Prenatal Progestin Exposure-Mediated Oxytocin Suppression Contributes to Social Deficits in Mouse Offspring

Abstract

Epidemiological studies have shown that maternal hormone exposure is associated with autism spectrum disorders (ASD). The hormone oxytocin (OXT) is a central nervous neuropeptide that plays an important role in social behaviors as well as ASD etiology, although the detailed mechanism remains largely unknown. In this study, we aim to investigate the potential role and contribution of OXT to prenatal progestin exposure-mediated mouse offspring. Our in vitro study in the hypothalamic neurons that isolated from paraventricular nuclei area of mice showed that transient progestin exposure causes persistent epigenetic changes on the OXT promoter, resulting in dissociation of estrogen receptor β (ERβ) and retinoic acid-related orphan receptor α (RORA) from the OXT promoter with subsequent persistent OXT suppression. Our in vivo study showed that prenatal exposure of medroxyprogesterone acetate (MPA) triggers social deficits in mouse offspring; prenatal OXT deficiency in OXT knockdown mouse partly mimics, while postnatal ERβ expression or postnatal OXT peptide injection partly ameliorates, prenatal MPA exposure-mediated social deficits, which include impaired social interaction and social abilities. On the other hand, OXT had no effect on prenatal MPA exposure-mediated anxiety-like behaviors. We conclude that prenatal MPA exposure-mediated oxytocin suppression contributes to social deficits in mouse offspring.

Prenatal exposure of diabetes and progestin‐mediated autistic biomarker in peripheral blood mononuclear cells

“…We established a schematic model for ASD screening based on combined gene expression in PBMC. Prenatal exposure of risk factors, including progestins (Huang et al, 2022; Zou et al, 2017), androgen (Xiang et al, 2020) and diabetes (Wang et al, 2019; Yu et al, 2022), trigger epigenetic changes and oxidative stress, resulting in gene suppression of ERRα, GPER, RORA and SOD2 in both brain tissues and HSC in offspring. Gene suppression in brain tissues mediates autism or ALBs in offspring, while epigenetic changes in HSC can be inherited by PBMC during the subsequent differentiation, resulting in gene suppression in PBMC, which can be a potential biomarker for ASD screening (see Figure 7).…”

Autism‐like behavior of murine offspring induced by prenatal exposure to progestin is associated with gastrointestinal dysfunction due to claudin‐1 suppression

“…Prenatal exposure of progestin 17-OHPC induces epigenetic changes both in the brain and in tight junction proteins, subsequently triggering ALB and GI dysfunction in mouse offspring [10,11,24,36]. Prenatal treatment with intestine-specific VDR deficiency mimics 17-OHPC exposure-mediated GI dysfunction, indicating that VDR-mediated CLDN1 suppression in IEC plays a critical role in GI dysfunction.…”

“…Sex hormones are associated with ASD development [8], and prenatal exposure to either progestins or androgens triggers autism-like behaviours and social deficits in rodent offspring [9][10][11]37]. 17-OHPC was initially used as an oral contraceptive hormone; in more recent years, it has become more widely used for prevention of preterm birth [7,38].…”

“…17-OHPC was initially used as an oral contraceptive hormone; in more recent years, it has become more widely used for prevention of preterm birth [7,38]. We have previously studied the effects of 20 mgÁkg À1 body weight of medroxyprogesterone acetate (MPA) as a prenatal treatment in rodents to mimic high doses of MPA exposure in humans [11]; in this study, 10 mgÁkg À1 body weight of 17-OHPC were used to mimic medium doses of progestin exposure to evaluate the possible effect on ALB in mouse offspring. Moreover, it has been reported that prenatal 17-OHPC treatment decreased cognition and altered prefrontal cortex anatomy in rat offspring [34], and a national cohort study in France reported that prenatal exposure to synthetic progestins is associated with neurodevelopmental disorders in children [12].…”

“…However, there is no evidence to show that higher levels of endogenous progestin (e.g., progesterone) are associated with increased risk for ASD. In addition, prenatal progestin exposure triggers autism‐like behaviours (ALB) and social deficits in rodent offspring [9–11]. This has been supported by evidence from a variety of epidemiological studies showing that prenatal progestin exposure may be associated with autism development [6,12].…”