period when the lower urinary tract is developing [19][20][21] and during other stages, in driving LUTD susceptibility and progression, opening an entirely new line of toxicology research towards understanding environmental factors that contribute to LUTD processes. This review is intended as a resource for toxicologists and other discipline specialists who are considering entry into the urologic disease research space and wishing to examine LUTD as a toxicology research endpoint.…”

“…There is emerging evidence that environmental chemicals can also change prostatic innervation to cause prostatic smooth muscle dysfunction, specifically by acting during the fetal and neonatal periods when prostate autonomic innervation is established. For example, we recently showed in C57BL/6J mice that gestational exposure to the widespread environmental contaminant TCDD (a single 1 µg/kg oral maternal dose on the 13th day of gestation) increases noradrenergic fiber density (nerve terminals) in the prostate of male mouse fetuses without changing the density of cholinergic or peptidergic fibers [160]. TCDD-induced prostatic noradrenergic hyperinnervation persists into adulthood and is coupled to hyperactivity of prostatic smooth muscle and abnormal urinary function in mice, including increased urinary frequency [160].…”

“…For example, we recently showed in C57BL/6J mice that gestational exposure to the widespread environmental contaminant TCDD (a single 1 µg/kg oral maternal dose on the 13th day of gestation) increases noradrenergic fiber density (nerve terminals) in the prostate of male mouse fetuses without changing the density of cholinergic or peptidergic fibers [160]. TCDD-induced prostatic noradrenergic hyperinnervation persists into adulthood and is coupled to hyperactivity of prostatic smooth muscle and abnormal urinary function in mice, including increased urinary frequency [160]. These findings are important because they support the concept that prostate neuroanatomical development is malleable, at least in mice, and that intrauterine chemical exposures can permanently reprogram prostate neuromuscular function to cause male LUTD in adulthood.…”

Polychlorinated Biphenyls (PCBs) Impact Prostatic Collagen Density and Bladder Volume in Young Adult Mice Exposed during in Utero and Lactational Development

“…A better understanding of causative agents which trigger these changes in prostatic growth or morphology could improve the ability to diagnose and treat a subset of patients suffering from LUTD. Increasing evidence suggests that early life exposure to environmental contaminants can influence prostate development, growth, and the onset and progression of abnormal voiding physiology in rodent models [ 7 , 8 , 9 , 10 , 11 ]. We have previously shown that young adult mice (6–7 weeks of age) exposed to polychlorinated biphenyls (PCBs), a ubiquitous environmental contaminant, through gestation and lactation display smaller, more frequent voiding phenotypes that were sex and dose-dependent [ 12 ].…”