Prenatal Lipopolysaccharides Exposure Induces Transgenerational Inheritance of Hypertension

Abstract

BACKGROUND: Adverse environmental exposure during the prenatal period can lead to diseases in the offspring, including hypertension. Whether or not the hypertensive phenotype can be transgenerationally transmitted is not known. METHODS: Pregnant Sprague Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) on gestation days 6, 8, 10, and 12 to generate the prenatal LPS exposure model. Blood pressure was monitored by both telemetry and tail-cuff method. RNA sequencing was performed to analyze transcriptome alteration in the kidney of the third generation. Tempol and spironolactone were used to test the potential prevention and therapeutic effect of targeting reactive oxygen species and mineralocorticoid receptor signaling, respectively. Molecular biological experiments were performed to illustrate the mechanism of epigenetic and transcription regulation. RESULTS: Prenatal LPS exposure can impair the ability to excrete a salt load and induce hypertension from the first to the third generations, with the fourth and fifth generations, inducing salt-sensitive hypertension. Compared with control pups, the transcriptome in the kidney of the hypertensive third-generation prenatal LPS–exposed offspring have upregulation of the Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) gene and activation of mineralocorticoid receptor signaling. Furthermore, we found that LPS exposure during pregnancy triggered oxidative stress that upregulated KDM3B (histone lysine demethylase 3B) in the oocytes of first-generation female rats, leading to an inheritable low level of H3K9me2 (histone H3 lysine 9 dimethylation), resulting in the transgenerational upregulation of Rac1 . Based on these findings, we treated the LPS-exposed pregnant rats with the reactive oxygen species scavenger, tempol, which successfully prevented hypertension in the first-generation offspring and the transgenerational inheritance of hypertension. CONCLUSIONS: These findings show that adverse prenatal exposure induces transgenerational hypertension through an epigenetic-regulated mechanism and identify potentially preventive and therapeutic strategies for hypertension.

Prenatal Lipopolysaccharide Exposure Alters Hepatic Drug-Metabolizing Enzyme Expression in Mouse Offspring via Histone Modifications

“…Abundant evidence has highlighted that pregnancy is a critical window of developmental plasticity [ 32 , 33 ]. For prenatal inflammation exposure-programmed diseases, such as hypertension, diabetes, and heart disease, the second trimester of gestation is the most sensitive time window [ 19 , 34 , 35 ]. In the current study, the exposure time of LPS was also selected in the second trimester of gestation.…”

“…Recent studies have confirmed that aberrant environmental factors during early life (including the fetus, infant, and child) can cause long-term changes in gene expression and influence adult-onset disease outcomes [ 16 , 17 , 18 , 19 ]. Notably, evidence has shown that early-life environmental factors can also have long-term impacts on DMEs expression, thus affecting drug efficacy in adulthood [ 5 , 20 , 21 ].…”

“…Maternal infection and inflammation are common complications during pregnancy. It is well demonstrated that maternal inflammation is likely associated with chronic diseases, including cardiovascular and metabolic diseases [ 19 , 22 , 23 ]. Thus, it is reasonable to assume that this population is more likely to be treated with medication.…”

Epigenetic “Transgenerational” Inheritance

“…The prenatal lipopolysaccharide evidently triggered reactive oxygen species, and the reactive oxygen species upregulated histone demethylase lysine-specific demethylase 3B. In their report, 6 the authors provide an interesting schematic model of how they believe their findings work. The model is not reiterated here; rather, I focus on the downstream molecular mechanism known from the cancer field (Figure ).…”

“…Cao and colleagues 6 report in this issue of Circulation that when prenatal lipopolysaccharide (endotoxin) was administered to pregnant dams (shock stress), dams even of the fifth generation of offspring developed salt-sensitive hypertension. The investigators found that the Ras-related C3 botulinum-toxin substrate-1 ( Rac1 ) gene is upregulated and that this product activates mineralocorticoid receptor signaling.…”