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. 2025 Dec 10;156(2):101267. doi: 10.1016/j.tjnut.2025.101267

Maternal Sucrose Intake during Pregnancy Alone Disrupts Testosterone and Allopregnanolone Levels in the Fetal Brain of Rats

Minseon M Jung 1,2,⁎, Marwa Idrissi 2, Yen-Nhi Hoang 3, Tao Huan 2,3, Désirée R Seib 2,4,5, Kiran K Soma 1,2,4,6
PMCID: PMC12975371  PMID: 41386554

Abstract

Background

Intake of added sugars, such as sucrose, is high globally. In rats, a maternal high-sucrose diet (HSD) from 10 wk before pregnancy to embryonic day (E)19.5 has widespread impacts on maternal, placental, and fetal blood and brain steroid levels, including glucocorticoids, androgens, and aldosterone.

Objectives

This study examined whether maternal HSD during pregnancy alone is sufficient to alter maternal, placental, and fetal steroids.

Methods

Pregnant rats received either a control diet (1% kcal sucrose) or an isocaloric, nutrient-matched HSD (26% kcal sucrose) between E0.5 and 19.5. On E19.5, we collected maternal serum, placenta, fetal blood and brain, and amniotic fluid. We microdissected the placenta and fetal brain and measured 14 steroids using liquid chromatography tandem mass spectrometry (n = 12–15/diet/sex).

Results

Maternal HSD during pregnancy alone did not alter maternal food intake, maternal body mass, and litter size (all P values ≥ 0.29, Student’s t-test) but increased the percentage of males in a litter (P = 0.03, Student’s t-test). Maternal HSD did not alter steroids in the maternal serum (all P values ≥ 0.21, Student’s t-test), placenta [all P values ≥ 0.07, 2-way analysis of variance (ANOVA)], and fetal blood (all P values ≥ 0.13, 2-way ANOVA). Nonetheless, maternal HSD increased testosterone in the fetal nucleus accumbens (P = 0.04, 2-way ANOVA), decreased allopregnanolone in the fetal amygdala (P = 0.01, 2-way ANOVA), and decreased 11-dehydrocorticosterone in the amniotic fluid (P = 0.05, 2-way ANOVA).

Conclusions

Maternal HSD during pregnancy alone does not affect steroid levels in the maternal serum, placenta, or fetal blood of rats, but disrupts testosterone and allopregnanolone levels in critical regions of the fetal brain that regulate reward-seeking and emotion. Thus, although a long-term maternal HSD is necessary for widespread endocrine effects, the fetal brain is sensitive to short-term increases in maternal sucrose consumption during pregnancy.

Keywords: sugar, maternal diet, stress, neurosteroids, steroid profiling

Introduction

Added sugar intake around the world exceeds recommendations (<10% of total energy intake) [1,2]. Females increase sweetened food consumption during pregnancy [3], and high maternal sugar intake is associated with pregnancy complications, gestational weight gain [4], and increased weight in children [5,6]. Conversely, individuals exposed to sugar rationing in utero and during early life have reduced risk of type 2 diabetes and hypertension [7].

Sucrose (table sugar) is a common added sugar. The metabolic and cardiovascular effects of sucrose are well studied [8,9], but little is known about its impacts on the brain and behavior. In humans, sugar intake is associated with depression, addiction-related behaviors, and impulsivity [10,11]. In adult rodents, sucrose intake alters synaptic transmission, memory, and locomotion [[12], [13], [14], [15]]. Very few studies have examined how maternal sucrose consumption affects the vulnerable offspring brain. In rodents, in utero or perinatal sucrose exposure increases locomotion [16], impairs spatial memory [[17], [18], [19]], and increases hippocampal apoptosis [18].

There are limitations to these previous animal studies. First, some studies compared a standard rodent chow with a high-sugar diet, but these 2 diets also differed in caloric density and nutrient composition [[20], [21], [22]]. Moreover, some standard rodent chows and purified diets (e.g. AIN-76A) contain ≤500 g/kg of sucrose [[23], [24], [25]] and are not appropriate control diets. Second, in some studies, sugar was administered in drinking water [12,16,[24], [25], [26]], which reduces food consumption [[25], [26], [27]] and thus decreases intakes of protein, fat, and micronutrients. Third, some studies gave diets with 60% to 70% kcal from sugar [17,20,22,28], which is far above average human intakes. Lastly, some studies used diets that are high in sugar and fat [21,29], which cannot isolate the effects of sugar.

