High Choline During Pregnancy Reduces Characteristics of the Metabolic Syndrome in Male Wistar Rat Offspring Fed a High Fat Post-Weaning Diet

Abstract Objectives The prenatal period is a critical time for fetal development, programming the offspring's later-life health in response to the postnatal environment. We have shown that a high maternal choline diet programs long-term energy regulation leading to higher food intake and weight-gain in mature rat offspring fed a normal fat diet. However, the offspring's response to an obesogenic post-weaning diet has not been described. We aim to elucidate the interaction between the choline content of the gestational diet (GD) and fat content of the post-weaning diet (PWD) on male Wistar rat offspring's long-term metabolic phenotype. Methods Pregnant Wistar rats were fed an AIN-93G diet with either recommended choline (RC, 1g/kg diet choline bitartrate) or high choline (HC, 2.5-fold). Male pups were weaned to either a normal (10%) fat (RC-NF and HC-NF) or a high (45%) fat (RC-HF and HC-HF) diet for 17 weeks. Dependent measures were body weight, food intake, visceral adiposity, plasma glucoregulatory hormones and triglycerides, and plasma and hepatic free fatty acids (FFAs). Data were analyzed with 2-way ANOVA for main effects of GD and PWD and their interaction. Measures with significant interaction effects were followed by a Student's T-test comparing groups stratified by PWD. Results HC-HF offspring had lower body weight (7%, P < 0.05), and visceral adiposity (15%, P < 0.05), but no difference in food intake compared to RC-HF. HC-HF offspring had lower insulin (18%, P < 0.05), HOMA-IR (24%, P < 0.01), and plasma triglycerides (30%, P < 0.05) but no difference in leptin. Total hepatic ω-3 FFAs (30%, P < 0.05) were higher and ω-6/ω-3 (P < 0.01) was lower in HC-HF compared to RC-HF, indicating an ameliorated metabolic phenotype in HC-HF offspring. In contrast, HC-NF offspring had higher food intake (8%, P < 0.01) and body weight (6%, P < 0.05) and no difference in adiposity compared to RC-NF. They also had higher plasma leptin adjusted for adiposity (22%, P < 0.05) but not insulin or HOMA-IR compared to RC-NF. Hepatic C16:1n-7/C16:0 ratio was higher in HC-NF compared to RC-NF, suggestive of dysregulated lipid metabolism. Conclusions Gestational choline supplementation is associated with improved long-term metabolic regulation in male Wistar rat offspring fed a high fat post-weaning diet. Funding Sources CIHR-Institute of Nutrition, Metabolism, and Diabetes.

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High Choline Intake during Pregnancy Reduces Characteristics of the Metabolic Syndrome in Male Wistar Rat Offspring Fed a High Fat But Not a Normal Fat Post-Weaning Diet

Nutrients ◽

10.3390/nu13051438 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1438

Author(s):

Rola Hammoud ◽

Emanuela Pannia ◽

Ruslan Kubant ◽

Adam Metherel ◽

Rebecca Simonian ◽

...

Keyword(s):

Metabolic Syndrome ◽

Fatty Acids ◽

Body Weight ◽

Food Intake ◽

Wistar Rats ◽

Later Life ◽

Wistar Rat ◽

Metabolic Phenotype ◽

Rat Offspring ◽

The Metabolic Syndrome

Maternal choline intakes are below recommendations, potentially impairing the child’s later-life metabolic health. This study aims to elucidate the interaction between the choline content of the gestational diet (GD) and fat content of the post-weaning diet (PWD) on metabolic phenotype of male Wistar rats. Pregnant Wistar rats were fed a standard rodent diet (AIN-93G) with either recommended choline (RC, 1 g/kg diet choline bitartrate) or high choline (HC, 2.5-fold). Male pups were weaned to either a normal (16%) fat (NF) or a high (45%) fat (HF) diet for 17 weeks. Body weight, visceral adiposity, food intake, energy expenditure, plasma hormones, triglycerides, and hepatic fatty acids were measured. HC-HF offspring had 7% lower body weight but not food intake, and lower adiposity, plasma triglycerides, and insulin resistance compared to RC-HF. They also had increased hepatic n-3 fatty acids and a reduced n-6/n-3 and C 18:1 n-9/C18:0 ratios. In contrast, HC-NF offspring had 6–8% higher cumulative food intake and body weight, as well as increased leptin and elevated hepatic C16:1 n-7/C16:0 ratio compared to RC-NF. Therefore, gestational choline supplementation associated with improved long-term regulation of several biomarkers of the metabolic syndrome in male Wistar rat offspring fed a HF, but not a NF, PWD.

