Maternal exposure to fine particulate matter (PM2.5) causes hypertension in offspring. However, paternal contribution of PM2.5 exposure to hypertension in offspring remains unknown. In the present study, male Sprague-Dawley rats were treated with PM2.5 suspension (10 mg/ml) for 12 weeks and/or fed with tap water containing an antioxidant tempol (1 mM/L) for 16 weeks. The blood pressure, 24 h-urine volume and sodium excretion were determined in male offspring. The offspring were also administrated with losartan (20 mg/kg/d) for 4 weeks. The expressions of angiotensin II type 1 receptor (AT1R) and G-protein–coupled receptor kinase type 4 (GRK4) were determined by qRT-PCR and immunoblotting. We found that long-term PM2.5 exposure to paternal rats caused hypertension and impaired urine volume and sodium excretion in male offspring. Both the mRNA and protein expression of GRK4 and its downstream target AT1R were increased in offspring of PM2.5-exposed paternal rats, which was reflected in its function because treatment with losartan, an AT1R antagonist, decreased the blood pressure and increased urine volume and sodium excretion. In addition, the oxidative stress level was increased in PM2.5-treated paternal rats. Administration with tempol in paternal rats restored the increased blood pressure and decreased urine volume and sodium excretion in the offspring of PM2.5-exposed paternal rats. Treatment with tempol in paternal rats also reversed the increased expressions of AT1R and GRK4 in the kidney of their offspring. We suggest that paternal PM2.5 exposure causes hypertension in offspring. The mechanism may be involved that paternal PM2.5 exposure-associated oxidative stress induces the elevated renal GRK4 level, leading to the enhanced AT1R expression and its-mediated sodium retention, consequently causes hypertension in male offspring.

Cardiovascular disease has become an uncontrolled global epidemic and a burgeoning cause of morbidity and mortality. Hypertension is the leading risk factor for cardiovascular disease and all-cause mortality worldwide [1]. Now, it is well accepted that hypertension, not a simple genetic disease, is a complex heterogeneous disorder caused by genetic, epigenetic, behavioral, and environmental factors and their intricate interactions [2–4].

Currently, an increasing number of studies have shown that fetal programming through different environmental exposures during a critical window in the early stages of life, including pre-conceptional, in utero and early post-natal periods, affect long-term health outcomes, including hypertension, in later adulthood, which is also named developmental origins of health and disease (DOHaD) [5,6]. Our and other studies have shown that mothers can transmit the influences induced by some factors such as infection, hyperglycemia, temperature and anxiety, to their offspring [7–10].

Exposure to ambient fine particles, particulate matter with an aerodynamic diameter of ≤2.5 μm (PM2.5), is one of the leading preventable threats to global health [11]. Evidence have shown that ambient fine particulate matter exposure increases the blood pressure in female subjects or animals [12,13]. Furthermore, our and other studies have found that maternal exposure to fine particulate matter causes elevated blood pressure in their offspring [14,15]. On the other hand, we also reported that long-term exposure of PM2.5 enhances the level of blood pressure in Sprague-Dawley (SD) rats [16]. However, whether or not paternal long-term PM2.5 exposure causes hypertension in their offspring remains unclear. We hypothesized that paternal exposure to environmental fine particulate matter may lead to increased blood pressure in offspring. Therefore, in the present study, we investigated paternal PM2.5 exposure-induced regulation on the blood pressure in male offspring and determined the underlying mechanisms.

PM2.5 sampling

The sampling period began on March 1, 2018 and ended on June 1, 2018. The PM2.5 sample collection site was located at Daping Hospital, about 1 km from the center of Chongqing city. The closest main road is 100 meters northeast of the hospital. The monitoring location has a radius of about 200 meters and is almost completely surrounded by residential areas.

The method of PM2.5 sampling has been reported in our previous studies [14,16]. In brief, a medium volume sampler (model TH-150; Tianhong Co, Wuhan, China) with a filtering system was used to collect PM2.5 samples on the filter (diameter, 150 mm). A total of 30 filters were used to collect PM2.5 samples. The flow of the medium volume sampler is modulated to 30 m3/h. After sampling, the filter was shredded into small pieces, and then ultrasound was carried out in the double distilled water soaking the pieces for 1 h using an ultrasonic machine (KQ-250DE; Shumei, Kunshan, Jiangsu, China). The extract was frozen, freeze-dried and concentrated, and the extraction efficiency was measured by weighing. The farinose solids were stored at −80°C for the next use.