To address these limitations, we designed a custom high-sucrose diet (HSD) containing a human-relevant level of sucrose [30] that is isocaloric, and macronutrient and micronutrient matched to a control diet (CON) [[31], [32], [33]]. Using these diets, we showed that long-term maternal HSD has impacts on maternal, placental, and fetal steroid levels at embryonic day (E)19.5 [31]. Maternal HSD starting 10 wk prepregnancy and during pregnancy increased glucocorticoids, which regulate metabolism and stress responses, in the maternal serum. Maternal HSD also decreased placenta mass and placental androgens. Furthermore, maternal HSD increased aldosterone, a mineralocorticoid and mediator of stress responses [34,35], in the fetal blood. Similarly, in the fetal brain, maternal HSD increased aldosterone and decreased testosterone in the nucleus accumbens (NAc), a critical node in the “reward circuit.” Lastly, maternal HSD increased the 11-dehydrocorticosteorne (DHC)/corticosterone ratio in several regions of the fetal brain.

Moreover, maternal HSD from 10 wk prepregnancy to offspring weaning increases baseline blood and brain corticosterone levels in adult female offspring and increases motivation for sugar and preference for palatable diets in adult male offspring [33]. Thus, maternal HSD has multiple effects on hormones and behavior of adult offspring.

It is unclear whether long-term maternal sucrose intake is necessary to impact the fetuses, or whether maternal sucrose intake during pregnancy alone is sufficient. In this study, we examined the effects of short-term (∼3 wk) maternal HSD on maternal, placental, and fetal steroids. We hypothesized that maternal sucrose intake during pregnancy alone is sufficient to alter steroids in maternal serum, placenta, fetal blood, and fetal brain. We measured 14 steroids using ultrasensitive and specific liquid chromatography tandem mass spectrometry (LC-MS/MS). We focused on fetal brain regions important for motivation, emotion, and homeostasis.

Methods

Diets

We used CON (1% kcal sucrose; D12450ki; Research Diets Inc.) or custom-designed HSD (26% kcal sucrose; D20061801i; Research Diets, Inc Supplementary Table 1). The CON and HSD are isocaloric (3.8 kcal/g) and macro/micronutrient matched (10% kcal fat, 20% kcal protein, and 70% kcal carbohydrates). In the HSD, 25% kcal from corn starch is replaced with sucrose. Female rats consumed CON and HSD for 19 d of pregnancy (detailed below).

Animals

Adult virgin female Long-Evans rats (Rattus norvegicus) (n = 16/diet; postnatal day 57–63, 188–262 g; Charles River Laboratories) were pair housed with ad libitum access to standard rodent chow (Rat diet 2918; Harlan Teklad Global) and water (reverse osmosis purification and chlorination sterilization) upon arrival. All animals were housed in clear, plastic ventilated Allentown cages with Beta chip for bedding. Animals were given paper towels and a polyvinylchloride tube for enrichment. The vivarium was temperature and humidity-controlled (21–22°C and 40%–60% relative humidity) with standard 12 h light:12 h darkness cycles (lights on 08:30–20:30). Sample size was determined based on the pregnancy success and findings of previous work [31,32].

Adult male Long-Evans rats (n = 32 total; postnatal days 77–84, 363–435 g; Charles River Laboratories) were housed under the same conditions and pair housed with another male. All procedures were approved by the University of British Columbia Animal Care Committee and were in accordance with the Canadian Council on Animal Care. The protocol was not preregistered.

Breeding and diet manipulation

After 1 wk of acclimation, all animals were handled daily for 3 d. Female rats were randomly assigned to either a CON or HSD and were gradually introduced to their respective diets by adding 6 diet pellets at the bottom of the cage for 3 d, starting on the last day of handling. Females underwent daily vaginal lavage to assess the stage of the estrous cycle. Males were single housed starting 2 to 3 d before mating. When a female rat was in proestrus or estrus, the subject was added to a male cage 2 to 3 h before lights off. The following morning (within 1 h of lights on), the female was lavaged to check for sperm. If sperm were present, then the subject was considered pregnant, removed from the male cage, and single housed. The day of pregnancy confirmation was defined as E0.5. The female was monitored for body mass increases to confirm pregnancy. If sperm were absent, then the female was still single housed, and we continued to monitor the female’s body mass and estrous cycle and repaired the female with the same male when she returned to proestrus or estrus. Each female was mated with a different male.

Starting on E0.5, females were fully transitioned onto their respective diets with ad libitum access until euthanasia at E19.5. Body mass was measured daily except for the day of euthanasia, and food consumption was measured on E6.5, 12.5, and 19.5. In sum, 30 animals became pregnant and carried fetuses until E19.5 (n = 15/diet).

