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Post‐exposure treatment with esomeprazole protects pregnant mice from mortality and from compromised fetal growth after exposure to chlorine gas.
Author(s) -
Molyvdas Adam,
Ren Changchun,
Dunigan Katelyn,
Tipple Trent,
Matalon Sadis,
Jilling Tamas
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.02312
Subject(s) - fetus , medicine , preeclampsia , esomeprazole , andrology , pregnancy , endocrinology , biology , genetics
Exposure to Chlorine (Cl 2 ) and Bromine (Br 2 ) causes significant cardiopulmonary injury to mice, rats, rabbits and humans triggering extensive systemic injury. After exposure to Br 2 pregnant mice develop preeclampsia‐like symptoms and increased mortality as compared to identically exposed male or non‐pregnant female mice (Lambert et al Hypertension 2018). Heme oxygenase (HO‐1), which has been shown recently to be induced by proton pump inhibitors such as esomeprazole (ESO), has been implicated as a protective molecule against halogen inhalation induced injury in non‐pregnant animals and, additionally, against the development of symptoms in models of preeclampsia in pregnant mice. Timed pregnant C57BL/6 mice were exposed to 400ppm Cl 2 for 10min at E14.5, then treated with vehicle or with 30mg/kg ESO by gavage 6h post exposure, then at every 24h thereafter. Survival and body weights were monitored until E18.5. Fetal weights were recorded at E18.5 after euthanasia. Finally, using nuclear factor (erythroid‐derived 2)–like 2 (Nrf2)‐knock out and Nrf2 competent murine transformed club cells (mtCC) we tested whether HO‐1 production was induced via Nrf2. Survival was significantly higher (P=0.0056) in Cl 2 exposed pregnant mice that received ESO (88.9% survival, n=9) compared to the vehicle treated animals (29.4% survival, n=17). Maternal exposure to Cl 2 severely compromises fetal growth (0.6366g±0.0666 (S.E.M.), n=5) when compared to normal fetuses (1.167g±0.0399 (S.E.M.), n=5) (P<0.0001). However, the weight of fetuses collected from Cl 2 exposed pregnant mice that received ESO (0.9264g±0.0542 (S.E.M.), n=8) compared to weights of fetuses from vehicle treated animals (0.6366g±0.0666 (S.E.M.), n=5) was significantly higher (P=0.0058). Finally, maternal weight, as normalized to weight recorded preexposure, in Cl 2 exposed ESO treated pregnant mice (93.64%±4.038% (S.E.M.), n=8) compared with the vehicle treated animals (81.31%±5.717% (S.E.M.), n=5) was not significantly different (P=0.1772). Additionally, we found that HO‐1 gene expression is induced in a dose dependent manner by ESO only in Nrf2‐competent cells (p<0.001). Our results suggest that ESO may be an effective countermeasure to increase maternal survival and improve fetal growth post halogen inhalation in pregnancy. Further mechanistic studies will have to explore organ/tissue specific role of HO‐1 induction in the protective effect. Support or Funding Information This work was supported by: 5U01ES027697 (to Tamas Jilling) and 5U01ES026458 (to Sadis Matalon)