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Variations in body weight, food intake and body composition after long-term high-fat diet feeding in C57BL/6J mice

Obesity ◽

10.1002/oby.20811 ◽

2014 ◽

Vol 22 (10) ◽

pp. 2147-2155 ◽

Cited By ~ 101

Author(s):

Yongbin Yang ◽

Daniel L. Smith ◽

Karen D. Keating ◽

David B. Allison ◽

Tim R. Nagy

Keyword(s):

Body Composition ◽

Body Weight ◽

Food Intake ◽

High Fat Diet ◽

High Fat

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Choline and Folic Acid Balance in Diets During Pregnancy Programs Food Intake Regulation in Wistar Rat Offspring (FS08-05-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz044.fs08-05-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Rola Hammoud ◽

Chih-Sheng Liao ◽

Emanuela Pannia ◽

Mandy Ho ◽

Neil Yang ◽

...

Keyword(s):

Body Weight ◽

Folic Acid ◽

Weight Gain ◽

Food Intake ◽

Body Weight Gain ◽

Control Diet ◽

Wistar Rat ◽

Rat Offspring ◽

Food Intake Regulation ◽

Intake Regulation

Abstract Objectives High gestational folic acid (FA) induces an obesogenic phenotype in male Wistar rat offspring. Imbalances between FA and other methyl-nutrients (i.e., choline) leading to perturbations in the 1-carbon cycle may account for the effects of high FA diets. Canadian women consume high (2–7-fold) intakes of FA, but most are not meeting recommended adequate intakes for choline. Choline is also absent from Canadian prenatal supplements. The objective of this study is to evaluate the effects of the interaction between choline and FA in maternal diets of rats on the 1-carbon cycle, and the programming of food intake, body weight gain and biomarkers of obesity in the offspring later in life. Methods Pregnant Wistar rat dams were fed the AIN-93 G diet with recommended (1X) choline and FA (RCRF, control), or a 5X FA diet with either 0.5X choline (LCHF), 1X choline (RCHF), or 2.5X choline (HCHF). Brain and blood were collected at birth. At weaning one male pup/dam from all groups was maintained on the control diet for 20 weeks then terminated. Dependent measures include weekly body weight-gain and food intake, plasma glucoregulatory hormones and 1-carbon metabolites at birth and post-weaning. Results Increasing choline content to 2.5-fold in a high (5-fold) gestational FA diet (HCHF) led to lower plasma insulin and leptin levels at birth compared to the LCHF and RCHF diets, respectively (P < 0.05). It also led to lower (25%, P = 0.03) plasma 5-methyltetrahydrofolate concentrations at birth compared to the RCHF diet, suggesting more efficient utilization of FA. Offspring born to dams maintained on a high folic acid diet with either low or recommended choline had higher weekly food intake (6%, P < 0.05) and body weight-gain (9%, P < 0.01). In contrast, offspring from dams fed the HCHF gestational diet were not different from those born to dams fed the RCRF (control) diet, highlighting the mitigating effects of a balanced choline and FA gestational diet. Conclusions Increased intakes of choline mitigate the effects of high FA diets. Maternal dietary choline interacts with FA on the long-term programming of food intake regulation in the offspring; emphasizing a need for more attention to improving choline intakes by women of child-bearing age. Funding Sources This research was funded by the Canadian Institute of Health Research, Institute of Nutrition, Metabolism and Diabetes (CIHR-INMD).

