Prenatal and postnatal mothering by diesel exhaust PM2.5-exposed dams differentially program mouse energy metabolism
- Minjie Chen†1, 2,
- Shuai Liang†2, 3,
- Huifen Zhou2, 4,
- Yanyi Xu1,
- Xiaobo Qin2,
- Ziying Hu2, 5,
- Xiaoke Wang2, 6,
- Lianglin Qiu2, 6,
- Wanjun Wang1,
- Yuhao Zhang7 and
- Zhekang Ying1, 2Email author
© The Author(s). 2017
Received: 21 October 2016
Accepted: 11 January 2017
Published: 18 January 2017
Obesity is one of the leading threats to global public health. It is consequent to abnormal energy metabolism. Currently, it has been well established that maternal exposure to environmental stressors that cause inappropriate fetal development may have long-term adverse effects on offspring energy metabolism in an exposure timing-dependent manner, known as developmental programming of health and diseases paradigm. Rapidly increasing evidence has indicated that maternal exposure to ambient fine particles (PM2.5) correlates to abnormal fetal development. In the present study, we therefore assessed whether maternal exposure to diesel exhaust PM2.5 (DEP), the major component of ambient PM2.5 in urban areas, programs offspring energy metabolism, and further examined how the timing of exposure impacts this programming.
The growth trajectory of offspring shows that although prenatal maternal exposure to DEP did not impact the birth weight of offspring, it significantly decreased offspring body weight from postnatal week 2 until the end of observation. This weight loss effect of prenatal maternal exposure to DEP coincided with decreased food intake but not alteration in brown adipose tissue (BAT) morphology. The hypophagic effect of prenatal maternal exposure to DEP was in concord with decreased hypothalamic expression of an orexigenic peptide NPY, suggesting that the prenatal maternal exposure to DEP impacts offspring energy balance primarily through programming of food intake. Paradoxically, the reduced body weight resulted from prenatal maternal exposure to DEP was accompanied by increased mass of epididymal adipose tissue, which was due to hyperplasia as morphological analysis did not observe any hypertrophy. In direct contrast, the postnatal mothering by DEP-exposed dams increased offspring body weight during lactation and adulthood, paralleled by markedly increased fat accumulation and decreased UCP1 expression in BAT but not alteration in food intake. The weight gain induced by postnatal mothering by DEP-exposed dams was also expressed as an increased adiposity. But it concurred with a marked hypertrophy of adipocytes.
Prenatal and postnatal mothering by DEP-exposed dams differentially program offspring energy metabolism, underscoring consideration of the exposure timing when examining the adverse effects of maternal exposure to ambient PM2.5.
KeywordsDiesel exhaust PM2.5 Maternal exposure Obesity Developmental programming
Obesity is one of the leading threats to global public health . Numerous studies have demonstrated that it may originate from early-life exposure to environmental stressors that cause inappropriate fetal and/or neonatal development, referred to as the developmental programming of health and diseases (DOHaD) paradigm . Air pollution is one of the leading preventable threats to global health . A rapidly increasing number of epidemiological studies have shown that prenatal exposure to ambient fine particulate matter with a diameter ≤ 2.5 μm (PM2.5) is associated with a variety of manifestations of abnormal fetal development such as abortion, placental dysfunction, low birth weight and pre-term birth [4–12]. Toxicological studies have also demonstrated that gestational exposure to concentrated ambient PM2.5 or diesel exhaust impacts fetal and/or placental development in a variety of animal models [13–19]. According to the DOHaD paradigm, these demonstrations of disruption of fetal development by gestational exposure to PM2.5 strongly suggest that it may be a risk factor for developmental programming of diseases encompassing obesity. Supporting this, gestational exposure to ambient pollutants have been shown to increase body weight [13, 14], and aggravate high fat diet-induced obesity . However, how gestational PM2.5 exposure impacts energy metabolism and subsequently adiposity in adult offspring has not yet systemically investigated.
In addition to the gestation period, infancy has been shown to be vulnerable to developmental programming by environmental stressors . Furthermore, several studies have indicated that the timing of exposure to environmental stressor determines not only the severity but also the nature of developmental programming . For example, maternal exposure to famine in early gestation results in increased body mass index (BMI), whereas exposure to famine in late gestation and early infancy leads to decreased BMI . Interestingly, while several studies have demonstrated adverse health effects of gestational exposure to PM2.5, as mentioned above, few studies have investigated whether postnatal mothering by PM2.5-exposed dams programs offspring diseases.
