Abstract
If and how obesity and elevated androgens in women with polycystic ovary syndrome (PCOS) affect their offspring’s psychiatric health is unclear. Using data from Swedish population health registers, we showed that daughters of mothers with PCOS have a 78% increased risk of being diagnosed with anxiety disorders. We next generated a PCOS-like mouse (F0) model induced by androgen exposure during late gestation, with or without diet-induced maternal obesity, and showed that the first generation (F1) female offspring develop anxiety-like behavior, which is transgenerationally transmitted through the female germline into the third generation of female offspring (F3) in the androgenized lineage. In contrast, following the male germline, F3 male offspring (mF3) displayed anxiety-like behavior in the androgenized and the obese lineages. Using a targeted approach to search for molecular targets within the amygdala, we identified five differentially expressed genes involved in anxiety-like behavior in F3 females in the androgenized lineage and eight genes in the obese lineage. In mF3 male offspring, three genes were dysregulated in the obese lineage but none in the androgenized lineage. Finally, we performed in vitro fertilization (IVF) using a PCOS mouse model of continuous androgen exposure. We showed that the IVF generated F1 and F2 offspring in the female germline did not develop anxiety-like behavior, while the F2 male offspring (mF2) in the male germline did. Our findings provide evidence that elevated maternal androgens in PCOS and maternal obesity may underlie the risk of a transgenerational transmission of anxiety disorders in children of women with PCOS.
Highlights
Polycystic ovary syndrome (PCOS) is recognized as a heterogeneous disorder affecting over 15% of women in the general population and over 25% of women with obesity[1,2]
Daughters of women with PCOS are diagnosed with anxiety disorders We conducted a Swedish nationwide register-based cohort study to assess if daughters of women with PCOS have a higher risk of being diagnosed with anxiety disorders
1.32% of children (n = 117) born to a mother with PCOS had a diagnosis of anxiety made in inpatient or outpatient hospital-based specialized care, compared to 0.97% (n = 912) of children born to mothers without a PCOS diagnosis
Summary
Polycystic ovary syndrome (PCOS) is recognized as a heterogeneous disorder affecting over 15% of women in the general population and over 25% of women with obesity[1,2]. Over 60% of women with PCOS are diagnosed with at least one psychiatric disorder[3,4]. Elevated circulating androgens is the most prominent feature of PCOS, which persists throughout reproductive life and even after menopause[5,6], and reproductive, metabolic and psychiatric dysfunction are all positively correlated with hyperandrogenaemia[4,5,6,7]. Prenatal androgen exposure has been proposed to have a potential causal influence on the development of neuropsychiatric disorders in children born to women with PCOS in a Swedish register-based studies[8,9,10]. A recent study has reported that children born to women with PCOS had higher risk for childhood anxiety diagnoses[11], and maternal PCOS, independently, and jointly with maternal obesity, has been
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