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Early postweaning exercise improves central leptin sensitivity in offspring of rat dams fed high-fat diet during pregnancy and lactation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00566.2012 ◽

2013 ◽

Vol 305 (9) ◽

pp. R1076-R1084 ◽

Cited By ~ 20

Author(s):

Bo Sun ◽

Nu-Chu Liang ◽

Erin R. Ewald ◽

Ryan H. Purcell ◽

Gretha J. Boersma ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Body Weight Gain ◽

Metabolic Phenotype ◽

Chow Diet ◽

Free Access ◽

Sprague Dawley ◽

High Fat ◽

Leptin Sensitivity ◽

Pregnancy And Lactation

Maternal high-fat (HF) diet has long-term consequences on the metabolic phenotype of the offspring. Here, we determined the effects of postweaning exercise in offspring of rat dams fed HF diet during gestation and lactation. Pregnant Sprague-Dawley rats were maintained on chow or HF diet throughout gestation and lactation. All pups were weaned onto chow diet on postnatal day (PND) 21. At 4 wk of age, male pups were given free access to running wheels (RW) or remained sedentary (SED) for 3 wk, after which all rats remained sedentary, resulting in four groups: CHOW-SED, CHOW-RW, HF-SED, and HF-RW. Male HF offspring gained more body weight by PND7 compared with CHOW pups and maintained this weight difference through the entire experiment. Three weeks of postweaning exercise did not affect body weight gain in either CHOW or HF offspring, but reduced adiposity in HF offspring. Plasma leptin was decreased at the end of the 3-wk running period in HF-RW rats but was not different from HF-SED 9 wk after the exercise period ended. At 14 wk of age, intracerebroventricular injection of leptin suppressed food intake in CHOW-SED, CHOW-RW, and HF-RW, while it did not affect food intake in HF-SED group. At death, HF-RW rats also had higher leptin-induced phospho-STAT3 level in the arcuate nucleus than HF-SED rats. Both maternal HF diet and postweaning exercise had effects on hypothalamic neuropeptide and receptor mRNA expression in adult offspring. Our data suggest that postweaning exercise improves central leptin sensitivity and signaling in this model.

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Increased expression of receptors for orexigenic factors in nodose ganglion of diet-induced obese rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90796.2008 ◽

2009 ◽

Vol 296 (4) ◽

pp. E898-E903 ◽

Cited By ~ 73

Author(s):

Gabriel Paulino ◽

Claire Barbier de la Serre ◽

Trina A. Knotts ◽

Pieter J. Oort ◽

John W. Newman ◽

...

Keyword(s):

Body Weight ◽

Weight Gain ◽

Food Intake ◽

High Fat Diet ◽

Afferent Pathway ◽

High Fat ◽

Low Fat ◽

Low Fat Diet ◽

Vagal Afferent

The vagal afferent pathway is important in short-term regulation of food intake, and decreased activation of this neural pathway with long-term ingestion of a high-fat diet may contribute to hyperphagic weight gain. We tested the hypothesis that expression of genes encoding receptors for orexigenic factors in vagal afferent neurons are increased by long-term ingestion of a high-fat diet, thus supporting orexigenic signals from the gut. Obesity-prone (DIO-P) rats fed a high-fat diet showed increased body weight and hyperleptinemia compared with low-fat diet-fed controls and high-fat diet-induced obesity-resistant (DIO-R) rats. Expression of the type I cannabinoid receptor and growth hormone secretagogue receptor 1a in the nodose ganglia was increased in DIO-P compared with low-fat diet-fed controls or DIO-R rats. Shifts in the balance between orexigenic and anorexigenic signals within the vagal afferent pathway may influence food intake and body weight gain induced by high fat diets.

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Characterization of the resistance to the anorectic and endocrine effects of leptin in obesity-prone and obesity-resistant rats fed a high-fat diet

Journal of Endocrinology ◽

10.1677/joe.1.05819 ◽

2004 ◽

Vol 183 (2) ◽

pp. 289-298 ◽

Cited By ~ 25

Author(s):

G Tulipano ◽

A V Vergoni ◽

D Soldi ◽

E E Muller ◽

D Cocchi

Keyword(s):