Animal treatment

Six-week-old SD rats were purchased from the Animal Centre of The Third Military Medical University, Chongqing, China. All procedures used in this study were approved by the Third Military Medical University Animal Use and Care Committee. All experiments conformed to the guidelines for the ethical use of animals. Animals were maintained and treated in the Animal Centre of Daping Hospital.

Male SD rats with body weight of 160–190 g were divided into PM2.5 treatment group and control group with 10 rats in each group. The models were established with PM2.5 suspension and PBS solution by drip irrigation, respectively. After anesthesia with isoflurane inhalation, the head and neck were backward exposed to the airway, and the tongue was fixed with rubber band. Then PM2.5 suspension (10 mg/ml) 30 μl was slowly infused into the tongue base of the rats. The control group was infused with the same amount of PBS solution as vehicle-treated. After 12 weeks (twice a week) of drip irrigation, male rats were mated with normal SD female rats at a ratio of 1:2, and two groups of offspring were obtained, respectively. To avoid the influence of estrogen on the blood pressure, we only used the male offspring in our present study. Then, at the age of 12 weeks, the male offspring of vehicle-treated paternal rats were assigned into control group (vehicle-exposed paternal offspring administrated with vehicle) and control+losartan group (vehicle-exposed paternal offspring administrated with losartan); the offspring of PM2.5-treated paternal rats were divided into PM2.5 group (PM2.5- exposed paternal offspring administrated with vehicle) and PM2.5+losartan group (PM2.5-exposed paternal offspring administrated with losartan). Treatment with losartan in offspring means that offspring of PM2.5-treated paternal rats were selected to receive intragastric administration with losartan (20 mg/kg/d) for 4 weeks (once a day). The diagram of the above animal experiment is shown in Flow diagram 1.

The diagram of the animal experiment set 1

Flow diagram 1
The diagram of the animal experiment set 1

Control offspring: the vehicle-treated paternal offspring treated with saline; control+losartan offspring: the vehicle-treated paternal offspring treated with losartan (20 mg/kg/d, 4 weeks, once a day); PM2.5 offspring: the PM2.5-exposed paternal offspring treated with saline; PM2.5+losartan offspring: the PM2.5-exposed paternal offspring treated with losartan (20 mg/kg/d, 4 weeks, once a day).

Flow diagram 1
The diagram of the animal experiment set 1

Control offspring: the vehicle-treated paternal offspring treated with saline; control+losartan offspring: the vehicle-treated paternal offspring treated with losartan (20 mg/kg/d, 4 weeks, once a day); PM2.5 offspring: the PM2.5-exposed paternal offspring treated with saline; PM2.5+losartan offspring: the PM2.5-exposed paternal offspring treated with losartan (20 mg/kg/d, 4 weeks, once a day).

In another set of animal experiment, paternal rats were treated with both PM2.5 and an antioxidant tempol (Flow diagram 2). In brief, six-week-old paternal rats treated with PM2.5 or vehicle were randomly assigned into the following experimental groups: paternal rats were exposed with vehicle for 12 weeks and fed with normal tap water or tap water containing 1 mM/l tempol (Sigma, Poole, Dorset, U.K.) for 16 weeks; paternal rats were exposed with PM2.5 for 12 weeks and fed with normal tap water or tap water containing 1 mM/L tempol for 16 weeks. After above treatments, paternal rats were then mated with normal female SD rats, and offspring were obtained. Then, at the age of 12 weeks, the blood pressure measurement and urine/blood analysis of male offspring were performed. There are four groups of offspring as shown accordingly: control group (offspring of vehicle-exposed- and vehicle-treated paternal rats), PM2.5 group (offspring of PM2.5-exposed- and vehicle-treated paternal rats), control+tempol group (offspring of vehicle-exposed- and tempol-treated paternal rats) and PM2.5+tempol group (offspring of PM2.5-exposed- and tempol-treated paternal rats).

The diagram of the animal experiment set 2

Flow diagram 2
The diagram of the animal experiment set 2

Control offspring: offspring of paternal rats treated with vehicle and PBS; Control+ tempol offspring: offspring of paternal rats treated with tempol (1 mM/L, 16 weeks); PM2.5 offspring: offspring of paternal rats treated with PM2.5; PM2.5+tempol offspring: offspring of paternal rats treated with both PM2.5 and tempol (1 mM/L, 16 weeks).

