LPS Exposure Increases Maternal Corticosterone Levels, Causes Placental Injury and Increases IL-1Β Levels in Adult Rat Offspring: Relevance to Autism

Abstract

Maternal immune activation can induce neuropsychiatric disorders, such as autism and schizophrenia. Previous investigations by our group have shown that prenatal treatment of rats on gestation day 9.5 with lipopolysaccharide (LPS; 100 μg/kg, intraperitoneally), which mimics infections by gram-negative bacteria, induced autism-like behavior in male rats, including impaired communication and socialization and induced repetitive/restricted behavior. However, the behavior of female rats was unchanged. Little is known about how LPS-induced changes in the pregnant dam subsequently affect the developing fetus and the fetal immune system. The present study evaluated the hypothalamic-pituitary-adrenal (HPA) axis activity, the placental tissue and the reproductive performance of pregnant Wistar rats exposed to LPS. In the adult offspring, we evaluated the HPA axis and pro-inflammatory cytokine levels with or without a LPS challenge. LPS exposure increased maternal serum corticosterone levels, injured placental tissue and led to higher post-implantation loss, resulting in fewer live fetuses. The HPA axis was not affected in adult offspring. However, prenatal LPS exposure increased IL-1β serum levels, revealing that prenatal LPS exposure modified the immune response to a LPS challenge in adulthood. Increased IL-1β levels have been reported in several autistic patients. Together with our previous studies, our model induced autistic-like behavioral and immune disturbances in childhood and adulthood, indicating that it is a robust rat model of autism.

Maternal Immune Activation Produces Cerebellar Hyperplasia and Alterations in Motor and Social Behaviors in Male and Female Mice

“…In addition to causing elevations in pro-inflammatory cytokines, poly(I:C) activates the maternal hypothalamic pituitary axis and elevates corticosterone levels in rodents [97]. Inflammatory stimuli also elevate corticosterone during pregnancy [98], but it is unlikely that maternal corticosterone enters the fetal brain [99]. The placenta also expresses toll-like receptors (TLRs), including TLR3 [100], and there is evidence that inflammatory stimuli cause alterations in placental morphology [98] and function [96] that could have an impact upon the fetal environment, for example to cause hypoxia or other alterations.…”

Toll-like receptor 4-mediated immune stress in pregnant rats activates STAT3 in the fetal brain: role of interleukin-6

“…In normal conditions, the feto-placental enzyme 11β-hydroxysteroid dehydrogenase 2 shields fetuses from maternal GCs by inactivating maternal corticosterone (28). However, TLR-4-stimulated proinflammatory cytokines have the ability to alter the integrity of the placental barrier which could result in enhanced placental permeability to corticosterone (29). Thus, there is a possibility that maternally born corticosterone crosses the placenta and directly alters fetal brain development when the maternal immune system is activated (28,30).…”

Factors in Early-Life Programming of Reproductive Fitness

“…Prenatally, LPS does not cross the placenta, and its effects on the foetus are mediated by the maternal immune response, including an increase in pro-inflammatory cytokines, fever and the glucocorticoid feedback on the immune system [103,104]. Maternal cytokines and glucocorticoids can then cross the placental barrier to some extent, with placental permeability to these factors changing across the course of pregnancy [105].…”