Epidemiologic data and animal studies both support the hypothesis that conditions that prevail in the womb during prenatal development may program adult metabolic processes and contribute to adult disease. Long latency periods between the environmental trigger and the onset of subsequent disease is recognized in the pathogenesis of certain cancers, and many lines of evidence indicate that early life events play a powerful role in influencing later susceptibility to certain chronic diseases.

In humans, low birthweight and relative thinness at birth is associated with increased rates of coronary heart disease, stroke, type 2 diabetes mellitus, adiposity, and osteoporosis in adult life. Animal models have confirmed the association of newborn infant growth restriction with the development of adult metabolic syndrome and have begun to determine the underlying mechanisms of developmental programming. Although the effects of fetal growth restriction have been examined extensively, additional gestational stressors may have an impact on the developing fetus. For example, fetal glucocorticoid exposure or in utero hypoxemia may program offspring physiologic condition and disease expression. Maternal inflammation/infection occurs commonly during the 9-month human gestation period, with viral disorders and systemic bacterial infections (eg, pneumonia or pyelonephritis) that manifest prenatally and chorioamniotic infections that manifest before or during labor. Our previous work in rats demonstrated that maternally administered lipopolysaccharides can induce fetal inflammatory responses, which is evident by dramatic increases in fetal blood proinflammatory cytokines and increases in the expression of these cytokines in the fetal brain.

The innate immune response develops during the fetal life and neonatal period, although maturation is not achieved until months after birth. The reduced fetal immune reactivity may reflect the demands of in utero existence, which include the need to avoid potentially harmful inflammatory immune reactions. Despite normal basal expression of Toll-like receptors (TLR) and membrane cluster of differentiation 14, innate immune responses of neonatal mononuclear cells to lipopolysaccharide are characterized by markedly reduced release of the proinflammatory T-helper 1–polarizing cytokines, tumor necrosis factor–alpha (TNF-α), and interferon-γ, with relative preservation of antiinflammatory T-helper 2–polarizing cytokines. Lipopolysaccharides and other inflammatory mediators may cross the placenta and initiate a cascade of events that result in fetal oxidative stress, which is thought to play an important role in the capability of the fetus to cope with the current environment.

In neonates, the innate immune response is the main defense mechanism against infections. Attachment of lipopolysaccharide to the TLR4 on the surface of the monocyte facilitates a cascade of events that initiate and mediate the inflammatory response. We sought to determine whether maternal lipopolysaccharide exposure potentially modulates and programs neonatal offspring immune responses to subsequent lipopolysaccharide stimulation.