Developmental 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin exposure of either parent enhances the risk of necrotizing enterocolitis in neonatal mice

Abstract

Background: Necrotizing enterocolitis (NEC) is a rare, but potentially fatal intestinal inflammatory condition most often arising in premature infants. Infants provided formula are also at greater risk of developing this disease. Although the majority of formula-fed, preterm infants do not develop NEC, up to 30% of infants with the disease do not survive. Thus, identifying additional, currently unrecognized factors, which may predispose a specific infant to NEC development would be a significant clinical advancement. In this regard, we have previously reported that offspring of female or male mice with a history of developmental exposure to the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exhibit altered sensitivity to inflammatory challenges and are frequently born premature. Herein, we examined the possibility that, compared to unexposed mice (F1 NONE), developmental TCDD exposure of either parent (maternal, F1M TCDD , or paternal, F1P TCDD) would enhance the risk of NEC in offspring (F2 TCDD mice) in association with supplemental formula feeding. Methods: Beginning on postnatal day 7, all neonates were randomized to maternal milk only or maternal milk with up to 20 supplemental formula feedings. All pups remained with the Dams and were additionally allowed to nurse ad libitum. Results: Formula-fed F2 NONE pups rarely developed NEC while this disease was common in formula-fed F2M TCDD and F2P TCDD mice. Unexpectedly, 50% of F2M TCDD pups that were not provided supplemental formula also developed NEC. Conclusions: Our studies provide evidence that a history of parental TCDD exposure enhances the risk of NEC in offspring and suggest exposure to environmental immunotoxicants such as TCDD may also contribute to this inflammatory disease in humans.

A Preconception Paternal Fish Oil Diet Prevents Toxicant-Driven New Bronchopulmonary Dysplasia in Neonatal Mice

“…Several studies have suggested that placental dysfunction precedes (and contributes to) the development of new BPD [21][22][23][24]. The onset and severity of developmental lung diseases, such as new BPD, have also been linked to exposure to pollution in humans and experimental animal models [25][26][27][28][29]. Our laboratory found that the offspring of male mice that were exposed to TCDD in utero were also susceptible to new BPD [29].…”

“…To assess the development of new BPD, we performed necropsies on PND 11 as our previous studies revealed that the disease was prevalent by this time in F2TCDD pups [29]. On PND 11 at 1100 h local time, CT and F2TCDD pups were weighed and observed for external signs of new BPD (labored breathing and/or delayed growth), then euthanized by decapitation performed under deep anesthesia as per the AAALAC guidelines.…”

“…The onset and severity of developmental lung diseases, such as new BPD, have also been linked to exposure to pollution in humans and experimental animal models [25][26][27][28][29]. Our laboratory found that the offspring of male mice that were exposed to TCDD in utero were also susceptible to new BPD [29]. Herein, we examined the efficacy of a paternal fish oil diet to prevent this potentially fatal neonatal disease.…”

Indole-3-Carbinol–Dependent Aryl Hydrocarbon Receptor Signaling Attenuates the Inflammatory Response in Experimental Necrotizing Enterocolitis

“…In addition, exogenous AhR agonists can affect intestinal homeostasis and impact gastrointestinal diseases. Mokshagundam et al ( 50 ) demonstrated that in utero exposure to the environmental toxin 2,3,7,8-tetrachlorodibenzo- p -dioxin, a potent AhR agonist, promoted the development of NEC. In contrast, exogenous dietary AhR proligands, such as I3C, influence the postnatal expansion of intestinal innate lymphoid cells to protect against intestinal infections ( 11 , 39 , 51 ).…”

Low-dose cyclooxygenase-2 (COX-2) inhibitor celecoxib plays a protective role in the rat model of neonatal necrotizing enterocolitis

“…The estimated NEC incidence ranges from 0.3 to 2.4 infants per 1000 live births, accounting for approximately 7%-11% of neonates weighing < 1,500 g [ 1 ]. Unfortunately, the survival rate of NEC infants with birth weights less than 1,500 g is only approximately 70% [ 4 ]. Moreover, 25% of NEC infants develop short bowel syndrome (SBS) and neurodevelopmental disorders (NDs) [ 5 ].…”