Tissue collection

Dams were euthanized on E19.5, which is 2 to 3 d before parturition [36]. We selected E19.5 to avoid the increase in glucocorticoid levels close to birth [37], to include the increase in testosterone levels in male fetuses [38], and to match our previous study [31]. On E19.5, dams were euthanized between 11:30 and 13:30 (3–5 h after lights on). Dams were rapidly and deeply anesthetized using 5% isoflurane and euthanized by rapid decapitation (within 3 min of initial cage disturbance) to minimize the effects of stress on steroid levels [39]. For maternal serum, trunk blood was collected and kept on wet ice (30–90 min) and centrifuged for 3 to 5 min at 5080 × g. The serum was immediately frozen on dry ice and stored at −70°C.

Then, the uterine horns were dissected, and the litter size and number of resorptions were recorded. For each fetus, the amniotic fluid was collected using an 18G needle and a syringe. Next, the placenta was removed and rinsed twice in 1× phosphate-buffered saline to remove blood. The fetus was decapitated for the brain, and trunk blood was collected using a P20 pipette. The fetal tail was collected to determine sex by genotyping. All samples were immediately frozen on dry ice and stored at −70°C. One female and one male fetus per dam and their respective placenta and amniotic fluid were used for steroid analysis to control for litter effects (n = 12–15/diet/sex).

Placenta and brain microdissection

Placenta was weighed, coated with Optimal Cutting Temperature compound, and sectioned at 300 μm in a cryostat at −14°C. Each section contained both junctional and labyrinth zones. A 1 mm diameter biopsy punch tool (Miltex, Fisher Scientific) was used to dissect the junctional and labyrinth zones [31,40]. Twenty punches were collected per zone (3.66 mg/zone).

The fetal head was also coated with Optimal Cutting Temperature compound and sectioned coronally at 300 μm in a cryostat at −14°C. The NAc, amygdala (AMY), hypothalamus (HYP), ventral hippocampus (vHPC), and ventral tegmental area (VTA) were microdissected bilaterally with a 1 mm diameter biopsy punch tool. The NAc and VTA are nodes of the mesocorticolimbic “reward” circuit. The AMY and vHPC regulate emotion and anxiety. The HYP is important for homeostasis and the stress response. Depending on the region, a total of 4 to 8 punches were collected (0.8–1.6 mg/region). The samples were stored in 2 mL polypropylene microcentrifuge tubes containing 5 zirconium ceramic oxide beads (1.4 mm diameter) at −70°C.

Steroid quantification via LC-MS/MS

Steroids were extracted as previously described [[31], [32], [33],41]. The sample order was randomly assigned, and experimenters were blinded. We measured steroids in 5 μL of maternal serum, 10 μL of amniotic fluid, 5 μL of fetal blood, 3.66 mg of each placental zone, and 0.8 to 1.6 mg of fetal brain. Briefly, for each sample, 1 mL of HPLC-grade acetonitrile and 20 to 200 pg of deuterated internal standards [dehydroepiandrosterone (DHEA)-d6, progesterone-d9, pregnenolone-d4, corticosterone-d8, testosterone-d5, 17β-estradiol-d4, aldosterone-d7, allopregnanolone-d4] were added. Samples were homogenized in a bead homogenizer for 30 s at 4 m/s and then centrifuged for 5 min at 16,100 × g. Then, 1 mL of supernatant was transferred to precleaned glass culture tubes. Next, 500 μL of HPLC-grade hexane was added, samples were vortexed and centrifuged, and hexane was discarded. Samples were dried in a vacuum centrifuge at 60°C for 45 min. Steroids were resuspended in 55 μL 25% HPLC-grade methanol, centrifuged at 16,100 × g, and 50 μL of supernatant was transferred to HPLC vials with glass inserts. Samples were stored at −20°C.

A calibration curve from 0.05 to 5000 pg per tube was used for: DHEA, pregnenolone, progesterone, 11-deoxycorticosterone (DOC), corticosterone, DHC, androstenedione, testosterone, estrone, 17β-estradiol, estriol, aldosterone, allopregnanolone, and tetrahydrodeoxycorticosterone (Supplementary Figure 1). These steroids are important for pregnancy and placental and fetal development [42,43], and their levels are affected by maternal stress and diet [[44], [45], [46]]. Duplicates of blanks, double blanks, and quality controls, and triplicates of interassay serum controls (pooled maternal serum) were included. Quality controls were considered acceptable when within 20% of expected values.

