Maternal cadmium exposure alters regional placental solute carrier gene expression differentially by sex
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The placenta is a critical organ during pregnancy that is not only important for regulating fetal nutritional availability but is also essential in providing a barrier from harmful substances to ensure fetal health and survival. Nutrient transport proteins, such as solute carrier proteins (Slc), are key players in the exchange of nutrients within the placenta. However, Slc can be used by harmful substances such as cadmium (Cd) to get into cells via “ionic and molecular mimicry”. Cadmium is a toxic heavy metal found ubiquitously in the environment due to human industrial activities. Cadmium exposure is known to cause systemic toxicity and exposure during pregnancy can lead to lasting postnatal effects. However, the role of the placenta in driving these responses are largely unknown. In this study, CD-1 mice were exposed to cadmium chloride (CdCl2) (0.0 ppm or 5.0 ppm) in drinking water two weeks prior to gestation and through gestation day 18 (n=7 per group). Placental tissues were collected, and RNA was isolated from decidual-enriched and labyrinth-enriched regions from male and female fetuses for transcriptomics. Slc genes were selected from the dataset and considered statistically significant for P ≤ 0.01 and fold change ≤-1.5 or ≥1.5. In this study, CdCl2 exposure increased fetal weight in both males and females with no change in placental weight or efficiency. Transcriptomic analysis revealed that placental regions significantly impact Slc gene expression in control mice. Male placentas had 41 Slc genes enriched in the decidual region and 81 Slc genes enriched in the labyrinth region. Similarly, female placentas had 53 Slc genes enriched in the decidual region and 75 Slc genes enriched in the labyrinth region. With maternal cadmium exposure, the greatest dysregulation of Slc genes was found in the males in both placental regions. In the decidual-enriched region, 6 Slc genes were downregulated (Slc7a11, Slc10a6, Slc25a31, Slc26a4, Slc16a2, and Slc35g1). In the labyrinth-enriched region, 5 genes were downregulated (Slc35a3, Slc16a3, Slc25a31, Slc16a4, and Slc35a3) and 5 genes were upregulated (Slc3a2, Slc39a14, Slc25a22, Slc11a2, and Slc9a3). Slc gene expression in females was less impacted by maternal cadmium exposure, with only 1 gene (Slc26a11) downregulated in the decidual-enriched region and 3 genes (Slc25a12, Slc12a2, and Slc24a2) upregulated in the labyrinth-enriched region. Interestingly, higher expression of Slc9a3, which is a sodium-hydrogen exchanger, in the male labyrinth was positively correlated with male fetal weight. In contrast, none of the Slc genes were associated with fetal weight in females. These data suggest that cadmium-driven effects on nutrient transporters may contribute to increased fetal weights, particularly in the males. However, it is likely that these proteins are not the only placental factors that regulate fetal weight gain, and other pathways are currently under investigation. This abstract does not reflect U.S. EPA policy.