Prenatal androgen exposure causes a sexually dimorphic transgenerational increase in offspring susceptibility to anxiety disorders

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.