Steroids were quantified using a SCIEX 6500 QTRAP triple quadrupole tandem mass spectrometer (SCIEX LLC). Positive electrospray ionization was used except for estrone, 17β-estradiol, and estriol, which were quantified using negative electrospray ionization. Each analyte was monitored using 2 multiple reaction monitoring transitions. Internal standards were monitored using 1 multiple reaction monitoring transition. Peaks were absent in all blanks and double blanks, and quality controls were acceptable. All samples were measured in a single measurement.

Sucrose quantification via LC-MS/MS

Maternal serum (20 μL) was mixed with 160 μL ice-cold methanol and stored at −20°C for 4 h for protein precipitation and then centrifuged at 14,000 × g for 15 min at 4°C. The supernatant was transferred to new tubes and dried at 24°C for 3 h. Samples were reconstituted in 100 μL acetonitrile/H2O (1:1, v/v) on the day of analysis. All solvents were LC-MS grade. A method blank was prepared by subjecting an empty vial to the same extraction procedure. A total of 10 μL aliquots of all maternal serum were combined to create quality control. The sucrose stock solution was prepared at 500 ng/mL in acetonitrile/H2O (1:1, v/v) using a pure standard and diluted to 70 ng/mL for retention time confirmation during analysis. Each serum sample was measured in a single measurement.

Targeted sucrose quantification was performed on a Thermo Scientific TSQ Quantis Triple Quadrupole mass spectrometer operated in electron spray ionization and multiple reaction monitoring mode, coupled to a Vanquish Horizon ultrahigh performance liquid chromatography system (Thermo Fisher Scientific). The 2 most intense product fragments were selected for multiple reaction monitoring transitions. Quality control samples were run every 6 injections, and the standard solution was analyzed at the beginning and end of the run. The relative SD for the quality controls was <10%, which is acceptable. Further details are in the Supplementary Materials and Methods.

Data analysis

For steroid analysis, chromatograms were analyzed using MultiQuant software. Lower limit of quantification (LLOQ) is defined as the lowest point on the calibration curve that can be accurately and reliably measured with a signal-to-noise ratio >5. DHEA, estriol, and tetrahydrodeoxycorticosterone were below the LLOQ in all samples. Aldosterone and 17β-estradiol were above the LLOQ in the maternal serum and amniotic fluid only. DOC, corticosterone, DHC, progesterone, and androstenedione were above the LLOQ in all samples. For testosterone, pregnenolone, allopregnanolone, and estrone, ≥50% of samples were above the LLOQ, and values below the LLOQ were imputed using quantile regression imputation of left-censored missing data [47]. One dam and the corresponding placenta and fetal samples were excluded from steroid analysis because of complications during euthanasia and excessive handling stress.

For sucrose analysis, raw data were exported as .csv files from chromatograms using Thermo Freestyle. Peak areas and retention times were extracted using a custom Python script. Sucrose identity was confirmed by retention time matching with the standard.

Statistical analysis was conducted on GraphPad Prism 10.4.0, and α was set at ≤0.05. If the data did not meet the normality or homogeneity of variance assumptions, then the data were log-transformed before analyses. All data are presented using nontransformed data (mean ± standard mean error). For maternal and pregnancy outcomes and maternal serum analysis (steroids and sucrose), 2-tailed Student’s t-tests were conducted. For placenta, fetal blood, fetal brain, and amniotic fluid steroid data, 2-way analysis of variance was conducted to assess the main effects of diet and sex, and their interaction.

Results

Maternal and pregnancy outcomes

Maternal HSD during pregnancy alone did not affect daily food intake of dams [Figure 1A; t(28) = 0.21, P = 0.83] and body mass gain of dams from E0.5 to E18.5 [Figure 1B; t(28) = 1.08, P = 0.29]. The HSD increased sucrose levels in the maternal serum [Figure 1C; t(28) = 10.32, P < 0.0001].

FIGURE 1.

FIGURE 1

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Maternal and pregnancy outcomes. Maternal HSD during pregnancy alone did not alter (A) daily food intake of dams, (B) total body mass gain of dams from E0.5 to E18.5, but (C) increased sucrose levels in the maternal serum. Maternal HSD during pregnancy alone did not change (D) litter size, and (F) number of resorptions, but (E) increased the percentage of male offspring per litter. Data are presented as mean ± SEM. n = 15/diet. Data were analyzed using Student’s t-tests. ∗P ≤ 0.05, ∗∗∗∗P ≤ 0.0001. CON, control diet; cps: counts per second; HSD, high-sucrose diet.

Maternal HSD during pregnancy alone did not alter litter size [Figure 1D; t(28) = 0.81, P = 0.42] but increased the percentage of male fetuses in a litter [Figure 1E; t(28) = 2.25, P = 0.03]. The number of resorptions did not differ between the diet groups [Figure 1F; t(16) = 0.29, P = 0.78].

