Does the Micronutrient Molybdenum Have a Role in Gestational Complications and Placental Health?
Abstract
:1. Introduction
2. Molybdenum: Ubiquitous Yet Unknown
2.1. Discovery of Molybdenum and Chemical Versatility
2.2. Bioavailability and Intake of Molybdenum
2.3. Current Nutritional Parameters
2.4. Rare, But Present: Molybdenum Deficiency and Overexposure
2.5. Gaps in the Research—Molybdenum in Pregnancy
3. Molybdenum Exposure during Pregnancy and Disease
3.1. The (Understandable) Overexposure Bias
3.2. Molybdenum as a Mediator of Hyperglycaemia and Hyperlipidemia, and Its Role in GDM
3.3. Molybdenum and Antioxidant Activity
3.4. Molybdenum and Foetal Development
Authors | Method of Detection | Population Number | Population Details | Matrix | Country | Results |
---|---|---|---|---|---|---|
Al-Saleh et al., 2004 [102] | AAS | 39 healthy non-obese subjects | Late third trimester (39.2 + 0.3 weeks) | Blood/serum | Kuwait | Significant positive correlation was found between maternal and umbilical cord levels of Mo, and placental weight. Maternal blood Mo did not correlate with birth weight. |
Goodrich et al., 2019 [147] | ID LC-MS/MS | 56 healthy subjects | First trimester | Spot urine | US | No association found between urinary Mo in 1st trimester and 2nd trimester foetal biometrics or birth weight at term. |
Kim et al., 2018 [150] | ICP-MS | 390 subjects (99 preterm birth, 291 control) | Early third trimester (median 26 weeks) | Spot urine | US | No significant association found between urinary Mo and risk of preterm birth. |
Kim et al., 2020 [149] | ICP-MS | 390 healthy subjects | Early third trimester (median 26 weeks) | Urine | US | Positive association between urinary Mo and foetal z scores, inc. femur length (significant), abdominal circumference and head circumference. |
Kot et al., 2019 [14] | ICP-AAS | 83 healthy subjects | Late third trimester (39 ± 1.8 weeks) | Umbilical, placental and foetal membrane tissue | Poland | Negative association found between placental Mo concentration and placental width. |
McAlpine et al., 2019 [137] | ICP-MS | 127 subjects (89 used supplements, 38 did not) | Late second and early third trimester, 180–210 days gestation (25–30 weeks) | Fasting serum | Australia | No significant association found between Mo in serum or dietary levels, and the incidence of negative outcomes (low birthweight infants, pre-term birth, hypertensive disorders). |
McKeating et al., 2021 [146] | ICP-MS | <128 subjects, crossover (10 with SGA, 18 with low placental weight, 13 preterm birth, 87 controls) | Second trimester (18 weeks) | Plasma, urine | Australia | Plasma (but not urine) Mo concentrations were significantly lower in pregnancies with low placental weight in comparison to controls. Plasma Se:Mo ratio had 87.3% predictive capability for determining placental weight. |
McKeating et al., 2021 [151] | ICP-MS | 328 samples (38 who developed PE, 91 who delivered with SGA, 193 healthy controls) | Late third trimester (36 weeks) | Plasma | Australia | No significant differences found between plasma Mo of controls, and negative outcome (pre-eclampsia and small-for-gestational-age) groups at 36 weeks. An increase in plasma Mo was noted with PE outcome (non-significant). |
Shirai et al., 2010 [152] | ICP-MS | 78 healthy subjects | Variable collection (9–40 weeks) | Spot urine | Japan | No significant association found between urinary Mo and birth size. |
Zhao et al., 2021 [148] | ICP-MS | 220 subjects | Second trimester (24.9 ± 0.8 weeks) | Spot urine | China | Negative association found between urinary Mo levels and foetal AC (significant) and EFW during the second trimester of pregnancy. |
Authors | Method of Detection | Population Number | Population Details | Matrix | Country | Results |
---|---|---|---|---|---|---|
Liu et al., 2020 [156] | ICP-MS | 332 subjects (166 with NTD-affected pregnancies, and 166 controls) | Collection across first, second and third trimesters | Umbilical cord tissue | China | Median concentrations of Mo in umbilical cord tissue were significantly higher in controls than NTD-affected pregnancies. Mo concentration was significantly correlated with gestation in NTD cases. No relationship between Mo and NTD risk observed when adjusting for confounders. |
Ovayolu et al., 2019 [157] | ICP-MS | 75 subjects (36 with NTD-affected pregnancies, and 39 controls) | Second trimester (NTD: 21.6 ± 6.6 weeks, controls: 19.6 ± 2.4 weeks) | Amniotic fluid | Turkey | Mean concentrations of Mo in amniotic fluid were significantly higher in controls than NTD-affected pregnancies. |
Tian et al., 2021 [154] | ICP-MS | 750 subjects (273 with NTD-affected pregnancies, and 477 controls) | Collection across first, second and third trimesters | Serum | China | Median concentrations of Mo in maternal serum were significantly higher in controls than NTD-affected pregnancies. Mo was found to have a significant protective effect against NTDs. |