Given that both PM2.5 pollution and obesity will continue to be the leading health concerns in the foreseeable future, additional studies are warranted to document the developmental programming of energy metabolism by maternal exposure to PM2.5 and its timing-dependency. In the present study, we therefore examined the long-term effects of prenatal and postnatal mothering by diesel exhaust PM2.5 (DEP)-exposed dams on offspring development and energy metabolism. Our results unexpectedly showed different developmental programming of energy metabolism by prenatal and postnatal mothering of DEP-exposed dams, and thus not only raised more health concerns about maternal exposure to PM2.5 but also underscored consideration of the timing of exposure when examining the health effects of maternal exposure to air pollutants.
University of Maryland, Baltimore (UMB) is an AAALAC accredited institution. All procedures of this study were approved by the Institutional Animal Care and Use Committee (IACUC) at UMB, and all the animals were treated humanely and with regard for alleviation of suffering. C57Bl/6j mice (4-week-old, 12 male and 12 female) were purchased from the Jackson Laboratories (Stock #000664) and were housed in animal facilities at UMB, which maintained the 12-h light/12-h dark light cycle and the temperature and humidity within the recommended limits. Breeding cages were set up with one male and one female at the age of 12 weeks. Offspring were weaned once they were 3 weeks old.
Maternal DEP intratracheal instillation
DEP were obtained from the National Institute of Standards and Technology (DEP; SRM 2975; NIST, Gaithersburg, MD, USA). They were stored at 4 °C and kept away from direct sunlight. To perform instillation, they were suspended in sterile normal saline. Prior to removal of subsamples for analysis, the contents of the bottle were mixed thoroughly. To minimize aggregation, particle suspensions were sonicated (Clifton Ultrasonic Bath, Clifton, NJ, USA) for 20 min on the day of instillation and vortexed 30 s before each instillation. The dams were the only members of the pair instilled. The instillation of DEP was performed as previously described with minor modifications . Briefly, to instill DEP, the animals were anesthetized with 3% isoflurane, and placed supine with extended neck on an angled board. A Becton Dickinson 18 Gauge cannula was inserted via the mouth into the trachea. DEP suspension (20 μg in 50 μl, representing an average daily dose of 8.6 μg/mouse and approximately equating to inhalational exposure to 160 μg/m3 PM2.5)  or saline (50 μl) were intratracheally instilled via a sterile syringe and followed by an air bolus of 150 μl. The intubation catheter was removed and the mouse transferred to a vertical hanging position with the head up for 5 min, ensuring that the delivered material was maintained in the lung and did not block the airways. The deposition and distribution of instilled material was verified by installing Evans blue (data not shown). Either DEP or saline was instilled 3 times/week (Monday, Wednesday, and Friday) beginning at the age of 5 weeks and ending once offspring were weaned. As mating started at the age of 12 weeks, there was approximately a 7-week pre-conceptional instillation.
Analysis of offspring growth trajectory and food intake
The body weights of offspring were measured weekly from birth until 16 week old. Food intake assessment was performed when they were 18–20 week old. Briefly, each mouse was housed in one normal cage, and the weight of diet was recorded daily for 7 consecutive days. Food intake was calculated as the difference between two consecutive days. The average food intake of the last five days was presented. All offspring were euthanized when they were 20–22 weeks old.
Epididymal adipose tissue and brown adipose tissue (BAT) were fixed in 4% paraformaldehyde, embedded in paraffin, cut into 5-μm sections, and stained with hematoxylin and eosin. The histology sections were viewed at 20× magnification, and images were obtained with a SPOT digital camera (Diagnostic Instruments, Sterling Heights, MI) by one person who was blind to the grouping. The total number and cross-sectional areas of adipocytes in epididymal adipose tissues were calculated as previously described. The fat droplet areas of BAT were obtained using Imagej software, and the results were expressed as the percentage of total area.
a house-keeping gene encoding enzyme for the oxidative phosphorylation of glyceraldehyde-3-phosphate
a polypeptide hormone precursor involved in energy homeostasis
a neuropeptide that regualtes food intake
agouti related neuropeptide
a neuropeptide that regulates feeding behavior
a pro-inflammatory cytokine
a pro-inflammatory cytokine
tumor necrosis factor alpha
a pro-inflammatory cytokine
suppressor of cytokine signaling 3
cytokine-inducible negative regulators of cytokine signaling
an adipokine involved in regulation of body weight
an adipokine involved in regulation of fatty acid catabolism and glucose levels
fatty acid synthase
the synthesis of palmitate from acetyl-CoA and malonyl-CoA
peroxisome proliferator activated receptor gamma
a regulator of adipocyte differentiation.
sterol regulatory element binding transcription factor 1c
a transcription factor that binds to the sterol regulatory element-1 (SRE1), which is involved in sterol biosynthesis
A biotin-containing enzyme which catalyzes the rate-limiting step in fatty acid synthesis.
