Renal Transplacental Carcinogenicity of 3,3-Dimethyl-1-Phenyltriazene in Rats: Relationship of Renal Mesenchymal Tumor to Congenital Mesoblastic Nephroma and Intralobar Nephrogenic Rests

Abstract

Exposure of rat embryos to 3,3-dimethyl-1-phenyltriazene (DMPT) results in numerous malformations, but the urogenital system is not affected. In contrast, exposure of rat fetuses to DMPT has been reported to result in renal neoplasms, which were not further classified. To better understand this discrepancy in organotropism of the teratogenic and transplacental carcinogenic processes, the present study was undertaken to characterize the neoplasms induced in rat fetuses exposed to DMPT in utero. Renal neoplasms and persistent mesenchyme were observed in 19.2 and 11.5%, respectively, of the offspring of rats treated with 1 mg DMPT/ kg body weight intraperitoneally on gestation days 16, 18, and 20. The majority of these renal lesions were observed in females. The renal neoplasms were mixtures of various types of mesenchymal tissue derivatives including smooth muscle and fibrous connective tissue. These neoplasms would be classified as renal mesenchymal tumors in rats. Brain neoplasms (numerous types), compound odontomas, and micrognathism were observed predominantly in male offspring from the same group. This treatment also resulted in decreased body weights, increased incidence of sudden loss of body weight, tremors and ataxia, and hypoplastic testes. Exposure to single intraperitoneal doses of DMPT on gestation day 20 did not produce a classic dose-response pattern: Minimal effects were observed with 10 mg DMPT/kg (occasional renal mesenchymal tumors and brain neoplasms), marked effects were observed with 30 mg DMPT/kg (lower incidence rate of most of the alterations observed with 1 mg/kg on gestation days 16, 18, and 20), and no effects were observed with 60 mg DMPT/kg. DMPT administered intraperitoneally at 1 mg/kg body weight on gestation days 16, 18, and 20 is an animal model of transplacental chemically induced renal neoplasms, which provide lesions with similarities to both intralobar nephrogenic rests and congenital mesoblastic nephroma of humans. Why the kidney is a carcinogenic target and not a teratogenic target remains unknown.

Arachidonic acid supplementation does not affect N-methyl-N-nitrosourea-induced renal preneoplastic lesions in young Lewis rats

“…In this preliminary study, a single injection of 50 mg/kg MNU given to Lewis rats at birth induced a high incidence of mortality and mammary cancers with severe hematotoxicity. Rats are most sensitive to the induction of renal tumors when alkylating agents are administered at the early weeks after birth, when the rate of cell division in the immature kidney is the highest (10,22). Like this experimental protocol, a short-term study (60 days) with 35 mg/kg MNU as a non-lethal lower dose without the incidence of mammary cancers, may therefore be extremely useful for testing the promotion, progression or inhibitory effects of chemical and physical agents on cell proliferation and transformation in rat kidneys.…”

“…It is characterized by discrete clusters of highly basophilic blast cells surrounding mature ducts and organoid differentiation as epithelial rosettes, primitive basophilic tubules, attempted glomerulus formation or mature epithelial ducts (20,21). Nephroblastomatosis is a small, solitary, basophilic cell mass consisting of densely crowded blast cells with ill-defined cytoplasm and basophilic nuclei and a few signs of early organoid differentiation into epithelial rosettes (20,22,23). Nephroblastomatosis has the potential to develop into a nephroblastoma as it grows, and is regarded as a preneoplastic lesion of nephroblastoma (24).…”

“…Nephroblastomatosis has the potential to develop into a nephroblastoma as it grows, and is regarded as a preneoplastic lesion of nephroblastoma (24). Mesenchymal tumors originate from foci of atypical fibroblast-like cells in the interstitium of the outer stripe of outer medulla, similar to a renal tumor of infancy described as congenital mesoblastic nephroma (22,25,26). Mesenchymal tumors are characterized by heterogeneous connective tissue cell composition with a predominance of spindle cells, primitive mesenchyme, and smooth muscle fibers and occasional rhabdomyoblasts, striated muscle, cartilage, osteoid or hemangiosarcoma-like areas (20,21).…”

Transplacental Carcinogenicity of N-Ethyl-N-Nitrosourea in Sprague-Dawley Rats

“…As an example of chemical induction, Stoica and Koestner 20 reported that a single high dose (180 mg/kg) of intraperitoneal ENU caused ameloblastic odontoma in 30-day-old male rats. Moreover, Frank et al 8 described that odontomas in the dentitious tissue occurred in 3/18 male SD rats following a transplacental exposure to 3,3-dimethyl-1-phenyltriazene on days 16, 18, and 20 of gestation. No data are available on ameloblastic odontoma with ENU in other species, though methylnitrosourea caused this tumor in Syrian golden hamsters 23 .…”

Intralobar Nephroblastematosis in a Nine-week-old Wistar Rat

“…These anatomic locations of perilobar and intralobar can also be applicable to the rat kidney, which is unipyramidal in nature. Superficial cortical areas in the rat kidney are perilobar, and the corticomedullary region are intralobar (Frank et al 1992). Intralobar nephroblastematosis (ILNB) is a precursor lesion to the development of NB in rats.…”