Effects of Peripartal Sertraline on Maternal Calcium Metabolism and Maternal Bone Health

Abstract

Abstract Lactation taxes mothers’ bone health, causing them to lose up to 10% of their bone mass for milk calcium. Selective serotonin reuptake inhibitor antidepressants (SSRIs) are commonly used during pregnancy and lactation but independently decrease bone mass. We previously demonstrated that both maternal and offspring bone densities were compromised by maternal treatment with the SSRI fluoxetine throughout pregnancy and lactation. In this study, we examined whether sertraline similarly affect maternal and offspring bone. Female C57BL/6 dams (n=23/group) were treated with sertraline (10 mg/kg/d) or a vehicle (DMSO) for 41 d (E0-lactation(L) 21). Pups were euthanized at weaning (L21). Dams were euthanized at peak lactation (L10, n=4/group), weaning (L21, n=9/group) or 3 mo post-weaning (n=10/group) for analysis. Sertraline treatment did not affect dams’ weight gain during pregnancy or lactation and did not impact milk production/consumption, measured by weigh-suckle-weigh. Unlike fluoxetine, which increases circulating calcium, sertraline treatment reduced serum calcium concentration at L21 compared with control (p<0.05). Mammary calcium genes were not altered at L10, but at L21 we observed decreased mammary expression of the calcium transporters Orai1, Spca1, Spca2, and Serca2 (p<0.05), and a tendency for decreased Pthlh (a calcium-regulating peptide; p=0.08). In the intestinal duodenum, Calb1 (a cytosolic calcium trafficking protein) expression was increased at L10 and L21 (p<0.05), and the calcium transporters Trpv6, Pmca1 and Spca2 were increased by L21 (p<0.05). Sertraline treatment did not affect L21 calcium concentration in either tissue, although the mammary gland calcium was 3.5 times that of the duodenum. Previously, we reported that circulating markers of bone formation (P1NP) or bone resorption (CTX) were unchanged in sertraline-treated dams at L21. This is unlike fluoxetine, which decreased P1NP without altering CTX. Furthermore, compared with control, sertraline treatment did not alter expression of bone resorption or formation genes (e.g. Trap, Rank/RankL, Alp, Runx2) in maternal femoral bone at L21 or 3 mo post-weaning. Interestingly, in utero exposure to sertraline reduced litter size (5.4 vs 6.8 pups/dam, p<0.01) and increased pup mortality (20% vs 5% dead pups/litter, p<0.01) during the first 24 hours postpartum compared with controls, but did not affect length of gestation or live birth rate. Exposure to sertraline during lactation did not alter weight gain in the surviving offspring, nor did it alter circulating calcium in the pups at weaning, suggesting an adequate supply of calcium in the milk from the dam. These data suggest that, compared with high-dose fluoxetine, low-dose peripartal sertraline has a milder impact on maternal bone and may reduce mammary calcium but could induce a failure to thrive in the offspring.