Autism spectrum disorder (ASD) includes a group of multifactorial neurodevelopmental disorders defined clinically by core deficits in social reciprocity and communication, restrictive interests and repetitive behaviors. ASD affects one in 54 children in the United States, one in 89 children in Europe, and one in 277 children in Asia, with an estimated worldwide prevalence of 1–2%. While there is increasing consensus that ASD results from complex gene x environment interactions, the identity of specific environmental risk factors and the mechanisms by which environmental and genetic factors interact to determine individual risk remain critical gaps in our understanding of ASD etiology. Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that have been linked to altered neurodevelopment in humans. Preclinical studies demonstrate that PCBs modulate signaling pathways implicated in ASD and phenocopy the effects of ASD risk genes on critical morphometric determinants of neuronal connectivity, such as dendritic arborization. Here, we review human and experimental evidence identifying PCBs as potential risk factors for ASD and discuss the potential for PCBs to influence not only core symptoms of ASD, but also comorbidities commonly associated with ASD, via effects on the central and peripheral nervous systems, and/or peripheral target tissues, using bladder dysfunction as an example. We also discuss critical data gaps in the literature implicating PCBs as ASD risk factors. Unlike genetic factors, which are currently irreversible, environmental factors are modifiable risks. Therefore, data confirming PCBs as risk factors for ASD may suggest rational approaches for the primary prevention of ASD in genetically susceptible individuals.

Bladder inflammation is associated with several lower urinary tract symptoms that greatly reduce quality of life, yet contributing factors are not completely understood. Environmental chemicals are plausible mediators of inflammatory reactions within the bladder. Here, we examine whether developmental exposure to polychlorinated biphenyls (PCBs) leads to changes in immune cells within the bladder of young mice. Female mice were exposed to an environmentally relevant mixture of PCBs through gestation and lactation, and bladders were collected from offspring at postnatal day (P) 28–31. We identify several dose- and sex-dependent PCB effects in the bladder. The lowest concentration of PCB (0.1 mg/kg/d) increased CD45+ hematolymphoid immune cells in both sexes. While PCBs had no effect on CD79b+ B cells or CD3+ T cells, PCBs (0.1 mg/kg/d) did increase F4/80+ macrophages particularly in female bladder. Collagen density was also examined to determine whether inflammatory events coincide with changes in the stromal extracellular matrix. PCBs (0.1 mg/kg/d) decreased collagen density in female bladder compared to control. PCBs also increased the number of cells undergoing cell division predominantly in male bladder. These results implicate perturbations to the immune system in relation to PCB effects on the bladder. Future study to define the underlying mechanisms could help understand how environmental factors can be risk factors for lower urinary tract symptoms.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants linked to deleterious health outcomes, including voiding dysfunction in developmentally exposed mice. Changes in prostate volume and/or extracellular matrix composition are associated with voiding dysfunction in men and animal models. Whether PCB-induced changes in voiding function in male mice occur in part via alterations to the prostate or an alternate mechanism is unclear. Therefore, we tested whether developmental exposure to the MARBLES PCB mixture altered prostate morphology in young adult offspring. C57Bl/6J female mice were dosed daily with the MARBLES PCB mixture at 0, 0.1, 1 or 6 mg/kg/d for two weeks prior to mating and through gestation and lactation, offspring were collected at 6 weeks of age. Ventral prostate mass was decreased in the 1 mg/kg/d PCB group compared to other PCB groups. There were no PCB-induced changes in prostate smooth muscle thickness, apoptosis, proliferation, or testes mass. PCBs impacted the prostate extracellular matrix; anterior prostate collagen density was decreased in the 1 mg/kg/d PCB group compared to all other groups. Normalized bladder volume was increased in male and female offspring in the 6 mg/kg/d PCB group compared to control. No change in water consumption, bladder mass or bladder smooth muscle thickness accompanied changes in bladder volume. Urine and serum creatinine concentrations were elevated but only in male mice. Together, these results suggest that developmental exposure to PCBs can influence prostate wet weight and prostate/bladder morphology, but PCBs do not promote prostate enlargement. Whether these changes persist throughout adult life and how they contribute to voiding function in animal models and humans is of future interest.

Many women suffer from symptoms associated with dysfunction of the lower urinary tract, including incontinence and overactive bladder, especially during pregnancy. While causes are likely multifactorial, environmental factors, such as exposure to polychlorinated biphenyls (PCBs), have been shown to alter voiding in adult female mice. However, the distribution of PCBs and their metabolites to the bladder and urine, as well as their effects on bladder drug-metabolizing enzyme expression after dosing with PCB mixtures, remains largely unexplored. Female C57BL/6J mice were exposed to MARBLES PCB mixture (0, 0.1, 1, and 6 mg/kg/d) through gestation and lactation, and post-weaning bladder, urine, blood, adipose, and liver were collected for measurement of PCBs and OH-PCBs, and for abundance of cytochrome P450 ( Cyp ) transcripts in liver and bladder. PCBs and OH-PCBs were detected in all tissues in a dose-dependent manner. Bladder, adipose, and liver retained parent PCBs while OH-PCBs were predominant in urine and blood. Cyp1a2 mRNA abundance was elevated in the liver of the high dose PCB group versus the vehicle, and the same trend was observed in the bladder. These results define the signatures of PCBs and OH-PCBs in the bladders and urine of post-weaning dams exposed to the MARBLES mixture of PCBs and provide a reference for comparison with accumulation in more commonly studied tissues. Our results also provide new insights into the regulation of Cyp1a2 in the liver and bladder, changes that may play a role in how environmental exposures in adulthood alter voiding function.

Lower urinary tract dysfunction (LUTD) is a multifactorial disease process that encompasses diverse symptoms ranging from issues with storage and sensation to impaired emptying of the bladder. Furthermore, symptoms tend to worsen with age and other comorbidities and in men can also be influenced by changes to the prostate, making diagnosis and treatment difficult to manage. Environmental factors are thought to contribute to disease risk. In mice, previous work has found that developmental exposure to polychlorinated biphenyls (PCBs) is capable of altering voiding function in offspring. However, the effects of PCB exposure in adulthood instead of development are not well known. Whether changes in voiding are a consequence of early or later life exposures remains an important area of study, as environmental chemicals and exposures can occur across the lifespan and can be mitigated. Here, we test whether PCB exposure in adulthood alters voiding or prostate morphology in male mice. C57Bl/6J adult male mice were exposed to the human-relevant MARBLES PCB mixture (0, 0.1, 1, and 6 mg/kg/d) orally daily for two months. Lower urinary tract function was then assessed through urodynamic testing including void spot assay, uroflowmetry, and anesthetized cystometry. Prostate lobes were collected for histology. The only change to voiding function was a reduction in void duration in the 6 versus 1 mg/kg/d PCB group but not to the vehicle control. Prostate, seminal vesicle, and testes wet weights were unchanged. However, PCB exposure reduced the number of Ki67-positive proliferating cells in the anterior and ventral prostate lobes only at the 1 mg/kg/d dose, with no change to caspase 3-positive cells or smooth muscle thickness. Together, these data indicate that 2-month exposure to PCBs in adult mice has little impact on voiding but is a sufficient exposure to produce changes in cell proliferation in the prostate. The mechanistic impacts of these changes remains to be investigated but could help better understand individual risk for LUTD.