Reproductive and developmental toxicology

Sodium molybdate added to the feed of rats from the time of weaning (80 or 140 ppm during 8 weeks) resulted in fewer litters and impaired growth of pups [Jeter and Davis,1954]. The effect of Dietary molybdenum had effects upon the hemoglobin, growth, reproduction and lactation of rats [Jeter and Davis, 1954; Schroeder and Mitchener, 1971]. Sodium molybdate did not induce embryonic toxicity when injected into the yolk sacs of 4- and 8-day-old chick embryos [Ridgway and Karnofsky, 1952]. Radioactive 99Mo administered orally to pregnant sows was not present in the fetus. However, demyelination of the cerebral nervous system was observed in the newborn lambs from pregnant ewes were fed a diet high in molybdate [Mills and Fell, 1960].

Jeter, M. A. and Davis, G. K., J. Nutr., 1954, 54, 215.
Schroeder, H. A., Mitchener, M. and Nason, A. P., J. Nutr., 1971, 101, 247.
Schroeder, H. A. and Mitchener, M., Arch. Environ. Health, 1971, 23, 102.
Ridgway, L. P. and Karnofsky, D. A., Ann. N.Y. Acad. Sci., 1952, 55, 203.
Mills, C. F. and Fell, B. F., Nature, 1960, 185, 20.

The effect of molybdenum on estrous activity and reproductive hormones: LH, FSH and estradiol in Wistar weanling female rats whose diet was supplemented, inter alia, with 500 ppm Na2MoO4. High dietary Mo prolonged the length of the estrous cycle and altered the cytological characteristics of the different phases of the cycle. Peak values of FSH were significantly lower in molybdenotic animals and Serum E(2) was lower [Igarza et al.,1996].

Igarza, L., Agostini, M., Becuvillalobos, D., Auza, N., Effects Of Molybdenosis On Luteinizing-Hormone, Follicle-Stimulating And Estradiol Hormones In Rats, Archivos De Medicina Veterinaria , 1996, 28, 101-106.

 Effects of Molybdenum on Reproduction and Molybdenum/Copper Enzyme Activity in the Female Rat

According to Wei et al molybdenum (Mo) inhibits mammary tumors. Analogies have been drawn between carcinogenesis and embryogenesis. The effect of Mo on non-ruminant reproduction has not been extensively investigated. The main objective of this study was to investigate the effect of dietary levels of Mo on the estrus cycle, fertility, and reproduction and some molybdenum and Copper (Cu) enzyme activity in the female rat.

T. V. Fungwe, F. Buddingh, M. T. Yang, S. P. Yang,  Effects of Molybdenum on Reproduction and Molybdenum/Copper Enzyme Activity in the Female Rat, Trace Elements in Man and Animals, 6 1988, pp 619-620.

Hepatic, placental, and fetal trace elements following molybdenum supplementation during gestation

The effect of dietary Mo (Na2MoO42H2O) added to drinking water at levels of 0, 5, 10, 50, or 100 mg on hepatic (gestating dams), placental, and fetal Mo, Cu, Zn, and Fe contents of Sprague-Dawley rats was studied. These elements were determined by a polarographic catalytic procedure for Mo and by atomic absorption spectrophotometry for Cu, Fe, and Zn. Hepatic Mo increased two to sixfold (5–100 mg Mo). There was a 1.5-fold increase in hepatic Cu, significant only at the 50 to 100 mg Mo/L treatment levels. Although the hepatic Fe content of the gestating rats significantly increased with Mo supplementation, the extent of the increase appeared to be influenced by the litter size, fetal weights, and the degree of fetal resorption. Zinc values did not differ at any of the treatment levels. Placental Mo increased 3–76-fold, Cu one to threefold. No differences were observed in placenta Fe or Zn. Fetal Mo increased two to six-fold (10–100 mg/L) and Cu increased one to fivefold. There were no differences in the Fe and Zn content although both of these elements appeared to decline as the level of supplemental Mo increased. Significant correlations were also observed between hepatic, placental, and fetal Mo, Cu, Fe, and Zn. These results suggest that changes in trace mineral status in gestation, owing to high Mo intake, do occur and such occurrences are also reflected in the fetus

Fungwe,Thomas V., Fred Buddingh, Meiling T. Yang, Shiang P. Yang, Hepatic, placental, and fetal trace elements following molybdenum supplementation during gestation, Biological Trace Element Research, 1989, 22, 189-199.

