Prenatal Inflammation Reprograms Hypothalamic-Pituitary-Gonadal Axis Development in Female Rats

Abstract

The hypothalamic-pituitary-gonadal (HPG) axis development during critical periods of ontogenesis can be disrupted by stress factors, including in particular maternal immune activation by infectious agents. Bacterial lipopolysaccharide (LPS, E.coli) exposure induces inflammation accompanied by proinflammatory cytokine release. The resulting elevated cytokine levels may lead to a disruption of epigenetic mechanisms regulating HPG axis development and to a reduced fertility in the offspring. This study focused on the long-term effects of prenatal LPS exposure on HPG axis development in female rats and the modulation of such effects by anti-inflammatory drugs: polyclonal IgG and monoclonal anti-IL6-receptor antibodies. LPS exposure on embryonic day 12 led to a decrease in the number of synaptic inputs on gonadotropin-releasing-hormone-producing neurons in the hypothalamus, high levels of follicular atresia, and suppressed steroidogenesis in the ovaries of adult female offspring. IgG treatment or IL6 receptor blockade by monoclonal antibodies 40 minutes after LPS exposure prevented these long-term negative effects of LPS. The data obtained suggest that IL6 is involved in the regulation of HPG axis development.

Keywords: Hypothalamic-pituitary-gonadal axis; IL6; IgG modulation; Long-term negative effects; Prenatal inflammation.