Maternal serum steroids

Maternal HSD during pregnancy alone did not alter levels of DOC, corticosterone, DHC, and aldosterone in the maternal serum (Figure 2A–D; all P values ≥ 0.40). The other steroids measured in the maternal serum were also unaffected by HSD (Supplementary Table 2).

FIGURE 2.

FIGURE 2

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Steroids in the maternal serum. Maternal HSD during pregnancy alone did not alter steroids in the maternal serum, including (A) DOC, (B) corticosterone, (C) DHC, and (D) aldosterone. Data are presented as mean ± SEM. n = 14–15/diet. Data were analyzed using Student’s t-tests. CON, control diet; DHC, 11-dehydrocorticosterone; DOC, 11-deoxycorticosterone; HSD, high-sucrose diet.

Placental mass and steroids

Maternal HSD during pregnancy alone did not change placenta mass [Figure 3A; diet: F(1,47) = 0.34, P = 0.54; sex: F(1,47) = 2.15, P = 0.15; diet × sex: F(1,47) = 0.98, P = 0.33]. We examined steroids in the junctional and labyrinth zones of the placenta (Figure 3B). Maternal HSD did not alter androstenedione and testosterone levels in both zones of the placenta (Figure 3C–F; all P values ≥ 0.50). There was a main effect of sex for androstenedione and testosterone levels in the junctional zone (males > females, both P values ≤ 0.0002), but not in the labyrinth zone (both P values ≥ 0.13), as before [31]. There were no diet × sex interactions for androstenedione and testosterone levels in both zones (both P values ≥ 0.77). Qualitatively, androstenedione levels were higher than testosterone levels in both zones. Maternal HSD also did not affect other steroids measured in the placenta (Supplementary Table 3).

FIGURE 3.

FIGURE 3

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Androgens in the junctional zone and labyrinth zone of the placenta. (A) Maternal HSD during pregnancy alone did not alter placenta mass. (B) Cross-section of the placenta depicting the junctional and labyrinth zones. Maternal HSD during pregnancy alone did not alter (C,E) androstenedione and (D,F) testosterone levels in the junctional and labyrinth zones of the placenta. Androstenedione and testosterone levels were higher in males than in females in the labyrinth zone. Data are presented as mean ± SEM. n = 12–15/diet/sex. Data were analyzed using 2-way analysis of variances. Main effect of sex indicated in the figure, P ≤ 0.001. CON, control diet; HSD, high-sucrose diet.

Androgens and allopregnanolone in the fetal blood and brain

In the fetal blood, there were no main effects of diet on androstenedione, testosterone, or allopregnanolone (Figure 4A–C; all P values ≥ 0.41). In the NAc, maternal HSD increased testosterone levels [Figure 4E; diet: F(1,53) = 4.63, P = 0.04], but did not alter androstenedione and allopregnanolone levels [Figure 4D, F; both P values ≥ 0.12]. In the AMY, maternal HSD reduced allopregnanolone [Figure 4I; diet: F(1,53) = 6.66 P = 0.01] but had no effects on androstenedione and testosterone [Figure 4G,H; both P values P ≥ 0.13]. Maternal diet did not affect other steroids measured in the fetal blood and brain (Supplementary Table 4). In the fetal blood, there was a main effect of sex for corticosterone (Supplementary Table 4; males < females, P = 0.05).

FIGURE 4.

FIGURE 4

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Steroids in the fetal blood and brain. Maternal HSD during pregnancy alone did not affect (A) androstenedione, (B) testosterone, and (C) allopregnanolone in the fetal blood. Maternal HSD during pregnancy alone did not alter (D) androstenedione and (F) allopregnanolone but increased (E) testosterone in the NAc. Maternal HSD during pregnancy alone did not change (G) androstenedione and (H) testosterone but decreased (I) allopregnanolone in the AMY. Males have higher androstenedione and testosterone levels than females in the blood, NAc, and AMY. Data are presented as mean ± SEM. n = 14–15/diet/sex. Data were analyzed using 2-way analysis of variances. Main effect of diet and sex indicated in the figure, P ≤ 0.05, P ≤ 0.0001. AMY, amygdala; CON, control diet; HSD, high-sucrose diet; NAc, nucleus accumbens.

In the fetal blood, NAc, and AMY, there were main effects of sex for androstenedione and testosterone levels (males > females, all P values < 0.0001). There were no diet × sex interactions for androstenedione, testosterone, or allopregnanolone (all P values ≥ 0.16). Qualitatively, androstenedione levels were higher than testosterone levels in the fetal blood and brain.