Body Weight ◽

Food Intake ◽

Fat Content ◽

Leptin Resistance ◽

Calorie Intake ◽

Sprague Dawley ◽

High Fat ◽

Glucose Levels ◽

Anorectic Effect

Leptin produced by adipocytes controls body weight by restraining food intake and enhancing energy expenditure at the hypothalamic level. The diet-induced increase in fat mass is associated with the presence of elevated circulating leptin levels, suggesting the development of resistance to its anorectic effect. Rats, like humans, show different susceptibility to diet-induced obesity. The aim of the present study was to compare the degree of leptin resistance in obesity-prone (OP) vs obesity-resistant (OR) rats on a moderate high-fat (HF) diet and to establish if the effects of leptin on hypothalamo–pituitary endocrine functions were preserved. Starting from 6 weeks after birth, male Sprague–Dawley rats were fed on either a commercial HF diet (fat content: 20% of total calorie intake) or a standard pellet chow (CONT diet, fat content: 3%). After 12 weeks of diet, rats fed on HF diet were significantly heavier than rats fed on CONT diet. Animals fed on HF diet were ranked according to body weight; the two tails of the distribution were called OP and OR rats respectively. A polyethylene cannula was implanted into the right ventricle of rats 1 week before central leptin administration. After 12 weeks of HF feeding, both OR and OP rats were resistant to central leptin administration (10 μg, i.c.v.) (24 h calorie intake as a percent of vehicle-treated rats: CONT rats, 62 [50; 78]; OR, 93 [66; 118]; OP, 90 [70; 120] as medians and 95% confidence intervals (CIs) of six rats for each group). Conversely, after 32 weeks of diet both OR and OP rats were partially responsive to 10 μg leptin i.c.v. as compared with CONT rats (24 h calorie intake as a percent of vehicle-treated rats: CONT rats, 60 [50; 67]; OR, 65 [50; 80]; OP, 80 [60; 98] as medians and 95% CIs of six rats for each group); the decrease of food intake following 200 μg leptin i.p. administration was similar in all the three groups (calorie intake as a percent of vehicle-treated rats: 86 [80; 92] as median and 95% CI). The long-term intake of HF diet caused hyperleptinemia, hyperinsulinemia and higher plasma glucose levels in OP rats as compared with CONT rats. Plasma thyroxine (T4) was lower in all the rats fed the HF diet as compared with CONT. i.c.v. administration of leptin after 32 weeks of diet restored normal insulin levels in OP rats. Moreover, leptin increased plasma T4 concentration and strongly enhanced GH mRNA expression in the pituitary of OP as well as OR rats (180±10% vs vehicle-treated rats). In conclusion, long-term intake of HF diet induced a partial central resistance to the anorectic effect of leptin in both lean and fat animals; the neuroendocrine effects of leptin on T4 and GH were preserved.

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Pharmacological actions of the peptide hormone amylin in the long-term regulation of food intake, food preference, and body weight

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00297.2007 ◽

2007 ◽

Vol 293 (5) ◽

pp. R1855-R1863 ◽

Cited By ~ 62

Author(s):

Christine Mack ◽

Julie Wilson ◽

Jennifer Athanacio ◽

James Reynolds ◽

Kevin Laugero ◽

...

Keyword(s):

Body Weight ◽

Weight Gain ◽

Locomotor Activity ◽

Food Intake ◽

Energy Expenditure ◽

Food Preference ◽

Body Weight Gain ◽

The Body ◽

High Fat

The ability of amylin to reduce acute food intake in rodents is well established. Longer-term administration in rats (up to 24 days) shows a concomitant reduction in body weight, suggesting energy intake plays a significant role in mediating amylin-induced weight loss. The current set of experiments further explores the long-term effects of amylin (4–11 wk) on food preference, energy expenditure, and body weight and composition. Furthermore, we describe the acute effect of amylin on locomotor activity and kaolin consumption to test for possible nonhomeostatic mechanisms that could affect food intake. Four-week subcutaneous amylin infusion of high-fat fed rats (3–300 μg·kg−1·day−1) dose dependently reduced food intake and body weight gain (ED50for body weight gain = 16.5 μg·kg−1·day−1). The effect of amylin on body weight gain was durable for up to 11 wks and was associated with a specific loss of fat mass and increased metabolic rate. The body weight of rats withdrawn from amylin (100 μg·kg−1·day−1) after 4 wks of infusion returned to control levels 2 wks after treatment cessation, but did not rebound above control levels. When self-selecting calories from a low- or high-fat diet during 11 wks of infusion, amylin-treated rats (300 μg·kg−1·day−1) consistently chose a larger percentage of calories from the low-fat diet vs. controls. Amylin acutely had no effect on locomotor activity or kaolin consumption at doses that decreased food intake. These results demonstrate pharmacological actions of amylin in long-term body weight regulation in part through appetitive-related mechanisms and possibly via changes in food preference and energy expenditure.

