Prenatal exposure to barium and the occurrence of neural tube defects in offspring.

Neural tube defects (NTDs) have a complex etiology. Few studies have assessed alkaline earth metals exposures and occurrence of NTDs. We examined the association between prenatal exposure to magnesium (Mg), calcium (Ca), strontium (Sr) and barium (Ba) and risk for NTDs in a case-control study, and assessed the teratogenic effects of Ba on mice. Placentas were collected from 408 women with NTD-affected pregnancies and 593 women who delivered healthy infants, and concentrations of these metals were determined as prenatal exposure markers. The single effect of individual exposure and joint effect of coexposure to these metals were evaluated with logistic regression and Bayesian kernel machine regression (BKMR), respectively. Barium chloride (BaCl) was intragastrically administered to pregnant ICR mice and fetal mice were examined for NTDs. Median concentrations of Mg and Ba were higher in NTD cases than in controls (P < 0.001). In logistic regression, higher levels of Ba were associated with 1.6-fold increased risk for NTDs (95% confidence interval: 1.06-2.43). In BKMR, the joint effect of the four-metal mixture on NTD risk increased steadily with the levels of the mixture. A change in Ba concentration from the 25 to 75 percentile displayed a risk effect when the other three metals were fixed at the 25, 50 or 75 percentile, while such a change in Ca concentration showed a protective effect when the other metals were held at the 25 or 50 percentile. No interactions among metals were found. In the mouse experiment, dams treated with 200 mg/kg BaCl showed 16.8% of NTDs in fetal mice, compared to 2.6% in the untreated control group (P < 0.01). Taken together, higher mixture levels of the four alkaline earth metals were associated with increased risk for NTDs, with Ba being the major contributor for the joint effect. Intragastric administration of Ba can induce NTDs in mice.