Arsenate-induced Renal Agenesis in Rats192

The developmental origin of arsenate-induced renal agenesis was investigated. Pregnant Wistar rats were each injected once ip with 45 mgkg sodium arsenate a t day 10 (sperm day = day 0). Pregnancy was terminated a t various times following injection and the embryos recovered and serially sectioned. Renal agenesis resulted when the mesonephric duct failed to give rise to a ureteric bud with subsequent failure of induction of the metanephric blastema. The underlying defect was retardation in growth of the mesonephric duct, first observed 48 hours after arsenate injection. A shortened mesonephric duct also resulted in a failure of the mesonephros to attain normal size and in the male resulted in absence of the ductus deferens, seminal vesicle and a variable portion of the epididymis. Due to the intimate association of the mesonephric and growing paramesonephric ducts, a shortened mesonephric duct resulted in a shortened paramesonephric duct with resultant lack of a uterine horn. In recent years there has been a growing interest in studying the effects on embryonic development of a number of metals and metallike elements found in the environment (for review of the literature see Ferm, '72, '74). Several compounds of one such element, the metalloid arsenic, are teratogenic. Sodium cacodylate induced spina bifida in chick embryos (Ancel, '46). Sodium arsenate, a compound of inorganic arsenic in the pentavalent state, has been shown to be teratogenic in the hamster (Ferm and Carpenter, '68; Ferm et al., '71) and the rat (Beaudoin, '741, while both sodium arsenate and the trivalent compound, sodium arsenite, are teratogenic in the mouse (Hood and Bishop, '72; Hood, '72). One malformation resulting from treatment with sodium arsenate in both the hamster and the rat is renal agenesis, i.e., the absence of one or both kidneys. Renal agenesis produced as a result of teratogen administration has been reported only infrequently in the literature (Wilson, '54; Monie, '61). This study was undertaken to analyze the embryogenesis of arsenic-induced renal agenesis. MATERIALS AND METHODS Virgin female Wistar rats (Royalhart, New Hampton, New York) were used. The animals were maintained on Teklad Mouse and Rat Diet (Teklad Mills, Winfield, Iowa) ad libitum with supplemental feedings of lettuce. The TERATOLOGY, 16: 247-260. day of finding sperm in the vaginal smear was designated day 0 of pregnancy. In order to establish an optimum time and dosage for the production of renal agenesis intraperitoneal injections of an aqueous solution of dibasic sodium arsenate (J. T. Baker Co., Phillipsburg, New Jersey) were given a t 1O:OO A.M. on one of days 9, 10, or 11 of pregnancy. Dosages of 30, 40, or 50 mg/kg maternal body weight were used. Control animals received distilled water injections or no treatment. Rats were sacrificed a t day 20 a t which time resorptions were counted and fetuses were examined and weighed. One-third of the living fetuses were fixed in alcohol for subsequent staining with alizarin red S for skeletal examination, and the remaining two thirds were fixed in Bouins for razor blade sectioning. An intraperitoneal dose of 45 mglkg of sodium arsenate was estimated to be most effective for the production of renal agenesis with a minimum of embryonic death. This dose was used to obtain specimens for the microscopic study of the genesis of absent kidney. Rats were sacrificed on one of days 11 through 16 of gestation, i.e., 24, 48, 72, etc., Received Mar. 3, '11. Accepted June 24, '11. ' From a dissertation aubmitted by D. B. to the Horace H. Rackhsrn School of Graduate Studies of The University of Michigan in partial fulfillment of the requirements for the degree of Doetor of Philosophy. * Supported by NIH Grant8 GM 00312 and HD 00400. ' Present address: Anatomy Department, University of Virginia, Charlotteaville. Virginia 22901.