The role of dietary molybdenum on estrous activity, fertility, reproduction and molybdenum and copper enzyme activities of female rats

In this study, we investigated the effect of supplemental molybdenum (Mo) on estrous activity, fertility and reproduction, hepatic xanthine dehydrogenase/oxidase (XDH/OX), sulfite oxidase (SOX) and plasma ceruloplasmin (Cp) in female SD rats. Weanling female rats were assigned to five dietary treatment groups and fed an AIN-76A diet. They were given deionized water containing either no Mo or Mo at 5, 10, 50 and 100 mg/l. Mo significantly prolonged the estrous cycle when fed 10 mg/l or higher. Gestational weight gain was higher for the controls and the 5 mg/l, than for the 10–100 mg/l treatments. Histological data suggested that Mo supplemented at 10 mg/l or higher delayed fetal esophageal development, transfer of fetal hemopoiesis to bone marrow and myelination in the spinal cord. Intrauterine deaths were few, but the rate of fetal resorption increased with supplementation at 10 mg/l or higher. Mean hepatic XDH/XO, SOX and plasma Cu-Cp activity increased with Mo supplementation. This study suggests that supplemental Mo may influence estrous activity and embryogenesis. Hepatic XDH/OX, SOX and plasma ceruloplasmin may be affected differently in gestating and nongestating animals.

Fungwe, Thomas V., Fred Buddingh, Diane S. Demick,  Charles D. Lox, Meiling T. Yang, Shiang P. Yang, The role of dietary molybdenum on estrous activity, fertility, reproduction and molybdenum and copper enzyme activities of female rats, Nutrition Research, 1990, 10, 515–524.

90-Day subchronic toxicity study of sodium molybdate dihydrate in rats

This study investigated the subchronic toxicity of molybdenum (Mo) in Sprague-Dawley rats given sodium molybdate dihydrate in the diet for 90 days at dose levels of 0, 5, 17 or 60 mg Mo/kg(bw)/day. The study complied with OECD Test Guideline (TG) 408, with additional examination of estrus cycles and sperm count, motility, and morphology from OECD TG 416.

The overall no-observed-adverse-effect level was 17 mg Mo/kgbw/day, based on effects on body weight, body weight gain, food conversion efficiency and renal histopathology (females only) at 60 mg Mo/kg(bw)/day.

No treatment-related adverse effects on reproductive organ weights or histopathology, estrus cycles or sperm parameters were observed at any dose level.

No adverse effects were observed in the high dose animals after the 60-day recovery period, with the exception that male rats did not fully recover from reduced body weight.

Serum blood, liver and kidney samples were analyzed for molybdenum, copper, zinc, manganese, iron, cobalt and selenium; high levels of molybdenum and copper were found in the serum, blood, liver and kidneys of rats treated with 60 mg Mo/kg(bw)/day.

In conclusion, the LOAEL and NOAEL for molybdenum were determined to be 60 and 17 mg Mo/kg(bw)/day, respectively. (C) 2013 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-SA license

Murray, F. J., Sullivan, F. M., Tiwary, A. K., and Carey, S., 90-Day subchronic toxicity study of sodium molybdate dihydrate in rats, Regulatory Toxicology and Pharmacology, 2014, 70, 579-588

Developmental toxicity study of sodium molybdate dihydrate administered in the diet to Sprague Dawley rats

Molybdenum is an essential nutrient for humans and animals and is a constituent of several important oxidase enzymes.

It is normally absorbed from the diet and to a lesser extent from drinking water and the typical human intake is around 2 mu g/kg bodyweight per day.

No developmental toxicity studies to contemporary standards have been published and regulatory decisions have been based primarily on older studies where the nature of the test material, or the actual dose levels consumed is uncertain.

In the current study the developmental toxicity of sodium molybdate dihydrate as a representative of a broad class of soluble molybdenum(VI) compounds, was given in the diet to Sprague Dawley rats in accordance with OECD Test Guideline 414. Dose levels of 0, 3, 10, 20 and 40 mg Mo/kg bw/day were administered from GD6 to GD20.

No adverse effects were observed at any dose level on the dams, or on embryofetal survival, fetal bodyweight, or development, with no increase in malformations or variations.

Significant increases in serum and tissue copper levels were observed but no toxicity related to these was observed.

The NOAEL observed in this study was 40 mg Mo/kg bw/day, the highest dose tested. (C) The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/)

Murray, F. J., Tyl, R. W., Sullivan, F. M., Tiwary, A. K., and Carey, S., Developmental toxicity study of sodium molybdate dihydrate administered in the diet to Sprague Dawley rats, Reproductive Toxicology, 2014, 49, 202-208.