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Maternal Choline Intake Programs Hypothalamic Energy Regulatory Pathways and Long-Term Phenotype in Male Wistar Rat Offspring (OR35-04-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz048.or35-04-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Rola Hammoud ◽

Emanuela Pannia ◽

Chih-Sheng Liao ◽

Diptendu Chatterjee ◽

Mandy Ho ◽

...

Keyword(s):

Weight Gain ◽

Food Intake ◽

Energy Expenditure ◽

Wistar Rat ◽

In Utero ◽

Receptor Expression ◽

Rat Offspring ◽

Choline Intake ◽

Energy Regulatory

Abstract Objectives The prenatal period is a critical time of brain development. Maternal choline intake is associated with improvement in memory and cognitive function in the offspring. However, the role of choline in the regulation of physiological functions controlled by the hypothalamus has not been reported. The objective of this study is to elucidate the effects of choline intake on the in utero programming of hypothalamic energy regulatory neurons in male Wistar rat offspring. Methods Pregnant Wistar rats received an AIN-93G diet containing recommended choline (RC, 1 g/kg diet), low choline (LC, 0.5-fold), or high choline (HC, 2.5-fold). At birth, brain and blood was collected from male pups. Male pups from each dietary treatment were maintained on the control diet for 17-weeks. Dependent measures include post-weaning food intake, energy expenditure, weight-gain, plasma glucoregulatory hormones, brain choline and 1-carbon metabolite levels, and expression of hypothalamic energy regulatory neurons. Results At birth, pup brain concentrations of choline proportionally reflected the choline content in the maternal diets. HC pups had higher hypothalamic protein expression of the orexigenic neuropeptide-Y neuron than both groups (P < 0.05), but lower activation than LC pups (P < 0.05). Both HC and LC pups had lower plasma leptin concentrations than RC pups (P < 0.01), but LC pups had lower hypothalamic leptin receptor expression compared to both groups at birth (P < 0.05). During adulthood, offspring of HC dams had higher weekly food intake compared to RC (11%, P < 0.01), and higher weight-gain than both RC and LC groups (12%, P < 0.05). LC offspring had lower 24hr energy expenditure and locomotor activity than HC and RC groups (6%, P < 0.05). Conclusions Choline content of diets consumed by rats during pregnancy impacts in utero development of hypothalamic energy regulatory systems; long-term body weight-gain, food intake and energy expenditure in mature rat offspring. Funding Sources This research was supported by the Canadian Institute of Health Research, Institute of Nutrition, Metabolism and Diabetes (CIHR-INMD).

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Dietary Intakes of Folic Acid During Pregnancy Determines Maternal Re-Set of Metabolism Post-Birth in Wistar Rat Dams (FS08-06-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz044.fs08-06-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Emanuela Pannia ◽

Neil Yang ◽

Mandy Ho ◽

Rola Hammoud ◽

Ruslan Kubant ◽

...