PPARG coactivator 1 alpha
a transcriptional coactivator involved in energy metabolism.
estrogen receptor 1 (alpha)
a member of the nuclear hormone family of intracellular receptors
CCAAT/enhancer binding protein alpha
a transcription factor involved in body weight homeostasis.
Preadipocyte factor 1
Tissue harvesting, western blotting and leptin protein assessment
Animals were fasted overnight and i.p. injected with insulin (10 U/kg body weight). After 20 min, animals were euthanized by overdose of isoflurane. Blood was collected from heart and centrifuged at 3000 rpm for 5 min. Plasma was immediately stored in dry ice and then −80 °C. Hypothalamus was isolated as described before , and then snap-frozen in liquid nitrogen. All tissues were stored at −80 °C until further processing. Lysates of brown adipose tissue were prepared using RIPA buffer (Sigma, St. Louis, MO) supplemented with protease and phosphatase inhibitors (Sigma, St. Louis, MO). Protein samples were then separated by 10% SDS-polyacrylamide gel electrophoresis and electroblotted onto polyvinylidene fluoride membranes. Target protein was detected by rabbit UCP1 (Boster, CA). Secondary antibodies conjugated with horseradish peroxidase and chemiluminescence reagent (Amersham, Marlborough, MA) were used to visualize the target proteins. Densities of target protein bands were determined with Quantity One 4.4.1 (Bio-Rad, Hercules, CA). The internal control, β-actin, was used to normalize loading variations.
To assess the leptin protein expression in adipose tissue, lysates were prepared from epididymal adipose tissues using RIPA buffer (Sigma, St. Louis, MO) supplemented with protease and phosphatase inhibitors (Sigma, St. Louis, MO), and their leptin protein levels were assessed with ELISA kit (RayBio Mouse Leptin ELISA Kit, RayBiotech) per manufacturer’s instruction. The results were normalized by the concentration of total proteins, and presented as the percentage of the level in VV group.
All data are expressed as means ± SEMs unless noted otherwise. Statistical tests were performed using one-way or two-way analysis of variance (ANOVA) followed by Bonferroni correction or unpaired t-test using GraphPad Prism (version 5; GraphPad Software, La Jolla, CA, USA). The significance level was set at p < 0.05.
Differential developmental programming by prenatal and postnatal mothering of DEP-exposed dams
The characterization of breeding results
Dam weight (g)a
Pregnancy duration (days)b
Sex ratio (M/F)
25.02 ± 0.52
25.8 ± 3.0
6.2 ± 0.5
24.92 ± 0.54
27.8 ± 2.1
6.75 ± 2.5
Organ-specific effects of prenatal and postnatal mothering by DEP-exposed dams
To further document the developmental effects of prenatal and postnatal mothering by DEP-exposed dams, we measured the weights of main organs/tissues of offspring at the age of 22 weeks. Figure 2b-f show that neither prenatal nor postnatal mothering by DEP-exposed dams influenced the weights of lung, heart, liver, kidney, and testis in adult offspring. Figure 2g reveals that postnatal mothering by DEP-exposed dams significantly reduced the weight of spleen in adult offspring. Whereas it significantly increased the mass of brown adipose tissue (BAT, Fig. 2h), epididymal adipose tissue (Fig. 2i), and peri-renal adipose tissue (Fig. 2j). It also resulted in a trend of increase in the mass of subcutaneous adipose tissue (Fig. 2k). In contrast, prenatal mothering by DEP-exposed dams significantly decreased the mass of BAT, significantly increased the mass of epididymal adipose tissue, and did not significantly alter the weight of any other tested organ/tissue.
