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Protective effects of zinc against developmental toxicity:

Zinc has been shown to protect fetal cellular growth and development against cadmium-induced effects and fetotoxicity (Ahokas, 1980, Daston, 1982).

Ahokas and colleagues fed laboratory rats chronically low drinking water levels (0, 1.0, 10.0, and 100 µg/mL) of cadmium (Cd), a known embryotoxic trace element, through gestation (Ahokas, 1980). Maternal daily food and water consumption, total weight gain, maternal weight gain, and feed efficiency all decreased with increasing Cd consumption. Term fetal weight was significantly less than that of control subjects only in the group fed 100 µg Cd / mL drinking water. Total litter weight, however, gradually decreased with increasing Cd concentration due to reduced litter size. Fetal growth retardation was a result of decreased cell division (DNA) and cell growth (protein/DNA ratio). When dams were pair-fed the average daily amount of food consumed by those fed 100 µg Cd/mL drinking water, maternal weight gain and fetal weight, DNA, and protein/DNA ratio were increased, but not to control levels. Dietary zinc (Zn) supplementation (5.0 mg/mL drinking water) of Cd-fed dams increased maternal food consumption and fetal weight, DNA, and protein/DNA ratio to control levels. Fetal levels of Cd were extremely low (0.038 to 0.095 µg/g fetus) and did not increase with increasing Cd consumption, while placental Cd increased more than 10-fold. Fetal Zn was decreased in Cd-fed dams, and Zn supplementation increased fetal Zn levels, but not to control levels. These results suggest that Cd-induced fetal growth retardation is an indirect rather than a direct effect, resulting from reduced maternal food consumption and metabolism. Since dietary Zn blocks these effects, Cd may be a result of induced Zn deficiency.

Daston and colleagues injected pregnant rats 8 mg/kg cadmium chloride alone or with 12 mg/kg zinc chloride on gestation days 12-15 and sacrificed on gestation day 21. Cadmium treatment caused embryonic death, lung hypoplasia and diminished quantity of the major pulmonary surfactant phospholipid, phosphatidylcholine. Zinc treatment alone did not alter normal fetal development. Coadministration of zinc with cadmium prevented all of the previously observed cadmium-induced fetotoxicity. The placenta appeared to act as a barrier to cadmium movement, as cadmium was found in the placenta but not in fetal tissues. However, cadmium treatment decreased fetal zinc content. Simultaneous injection of zinc with cadmium maintained the fetal zinc concentration at the control level. Thus cadmium appears to exert its fetotoxic effects indirectly, through a fetal zinc deficiency.

King and colleagues investigated the mechanisms of zinc absorption and elimination and found that maintaining a constant state of cellular zinc nutrition, or homeostasis, is essential for normal function (King et al., 2000). In animals and humans, adjustments in zinc absorption and endogenous intestinal excretion are the primary means of maintaining zinc homeostasis. The adjustments in gastrointestinal zinc absorption and endogenous excretion are synergistic. Shifts in endogenous excretion appear to occur quickly with changes in intake just above or below optimal intake. The absorption of zinc responds more slowly, but it has the capacity to cope with large fluctuations in intake. With extremely low zinc intakes or with prolonged marginal intakes, secondary homeostatic adjustments may augment the gastrointestinal changes. These secondary adjustments include changes in urinary zinc excretion, a shift in plasma zinc turnover rates and, possibly, an avid retention of zinc released from selected tissues, such as bone, in other tissues to maintain function.

Hepatic concentrations of zinc (Zn) were studied in 38 foetuses and infants, who died of various causes, from 26 weeks of gestation up to 16 weeks postnatally (Dorea, 1987). There was a comparable range of Zn values for both pre-term (6 foetuses of 28-32 weeks gestation) and the 21 term babies (10 to 300 µg/g fresh tissue). The value of 10 µg/g was found only in one 4-month-old infant. The socioeconomic status did not influence significantly the concentration of liver Zn in babies born at term. However, size of babies as measured by liver weight showed that larger babies had higher mean Zn concentration (104 ± 78 µg/g) than smaller babies (74 ± 59 µg/g), which was, however, non-significant..

Perveen and colleagues investigated the transport of the essential trace element zinc from mother to foetus (Perveen, 2002). The transport of zinc already varies throughout gestation and the role of the transport proteins in the neonate and the mother may also change during pregnancy. The authors determined cord blood plasma zinc concentrations in premature and full-term new-borns, and correlated these values with those of maternal blood plasma at birth. Also, they examined whether cord blood plasma concentration of these elements varied with gestational age. The 35 mother-infant pairs included in this study were 11 in the 38–42-week gestational age (GA), 9 in the 34–37-week GA, 11 in the 29–33-week GA group and 4 in the 24–28-week GA. They found via trend analysis that cord plasma zinc decreased with GA at birth. There were no differences with GA in maternal plasma zinc. Thereby, the vigorous mother-to-foetus uphill zinc transfer is clear throughout the last trimester.

Background information on the detection of male reproductive effects and derivation of interspecies extrapolation factors

Mangeldorf and Buschmann analysed the suitability of different study designs and endpoints to detect effects on male reproduction in animal species (Mangeldorf and Buschmann 2002). Moreover, LOAELs in animals and in humans have been compared in order to find general principles for the extrapolation from animals to humans. It was found, that histopathology of the testes was the most sensitive endpoint. If appropriate fixation and embedding techniques are used, effects can be detected already after 4 weeks of treatment with high sensitivity. Other sensitive parameters were weights of reproductive organs including accessory glands i.e. testis, epididymis, prostate, seminal vesicle weight and sperm parameters such as sperm count, sperm morphology and sperm motility, the latter being especially important as it is more sensitive than histopathology in some cases. Due to the high variation of several of these parameters, only pronounced effects can be detected. Laboratory animals are still fertile even if the sperm counts drop by 90 to 99%. Consequently, in fertility studies, fertility parameters showed lower sensitivity than the other parameters. In most cases not a single endpoint but rather several endpoints were affected. Only a few studies were available which characterize the human situation. There is considerable interindividual variability but also in one individual from measurement to measurement. Sperm count, motility, morphology and volume are associated with fertility in humans, but other not yet known factors may contribute as well.

Interspecies extrapolation factors (IEF) have been derived for the most sensitive endpoint in laboratory animals. The small database available and limitations of the studies prevent any final conclusion. As a tendency, if calculated on the basis of caloric demand, many IEF were near 1, indicating that humans are generally not more susceptible to reproductive toxicants than laboratory animals as was originally assumed. Therefore, the same standard assessment factors for species differences as for other endpoints may be applied. According to results of this evaluation, for the purpose of hazard identification a subacute study with concentrations which produce significant general toxicity may be sufficient. If effects have been found, for the purpose of risk assessment the NOAEL has to be identified by testing sensitive endpoints, such as refined histopathology, sperm motility and weight of testes, epididymides, prostate and seminal vesicles. Although a subchronic study is preferable, a subacute study may be sufficient. For extrapolation from subacute to subchronic studies, an assessment factor of > 2 was derived. If only one- or multi-generation studies without detailed histopathology and sperm parameters are available, an assessment factor of > 3 should be applied for adjusting to the low sensitivity of laboratory animals due to their high sperm reserve. A recommendation for future research is the development of a rabbit model which allows sequential sperm analysis and better observation of behaviour than the rodent models.