Tian et al., 2022 [158] | ICP-MS | 213 subjects (99 with NTD-affected pregnancies, 114 controls) | Collection across first, second and third trimesters | Serum | China | No significant difference between median concentrations of Mo in maternal serum from healthy controls and NTD-affected pregnancies. |
Yan et al., 2017 [155] | ICP-MS | 452 subjects (191 with NTD-affected pregnancies, 261 controls) | First trimester (4 weeks preconception to 8 weeks post) | Hair | China | Mo concentrations in maternal hair samples from healthy controls were significantly higher than in NTD-affected pregnancies, and specifically spina bifida-affected pregnancies. When adjusting for confounders, Mo hair content was inversely associated with NTD risk. Mo deficiency was associated with increased risk of NTD subtypes anencephaly and spina bifida. |
Yin et al., 2020 [159] | ICP-MS | 1001 subjects (408 with NTD-affected pregnancies, and 593 controls) | Collection across first, second and third trimesters | Placental tissue | China | Median concentrations of Mo in placental tissue were significantly higher in NTD-affected pregnancies in comparison to controls. Mo concentrations were significantly higher in females than males. Increased Mo concentrations were associated with higher risk of NTDs in multivariable logistic regression model, but was close to null in BKMR model. |
4. The Role of Molybdoenzymes in Physiology
Molybdoenzyme | Tissue Locations | Cellular Compartments | Substrates (Not Exhaustive) | Products (Not Exhaustive) | Associated Reactive Species | Pathologies | Pregnancy-Related Research |
---|---|---|---|---|---|---|---|
Aldehyde Oxidase | liver, gut, lungs, brain, adipose tissue, skin, placenta [17,20] | Cytosol [17] | organic aldehydes, azaheterocycles, exogenous toxins (e.g., vanillin), nitrite, prodrugs [17,20] | carboxylic acid, lactams, vanillic acid, nitric oxide [17,20,145] | O2•−, H2O2 [169] | Implicated in development of obesity, cancer, lateral sclerosis and ageing [20]. | Gene expression increased in placental tissue of stillbirth and late-term pregnancy; associated with increased lipid peroxidation in late-term and stillbirth placentae [170]. |
Xanthine Oxidoreductase | liver, gut, lungs, kidney, breast, placenta [54,171,172] | Cytosol, Peroxisomes [171] | hypoxanthine, xanthine, nitrite [171] | xanthine, uric acid, nitric oxide [145] | O2•−, H2O2 [56,169] | Excess uric acid leads to gout, hyperuricemia; deficiency of enzyme leads to excess xanthine and potential renal failure [52,53]. | Increased expression and activity of XOR found in placentae (invasive cytotrophoblasts) of pre-eclamptic women [173]. Hyperuricemia associated with pre-eclampsia and GDM [174]. |
Sulfite Oxidase | liver, kidney, heart, skeletal muscle, brain, placenta [175] | Mitochondria (intermembrane space) [176] | sulfite, nitrite | sulfate, nitric oxide [177] | O2•−, H2O2 in plant SO [178,179] | Deficiency leads to toxic sulfite accumulation and brain damage, neurological abnormalities, myoclonic seizures, and neonatal or early-childhood mortality [50,180]. | Deficiency leads to toxic sulfite accumulation and brain damage, neurological abnormalities, myoclonic seizures and neonatal or early-childhood mortality following uneventful pregnancies. Brain damage begins in utero [180]. |
Mitochondrial Amidoxime Component 1 & 2 | liver, kidney, adipose tissue [181] | mitochondria (outer mitochondrial membrane), Peroxisomes (mARC2) [182,183] | nitrite; N-hydroxylated compounds/prodrugs [183] | nitric oxide; corresponding nucleoside/drug [183,184,185] | Not explored | Implicated in lipid metabolism and fatty liver disease [186], mARC1 deficiency was found to lower blood cholesterol levels and protect against cirrhosis [187]. | mARC1 was detected in both adult and foetal livers; mARC2 protein was only present in adult liver [181]. |
4.1. Molybdoenzyme Associations with Redox Status in Pregnancy
4.1.1. Aldehyde Oxidase
4.1.2. Xanthine Oxidoreductase
4.1.3. Sulfite Oxidase
4.2. Mitochondrial Amidoxime-Reducing Component 1 and 2, and Lipogenesis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Authors | Method of Detection | Population Number | Population Details | Matrix | Country | Results |
---|---|---|---|---|---|---|
Ajibola et al., 2014 [128] | AAS | 148 subjects (98 diabetes, 50 control) | Diabetes: 65.3% female, control: no details provided; diabetes: 55.92 ± 12.82 years, control: 42.06 ± 7.31 years | Plasma (fasting) | Nigeria | Significantly increased Mo in diabetics in comparison to control. |
