Exposure to PCB126 during the nursing period reversibly impacts early-life glucose tolerance.

Polychlorinated biphenyls (PCBs) are persistent environmental organic pollutants known to have detrimental health effects. Using a mouse model, we previously demonstrated that PCB126 exposure before and during pregnancy and throughout the perinatal period adversely affected offspring glucose tolerance and/or body composition profiles. The purpose of this study was to investigate the glucose tolerance and body composition of offspring born to dams exposed to PCB126 during the nursing period only. Female ICR mice were bred, and half of the dams were exposed to either vehicle (safflower oil) or 1 µmole PCB126 per kg of body weight via oral gavage on postnatal days (PND) 3, 10, and 17 (n = 9 per group). Offspring body weight, lean and fat mass, and glucose tolerance were recorded every three weeks. PCB126 treatment did not alter dam nor offspring body weight (p > 0.05). PCB126-exposed male and female offspring displayed normal body composition (p > 0.05) relative to vehicle-exposed offspring. However, both male and female offspring that were exposed to PCB126 during the nursing period had significantly impaired glucose tolerance at 3 and 9 weeks of age (p < 0.05). At 6 and 12 weeks of age, no impairments in glucose tolerance existed in offspring (p > 0.05). Our current study demonstrates that exposure to PCB126 through the mother's milk does not affect short- or long-term body composition but impairs glucose tolerance in the short-term.

Maternal polychlorinated biphenyl 126 (PCB 126) exposure modulates offspring gut microbiota irrespective of diet and exercise.

The gut microbiota plays an important role throughout the lifespan in maintaining host health, and several factors can modulate microbiota composition including diet, exercise, and environmental exposures. Maternal microbiota is transferred to offspring during early life; thus, environmental exposures before gestation may also modulate offspring microbiota. Here we aimed to investigate the effects of maternal exposure to dioxin-like polychlorinated biphenyls (PCBs) on the microbiota of aged offspring and to determine if lifestyle factors, including maternal exercise or offspring high-fat feeding alter these associations. To test this, dams were exposed to PCB 126 (0.5 µmole/kg body weight) or vehicle oil by oral gavage during preconception, gestation, and during lactation. Half of each group was allowed access to running wheels for ≥ 7 days before and during pregnancy and up through day 14 of lactation. Female offspring born from the 4 maternal groups (PCB exposure or not, with/without exercise) were subsequently placed either on regular diet or switched to a high-fat diet during adulthood. Microbiota composition was quantified in female offspring at 49 weeks of age by 16 S rRNA sequencing. Maternal exposure to PCB 126 resulted in significantly reduced richness and diversity in offspring microbiota regardless of diet or exercise. Overall compositional differences were largely driven by offspring diet, but alterations in specific taxa due to maternal PCB 126 exposure, included the depletion of Verrucomicrobiaceae and Akkermansia muciniphila, and an increase in Anaeroplasma. Perturbation of microbiota due to PCB 126 may predispose offspring to a variety of chronic diseases later in adulthood.

PCB126 exposure during pregnancy alters maternal and fetal gene expression.

Polychlorinated biphenyls (PCBs) are organic pollutants that can have lasting impacts on offspring health. Here, we sought to examine maternal and fetal gene expression differences of aryl hydrocarbon receptor (AHR)-regulated genes in a mouse model of prenatal PCB126 exposure. Female mice were bred and gavaged with 1 µmole/kg bodyweight PCB126 or vehicle control on embryonic days 0 and 14, and maternal and fetal tissues were collected on embryonic day 18.5. Total RNAs were isolated, and gene expression levels were analyzed in both maternal and fetal tissues using the NanoString nCounter system. Interestingly, we found that the expression levels of cytochrome P450 (Cyp)1a1 and Cyp1b1 were significantly increased in response to PCB exposure in the tested maternal and fetal tissues. Furthermore, PCB exposure altered the expression of several other genes related to energy balance, oxidative stress, and epigenetic regulation in a manner that was less consistent across tissue types. These results indicate that maternal PCB126 exposure significantly alters gene expression in both developing fetuses and pregnant dams, and such changes vary in intensity and expressivity depending on tissue type. The altered gene expression may provide insights into pathophysiological mechanisms by which in utero PCB exposures contribute to PCB-induced postnatal metabolic diseases.

Effects of maternal controlled exercise on offspring adiposity and glucose tolerance.

While metabolic disorders such as obesity and diabetes are costly and deadly to the current population, they are also extremely detrimental to the next generation. Much of the current literature focuses on the negative impact of poor maternal choices on offspring disease, while there is little work examining maternal behaviors that may improve offspring health. Research has shown that voluntary maternal exercise in mouse models improves metabolic function in offspring. In this study, we hypothesized that controlled maternal exercise in a mouse model will effect positive change on offspring obesity and glucose homeostasis. Female mice were separated into three groups: home cage, sedentary, and exercise. The sedentary home cage group was not removed from the home cage, while the sedentary wheel group was removed from the cage and placed in an immobile wheel apparatus. The exercise group was removed from the home cage and run on the same wheel apparatus but with the motor activated at 5-10 m/min for 1 h/d prior to and during pregnancy. Offspring were subjected to oral glucose tolerance testing and body composition analysis. There was no significant difference in offspring glucose tolerance or body composition as a consequence of the maternal exercise intervention compared to the sedentary wheel group. There were no marked negative consequences of the maternal controlled exercise intervention. Further research should clarify the potential advantages of the controlled exercise model and improve experimental techniques to facilitate translation of this research to human applications.

