title: Evidence of sexual dimorphism in placental vitamin D metabolism: Testosterone inhibits calcitriol-dependent cathelicidin expression.
abstract: Male fetus and neonates show increased immune vulnerability compared to females, which results in a higher risk of perinatal infections. These differences could partially be due to sex steroids differential modulation of vitamin D metabolism; since calcitriol, the most active vitamin D metabolite, regulates immune responses and transcriptionally induces the antimicrobial peptide cathelicidin in the human placenta. Calcitriol availability depends on CYP27B1 and CYP24A1 expression, the cytochromes involved in its synthesis and degradation, respectively. However, the effects of testosterone upon these enzymes and the final biological outcome upon the calcitriol-dependent immune-target cathelicidin in the placenta have not been studied. In this study we show that testosterone significantly inhibited CYP27B1 while stimulated CYP24A1 gene expression in cultured trophoblasts. These effects were accompanied by CREB activation through cAMP-independent and androgen receptor-dependent mechanisms. Male placental cotyledons showed reduced basal CYP27B1 and cathelicidin gene expression compared to females (P<0.05). Testosterone concentration was higher in the cord blood of male neonates (P=0.007), whereas cathelicidin levels were lesser compared to females (P=0.002). Altogether our results suggest that male placentas produce less cathelicidin due to decreased calcitriol bioavailability. We propose that the observed sex-dependent differences in placental vitamin D metabolism contribute in fetal responses to infections and could partially explain why the increased male fetuses immune vulnerability. Moreover, gestational hyperandrogenemia could adversely affect placental vitamin D metabolism independently of fetal sex.
authors.affiliation: Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Av. Vasco de Quiroga 15, Col. Sección XVI, Tlalpan 14080, México City, Mexico; Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Av. Universidad 3000, Coyoacán 04360,.Mexico City, Mexico.
authors.forename: Andrea
authors.initials: A
authors.lastname: Olmos-Ortiz
authors.affiliation: Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Av. Vasco de Quiroga 15, Col. Sección XVI, Tlalpan 14080, México City, Mexico.
authors.forename: Janice
authors.initials: J
authors.lastname: García-Quiroz
authors.affiliation: Departamento de Biología Celular, Instituto Nacional de Cardiología "Ignacio Chávez", Juan Badiano 1, Col. Sección XVI, Tlalpan 14080,Mexico City, Mexico.
authors.forename: Rebeca
authors.initials: R
authors.lastname: López-Marure
authors.affiliation: Unidad Académica de Ciencias Químicas, Universidad Autónoma de Zacatecas, Carr. Guadalajara Km. 6, Ejido la Escondida 98160, Zacatecas, Zacatecas, Mexico.
authors.forename: Irma
authors.initials: I
authors.lastname: González-Curiel
authors.affiliation: Unidad de Investigación Médica-Zacatecas, Instituto Mexicano del Seguro Social, UIMZ-IMSS, Interior de la Alameda 45, Zacatecas, Zacatecas, Mexico.
authors.forename: Bruno
authors.initials: B
authors.lastname: Rivas-Santiago
authors.affiliation: Unidad de Investigación Médica en Medicina Reproductiva, UMAE, Mexico.
authors.forename: Aleida
authors.initials: A
authors.lastname: Olivares
authors.affiliation: Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Av. Vasco de Quiroga 15, Col. Sección XVI, Tlalpan 14080, México City, Mexico.
authors.forename: Euclides
authors.initials: E
authors.lastname: Avila
authors.affiliation: Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Av. Vasco de Quiroga 15, Col. Sección XVI, Tlalpan 14080, México City, Mexico.
authors.forename: David
authors.initials: D
authors.lastname: Barrera
authors.affiliation: Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Av. Vasco de Quiroga 15, Col. Sección XVI, Tlalpan 14080, México City, Mexico.
authors.forename: Ali
authors.initials: A
authors.lastname: Halhali
authors.affiliation: División de Obstetricia, Hospital de Gineco Obstetricia No. 4 Luis Castelazo Ayala, IMSS, Río Magdalena No. 289, Col. Tizapán, Álvaro Obregón 01090,Mexico City, Mexico.
authors.forename: Felipe
authors.initials: F
authors.lastname: Caldiño
authors.affiliation: Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Av. Vasco de Quiroga 15, Col. Sección XVI, Tlalpan 14080, México City, Mexico.
authors.forename: Fernando
authors.initials: F
authors.lastname: Larrea
authors.affiliation: Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Av. Vasco de Quiroga 15, Col. Sección XVI, Tlalpan 14080, México City, Mexico. Electronic address: lorenzadiaz@gmail.com.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Díaz
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics* / Q000276:immunology; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins / Q000235:genetics* / Q000276:immunology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000276:immunology; D005260:Female; D005333:Fetus; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D011247:Pregnancy; D061251:Primary Cell Culture; D011944:Receptors, Androgen / Q000235:genetics / Q000276:immunology; D012727:Sex Characteristics; D015398:Signal Transduction; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology*; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D014807:Vitamin D / Q000378:metabolism* / Q000494:pharmacology; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics* / Q000276:immunology
chemical_list: C410798:AR protein, human; D023181:Antimicrobial Cationic Peptides; C115163:CREB1 protein, human; D054804:Cathelicidins; D017362:Cyclic AMP Response Element-Binding Protein; D011944:Receptors, Androgen; D014807:Vitamin D; D013739:Testosterone; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; C000600378:CYP27B1 protein, human
keywords: Androgen; Cord blood; LL-37; Male; cAMP