Peripartum dietary supplementation of a small molecule inhibitor of tryptophan hydroxylase 1 compromises infant, but not maternal, bone.

Long-term effects of breastfeeding on maternal bone are not fully understood. Excessive maternal bone loss stimulated by serotonin signaling during lactation may increase bone fragility later in life. We hypothesized inhibiting non-neuronal serotonin activity by feeding a small molecule inhibitor of the rate-limiting enzyme in serotonin synthesis (tryptophan hydroxylase 1; TPH1) would preserve maternal bone post-weaning without affecting neonatal bone. Small molecule TPH1 inhibitor LP778902 (~100 mg/kg) or control chow was fed to C57BL/6 dams throughout pregnancy and lactation and blood collected on days 1 and 21 of lactation. Dams returned to a common diet post-weaning, and were aged to 3 months or 9 months post-weaning. Pups were euthanized at weaning. The effect of TPH1 inhibition on dam and pup femoral bone was determined by micro-computed tomography. Peripartum dietary supplementation with LP778902 decreased maternal serum serotonin concentrations (P=0.0007) and reduced bone turnover, indicated by serum P1NP (P=0.01) and CTX (P=0.02) concentrations, on day 21 of lactation. Repressed bone turnover from TPH1 inhibition was not associated with structural changes in maternal femur at either 3 or 9 months post-weaning. By contrast, neonates exposed to peripartum LP778902 demonstrated differences in trabecular and cortical femoral bone compared to pups from control dams, with fewer (P=0.02) and thinner (P=0.001) trabeculae as well as increased trabecular spacing (P=0.04). Additionally, cortical porosity was increased (P=0.007) and cortical TMD was decreased (P=0.005) in pups of LP778902 dams. Small molecule TPH1 inhibitors should be carefully considered in pregnant and lactating women, given potential risks to neonatal bone development.