DHC/corticosterone ratio in the fetal blood and brain

There were no main effects of diet or diet × sex interactions on DHC/corticosterone ratio in the fetal blood and fetal brain regions (Table 1; all P values ≥ 0.11). There was a main effect of sex in the HYP [Table 1; sex: F(1,53) = 4.40, P = 0.04], but not in other brain regions. In the fetal blood, corticosterone levels were greater than DHC levels (ratio <1). In contrast, in all brain regions, DHC levels were greater than corticosterone levels (ratio >1).

TABLE 1.

DHC/corticosterone ratio in the blood and brain of fetal offspring exposed to maternal CON or HSD

Tissue CON male HSD male CON female HSD female Diet
 Sex
 Diet × Sex
F P F P F P
Blood 0.22 ± 0.01 0.20 ± 0.02 0.20 ± 0.01 0.18 ± 0.01 1.55 0.22 1.56 0.22 0.01 0.92
NAc 1.31 ± 0.12 1.10 ± 0.14 1.23 ± 0.14 1.04 ± 0.09 2.68 0.11 0.42 0.52 0.19 0.66
AMY 1.55 ± 0.14 1.46 ± 0.13 1.39 ± 0.11 1.36 ± 0.09 0.29 0.59 1.20 0.28 0.05 0.82
HYP 2.07 ± 0.18 1.78 ± 0.15 1.57 ± 0.14 1.61 ± 0.15 0.73 0.40 4.40 0.04 0.90 0.35
vHPC 1.25 ± 0.12 1.13 ± 0.12 1.12 ± 0.10 1.13 ± 0.08 0.26 0.61 0.22 0.64 0.65 0.42
VTA 1.62 ± 0.13 1.39 ± 0.12 1.58 ± 0.19 1.47 ± 0.11 1.02 0.32 0.00 0.95 0.65 0.42
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n = 14–15/diet/sex. Data are presented as mean ± SEM. Data were analyzed using 2-way analysis of variances.

Abbreviations: AMY, amygdala; CON, control diet; DHC, 11-dehydrocorticosterone; HSD, high-sucrose diet; HYP, hypothalamus; NAc, nucleus accumbens; vHPC, ventral hippocampus; VTA, ventral tegmental area.

DHC in the amniotic fluid

Maternal HSD reduced DHC levels in the amniotic fluid [Figure 5C; diet: F(1,54) = 4.08, P = 0.05], but did not affect DOC, corticosterone, and aldosterone levels (Figure 5A, B, D; all values P ≥ 0.25). There were no main effects of sex or diet × sex interactions for DOC, corticosterone, DHC, and aldosterone (all P values ≥ 0.06). Maternal HSD did not affect other steroids measured in the amniotic fluid (Supplementary Table 5).

FIGURE 5.

FIGURE 5

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Steroids in the amniotic fluid. Maternal HSD during pregnancy alone did not affect (A) DOC, (B) corticosterone, and (D) aldosterone levels in the amniotic fluid but reduced (C) DHC levels in the amniotic fluid. Data are presented as mean ± SEM. n = 14–15/diet/sex. Data were analyzed by 2-way analysis of variances. Main effect of diet indicated in the figure, P ≤ 0.05. CON, control diet; DHC, 11-dehydrocorticosterone; DOC, 11-deoxycorticosterone; HSD, high-sucrose diet.

Discussion

We investigated the effects of a short-term (∼3 wk) maternal HSD during pregnancy alone. First, short-term maternal HSD increases the percentage of male offspring. Second, maternal, placental, and fetal blood steroid levels, as well as DHC/corticosterone ratio in the fetal blood and brain, are not affected by short-term maternal HSD. Third, short-term maternal HSD increases testosterone in the NAc and decreases allopregnanolone in the AMY of the fetal brain. Lastly, short-term maternal HSD decreases DHC in the amniotic fluid. Thus, short-term maternal HSD is sufficient to impact steroids in critical regions of the fetal brain. In contrast, long-term maternal HSD (∼13 wk) has widespread effects on maternal, placental, and fetal steroids [31].

Maternal HSD during pregnancy alone does not alter maternal food intake and body mass but increases the percentage of male offspring

Maternal HSD does not affect maternal food intake and body mass, as before [31,32]. Thus, group differences cannot be attributed to increased maternal caloric intake or adiposity.