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Folic Acid ◽

Food Intake ◽

Metabolic Pathways ◽

Wistar Rat ◽

Metabolic Effects ◽

Metabolic Phenotype ◽

Maternal Metabolism ◽

Carbon Pathways

Abstract Objectives Nutrition during pregnancy alters the “re-set” of maternal metabolism and in turn the mother's metabolic phenotype later in life. Folic acid (FA, synthetic folate) consumed at intakes above requirements during pregnancy by rats leads to increased weight gain and altered DNA methylation in central and peripheral pathways regulating food intake. The objectives of this study were to examine the effects of intakes below and above FA dietary requirements on the re-set of energy metabolic pathways in Wistar rat mothers early post-birth. Methods Pregnant Wistar rats (n = 12/group) were fed an AIN93G diet with 5 levels of FA: 0X, 1X (control, 2 mg FA/kg), 2.5X, 5X or 10X. Dams were fed 1X-FA during lactation up to 1-week post-weaning (PW) when maternal metabolism is thought to re-set to homeostasis and then terminated. Weekly body weight, food intake, expression of hypothalamic food-intake neurons, mRNA and protein expression of folate-related and energy metabolic genes, and glucoregulatory hormones were measured. The homeostatic model assessment of insulin resistance (HOMA-IR) was used as a surrogate index of insulin resistance. Results Below (0X) and above (5X and 10X) FA requirements during pregnancy suppressed expression of hepatic folate metabolism (methyltetrahydrofolate (MTHF) reductase, and methionine synthase; P < 0.05) genes and led to higher 5-MTHF (P < 0.005) in blood compared to control suggesting dysregulation of 1-carbon pathways. Dams fed 0X- and 5X-FA also had higher plasma insulin and HOMA-IR than controls and changes in glucose and lipid metabolism-regulating genes in muscle (Glucose transporter-4, and Peroxisome-proliferator activated receptors; P < 0.05) but not liver or adipose at 1-week PW. The diets did not affect expression of hypothalamic food intake neurons nor body weight or food intake of the dams from birth to 1-week PW. Conclusions FA below (0X) or above (5X, 10X) requirements during pregnancy induce dysregulation of 1-carbon pathways and delay re-set of energy metabolic pathways in Wistar rat dams by 4-weeks after birth, potentially programming long-term negative metabolic effects. Funding Sources This research was supported by: Canadian Institute of Health Research, Institute of Nutrition, Metabolism and Diabetes (CIHR-INMD); EP supported by NSERC Alexander Graham Bell Canada Graduate Scholarships-Doctoral Program (CGS D).

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High Intakes of [6S]-5-Methyltetrahydrofolic Acid Compared with Folic Acid during Pregnancy Programs Central and Peripheral Mechanisms Favouring Increased Food Intake and Body Weight of Mature Female Offspring

Nutrients ◽

10.3390/nu13051477 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1477

Author(s):

Emanuela Pannia ◽

Rola Hammoud ◽

Ruslan Kubant ◽

Jong Yup Sa ◽

Rebecca Simonian ◽

...

Keyword(s):

Body Weight ◽

Folic Acid ◽

Food Intake ◽

Leptin Receptor ◽

Liver Weight ◽

Female Offspring ◽

Mature Female ◽

Cytokine Signaling ◽

Light Cycle ◽

Energy Regulation

Supplementation with [6S]-5-methyltetrahydrofolic acid (MTHF) is recommended as an alternative to folic acid (FA) in prenatal supplements. This study compared equimolar gestational FA and MTHF diets on energy regulation of female offspring. Wistar rats were fed an AIN-93G diet with recommended (2 mg/kg diet) or 5-fold (5X) intakes of MTHF or FA. At weaning, female offspring were fed a 45% fat diet until 19 weeks. The 5X-MTHF offspring had higher body weight (>15%), food intake (8%), light-cycle energy expenditure, and lower activity compared to 5X-FA offspring (p < 0.05). Both the 5X offspring had higher plasma levels of the anorectic hormone leptin at birth (60%) and at 19 weeks (40%), and lower liver weight and total liver lipids compared to the 1X offspring (p < 0.05). Hypothalamic mRNA expression of leptin receptor (ObRb) was lower, and of suppressor of cytokine signaling-3 (Socs3) was higher in the 5X-MTHF offspring (p < 0.05), suggesting central leptin dysregulation. In contrast, the 5X-FA offspring had higher expression of genes encoding for dopamine and GABA- neurotransmitter receptors (p < 0.01), consistent with their phenotype and reduced food intake. When fed folate diets at the requirement level, no differences were found due to form in the offspring. We conclude that MTHF compared to FA consumed at high levels in the gestational diets program central and peripheral mechanisms to favour increased weight gain in the offspring. These pre-clinical findings caution against high gestational intakes of folates of either form and encourage clinical trials examining their long-term health effects when consumed during pregnancy.

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