Flow diagram 2
The diagram of the animal experiment set 2

Control offspring: offspring of paternal rats treated with vehicle and PBS; Control+ tempol offspring: offspring of paternal rats treated with tempol (1 mM/L, 16 weeks); PM2.5 offspring: offspring of paternal rats treated with PM2.5; PM2.5+tempol offspring: offspring of paternal rats treated with both PM2.5 and tempol (1 mM/L, 16 weeks).

After paternal or offspring rats were sacrificed under pentobarbital anesthesia (60 mg/kg), the kidneys were homogenized in ice-cold lysis buffer with proteinase inhibitor cocktail (Thermo Scientific, Waltham, MA, U.S.A.), sonicated, placed on ice for 1 h and centrifuged at 12,000 rpm for 30 min at 4°C. The upper layer of the pellet was re-suspended in the homogenization buffer, which was considered as the total protein of renal tissue. Finally, the supernatants were stored at −70°C until use for immunoblotting.

Blood pressure measurement and urine/blood analysis

To ensure the reliability of the measurements, rats were trained for one week to acclimatize them to the process of measurement. Blood pressure was measured using a computerized noninvasive tail-cuff manometry system (MODEL MK-2000; Muromachi Kikai Co. Ltd, Tokyo, Japan) in conscious rats between 2 and 5 PM every day, as reported in our previous studies [17,18].

Urine was collected in metabolic cages, and the 24 h urine volumes and sodium excretions were also measured at the indicated times. The urine sodium concentration in the urine was analyzed by a flame photometer 480 (Ciba Corning Diagnostics, Norwood, MA, U.S.A.). Serum creatinine and urea nitrogen levels were measured with commercially available kits (Nanjing Jiancheng Bioengineering Institute, Nanjing, China). In addition, random blood glucose was also measured with a glucose analyzer (Roche, Indianapolis, IN, U.S.A.).

Histological analysis

Kidneys of offspring rats and lungs of paternal rats were isolated, washed several times with PBS and fixed with 4% paraformaldehyde buffer for 48 h at 4°C. Then, samples were dehydrated and embedded in paraffin, cut into 5-μm-thick sagittal sections, and mounted on glass slides. Then deparaffinizing and rehydrating using xylene and different concentrations of ethanol. At last, slides were stained with hematoxylin and eosin (H&E). Slides were observed using a microscope (ECLIPSE Ti; Nikon, Tokyo, Japan).

Biochemical markers of oxidative stress

To assess the level of systematic oxidative stress, the lipid peroxidation product malondialdehyde (MDA) in the kidney was quantified using a commercially available kit (Nanjing Jiancheng Bioengineering Institute, Nanjing, China). To assess the level of antioxidants, renal samples from rats were used to measure superoxide dismutase (SOD) activity using a SOD assay kit (Dojindo Laboratories, Kumamoto, Japan) following the manufacturer’s instructions.

Immunoblotting

The protein expressions of angiotensin II type 1 receptor (AT1R), G-protein–coupled receptor kinase type 4 (GRK4), GAPDH and tubulin were determined by immunoblotting, as reported in our previous studies [14,16–18]. In brief, equal amounts of total extracted proteins (100 μg) were separated on SDS-PAGE and were transferred onto nitrocellulose membranes (Amersham Life Science, Arlington, TX). The blots were subjected to immunoblot analyses with the primary polyclonal antibodies for rabbit anti-AT1R (1:1000; Proteintech Group, Rosemont, IL, U.S.A.), anti-GRK4 (1:500; Abcam, Cambridge, U.K.), anti-GAPDH (1:1000; Beyotime, Shanghai, China) and for mouse anti-tubulin (1:1000; Beyotime, Shanghai, China) overnight at 4°C. The membranes were washed with phosphate buffered saline with Tween 20 (PBST, 0.05% Tween-20 in 10 mmol/L phosphate-buffered saline) and then incubated with infrared-labeled secondary antibodies for 1 h at room temperature. The bound complex was detected using the Odyssey Infrared Imaging System (Li-Cor Biosciences). The images were analyzed using the ImageJ Application Software (National Institutes of Health, Bethesda, MD) to obtain the integrated intensities.

