Cadmium associated with inhaled cadmium oxide nanoparticles impacts fetal and neonatal development and growth

Abstract

One industrially important metal oxide nanoparticle (NP) is cadmium oxide (CdO). A study was performed using timed-pregnant CD-1 mice to determine if Cd associated with inhaled CdO NP could reach the placenta and adversely affect the developing fetus and/or neonate. Pregnant mice were exposed by inhalation either every other day to 100 μg of freshly generated CdO/m(3) (exposure 1) or daily to 230 μg CdO/m(3) (exposure 2). In each exposure, mice were exposed to CdO NP or carrier gas (control) for 2.5 h from 4.5 days post coitus (dpc) through 16.5 dpc. At 17.5 dpc, fetuses and placentas from both exposures 1 and 2 were collected, measured, and weighed. A subgroup from the second exposure was allowed to give birth, and neonates were weighed daily until weaning. Cadmium in the uterus and placenta, as well as in other maternal organs, was elevated in NP-treated mice, but was undetectable in fetuses at 17.5 dpc. Daily inhalation of 230 μg CdO NP/m(3) decreased the incidence of pregnancy (i.e., no evidence of implantation) by 23%, delayed maternal weight gain, altered placental weight, and decreased fetal length, as well as delayed neonatal growth. This study demonstrates that inhalation of CdO NP during pregnancy adversely affects reproductive fecundity and alters fetal and postnatal growth of the developing offspring.

FIG. 1.

Experimental design and exposure schematic. (A) Exposure to CdO NP or to filtered air began at 4.5 dpc and ended at either 16.5 dpc for mice being euthanized or 17.5 dpc for those giving birth. (B) CdO NP generation and nose-only exposure system.

FIG. 2.

Translocation of NP-associated Cd and tissue burdens. (A) Data represent mean (n = 5–21 mice per tissue per NP concentration) tissue Cd levels normalized to total amount of tissue (mg, solid tissue or μl, whole blood) ± SE. As control values between exposures 1 and 2 were not significantly different, values were pooled for statistical analyses. Comparisons between groups were analyzed using Duncan's multiple range test, and bars with different letters are significantly different at p < 0.05. (B) Organ-to-BW ratios of pregnant mice euthanized at 17.5 dpc. Data are the means (n = 5–21 mice per treatment group) ± SE. Bars with different letters are significantly different (p < 0.05) from each other by Fisher's least significant difference.

FIG. 3.

Inhalation of 230 μg CdO NP/m³ decreased maternal BW and delayed weight gain during pregnancy. As control values from exposures 1 and 2 were not different, data were pooled for statistical analyses. Daily comparisons were made between the two particle concentrations and control using Duncan's multiple range test. Data represent the means (n = 8–19 mice per time point) ± SE. *p < 0.05.

FIG. 4.

Maternal inhalation of 230 μg CdO NP/m³ alters (A) placental weight and (B) fetal crown to rump length. Embryos at 10.5 dpc could not be reliably removed from their chorions and thus were not measured. Data represent means (n = 4–8 litters) ± SE. * p ≤ 0.05.

FIG. 5.

Effects of maternal inhalation of 230 μg CdO NP/m³ on (A) percent change in BW compared with birth weight and (B) percent change in daily BW. Data represent the means ± SE. (C) Neonatal whole-body Cd burden at PNDs 1, 5, and 10. Data represent the means (n = 1 pup from 6 to 8 litters per mean) ± SE. *Significant difference (p < 0.05) between control pups and offspring from mothers exposed to CdO NP. Bars with different letters represent differences in tissue Cd concentration across neonatal ages.