Decreased Vitamin D Levels and Altered Placental Vitamin D Gene Expression at High Altitude: Role of Genetic Ancestry
High-altitude hypoxia challenges reproduction; particularly in non-native populations. Although high-altitude residence is associated with vitamin D deficiency, the homeostasis and metabolism of vitamin D in natives and migrants remain unknown. We report that high altitude (3600 m residence) negativ...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-02-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/4/3389 |
| _version_ | 1797620524294078464 |
|---|---|
| author | Eugenia Mata-Greenwood Hans C. A. Westenburg Stacy Zamudio Nicholas P. Illsley Lubo Zhang |
| author_facet | Eugenia Mata-Greenwood Hans C. A. Westenburg Stacy Zamudio Nicholas P. Illsley Lubo Zhang |
| author_sort | Eugenia Mata-Greenwood |
| collection | DOAJ |
| description | High-altitude hypoxia challenges reproduction; particularly in non-native populations. Although high-altitude residence is associated with vitamin D deficiency, the homeostasis and metabolism of vitamin D in natives and migrants remain unknown. We report that high altitude (3600 m residence) negatively impacted vitamin D levels, with the high-altitude Andeans having the lowest 25-OH-D levels and the high-altitude Europeans having the lowest 1α,25-(OH)<sub>2</sub>-D levels. There was a significant interaction of genetic ancestry with altitude in the ratio of 1α,25-(OH)<sub>2</sub>-D to 25-OH-D; with the ratio being significantly lower in Europeans compared to Andeans living at high altitude. Placental gene expression accounted for as much as 50% of circulating vitamin D levels, with <i>CYP2R1</i> (25-hydroxylase), <i>CYP27B1</i> (1α-hydroxylase), <i>CYP24A1</i> (24-hydroxylase), and <i>LRP2</i> (megalin) as the major determinants of vitamin D levels. High-altitude residents had a greater correlation between circulating vitamin D levels and placental gene expression than low-altitude residents. Placental 7-dehydrocholesterol reductase and vitamin D receptor were upregulated at high altitude in both genetic-ancestry groups, while megalin and 24-hydroxylase were upregulated only in Europeans. Given that vitamin D deficiency and decreased 1α,25-(OH)<sub>2</sub>-D to 25-OH-D ratios are associated with pregnancy complications, our data support a role for high-altitude-induced vitamin D dysregulation impacting reproductive outcomes, particularly in migrants. |
| first_indexed | 2024-03-11T08:43:47Z |
| format | Article |
| id | doaj.art-3a8b97c2d0874409a04846c947923a41 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T08:43:47Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-3a8b97c2d0874409a04846c947923a412023-11-16T20:59:18ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01244338910.3390/ijms24043389Decreased Vitamin D Levels and Altered Placental Vitamin D Gene Expression at High Altitude: Role of Genetic AncestryEugenia Mata-Greenwood0Hans C. A. Westenburg1Stacy Zamudio2Nicholas P. Illsley3Lubo Zhang4Lawrence D. Longo Center for Perinatal Biology, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USALawrence D. Longo Center for Perinatal Biology, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USAPlacental Research Group LLC, Maplewood, NJ 07040, USAPlacental Research Group LLC, Maplewood, NJ 07040, USALawrence D. Longo Center for Perinatal Biology, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USAHigh-altitude hypoxia challenges reproduction; particularly in non-native populations. Although high-altitude residence is associated with vitamin D deficiency, the homeostasis and metabolism of vitamin D in natives and migrants remain unknown. We report that high altitude (3600 m residence) negatively impacted vitamin D levels, with the high-altitude Andeans having the lowest 25-OH-D levels and the high-altitude Europeans having the lowest 1α,25-(OH)<sub>2</sub>-D levels. There was a significant interaction of genetic ancestry with altitude in the ratio of 1α,25-(OH)<sub>2</sub>-D to 25-OH-D; with the ratio being significantly lower in Europeans compared to Andeans living at high altitude. Placental gene expression accounted for as much as 50% of circulating vitamin D levels, with <i>CYP2R1</i> (25-hydroxylase), <i>CYP27B1</i> (1α-hydroxylase), <i>CYP24A1</i> (24-hydroxylase), and <i>LRP2</i> (megalin) as the major determinants of vitamin D levels. High-altitude residents had a greater correlation between circulating vitamin D levels and placental gene expression than low-altitude residents. Placental 7-dehydrocholesterol reductase and vitamin D receptor were upregulated at high altitude in both genetic-ancestry groups, while megalin and 24-hydroxylase were upregulated only in Europeans. Given that vitamin D deficiency and decreased 1α,25-(OH)<sub>2</sub>-D to 25-OH-D ratios are associated with pregnancy complications, our data support a role for high-altitude-induced vitamin D dysregulation impacting reproductive outcomes, particularly in migrants.https://www.mdpi.com/1422-0067/24/4/3389high altitudegenetic ancestryvitamin Dmetabolismplacenta |
| spellingShingle | Eugenia Mata-Greenwood Hans C. A. Westenburg Stacy Zamudio Nicholas P. Illsley Lubo Zhang Decreased Vitamin D Levels and Altered Placental Vitamin D Gene Expression at High Altitude: Role of Genetic Ancestry International Journal of Molecular Sciences high altitude genetic ancestry vitamin D metabolism placenta |
| title | Decreased Vitamin D Levels and Altered Placental Vitamin D Gene Expression at High Altitude: Role of Genetic Ancestry |
| title_full | Decreased Vitamin D Levels and Altered Placental Vitamin D Gene Expression at High Altitude: Role of Genetic Ancestry |
| title_fullStr | Decreased Vitamin D Levels and Altered Placental Vitamin D Gene Expression at High Altitude: Role of Genetic Ancestry |
| title_full_unstemmed | Decreased Vitamin D Levels and Altered Placental Vitamin D Gene Expression at High Altitude: Role of Genetic Ancestry |
| title_short | Decreased Vitamin D Levels and Altered Placental Vitamin D Gene Expression at High Altitude: Role of Genetic Ancestry |
| title_sort | decreased vitamin d levels and altered placental vitamin d gene expression at high altitude role of genetic ancestry |
| topic | high altitude genetic ancestry vitamin D metabolism placenta |
| url | https://www.mdpi.com/1422-0067/24/4/3389 |
| work_keys_str_mv | AT eugeniamatagreenwood decreasedvitamindlevelsandalteredplacentalvitamindgeneexpressionathighaltituderoleofgeneticancestry AT hanscawestenburg decreasedvitamindlevelsandalteredplacentalvitamindgeneexpressionathighaltituderoleofgeneticancestry AT stacyzamudio decreasedvitamindlevelsandalteredplacentalvitamindgeneexpressionathighaltituderoleofgeneticancestry AT nicholaspillsley decreasedvitamindlevelsandalteredplacentalvitamindgeneexpressionathighaltituderoleofgeneticancestry AT lubozhang decreasedvitamindlevelsandalteredplacentalvitamindgeneexpressionathighaltituderoleofgeneticancestry |