Neonatal Cyclophosphamide Exposure Produces Voiding Dysfunction Lasting Into Adulthood
Stephan Butler, MS, Jason Van Batavia, MD, Joanna Fesi, BS, Stephen Zderic, MD.
Children's Hospital of Philadelphia, Philadelphia, PA, USA.
BACKGROUND: Voiding dysfunction remains a common reason for pediatric urology consultation and evidence suggests for some of these patients, the symptoms never go away. In a review of women with overactive bladder and chronic pelvic pain, Fitzgerald et al found that these patients were more likely to have had a history of childhood voiding dysfunction and urinary tract infection compared to a control population. Might recurrent episodes of inflammation at a critical time in development lead to long term voiding dysfunction? We sought to test this hypothesis in a murine model using cyclophosphamide (CPM).
METHODS: Wild type C57 timed pregnant dams delivered and the pups were administered 50mg/kg of CPM on days 7 and 10 of life. Controls were handled in an similar manner but were not given CPM. Female mice were then studied between 8 and 10 weeks of age using metabolism cages (UroVoid, Medical Associates) to assess the voiding frequency per 24 hours and average voided volumes. Catheters were implanted to allow for in vivo cystometry.
RESULTS: Median voided volumes declined from 157 microliters in the control group (N=8) to 77 in the CPM treated group (N=10) (P = 0.0218 by Mann Whitney testing). These results are summarized in figure 1 for all voids (A) and by individual mice (B). Median voiding frequency increased from 13 voids/24 hours in the control group to 26.5 voids/24 hours in the CPM group (P = 0.005 by Mann Whitney testing). In vivo cystometry revealed a longer inter-contraction interval for the control versus the CPM group which is consistent with the voiding data from the metabolism cages, and showed no changes in voiding pressures between the groups.
CONCLUSIONS: In summary whereas adult models of CPM cystitis produce short lived changes in the voiding pattern, exposure to CPM in neonatal mice produces changes in the voiding phenotype that last into adulthood. This becomes a useful model for studying the impact of inflammation in early life on bladder function in adult females. Repeating these experiments with the use of transgenic or double transgenic strains will allow us to study the neurophysiology of this resulting voiding dysfunction using either optogenetic techniques to modulate the voiding phenotype or photometry methods to record the EEG from select nodal points.
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