The Science of DioxinMarch 22, 2016 | |
Paper Claims that IUL TCDD Exposure Sensitized Mice to Urinary Tract Dysfunction
A study published in the journal Toxicological Sciences reportedly has found that in utero and lactational (“IUL”) exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (“TCDD”) sensitized genetically-susceptible mice to exogenous-hormone-induced urinary tract dysfunction later in life.
The authors of the paper, “In utero and Lactational TCDD Exposure Increases Susceptibility to Lower Urinary Tract Dysfunction in Adulthood,” are William A. Ricke, Calvin W. Lee, Tyler R. Clapper, Andrew J. Schneider, Robert W. Moore, Kimberly P. Keil, Lisa L. Abler, Jalissa L. Wynder, Arnaldo López Alvarado, Isaac Beaubrun, Jenny Vo, Tyler M. Bauman, Emily A. Ricke, Richard E. Peterson, and Chad M. Vezina.
The authors explained that, to test their hypothesis that IUL TCDD exposure exacerbated urinary dysfunction in adult mice, mice that were genetically predisposed to prostate neoplasia were exposed IUL to TCDD (one µg/kg po) or corn oil vehicle (five ml/kg) after a single maternal dose on 13 dpc and subsequently were aged without further manipulation, or at eight weeks of age were exposed to exogenous 17β-estradiol (2.5 mg) and testosterone (25 mg) (“T+E2”) via slow release subcutaneous implants.
According to the paper, IUL TCDD exposure in the absence of exogenous hormone treatment reduced voiding pressure in adult mice, but otherwise had little effect on mouse lower urinary tract (“LUT”) anatomy or function.
By comparison, the authors said, IUL TCDD exposure followed by exogenous hormone treatment increased relative kidney, bladder, dorsolateral prostate, and seminal vesicle weights, hydronephrosis incidence, and prostate epithelial cell proliferation, thickened prostate periductal smooth muscle, and altered prostate and bladder collagen fiber distribution.
The authors claimed that their results indicated that IUL TCDD exposure increased the severity of adult urinary dysfunction in TCDD and T+E2-treated mice, and provided “some of the first evidence that exposure to an environmental contaminant during a male’s fetal and neonatal development may adversely impact lifelong urinary health.”
They also declared that their results, together with other experimental and epidemiological data, pointed to a paradox: “that factors such as TCDD may be both harmful and beneficial, with exposure age serving as the key determinant of outcome.” They pointed out that previous studies “have shown that men with known or suspected adult TCDD exposure may be at a reduced risk of developing [benign prostatic hypertrophy (“BPH”)].”
The authors concluded by observing that their study also pointed to “hormonal regulation” as a possible way to slow or prevent LUTS.
NAS Low Dose Committee Holds Workshop on Potential Case Studies
An ad hoc “low dose” committee under the auspices of the National Research Council (“NRC”) has held a workshop exploring three chemicals as potential case studies for “unraveling endocrine-related low dose toxicity.”
The low dose committee was formed to develop a strategy for evaluating whether the current regulatory toxicity-testing practices of the Environmental Protection Agency (“EPA”) allowed for “adequate consideration of evidence of low-dose adverse human effects that act through an endocrine-mediated pathway.”
According to the committee’s charter, it is required to direct reviews of chemicals/populations/end points for human and animal data streams and it must evaluate the results of the reviews, demonstrate how human and animal data streams can be integrated, determine whether the evidence supports a likely causal association, and evaluate the nature and relevance of the dose-response relationship or relationships. The committee also is to consider how to use adverse outcome pathway (“AOP”) or other mechanistic data, including high-throughput data and pharmacokinetic information, to elucidate under what circumstances human and animal data may be concordant or discordant.
Now, the committee has held a workshop that explored three candidate chemicals – phthalates, TCDD, and bisphenol A – as potential case studies for those reviews. Panelists explored questions about critical health outcomes, windows of exposure, and other factors necessary to evaluate the proposed chemicals.