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.
Highlights
Autism spectrum disorders (ASD) are a series of neurodevelopmental disorders characterized by symptoms including social deficits and restricted or repetitive behaviors [1, 2]
We conduct immunostaining of OXT for the hypothalamic neurons that isolated from paraventricular nucleus (PVN) area of mice, and the results showed that almost all the neurons had OXT expression, indicating a successful OXT neuron preparation
We evaluated the potential effect of medroxyprogesterone acetate (MPA) on oxytocin receptor (OXTR) expression and the results showed that MPA had no effect, while Estrogen receptor b (ERb) expression significantly increased OXTR mRNA levels
Summary
Autism spectrum disorders (ASD) are a series of neurodevelopmental disorders characterized by symptoms including social deficits and restricted or repetitive behaviors [1, 2]. While the potential mechanism for ASD remains unclear, many factors, including environmental exposure, sex, and epigenetic modifications, are reported to be associated with ASD development [1, 3, 4]. We have previously reported that maternal exposure to either progestin [7, 8] or androgens [9] contribute to autism-like behaviors in offspring; and the epidemiological study shows that maternal hormonal exposure may be associated with autism development [10]. Primarily including estrogens and progestins, were originally used starting around 60 years ago for birth control by preventing ovulation; this time period has been reported to coincide with the dramatic increase in ASD prevalence [8, 10]. We hypothesize that maternal exposure to oral contraceptive hormones, especially progestin, may be associated with autism development
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