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Maternal cadmium, placental PCDHAC1, and fetal development.

ABSTRACT: Cadmium (Cd) is a ubiquitous environmental contaminant implicated as a developmental toxicant, yet the underlying mechanisms that confer this toxicity are unknown. Mother-infant pairs from a Rhode Island birth cohort were investigated for the potential effects of maternal Cd exposure on fetal growth, and the possible role of the PCDHAC1 gene on this association. Mothers with higher toenail Cd concentrations were at increased odds of giving birth to an infant that was small for gestational age or with a decreased head circumference. These associations were strongest amongst those with low levels of DNA methylation in the promoter region of placental PCDHAC1. Further, we found placental PCDHAC1 expression to be inversely associated with maternal Cd, and PCDHAC1 expression positively associated with fetal growth. Our findings suggest that maternal Cd affects fetal growth even at very low concentrations, and some of these effects may be due to the differential expression of PCDHAC1.

SUBMITTER: Everson TM

PROVIDER: S-EPMC5226342 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Maternal cadmium, placental PCDHAC1, and fetal development.

Everson Todd M TM Armstrong David A DA Jackson Brian P BP Green Benjamin B BB Karagas Margaret R MR Marsit Carmen J CJ

Reproductive toxicology (Elmsford, N.Y.) 20160817

Cadmium (Cd) is a ubiquitous environmental contaminant implicated as a developmental toxicant, yet the underlying mechanisms that confer this toxicity are unknown. Mother-infant pairs from a Rhode Island birth cohort were investigated for the potential effects of maternal Cd exposure on fetal growth, and the possible role of the PCDHAC1 gene on this association. Mothers with higher toenail Cd concentrations were at increased odds of giving birth to an infant that was small for gestational age or ...[more]

PMID: 27544570

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Project description:Prenatal alcohol exposure (PAE) causes developmental abnormalities known as fetal alcohol spectrum disorder (FASD). Maternal iron status modulates the severity of these defects in the offspring. Because the placenta is central in supporting fetal development, we investigated whether maternal iron status similarly modulates alcohol's effects in the placenta. We hypothesized that PAE causes placental insufficiency by decreasing placental weight and efficiency, and we hypothesized that these are worsened by maternal iron deficiency (ID) and alleviated by dietary iron fortification (IF). We also determined whether altered placental iron flux and inflammatory balance contribute to placental insufficiency. Pregnant Long-Evans rats consumed an iron-deficient (ID; 2-6 ppm), iron-sufficient (IS; 100 ppm), or iron-fortified (IF; 500 ppm) diet. Alcohol (5 g/kg body weight) or isocaloric maltodextrin (MD) was gavaged daily from gestational day (GD) 13.5-19.5. Placental outcomes were evaluated on GD20.5. PAE reduced fetal weight (p < 0.0001), placental weight (p = 0.0324), and placental efficiency (p = 0.0043). PAE downregulated placental transferrin receptor (p = 0.0032); it also altered placental Il1b and Tnf expression and the Il6:Il10 ratio (p = 0.0337, 0.0300, and 0.0034, respectively) to generate a response favoring inflammation. ID-PAE further reduced fetal growth and placental efficiency and induced a heightened pro-inflammatory placental profile. IF did not rescue the alcohol-reduced fetal weight, but it normalized placental efficiency and decreased placental inflammation. These placental cytokines correlated with fetal and placental growth, and explained 45% of the variability in fetal weight and 20% of the variability in placental efficiency. In summary, alcohol induces placental insufficiency and is associated with a pro-inflammatory cytokine profile exacerbated by maternal ID and mitigated by maternal IF. Because the placenta is closely linked to intrauterine growth, the placental insufficiency reported here may correlate with the lower birth weights in a subgroup of individuals who experienced PAE.

Project description:Maternal hypothyroidism is associated with fetal growth restriction, placental dysfunction, and reduced kisspeptin/Kiss1R at the maternal-fetal interface. Kisspeptin affects trophoblastic migration and has antioxidant and immunomodulatory activities. This study aimed to evaluate the therapeutic potential of kisspeptin in the fetal-placental dysfunction of hypothyroid Wistar rats. Hypothyroidism was induced by daily administration of propylthiouracil. Kisspeptin-10 (Kp-10) treatment was performed every other day or daily beginning on day 8 of gestation. Feto-placental development, placental histomorphometry, and expression levels of growth factors (VEGF, PLGF, IGF1, IGF2, and GLUT1), hormonal (Dio2) and inflammatory mediators (TNFα, IL10, and IL6), markers of hypoxia (HIF1α) and oxidative damage (8-OHdG), antioxidant enzymes (SOD1, Cat, and GPx1), and endoplasmic reticulum stress mediators (ATF4, GRP78, and CHOP) were evaluated on day 18 of gestation. Daily treatment with Kp-10 increased free T3 and T4 levels and improved fetal weight. Both treatments reestablished the glycogen cell population in the junctional zone. Daily treatment with Kp-10 increased the gene expression levels of Plgf, Igf1, and Glut1 in the placenta of hypothyroid animals, in addition to blocking the increase in 8-OHdG and increasing protein and/or mRNA expression levels of SOD1, Cat, and GPx1. Daily treatment with Kp-10 did not alter the higher protein expression levels of VEGF, HIF1α, IL10, GRP78, and CHOP caused by hypothyroidism in the junctional zone compared to control, nor the lower expression of Dio2 caused by hypothyroidism. However, in the labyrinth zone, this treatment restored the expression of VEGF and IL10 and reduced the GRP78 and CHOP immunostaining. These findings demonstrate that daily treatment with Kp-10 improves fetal development and placental morphology in hypothyroid rats, blocks placental oxidative damage, and increases the expression of growth factors and antioxidant enzymes in the placenta.

Dataset Information

Maternal cadmium, placental PCDHAC1, and fetal development.

Publications

Maternal cadmium, placental PCDHAC1, and fetal development.

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