Adipose effects of prenatal and postnatal mothering by DEP-exposed dams
Prenatal but not postnatal mothering by DEP-exposed dams reduces offspring food intake
Postnatal but not prenatal mothering by DEP-exposed dams increases offspring BAT whitening
The main findings in the present study include that 1) both prenatal and postnatal mothering by DEP-exposed dams programs offspring energy metabolism; 2) the programing of energy metabolism by them however are markedly different: while prenatal mothering by DEP-exposed dams leads to a weight loss, postnatal mothering by DEP-exposed dams results in a weight gain; 3) prenatal mothering by DEP-exposed dams specifically increased the mass of epididymal adipose tissue through hyperplasia, whereas postnatal mothering by DEP-exposed dams increased the mass of all tested fat pads through hypertrophy; 4) while prenatal mothering by DEP-exposed dams programs offspring energy balance primarily through reduction in food intake, postnatal mothering by DEP-exposed dams influence offspring energy balance primarily through induction of BAT whitening.
Abnormal energy metabolism is central in the pathogenesis of numerous diseases such as obesity, diabetes, and cancer. Exposure to ambient PM2.5 pollution has been shown to cause a variety of abnormalities in energy metabolism that may contribute to the pathogenesis of cardiometabolic diseases . The present study further reveals that maternal exposure to DEP causes marked long-term effects on offspring energy metabolism through an exposure timing-dependent manner. As DEP are an important constituent of ambient PM2.5 in many urban areas such as New York City , those data thus markedly extend our understanding of ambient pollution-induced energy metabolic effects, but also provoke transgenerational health concerns over maternal exposure to ambient pollution.
In the present study, we demonstrate that DEP exposure covering a 7-week pre-conception period and the whole gestation did not significantly change the birth weight of offspring but led to a weight loss observed as early as two weeks after birth. This perfectly replicates the previous inhalation exposure study using DEP from the same source , validating our exposure method in assessing DEP toxicity. These data however are inconsistent with another inhalation exposure study showing that gestational DEP exposure reduces offspring birth weight . Notably, DEP used in the latter is from different source, suggesting that the composition of DEP may play a critical role in determination of its effects on offspring.
To our knowledge, the present study is the first one providing the birth-to-adult growth trajectory of offspring mothered by DEP-exposed dams. Extending previous knowledge , the growth trajectory shows that the body weight effects of maternal exposure to DEP are long-lasting. This is perfectly consistent with the DOHaD paradigm . Latency between exposure and disease/dysfunction is another important component of the DOHaD paradigm. In agreement with the DOHaD paradigm, the present study shows an obvious latency between maternal exposure to DEP and a variety of metabolic abnormalities in offspring. As such, our data reaffirm that maternal exposure to DEP is an environmental stressor for developmental programming of cardiometabolic diseases, raising more serious concerns about its transgenerational effects.
The present data show that prenatal maternal exposure to DEP reduced offspring food intake but not BAT whitening, accompanied by decreased hypothalamic expression of an orexigenic neuropeptide NPY, suggesting that prenatal maternal exposure to DEP may primarily program energy intake. These data are consistent with numerous studies showing that maternal exposure to environmental stressors exerts long-term energy metabolic effects on offspring through programming of hypothalamic circuits regulating energy balance . Further studies are undergoing to identify the structural and/or functional alterations in the hypothalamus that may account for the decreased expression of NPY and food intake.
It is noteworthy that the present study also demonstrates that prenatal maternal exposure to DEP significantly reduced the hypothalamic expression of several pro-inflammatory cytokines including TNFα, IL-6 and IL-1β. Rapidly increasing evidence has indicated that hypothalamic inflammation plays a critical role in regulation of energy balance. Current evidence suggests that the relationship between hypothalamic inflammation and energy balance is context-dependent: while hypothalamic inflammation observed in many severe chronic illnesses reduces food intake and leads to a negative energy balance, obesity-associated hypothalamic inflammation has been shown to increase food intake . The mechanism whereby hypothalamic inflammation context-dependently regulates food intake has not yet fully understood. It has been believed that the different effects of hypothalamic inflammations on energy balance reflect their different levels of inflammation in hypothalamus: while high level of inflammation reduces food intake, low level of inflammation increases food intake. Therefore, the decrease of hypothalamic inflammation in offspring prenatally exposed to DEP may be responsible for their reduction in food intake and consequent lower body weight. Further studies are thus warranted to determine the role of this decreased hypothalamic inflammation in programming of energy balance by prenatal maternal exposure to DEP.
