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Highlights Effects of Cd and Zn on testicular development were assessed. Cd accumulation and Zn depletion in testis during lactation were noted. Cd-induced abnormal seminiferous tubules and a plasmatic testosterone decrease. Zn supply induced a significant protection against Cd toxicity. Cd toxicity observed in pups is mediated by disruption of maternal Zn metabolism. *Research Highlights AbstractTo assess the effects of exposure to Cd and Zn on rat testicular development, offspring, from mothers receiving either tap water, Cd, Zn or Cd+Zn during gestation and lactation periods, were observed on gestational day (GD) 20 and on postnatal days (PND) 12, 21 and 35. During gestation, Cd induced maternal hypozincemia and less transfer of Zn to the fetus. During lactation, progressive Cd accumulation and Zn depletion in testis at PND12 and PND21 werenoted. An increase of abnormal seminiferous tubules and a decrease in testis weight and plasmatic testosterone concentration were also observed at PND21 and PND35 respectively. Interestingly, Zn supply induced a significant protection against Cd toxicity. These results suggest that the toxic effects of Cd observed during development are mediated by the disruption of Zn metabolism, which is established in mothers during pregnancy causing Zn deficiency in fetuses and continues to become more pronounced during lactation.

The present study was conducted to provide potential mechanism that may be responsible for Cd retention and Cd-induced Zn redistribution in tissues of suckling rat. For this purpose, suckling rats from mother receiving either tap water, Cd, or Cd + Zn during lactation period were sacrificed on postnatal day (PND) 14 and PND 21 for performing chemical and molecular analysis. Our results show that Cd exposure, although it does not affect the milk consumption, it clearly alters the lactational transfer, absorption, and distribution of Zn in the suckling rat organism. At the molecular level, Cd caused upregulation of ZIP 3, ZIP 4, and ZIP 8 gene expressions in the mammary gland of mothers rats and in the intestine of their pups but decreased the expression of ZnT 2 and ZnT 4 only in the mammary tissue at PND 14 and PND 21. Zn supply reversed the Cd-induced decrease in the neonatal Zn apparent absorption and restores the gastrointestinal, brain, and plasma levels of this essential element in the suckling rat organism at PND 14 and PND 21. Also, with this treatment, the gene expressions of ZnT 1 in the mammary gland and ZnT 4 in the neonatal intestine were found to be upregulated at PND 21. Furthermore, our results show that Cd or Cd + Zn treatment increase the neonatal hepatic MTs accumulation at PND 14 only. These results imply that the downregulation of ZnT as well as the overexpression of ZIP transporters, in responses to the Zn depletion induced by Cd in the tissues of lactating rat and their offspring, play a major role in Cd accumulation and Zn redistribution in tissues of suckling rat.

The objective of this study was to determine if the brain development impairment induced by early-life exposure to cadmium (Cd) could result from changes in the expression pattern of distinct zinc (Zn)-dependent proteins. For this purpose, adult female rats receiving either tap water, Cd, Zn, or Cd + Zn in their drinking water during gestation and lactation periods were used. After birth, the male offspring were screened for locomotors and sensorial defects. At postnatal day 21 (PND 21), the male pups were sacrificed and their brains, liver, and plasma were taken for chemical, biochemical, and molecular analyses. Our results show that exposure to Cd significantly increased the metal accumulation and decreased Zn concentrations in the brain of male pups from Cd-treated mothers. Besides, Cd exposure reduced significantly the locomotor activity of the offspring in open-field test, the body weight, and the cranio-caudal length at PND21. Insulin-like growth factor-I (IGF-1) levels in the plasma and liver were also decreased in male pups from Cd-treated mothers. Cd-induced brain development disruption was accompanied by a significant increase of the superoxide dismutase (SOD) activity, induction of the metallothionein (MT) synthesis, and, at the molecular level, by an upregulation of Zrt-,Irt-related protein 6 (ZIP6) gene and a significant downregulation of the expression of the Zn transporter 3 (ZnT3) and brain-derived neurotrophic factor (BDNF) genes in the brain. No significant changes on the expression of genes encoding other Zn-dependent proteins and factors such as ZnT1, ZIP12, NF-κB, and Zif268. Interestingly, Zn supplementation provided a total or partial correction of the changes induced by the Cd exposure. These data indicated that changes in expression of ZnT3 and ZIP6 as well as alteration of other transcription factors, such as BDNF, or Zn-dependent proteins, such as SOD and MTs, in response to Cd exposure might be an underlying mechanism of Cd-induced brain development impairment.

This study explored the potential toxicity of Cd on the Zn bone depletion in prenatal bone formation. Female rats received either tap water, Cd, Zn, or Cd + Zn in their drinking water during gestation, and some markers of bone formation were studied in their fetuses removed at the 20th day of pregnancy (GD20). Cd exposure induced maternal hypozincemia and Zn depletion in the femur of the fetuses. A striking inhibition of bone formation in fetuses, expressed by decreases in femur length, width, and area, by the shortening of diaphysis, and by a decrease in length and area of distal and proximal proliferative zones, was observed in fetuses from Cd-exposed mothers. At the molecular level, Cd caused upregulation of MT-1 and ZIP2 genes and significantly depressed the expression of the ZnT5, colα1, osteocalcin, and ALP genes in the femur. Interestingly, Zn treatment ameliorated the Cd-induced maternal hypozincemia and femoral changes and partially restored the normal histomorphometry of the femur. These results suggest that the observed toxic effects of Cd are, at least in part, mediated by the disruption of maternal Zn metabolism during pregnancy leading to Zn depletion and thus to perturbation of prenatal bone formation.