Zika virus infection leads to hormone deficiencies of the hypothalamic-pituitary-gonadal axis and diminished fertility in mice

Abstract

ABSTRACT Zika virus (ZIKV) infection in pregnant women during the first trimester can cause congenital malformations including microcephaly, which has focused global attention on this emerging pathogen. By contrast, ZIKV infection in pregnant women during the third trimester can cause neurodevelopmental delays and cryptorchidism in newborns without microcephaly. Here, we evaluated the long-term fertility consequences of ZIKV infection in male suckling mice, which is equivalent to congenital ZIKV infection in children, from multiple perspectives including the hypothalamic-pituitary-gonadal axis, testis, sperm, and social behaviors. We observed the persistence of ZIKV in the hypothalamus of mice, which caused long-term hormone deficiencies of the hypothalamic-pituitary-gonadal axis. Hormone deficiencies led to limited delays in testicular development, a decrease in sperm quality and quantity, and abnormal social abilities. These damages could progress to diminished fertility in male mice, as judged by lower pregnancy rate, prolonged time to delivery, and decreased offspring quality. Currently, the extent to which these observations in mice translate to humans remains unclear, but longitudinal studies of hormone levels and reproductive health in ZIKV-exposed children seem warranted. IMPORTANCE Zika virus (ZIKV) infection in pregnant women during the third trimester can cause neurodevelopmental delays and cryptorchidism in children without microcephaly. However, the consequences of congenital ZIKV infection on fertility in these children remain unclear. Here, using an immunocompetent mouse model, we reveal that congenital ZIKV infection can cause hormonal disorders of the hypothalamic-pituitary-gonadal axis, leading to reduced fertility and decreased sexual preference. Our study has for the first time linked the hypothalamus to the reproductive system and social behaviors after ZIKV infection. Although the extent to which these observations in mice translate to humans remains unclear, these findings did suggest that the reproductive health and hormone levels of ZIKV-exposed children should receive more attention to improve their living quality.