Prenatal dexamethasone exposure in rats results in long‐term epigenetic histone modifications and tumour necrosis factor‐α production decrease

Abstract

SummaryGlucocorticoid (GC) is often given when preterm delivery is expected. This treatment is successful in stimulating the development of the fetal lung. However, reports and related research regarding the prolonged effects of prenatal GC on the development of immunity are very limited. Some data, derived from infants whose mothers were given immunosuppressants during pregnancy for the treatment of autoimmune disorders, suggest that prenatal exposure to GC may have only a limited effect on the development of the immune system. What is unknown is whether the immune modulation effects of prenatal GC might appear at a later childhood stage and beyond. Here we evaluated the immune programming influenced by prenatal GC. Pregnant Sprague-Dawley rats received dexamethasone (DEX; 0Á1 mg/kg/day) or saline at gestational days 14-20. Male offspring were killed at day 7 or day 120 after birth. Spleens were collected for immune study. Of the inflammation mediators, matrix metalloproteinase-9, tumour necrosis factor-a (TNF-a) and granulocytemacrophage colony-stimulating factor mRNAs decreased in the prenatal DEX group at an early stage after birth. Upon concanavalin A stimulation, prenatal DEX treatment reduced TNF-a production, but not interferon-c production, by splenocytes at day 120 after birth compared with the vehicle group. Decreased levels of active chromatin signs (acetylation of histone H3 lysines, H3K4me1/3, and H3K36me3) in TNF-a promoter were compatible with the expressions of TNF-a. Our results suggest that prenatal DEX has a profound and lasting impact on the developing immune system even to the adult stage. Epigenetic histone modifications regulate TNF-a expression following prenatal DEX in rats.

Age-Dependent Effects of Prenatal Dexamethasone Exposure on Immune Responses in Male Rats

“…However, animal studies have reported several adverse effects of prenatal steroid treatment on the development of central nervous system, endocrinal system, and immune system (Coe and Lubach 2005;Antonow-Schlorke et al 2009). Our results agree with these observations Yu et al 2014a;Lui et al 2015;Sheen et al 2015).…”

“…Virgin Sprague-Dawley (SD) rats (12-16 weeks old; BioLASCO Taiwan Co., Ltd., Taipei, Taiwan) were housed and maintained in a facility accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International. The study protocol was described in a previous study (Yu et al 2014a). In brief, virgin SD female rats were allowed to mate with male rats for 24 hours and then were separated from the male rats and housed individually in a standard plastic home cage.…”

“…Splenocytes were isolated from the whole spleen as previously described (Yu et al 2014a). In brief, the spleen was washed with phosphate-buffered saline (PBS) and pressed with a syringe plunger through a 30-µm nylon mesh.…”

“…qRT-PCR was performed as previously described (Yu et al 2014a). In brief, 5 µg of extracted RNA sample was reversed transcribed with Moloney murine leukemia virus reverse transcriptase.…”

“…In our previous study with pregnant rats, prenatal dexamethasone (DEX) exposure through intraperitoneal injection induced splenomegaly in the offspring. Data revealed that prenatal glucocorticoid reduced the capacity of tumor necrosis factor (TNF)-α to produce splenocytes in adolescent rats, making the offspring more vulnerable to pathogenic invasion even during adult life (Yu et al 2014a). In this study, we investigated the effect of prenatal steroid on innate and adaptive immune function with rat spleen from infancy to adolescence and into adulthood [postnatal day 7 (D7), day 120 (D120), and day 180 (D180)].…”