Maternal hypothyroidism in rats impairs placental nutrient transporter expression, increases labyrinth zone size, and impairs fetal growth.

INTRODUCTION: Hypothyroidism during pregnancy is associated with fetal growth restriction (FGR). FGR is commonly caused by placental insufficiency and yet the role of hypothyroidism in placental regulation of fetal growth is unknown. This study aimed to investigate the effects of maternal hypothyroidism on placental nutrient transporter expression, placental morphology, and placental metabolism. METHODS: Hypothyroidism was induced in female Sprague-Dawley rats by adding methimazole (MMI) to drinking water at moderate (MOD, MMI at 0.005% w/v) and severe (SEV, MMI at 0.02% w/v) doses from one week prior to pregnancy and throughout gestation. Maternal and fetal tissues were collected on embryonic day 20 (E20). RESULTS: Hypothyroidism reduced fetal weight (PTrt<0.001) despite causing fetal hyperglycaemia (PTrt = 0.016). Placental weight was not affected by hypothyroidism however placental efficiency was reduced (PTrt<0.001), as was the junctional zone (JZ):labyrinth zone (LZ) weight ratio (PTrt = 0.005). LZ glycogen content was increased (PTrt = 0.029) and while mRNA expression of glucose transporters was reduced by hypothyroidism, only GLUT1 protein expression was reduced in male LZs. Maternal hypothyroidism reduced mitochondrial content (PTrt = 0.031), particularly in SEV males relative to CON males (P = 0.004). Protein expression of Complex V (P < 0.001) and Complex III (P = 0.002) of the electron transport chain were also reduced in males. Maternal hypothyroidism reduced LZ (PTrt<0.001) and fetal plasma triglycerides (P = 0.019) while fetal free fatty acids and the expression of LZ lipid transporters was not affected. DISCUSSION: Overall, maternal hypothyroidism may lead to FGR through reduced maternal T4 availability, changes to placental morphology, altered nutrient transporter expression and sex-specific effects on placental metabolism. Changes to LZ glycogen and triglyceride stores as well as mitochondrial content suggest a metabolic shift from oxidative phosphorylation to anaerobic glycolysis in males. These changes also likely impact fetal substrate availability and therefore fetal growth.

Prevalence and Patterns of Prenatal Alcohol Exposure in Australian Cohort and Cross-Sectional Studies: A Systematic Review of Data Collection Approaches.

This study sought to determine data collection approaches in Australian cohort studies and explore the potential impact on reported prenatal alcohol exposure (PAE) prevalence and patterns. Inclusion criteria were that studies related to a general Australian antenatal population where PAE was assessed and reported. Studies were excluded if they were not peer reviewed, examined the prevalence of PAE in pregnancies complicated by alcohol-use disorders, or were published in a language other than English. A systematic search of five electronic databases (PubMed, Embase, CINAHL, Web of Science, and Scopus) was conducted. Risk of bias was assessed using the Effective Public Health Practice Project quality assessment tool. Results were synthesised using MetaXL. Data from 16 separate birth cohorts (n = 78 articles) were included. Included cohorts were either general cohorts that included alcohol as a variable or alcohol-focused cohorts that were designed with a primary focus on PAE. PAE prevalence was estimated as 48% (95% CI: 38 to 57%). When subgroup analysis was performed, estimates of PAE prevalence when self-administered surveys and interviews were used for data collection were 53% (95% CI: 41% to 64%) and 43% (95% CI: 28% to 59%), respectively. Use of trained assessors was an influencing factor of the prevalence estimates when data were collected via interview. Alcohol-focused studies reported higher prevalence of PAE, regardless of method of survey administration. Where interviewer training is not possible, self-administered questionnaires will likely provide the most reliable PAE estimates. No funding sources are relevant to mention. Review was registered with PROSPERO (CRD42020204853).

Maternal choline supplementation in a rat model of periconceptional alcohol exposure: Impacts on the fetus and placenta.

BACKGROUND: Maternal choline supplementation in rats can ameliorate specific neurological and behavioral abnormalities caused by alcohol exposure during pregnancy. We tested whether choline supplementation ameliorates fetal growth restriction and molecular changes in the placenta associated with periconceptional ethanol exposure (PCE) in the rat. METHODS: Sprague Dawley dams were given either 12.5% ethanol (PCE) or 0% ethanol (Con) in a liquid diet from 4 days prior to 4 days after conception. At day 5 of pregnancy, dams were either placed on a standard chow (1.6 g choline/kg chow) or an intermediate chow (2.6 g choline/kg chow). On day 10 of pregnancy, a subset of the intermediate dams were placed on a chow further supplemented with choline (7.2 g choline/kg chow), resulting in 6 groups. Fetuses and placentas were collected on day 20 of pregnancy for analysis. RESULTS: Choline supplementation resulted in increased fetal weight at late gestation, ameliorating the deficits due to PCE. This was most pronounced in litters on a standard chow during pregnancy. Choline also increased fetal liver weight and decreased fetal brain:liver ratio, independent of alcohol exposure. Placental weight was reduced as choline levels in the chow increased, particularly in female placentas. This resulted in a greater ratio of fetal:placental weight, suggesting increased placental efficiency. Global DNA methylation in the placenta was altered in a sex-specific manner by both PCE and choline. However, the increased glycogen deposition in female placentas, previously reported in this PCE model, was not prevented by choline supplementation. CONCLUSIONS: Our results suggest that choline has the potential to ameliorate fetal growth restriction associated with PCE and improve placental efficiency following prenatal alcohol exposure. Our study highlights the importance of maternal nutrition in moderating the severity of adverse fetal and placental outcomes that may arise from prenatal alcohol exposure around the time of conception.

