Response to comments of peter g. Mantle.
ABSTRACT The apparently high yield of testis tumors (25%) in rats exposed long-term to Ochratoxin A (OTA) is uninterpretable without data on tumor yield in unexposed rats. Conversely, our demonstration that prenatal exposure to OTA induces DNA adducts in the testes of newborn mice and the absence of these adducts in the testes of mice not exposed prenatally to OTA, is evidence for the presumptive carcinogenicity of OTA in the testis. Together with recent data showing that prenatal exposure to OTA depresses expression of DMRT1, a tumor suppressor gene in the testis, our findings suggest that OTA may be a cause of testicular cancer.
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ABSTRACT: Ochratoxin A (OTA) is a nephrotoxin and carcinogen that is associated with Balkan endemic nephropathy and urinary tract tumors. OTA crosses the placenta and causes adducts in the liver and kidney DNA of newborns. Because the testis and kidney develop from the same embryonic tissue, we reasoned that OTA also may cause adducts transplacentally in the testis. We tested the hypothesis that acute exposure to OTA, via food and via exposure in utero, causes adducts in testicular DNA and that these lesions are identical to those that can be produced in the kidney and testis by the consumption of OTA. Adult mice received a single dose of OTA (from 0-1,056 microg/kg) by gavage. Pregnant mice received a single i.p. injection of OTA (2.5 mg/kg) at gestation day 17. DNA adducts were determined by (32)P-postlabeling. Gavage-fed animals sacrificed after 48 hours accumulated OTA in kidney and testis and showed DNA adducts in kidney and testis. Some OTA metabolites isolated from the tissues were similar in both organs (kidney and testis). The litters of mice exposed prenatally to OTA showed no signs of overt toxicity. However, newborn and 1-month old males had DNA adducts in kidney and testis that were chromatographically similar to DNA adducts observed in the kidney and testis of gavage-fed adults. One adduct was identified previously as C8-dG-OTA adduct by LC MS/MS. No adducts were observed in males from dams not exposed to OTA. Our findings that in utero exposure to OTA causes adducts in the testicular DNA of male offspring support a possible role for OTA in testicular cancer.Toxins. 01/2010; 2(6):1428-1444.
Article: Pathological Outcomes in Kidney and Brain in Male Fischer Rats Given Dietary Ochratoxin A, Commencing at One Year of Age[show abstract] [hide abstract]
ABSTRACT: Malignant renal carcinoma, manifest in morbid ageing rats, is the striking component of an otherwise silent response after about nine months of exposure to ochratoxin A in the first year of life (daily intake ~100–250 µg/kg body weight). Reasons for the long latency are unclear, as is whether there would be a similar carcinogenic response if toxin exposure started at one year of age. Therefore, 24 male Fischer rats were given 100 µg ochratoxin A as a daily dietary contaminant for 35 weeks from age 50 weeks. Plasma ochratoxin A concentration reached a maximum value of ~8 µg/mL within one month of starting the toxin regimen. No renal carcinomas occurred. Four renal adenomas, two of which were only microscopic, were found among the six rats surviving for 110 weeks. The findings raise new questions about a difference between young adults and mature adults in sensitivity of male rats to the ochratoxin A-induced DNA damage necessary for renal carcinogenesis. A pilot histological study of perfuse-fixed brains of the toxin-treated rats showed no gross abnormalities, correlating with the consistent absence of behavioral or neurological disorders from chronic ochratoxin A exposure regimens in the range 100–250 µg/kg/day during the second half of life. Reasoned questioning concerning ochratoxin A as a neurotoxic mycotoxin is made.Toxins. 01/2010;
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ABSTRACT: The potency of ochratoxin A (OTA) as a renal carcinogen in the rat in response to lifetime administration by oral gavage is a basis of current concern about possible human risk from dietary exposure to the mycotoxin. In this study, dietary delivery of OTA was chosen as the mode of administration, since this mimics human intake of OTA-contaminated food more accurately than gastric intubation. Young male Fischer rats were given approximately 300 microg OTA/kg body weight (bwt) daily until they reached 333 g; thereafter their daily intake was held at about 100 microg. Renal tumours, mostly unilateral carcinomas, were first discovered at week 75 and total incidence reached 25%. Statistical comparison of total carcinoma incidence (20%) in this study with that of the classic US NTP study suggested that OTA was significantly less carcinogenic when administered in feed than when given by oral gavage. The finding may moderate perceptions of a putative risk of trace amounts of OTA in some foodstuffs to human health.Food Additives and Contaminants 02/2005; 22 Suppl 1:58-64. · 2.13 Impact Factor
