The Effect of Tobacco Use on the Expression of Placental Transporters in Alaska Native Women.

Prenatal tobacco use among Alaska Native (AN) women has decreased substantially over the past two decades. Previous research suggests that providing AN women with feedback regarding fetal exposure to tobacco may further promote cessation. Transporters in the placenta regulate fetal exposure to nutrients and xenobiotics, including compounds associated with tobacco use. We examined whether prenatal tobacco use impacts transporter expression in the placenta, and whether this is influenced by fetal sex, degree of tobacco exposure, or transporter genotype. At delivery, we obtained placental samples from AN research participants who smoked cigarettes, used commercial chew or iqmik (oral tobacco), or did not use tobacco during pregnancy. Transporter expression was evaluated using qRT-PCR and Western blotting and tested for correlations between transcript levels and urinary biomarkers of tobacco use. The impact of BCRP/ABCG2 and OATP2B1/SLCO2B1 genotypes on protein expression was also examined. Oral tobacco use was associated with decreased P-gp and increased MRP1, MRP3, LAT1, and PMAT mRNA expression. Transcript levels of multiple transporters significantly correlated with tobacco biomarkers in maternal and fetal urine. In women carrying male fetuses, both smoking and oral tobacco were associated with decreased P-gp. Oral tobacco was also associated with decreased LAT1 in women carrying female fetuses. BCRP and OATP2B1 genotypes did not appear to impact protein expression. In conclusion, prenatal tobacco use is associated with altered expression of multiple placental transporters which differs by fetal sex. As transcript levels of multiple transporters were significantly correlated with tobacco use biomarkers, eliminating prenatal tobacco use should alleviate these changes.

Neuropathological signatures revealed by transcriptomic and proteomic analysis in Pten-deficient mouse models.

PTEN hamartoma tumour syndrome is characterised by mutations in the human PTEN gene. We performed transcriptomic and proteomic analyses of neural tissues and primary cultures from heterozygous and homozygous Pten-knockout mice. The somatosensory cortex of heterozygous Pten-knockout mice was enriched in immune response and oligodendrocyte development Gene Ontology (GO) terms. Parallel proteomic analysis revealed differentially expressed proteins (DEPs) related to dendritic spine development, keratinisation and hamartoma signatures. However, primary astrocytes (ASTs) from heterozygous Pten-knockout mice were enriched in the extracellular matrix GO term, while primary cortical neurons (PCNs) were enriched in immediate-early genes. In ASTs from homozygous Pten-knockout mice, cilium-related activity was enriched, while PCNs exhibited downregulation of forebrain neuron generation and differentiation, implying an altered excitatory/inhibitory balance. By integrating DEPs with pre-filtered differentially expressed genes, we identified the enrichment of traits of intelligence, cognitive function and schizophrenia, while DEPs in ASTs were significantly associated with intelligence and depression.

Impact of Th-17 Cytokines on the Regulation of Transporters in Human Placental Explants.

Activated T helper 17 (Th-17) cytokines play a role in the pathophysiology of autoimmune and infectious diseases. While these diseases affect many women of childbearing age, little is known about the effect of these cytokines on placental transporters. As several pro-inflammatory cytokines impact the expression of ABC and SLC placental transporters, we hypothesized that these transporters may be similarly altered by elevated levels of circulating Th-17 cytokines. Cultured term human villous explants were treated with IL-17A, IL-22, or IL-23, alone or in combination. Samples were analyzed using qRT-PCR and Western blotting. The mRNA expression of OATP2B1 was significantly downregulated in explants by all individual cytokines and combination treatments, while decreased protein expression was seen with IL-23 and combination (p < 0.01). Combination treatment decreased the mRNA expression of BCRP and OAT4 but increased that of OCT3 (p < 0.01). Decreased accumulation of the OATP substrate, cascade blue, was seen in IL-23-treated choriocarcinoma JAr cells (p < 0.01). Elevated Th-17 cytokines, which are seen in infectious and autoimmune diseases, affect the expression and activity of OATP2B1, as well as mRNA expression of placental BCRP, OAT4, and OCT3. This dysregulation could impact the fetal exposure to endogenous and exogenous substrates.