Is the link between elevated TSH and gestational diabetes mellitus dependant on diagnostic criteria and thyroid antibody status: a systematic review and meta-analysis.

PURPOSE: Clinical studies have investigated the prevalence of gestational diabetes mellitus (GDM) in women with subclinical hypothyroidism (SCH). While some studies demonstrate a clear association, others do not. It is possible this may be due to varied diagnostic criteria for SCH and the presence of thyroid antibodies (TA). We conducted a meta-analysis, separating patients diagnosed with SCH using a diagnostic cut-off <4.0 mIU/L from those diagnosed using a cut-off >4.0 mIU/L and determined the association with GDM and factored TA status into our analysis. METHODS: A computerised search of five databases including PubMed, Embase, Cochrane Library, Web of Science and CINAHL returned 787 records. Two independent reviewers assessed abstracts and full texts against pre-specified inclusion and exclusion criteria. Ten cohort studies were included in the final analysis. The diagnostic criteria for SCH and incidence of GDM were extracted from each study. Study quality and risk of bias was assessed by two reviewers. RESULTS: TSH levels <4.0 mIU/L for SCH diagnosis was not associated with GDM unless patients were TA positive. Studies that used a diagnostic cut-off >4.0 mIU/L saw a significant increase in the odds of GDM, regardless of TA status (OR = 1.60, 95% CI 1.33-1.93). CONCLUSIONS: Women with TSH levels >4.0 mIU/L have an increased odds of GDM regardless of TA status but at TSH levels <4.0 mIU/L, GDM is dependent on TA status. The use of TSH levels to identify pregnancies at risk of GDM is a novel concept that warrants exploration.

Maternal selenium deficiency in mice promotes sex-specific changes to urine flow and renal expression of mitochondrial proteins in adult offspring.

Selenium deficiency during pregnancy can impair fetal development and predispose offspring to thyroid dysfunction. Given that key selenoproteins are highly expressed in the kidney and that poor thyroid health can lead to kidney disease, it is likely that kidney function may be impaired in offspring of selenium-deficient mothers. This study utilized a mouse model of maternal selenium deficiency to investigate kidney protein glycation, mitochondrial adaptations, and urinary excretion in offspring. Female C57BL/6 mice were fed control (>190 µg selenium/kg) or low selenium (<50 µg selenium/kg) diets four weeks prior to mating, throughout gestation, and lactation. At postnatal day (PN) 170, offspring were placed in metabolic cages for 24 hr prior to tissue collection at PN180. Maternal selenium deficiency did not impact selenoprotein antioxidant activity, but increased advanced glycation end products in female kidneys. Male offspring had reduced renal Complex II and Complex IV protein levels and lower 24 hr urine flow. Although renal aquaporin 2 (Aqp2) and arginine vasopressin receptor 2 (Avpr2) mRNA were not altered by maternal selenium deficiency, a correlation between urine flow and plasma free T4 concentrations in male but not female offspring suggests that programed thyroid dysfunction may be mediating impaired urine flow. This study demonstrates that maternal selenium deficiency can lead to long-term deficits in kidney parameters that may be secondary to impaired thyroid dysfunction. Considering the significant burden of renal dysfunction as a comorbidity to metabolic diseases, improving maternal selenium intake in pregnancy may be one simple measure to prevent lifelong disease.

Maternal High Linoleic Acid Alters Placental Fatty Acid Composition.

Fetal development is modulated by maternal nutrition during pregnancy. The dietary intake of linoleic acid (LA), an essential dietary n-6 polyunsaturated fatty acid (PUFA), has increased. We previously published that increased LA consumption during pregnancy does not alter offspring or placental weight but fetal plasma fatty acid composition; the developing fetus obtains their required PUFA from the maternal circulation. However, it is unknown if increased maternal linoleic acid alters placental fatty acid storage, metabolism, transport, and general placental function. Female Wistar-Kyoto rats were fed either a low LA diet (LLA; 1.44% of energy from LA) or high LA diet (HLA; 6.21% of energy from LA) for 10 weeks before pregnancy and during gestation. Rats were sacrificed at embryonic day 20 (E20, term = 22 days) and placentae collected. The labyrinth of placentae from one male and one female fetus from each litter were analyzed. High maternal LA consumption increased placental total n-6 and LA concentrations, and decreased total n-3 PUFA, alpha-linolenic acid (ALA), and docosahexaenoic acid (DHA). Fatty acid desaturase 1 (Fads1), angiopoietin-like 4 (Angptl4), and diacylglycerol lipase beta (Daglb) mRNA were downregulated in placentae from offspring from HLA dams. Maternal high LA downregulated the fatty acid transport protein 4 (Fatp4) and glucose transporter 1 (Slc2a1) mRNA in placentae. IL-7 and IL-10 protein were decreased in placentae from offspring from HLA dams. In conclusion, a high maternal LA diet alters the placental fatty acid composition, inflammatory proteins, and expressions of nutrient transporters, which may program deleterious outcomes in offspring.