It is particularly notable that although prenatal maternal exposure to DEP decreased offspring body weight, it paradoxically increased the mass of epididymal adipose tissue. These data somehow are consistent with lineage tracing studies showing that the pool of murine white adipocyte precursors is largely committed prenatally or just after birth , and thus warrant additional studies to examine the nature of insult of adipocyte precursors caused by prenatal maternal exposure to DEP. Interestingly, the present study also demonstrates that the adipose effect of prenatal maternal exposure to DEP appeared to be epididymal adipose tissue-specific. This reminisces about the heterogeneity of developmental origins of adipocytes , providing another piece of evidence that prenatal maternal exposure to DEP may damage early process of adipogenesis.
As no hypertrophy was observed, this increased mass of epididymal adipose tissue appears to be primarily due to hyperplasia. Animal adipocyte numbers have been shown to increase through puberty but be relatively steady in the mature fat pad [32, 33]. By far, how adipocyte numbers in the mature fat pad are regulated is not yet fully understood. Thus, the demonstration of maternal DEP exposure-induced adipose hyperplasia in adult offspring provides a valuable animal model to investigate how adipocyte numbers in the mature fat pad are regulated.
Another important finding in the present study is the demonstration of different energy metabolic effects of prenatal and postnatal mothering by DEP-exposed dams. Notably, although it is not uncommon to find that different timings lead to different consequences in developmental programing studies, to our knowledge, this is the first toxicological study showing that the timing of exposure to PM2.5 completely determines its long-term effects. Contrary to the most effects of prenatal mothering, postnatal mothering by DEP-exposed dams increased offspring body weight, did not impact their food intake but induced their BAT whitening. Those data together suggest that postnatal mothering by DEP-exposed dams induces a positive energy balance primarily though reduction in energy expenditure. Our data somehow are consistent with previous studies showing that postnatal catch-up growth programs susceptibility to obesity and impairment of BAT function in both humans and animal models [21, 34, 35]. Although still controversial, increasing evidence supports that brown adipocytes in both BAT and WAT (also known as “beige” component) contributes to regulation of human energy homeostasis . Therefore, our demonstration of BAT whitening programed by maternal exposure to CAP in mice may be relevant to regulation of energy homeostasis in humans.
Additionally, the present data reveal that the postnatal mothering by DEP-exposed dams increases the adiposity of offspring, which appears to be primarily consequent to hypertrophy. Notably, the adipose hypertrophy is accompanied by decreased expression of several adipogenesis markers. This is perfectly consistent with previous studies showing that high fat diet treatment induces adipose hypertrophy and meanwhile decreases the expression of adipogenesis markers . These data together suggest that the decreased expression of adipogenesis markers may be the consequence but not the cause of hypertrophy. Therefore, additional studies are still needed to delineate the mechanisms for this induction of adipose hypertrophy by the postnatal mothering by DEP-exposed dams.
In conclusion, the present study demonstrates the timing-dependency of developmental programming by mothering of DEP-exposed dams. These different long-term effects of prenatal and postnatal mothering by DEP-exposed dams underscore consideration of the exposure timing when examining the adverse effects of maternal exposure to ambient PM2.5.
Brown adipose tissue
Body mass index
Diesel exhaust PM2.5
The developmental programming of health and diseases
- PM2.5 :
Particulate matter with an aerodynamic diameter ≤ 2.5 μm
Tumor necrosis factor alpha
Uncoupling protein 1
This work was supported by the National Institutes of Health (R01ES024516 to ZY), the American Heart Association (13SDG17070131 to ZY), and the National Natural Science Foundation of China (Grant No. 81270342 to ZY, 21407082 to XW, 81302452 to LQ, and 81500216 to MC). ZY was also supported by the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning and Shanghai 3-Year Public Health Action Plan (GWTD2015S04).
Availability of data and materials
The datasets during and/or analysed during the current study available from the corresponding author on reasonable request.
MC, SL, HZ, ZH, XW, and LQ acquired and analyzed the data used in the present study. YX, WW, and YZ analyzed and interpreted the present results. MC and SL drafted the manuscript. YX, WW, YZ, and ZY were also major contributors in writing the manuscript. All authors read and approved the final manuscript.
Consent for publication
UMB is an AAALAC accredited institution. All procedures of this study were approved by the Institutional Animal Care and Use Committee (IACUC) at UMB, and all the animals were treated humanely and with regard for alleviation of suffering.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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