Toxins 2010, 2, 2337-2339; doi:10.3390/toxins2102337
Response to Comments of Peter G. Mantle
Gary G. Schwartz 1,*, Richard A. Manderville 2 and Annie Pfohl-Leszkowicz 3
1 Departments of Cancer Biology, Urology, and Epidemiology and Prevention, Wake Forest
University, Winston-Salem, NC 27157, USA
2 Department of Chemistry and Toxicology, University of Guelph, Guelph, Ontario, N1G 2W1,
Canada; E-Mail: email@example.com
3 University of Toulouse, Laboratory Chemical Engineering, Department Bioprocess & Microbial
System, UMR CNRS/INPT/UPS 5503, ENSA Toulouse, 1 avenue de l’Agrobiopôle, BP 32607,
31326, Auzeville-Tolosane, France; E-Mail: firstname.lastname@example.org
* Author to whom correspondence should be addressed; E-Mail: email@example.com;
Tel.: +1-336-716-7446; Fax: +1-336-716-5687.
Received: 17 September 2010 / Accepted: 28 September 2010 / Published: 29 September 2010
Abstract: The apparently high yield of testis tumors (25%) in rats exposed long-term to
Ochratoxin A (OTA) is uninterpretable without data on tumor yield in unexposed rats.
Conversely, our demonstration that prenatal exposure to OTA induces DNA adducts in the
testes of newborn mice and the absence of these adducts in the testes of mice not exposed
prenatally to OTA, is evidence for the presumptive carcinogenicity of OTA in the testis.
Together with recent data showing that prenatal exposure to OTA depresses expression of
DMRT1, a tumor suppressor gene in the testis, our findings suggest that OTA may be a
cause of testicular cancer.
Keywords: ochratoxin; testicular cancer; DNA adduct
We thank Pr. Mantle for his comments about our paper . In his commentary, Pr. Mantle refers to
perceived mis-citations of his papers. In particular, we cited his recent observation that 6/24 (25%) of
aged Fisher rats exposed to Ochratoxin A via the diet developed testicular tumors . We interpreted
this as a priori evidence of a tumorigenic effect of Ochratoxin A on the testis, although that paper had
no control group. We also noted his 2005 paper which also reported testicular tumors in rats exposed
to Ochratoxin A . Pr. Mantle writes in his commentary that, “it was clearly stated there [the 2005
paper] that testis tumours occurred equally in treated rats and in controls”. However, careful review of
Toxins 2010, 2
that paper with regard to testis tumors reveals only this comment: “In some older animals from both
control and treated groups, single or multiple seminomas occurred within one or both testes (p. 61)”.
Thus, absent data from a control group , and absent data on the incidence, multiplicity and histology
of tumors from an experimental and control group , it would be more accurate to conclude that no
inference about the role of Ochratoxin A in testicular tumors can be derived from the papers of
Mantle et al.
In contrast, our observations of DNA adducts in the testes of mice exposed prenatally to Ochratoxin
A, and the absence of any such adducts in the testes of control mice not exposed prenatally to
Ochratoxin A, are clear evidence of the carcinogenic potential of Ochratoxin A in the testes. The DNA
adducts that we observed are not evidence merely of exposure (as Pr. Mantle suggests), they are
markers of biological effect, as DNA adducts are widely considered to be markers of an increased risk
of cancer [4–6]. Furthermore, we note that prenatal exposure to Ochratoxin A in mice significantly
depresses expression of the DMRT1 gene in offspring, particularly male offspring . DMRT1 is a
doublesex and mab-3 related transcription factor that is expressed in Sertoli cells and undifferentiated
spermatogonia of the postnatal testis . DMRT1 is a tumor suppressor gene in the testis; loss of this
gene produces germ cell testicular tumors in mice . A large genome-wide study from the United
Kingdom recently confirmed a role for DMRT1 in testicular germ cell tumors in humans . Thus, in
addition to our study, considerable molecular evidence supports the hypothesis that Ochratoxin A may
be causally related to germ cell testicular tumors in mice and in men .
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