Inflammation at Birth is associated with Subnormal Development in Very Preterm Infants.

Preterm birth carries a risk for impaired developmental outcome. We have previously described an association between increased levels of pro-inflammatory cytokines during the first 72 postnatal hours and cerebral damage as detected by ultrasound in a cohort of 74 very preterm infants. Sixty-seven of 71 surviving children with a mean (SD) GA of 27.1 (2.0) weeks were examined at 2 years corrected age with a standardized neurological examination and with Bayley Scales of Infant Development. We hypothesized that pro-inflammatory cytokine concentrations at or shortly after birth would be associated with an adverse developmental outcome. Increased concentrations of TNF-alpha in cord blood OR (95% CI) 3.3 (1.1-10.2), p=0.013 and at 6 h 7.8 (0.9-71.8), p=0.015 and of IL-6 in cord blood 1.7 (1.0-2.9), p=0.048 were associated with psychomotor developmental index <85. Increased concentrations of TNF-alpha in cord blood OR (95% CI) 3.6 (1.002-12.8), p=0.044 and of IL-8 in cord blood 3.5 (1.2-10.6), p=0.023 were associated with cerebral palsy. Associations of TNF-alpha and IL-8 in cord blood with the respective outcome measures remained significant after adjustment for other clinical variables. Pro-inflammation at birth is associated with impaired functional outcome at 2 years of corrected age in children with very preterm birth

The Water Channel Aquaporin 1 Is a Novel Molecular Target of Polychlorinated Biphenyls for in Utero Anomalies*

Despite serious health risks in humans and wild life, the underlying mechanisms that explain the gene-environment effects of chemical toxicants are largely unknown. Polychlorinated biphenyls (PCBs) are one of the most ubiquitous environmental toxicants worldwide, with reported epidemiological evidence for reproductive and neurocognitive anomalies in humans. Here, we show that Aroclor 1254, a mixture of structurally distinct PCBs, causes preterm birth in interleukin (IL)-10-/- mice at a dose that does not show any adverse effects in wild type mice, highlighting the significance of IL-10 as an anti-toxicant cytokine. Aroclor 1254-treated IL-10-/- mice demonstrated increased amniotic fluid, intrauterine growth restriction, and reduced litter size with postnatal neuromotor defects. Further, our results identify aquaporin 1 (AQP1), a potent effector of fluid volume regulation and angiogenic activity, as a novel placental target of PCBs. In vivo or in vitro exposure to Aroclor 1254 coupled with IL-10 deficiency significantly reduced the protein content of AQP1. Reduced uterine AQP1 levels were associated with defective spiral artery transformation. Importantly, recombinant IL-10 reversed PCB-induced in vivo and in vitro effects. These data demonstrate for the first time that the IL-10-AQP1 axis is a novel regulator of PCB-induced in utero effects