Lack of Offspring Nrf2 Does Not Exacerbate the Detrimental Metabolic Outcomes Caused by In Utero PCB126 Exposure.

Human environmental exposures to toxicants, such as polychlorinated biphenyls (PCBs), increase oxidative stress and disease susceptibility. Such exposures during pregnancy and/or nursing have been demonstrated to adversely affect offspring health outcomes. Nuclear factor erythroid-2-related factor 2 (Nrf2) regulates the antioxidant response and is involved in the detoxification of coplanar PCBs, like PCB126. The purpose of this study was to investigate glucose tolerance and body composition in PCB-exposed offspring expressing or lacking Nrf2. We hypothesized that offspring lacking Nrf2 expression would be more susceptible to the long-term health detriments associated with perinatal PCB exposure. During gestation, whole-body Nrf2 heterozygous (Het) and whole-body Nrf2 knockout (KO) mice were exposed to vehicle or PCB126. Shortly after birth, litters were cross-fostered to unexposed dams to prevent PCB exposure during nursing. Offspring were weaned, and their body weight, body composition, and glucose tolerance were recorded. At two months of age, PCB exposure resulted in a significant reduction in the average body weight of offspring born to Nrf2 Het dams (p < 0.001) that primarily arose from the decrease in average lean body mass in offspring (p < 0.001). There were no differences in average body weight of PCB-exposed offspring born to Nrf2 KO dams (p > 0.05), and this was because offspring of Nrf2 KO dams exposed to PCB126 during pregnancy experienced a significant elevation in fat mass (p = 0.002) that offset the significant reduction in average lean mass (p < 0.001). Regardless, the lack of Nrf2 expression in the offspring themselves did not enhance the differences observed. After an oral glucose challenge, PCB-exposed offspring exhibited significant impairments in glucose disposal and uptake (p < 0.05). Offspring born to Nrf2 Het dams exhibited these impairments at 30 min and 120 min, while offspring born to Nrf2 KO dams exhibited these impairments at zero, 15, 30, 60 and 120 min after the glucose challenge. Again, the interactions between offspring genotype and PCB exposure were not significant. These findings were largely consistent as the offspring reached four months of age and demonstrate that the lack of offspring Nrf2 expression does not worsen the metabolic derangements caused by in utero PCB exposure as we expected. Future directions will focus on understanding how the observed maternal Nrf2 genotypic differences can influence offspring metabolic responses to in utero PCB exposure.

Exercise Improves Glucose Disposal and Insulin Signaling in Pregnant Mice Fed a High Fat Diet.

OBJECTIVE: Physical activity has been suggested as a non-pharmacological intervention that can be used to improve glucose homeostasis in women with gestational diabetes mellitus. The purpose of this study was to determine the effects of voluntary exercise on glucose tolerance and body composition in pregnant high fat diet fed mice. METHODS: Female mice were put on a standard diet or high fat diet for two weeks. The mice were then split into 4 groups; control standard diet fed, exercise standard diet fed, control high fat diet fed, and exercise high fat diet fed. Exercise mice had voluntary access to a running wheel in their home cage one week prior to mating, during mating, and throughout pregnancy. Glucose tolerance and body composition were measured during pregnancy. Akt levels were quantified in skeletal muscle and adipose tissue isolated from saline or insulin injected pregnant dams as a marker for insulin signaling. RESULTS: Consumption of the high fat diet led to significantly increased body weight, fat mass, and impaired glucose tolerance in control mice. However, voluntary running in the high fat diet fed dams significantly reduced weight gain and fat mass and ultimately improved glucose tolerance compared to control high fat diet fed dams. Further, body weight, fat mass, and glucose disposal in exercise high fat diet dams were indistinguishable from control dams fed the standard diet. High fat diet fed exercise dams also had significantly increased insulin stimulated phosphorylated Akt expression in adipose tissue, but not skeletal muscle, compared to control dams on high fat diet. CONCLUSION: The use of voluntary exercise improves glucose homeostasis and body composition in pregnant female mice. Thus, future studies could investigate potential long-term health benefits in offspring born to obese exercising dams.

Perinatal exercise improves glucose homeostasis in adult offspring.

Emerging research has shown that subtle factors during pregnancy and gestation can influence long-term health in offspring. In an attempt to be proactive, we set out to explore whether a nonpharmacological intervention, perinatal exercise, might improve offspring health. Female mice were separated into sedentary or exercise cohorts, with the exercise cohort having voluntary access to a running wheel prior to mating and during pregnancy and nursing. Offspring were weaned, and analyses were performed on the mature offspring that did not have access to running wheels during any portion of their lives. Perinatal exercise caused improved glucose disposal following an oral glucose challenge in both female and male adult offspring (P < 0.05 for both). Blood glucose concentrations were reduced to lower values in response to an intraperitoneal insulin tolerance test for both female and male adult offspring of parents with access to running wheels (P < 0.05 and P < 0.01, respectively). Male offspring from exercised dams showed increased percent lean mass and decreased fat mass percent compared with male offspring from sedentary dams (P < 0.01 for both), but these parameters were unchanged in female offspring. These data suggest that short-term maternal voluntary exercise prior to and during healthy pregnancy and nursing can enhance long-term glucose homeostasis in offspring.