Short-term maternal HSD increases the percentage of male fetuses. In contrast, long-term maternal HSD starting 10 wk before mating does not alter offspring sex ratio [31,32]. Thus, the duration of maternal sucrose intake might be important for offspring sex ratio. Another possible explanation is the age of the dams. Dams in the present study were ∼10 wk younger than those in our previous studies and had higher pregnancy success and larger litters, which may have contributed to group differences. The Trivers–Willard hypothesis proposes that better maternal condition leads to a greater proportion of male offspring to maximize reproductive success [48,49]. Blood glucose is a potential indicator of maternal condition and is increased by sucrose intake [50]. In vitro, higher glucose levels favor the survival of male bovine blastocysts [51]. In voles and mice, females with higher blood glucose produce a greater proportion of males [52,53]. Similarly, maternal fructose intake increases the proportion of males in rats [54].

Maternal HSD during pregnancy alone does not impact maternal and placental steroids

Short-term maternal HSD does not alter maternal circulating steroid levels at E19.5. In contrast, long-term maternal HSD starting 10 wk prepregnancy increases DOC and DHC levels in maternal serum at E19.5 [31]. Other rodent studies showed decreases in maternal circulating corticosterone levels following 6+ wk of sucrose intake [29,32].

Maternal HSD during pregnancy alone does not alter placenta mass at E19.5. In contrast, long-term maternal HSD reduces placenta mass at E19.5 [31]. In rats, maternal fructose intake during gestation alone decreases female placenta mass at E21.5 [27]. In vitro fertilized embryos implanted into fructose-fed mice have a smaller placenta at E14.5 [55]. Thus, a longer duration or higher maternal sugar intake is likely required to alter placental mass. Moreover, maternal HSD during pregnancy alone does not alter placental steroids, whereas long-term maternal HSD reduces placental androgens that promote placental development [31,42].

Maternal HSD during pregnancy alone alters fetal brain steroids

The NAc is a key node of the mesocorticolimbic system, an important circuit for executive function and reward processing. The NAc is particularly sensitive to sugar intake [15,56,57]. Moreover, the NAc is modulated by androgens [58,59] and expresses androgenic enzymes [60]. Maternal HSD during pregnancy alone increases testosterone levels in the fetal NAc, but not in the fetal blood and other brain regions. In contrast, long-term maternal HSD decreases testosterone levels in the fetal NAc [31] and reduces expression of Cyp17a1, an androgenic enzyme, in the NAc of adult male offspring [33]. Thus, testosterone production in the NAc is highly sensitive to maternal HSD in a time-dependent manner. Changes in androgen signaling in the NAc might alter food preferences and motivation for sugar rewards [33].

The AMY is important for emotional processing. Short-term maternal HSD reduces allopregnanolone levels in the fetal AMY, but not in the fetal blood and other brain regions. The AMY expresses the steroidogenic enzymes to synthesize allopregnanolone [61]. In mice, chronic unpredictable stress reduces allopregnanolone levels in the AMY [62]. Furthermore, allopregnanolone is implicated in anxiety and depression. Low serum allopregnanolone levels during pregnancy are associated with anxiety and depressive symptoms in pregnant and postpartum females [63,64]. Allopregnanolone administration to the AMY decreases anxiety-like behavior [65,66] and depressive-like behavior in rats [67]. Thus, the AMY is a key site of action for the anxiolytic and antidepressant effects of allopregnanolone.

Maternal HSD during pregnancy alone does not alter DHC/corticosterone ratio in the fetal blood and brain

Corticosterone can be metabolized into inactive DHC via 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2). Here, short-term maternal HSD does not affect glucocorticoid levels and the DHC/corticosterone ratio in the fetal blood and brain. In contrast, long-term maternal HSD alters glucocorticoids in fetal and adult offspring [31,33] and increases the DHC/corticosterone ratio in the fetal brain [31]. In mice, maternal sucrose intake pre- and during pregnancy decreases glucocorticoid receptor mRNA in the female fetal brain [29]. Maternal fructose or high-fructose corn syrup consumption during pregnancy and lactation increases circulating corticosterone [68,69] and increases 11β-HSD2 mRNA in the hippocampus [24,25] of adult rat male offspring. Overall, long-term maternal sugar intake has prominent effects on several aspects of glucocorticoid signaling in offspring.

Maternal HSD during pregnancy alone reduces DHC in the amniotic fluid

Short-term maternal HSD reduces DHC levels in the amniotic fluid. In contrast, long-term maternal HSD increases DHC levels in the amniotic fluid [31], suggesting that the duration of sucrose intake is important. Fetal urine contributes to the amniotic fluid [70] and a reduction in DHC in the amniotic fluid could indicate changes in fetal glucocorticoid excretion. In rats, maternal fructose or high-fructose corn syrup intake reduces 11β-HSD2 expression in offspring adrenal glands and kidneys, respectively [68,69]. Thus, maternal sugar intake might alter offspring corticosterone clearance through 11β-HSD2.