Flores et al., 2011 [129] | ICP-MS | 88 subjects (52 slight-to-moderate diabetes complications, 24 severe diabetes complications, 12 control | Either sex, no further details provided; 52 ± 8 years | 24 h urine, fasting serum | Mexico | Urinary Mo was significantly decreased in severe diabetics in comparison to moderate diabetics; Serum Mo was increased in diabetic patients in comparison to control, and significantly increased in severe vs. moderate diabetic subjects. |
Li et al., 2021 [127] | ICP-MS | 5356 subjects (2678 ‘metabolic syndrome’ diagnosed, 2678 control) | MetS: 55.2% male, 54.5 (10.9) years; control: 55.2% male, 54.8 (10.8) years | Plasma (fasting) | China | Plasma Mo inversely correlated with risk of Metabolic Syndrome, in a dose-response manner. |
Menke et al., 2015 [131] | ICP-MS | 9447 subjects (1364 diabetes, 8083 control) | Diabetes: 51.7% ± 1.75 female, 58.6 ± 0.54 years, control: 50.5 ± 0.69 female, 45.6 ± 0.30 years | Spot urine | US | Higher quartiles of Mo were associated with greater HOMA of insulin resistance; Mo was positively associated with diabetes prevalence. |
Wang et al., 2020 [133] | ICP-MS | 1237 subjects, random selection | Female only; diabetes: 50.0 years, control: 49.5 years | Spontaneously voided urine (first morning) | US | No association found between urinary Mo and diabetes. |
Wang et al., 2020 [132] | ICP-MS | 1262 subjects, random selection | Female only; 49.7 (2.8) years at baseline | Spontaneously voided urine (first morning) | US | Urinary Mo concentration was significantly inversely associated with HOMA of insulin resistance at baseline. |
Yang et al., 2023 [130] | ICP-MS | 1423 subjects, random selection | 56.5% male, 46.9 ± 17.2 years | Spot urine | US | High urinary Mo levels were associated with elevated FPG and HbA1c levels. |
Authors | Method of Detection | Population Number | Population Details | Matrix | Country | Results |
---|---|---|---|---|---|---|
Al-Saleh et al., 2004 [138] | AAS | 30 subjects (15 gestational diabetics, 15 control) | Late third trimester (gestational diabetics: 39.0 ± 0.3 weeks, control: 40.0 ± 0.4 weeks) | Blood/Serum | Kuwait | No significant difference found in maternal Mo serum concentrations between control and GDM group. Significantly increased Mo concentrations in umbilical vein and artery of GDM group in comparison to control. |
Al-Saleh et al., 2005 [140] | AAS | 31 subjects (14 insulin-dependent diabetics, 17 control) | Late third trimester (insulin-dependent diabetics: 38 ± 0.31 weeks, control: 40 ± 0.4 weeks) | Serum | Kuwait | No significant difference in maternal Mo serum concentrations between control and diabetic group. Significantly increased Mo concentrations in umbilical vein and artery of diabetic group in comparison to control. |
Al-Saleh et al., 2007 [139] | AAS | 21 subjects (10 obese gestational diabetics, 11 control obese) | Late third trimester (obese gestational diabetics: 38.0 ± 0.40 weeks, obese control: 40.0 ± 0.50) | Serum | Kuwait | Increased Mo serum concentration in maternal vein and umbilical artery of obese gestational diabetics in comparison to obese controls. |
McAlpine et al., 2019 [137] | ICP-MS | 127 subjects (89 used supplements, 38 did not) | Late second and early third trimester, 180–210 days’ gestation (25–30 weeks) | Serum (Fasting) | Australia | No evidence of significant association between Mo in serum or dietary levels and the incidence of GDM. |
Zheng et al., 2019 [135] | ICP-MS | 1857 healthy non-obese subjects | Late first trimester (median: 12 weeks’ gestation) | Plasma | US | Every 50% increase in molybdenum concentration was associated with 1.2 mg/dL lower mean glucose level (95% CI: −2.3, −0.1 mg/dL) |
Zheng et al., 2020 [136] | ICP-MS | 1720 healthy non-obese subjects | Late first trimester (median: 12 weeks’ gestation) | Plasma | US | Inverse association between Mo plasma levels and glucose levels, in three different statistical models. Strong associations were not observed in BKMR modelling in comparison to adaptive LASSO and GAM. |
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Foteva, V.; Fisher, J.J.; Qiao, Y.; Smith, R. Does the Micronutrient Molybdenum Have a Role in Gestational Complications and Placental Health? Nutrients 2023, 15, 3348. https://doi.org/10.3390/nu15153348
Foteva V, Fisher JJ, Qiao Y, Smith R. Does the Micronutrient Molybdenum Have a Role in Gestational Complications and Placental Health? Nutrients. 2023; 15(15):3348. https://doi.org/10.3390/nu15153348
Chicago/Turabian StyleFoteva, Vladimira, Joshua J. Fisher, Yixue Qiao, and Roger Smith. 2023. "Does the Micronutrient Molybdenum Have a Role in Gestational Complications and Placental Health?" Nutrients 15, no. 15: 3348. https://doi.org/10.3390/nu15153348
APA StyleFoteva, V., Fisher, J. J., Qiao, Y., & Smith, R. (2023). Does the Micronutrient Molybdenum Have a Role in Gestational Complications and Placental Health? Nutrients, 15(15), 3348. https://doi.org/10.3390/nu15153348