Aldosterone levels in the placental and fetal tissues

Aldosterone regulates blood pressure and the stress response. Circulating aldosterone levels increase following a stressor [35], particularly in the perinatal period [34]. High fructose intake drives aldosterone production and high blood pressure [71]. Long-term maternal HSD increases aldosterone levels in the placenta, fetal blood, fetal brain, and amniotic fluid [31], suggesting that long-term maternal HSD is a stressor that strongly increases aldosterone levels.

Short-term maternal HSD does not alter aldosterone levels in maternal serum and amniotic fluid, in contrast to long-term maternal HSD [31]. Thus, a longer sucrose intake might increase aldosterone levels. Here, aldosterone levels in the placental and fetal tissues are just below the LLOQ. The assay sensitivity in the present study was comparable to that in our previous study [31], but the background (“noise”) was slightly higher. In our previous study, aldosterone levels were slightly above the LLOQ in the CON group and were increased by long-term maternal HSD [31]. It is possible that aldosterone levels were unchanged by short-term maternal HSD and just below the LLOQ in both groups.

Limitations

Rat models allow controlled experiments and share many aspects of the endocrine system with humans [[72], [73]]. However, there are several limitations. First, pregnancy in rats is much shorter (∼21 d) than humans and several neurodevelopmental processes that occur during pregnancy in humans occur postnatally in rats [74]. Second, placental morphology and steroidogenic enzyme expression differ between rats and humans [41,75]. For example, the CYP17A1 enzyme is present in rat, but not human, placenta [75]. Another study limitation is only including 1 dose of sucrose, as opposed to a range.

In conclusion, maternal HSD during pregnancy alone does not alter maternal, placental, and fetal blood steroids, but does alter testosterone and allopregnanolone in key regions of the fetal brain and decreases DHC in the amniotic fluid in rats. Thus, specific fetal brain regions are sensitive to short-term maternal sucrose intake. In contrast, long-term maternal HSD has widespread effects on maternal, placental, and fetal steroids. Our findings, together with previous studies, demonstrate that sucrose intake during pregnancy impacts the developing offspring brain. Future studies will examine brain steroidogenic enzymes and reward-seeking and anxiety-like behaviors in offspring. Additionally, future studies can compare the effects of maternal sucrose, glucose, and fructose diets, as fructose might drive the effects of sucrose intake [69,71,76].

Author contributions

The authors’ responsibilities were as follows – MMJ, DRS, KKS: designed research; MMJ, MI, Y-NH: conducted research; MMJ, MI, DRS, TH, Y-NH: analyzed data; MMJ, TH, KKS: primary responsibility for final content; and all authors: wrote the paper and read and approved the final manuscript.

Data availability

Data described in the manuscript are publicly and freely available at https://doi.org/10.17605/OSF.IO/3PMN4.

Funding

This research was supported by a Project Grant from the Canadian Institute of Health Research (CIHR) to KKS (grant number: 168928); Discovery Grant from the National Sciences and Engineering Research Council of Canada (NSERC) to TH (grant number: RGPIN-2025-06908); University of British Columbia (UBC) Four-Year Doctoral Fellowship, Cordula and Gunther Paetzold Affiliated Fellowship, and Djavad Mowafaghian Centre for Brain Health General Award to MMJ; UBC Science Undergraduate Research Experience Award to MI; and postdoctoral fellowship from the Social Exposome Cluster and Human Early Learning Partnership (HELP) of UBC and University of Prince Edward Island Jeanne and J.-Louis Lévesque Research Chair in Human Health to DRS.

Conflict of interest

The authors report no conflicts of interest.

Acknowledgments

We thank Hui W. Chen for assistance with data collection; Dr. Asmita Poudel for assistance with mass spectrometry; Dr. Angela Devlin for comments on the manuscript; Dr. Melody Salehzadeh for help with Figure 1; Zeyu Yang for help with Figure 3B; University of British Columbia (UBC) Centre for Disease Modelling staff for animal husbandry; and UBC Genotyping facility for data collection.

Footnotes

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.tjnut.2025.101267.

Appendix A. Supplementary data

The following is the supplementary data to this article:

Multimedia component 1
mmc1.pdf (377.6KB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Multimedia component 1
mmc1.pdf (377.6KB, pdf)

Data Availability Statement

Data described in the manuscript are publicly and freely available at https://doi.org/10.17605/OSF.IO/3PMN4.

Articles from The Journal of Nutrition are provided here courtesy of American Society for Nutrition

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