Real-time (RT) quantitative PCR

Total RNA was isolated and quantified as described previously [18,19]. cDNA was synthesized from 2 μg of total RNA using cDNA synthesis kit (High Capacity RNA to cDNA Kit; Takara, Tokyo, Japan). PCRs were carried out using the Brilliant SYBR Green QPCR Master Mix kit (High Capacity RNA to cDNA Kit; Takara, Tokyo, Japan) in a total volume of 25 μl. For AT1R, the forward primer was 5′-TCCACCCAATGAAGTCTCGC-3′ and the reverse primer was 5′-ATTCTTGGTAAGGCCCAGCC-3′. For GRK4, the forward primer was 5′-ACTTCAGCAGACTGGAAGCA-3′, and the reverse primer was 5′-GGTGTCCAGGTTGACTCCTT-3′. For GAPDH served as a housekeeping/reference gene for normalization, the forward primer was 5′-GCCCAGCAAGGATACTGAGA-3′ and the reverse primer was 5′-GATGGTATTCGAGAGAAGGGAGG-3′. The amplification profile used on the BIO-RAD CFX96 (Bio-Rad Laboratories) was 95°C for 3 min followed by 40 cycles of 95°C per 10 s and 72°C per 30 s. qRT-PCR experiments were repeated for three times.

Statistical analysis

All data are expressed as means ± SEMs. Statistical significance between experimental groups was determined using the ANOVA with Tukey’s post hoc test or unpaired t test when only two groups were compared. Statistical analysis was carried out using a software program (GraphPad Prism version 7; GraphPad Software, San Diego, CA). A value of P<0.05 was considered statistically significant.

PM2.5 exposure increases the blood pressure and decreases sodium excretion in SD rats

Results of HE staining showed that PM2.5 exposure model was successfully established, which demonstrated that, as compared with the control rats, there was obvious particulate matter deposition in the lung of PM2.5-exposed SD rats (Figure 1).

Lung histology from control- and PM2.5-exposed SD rats

Figure 1
Lung histology from control- and PM2.5-exposed SD rats

Representative light microscopy sections of lung tissues from vehicle- and PM2.5-treated SD rats. Unabsorbed particles in the alveoli are presented in different power images. Red arrow means fine particulate matter deposition; magnification 400×.

Figure 1
Lung histology from control- and PM2.5-exposed SD rats

Representative light microscopy sections of lung tissues from vehicle- and PM2.5-treated SD rats. Unabsorbed particles in the alveoli are presented in different power images. Red arrow means fine particulate matter deposition; magnification 400×.

No difference was found between the control and PM2.5-treated rats, regarding to body weight, blood pressure, 24 h urine volume and sodium excretion before PM2.5 exposure (Table 1). However, long-term (12 weeks) PM2.5 exposure caused a remarkable elevation in both systolic blood pressure (SBP) and diastolic blood pressure (DBP) in SD rats (Figure 2A,B), accompanied with decreased sodium excretion, determined by basal levels of 24 h urine volume and sodium excretion (Figure 2C,D). Moreover, the differences in the levels of blood pressure between the control and PM2.5-treated rats progressively increased with time (Figure 2E). It is noticed that there was no difference in the weights of the PM2.5-treated rats and control rats (Figure 2F).

Table 1
Basic characteristics of the control- and PM2.5-treated SD rats before fine particulate matter exposure
CharacteristicsControlPM2.5
Body Weight (g) 168.00 ± 1.89 166.60 ± 1.61 
SBP (mm Hg) 101.20 ± 3.92 102.90 ± 4.55 
24 h urine volume (ml/kg weight) 23.03 ± 1.59 21.52 ± 1.55 
24 h sodium excretion (mmol/kg weight) 1.69 ± 0.12 1.64 ± 0.11 
CharacteristicsControlPM2.5
Body Weight (g) 168.00 ± 1.89 166.60 ± 1.61 
SBP (mm Hg) 101.20 ± 3.92 102.90 ± 4.55 
24 h urine volume (ml/kg weight) 23.03 ± 1.59 21.52 ± 1.55 
24 h sodium excretion (mmol/kg weight) 1.69 ± 0.12 1.64 ± 0.11 

These data were collected in 6-week-old vehicle (control)- and PM2.5-treated paternal SD rats before fine particulate matter exposure. Results are mean ± SEM, n=10.

Effect of PM2.5 exposure on the regulation of blood pressure and sodium excretion in SD rats

Figure 2
Effect of PM2.5 exposure on the regulation of blood pressure and sodium excretion in SD rats

(A and B) Systolic blood pressure (SBP) (A) and diastolic blood pressure (DBP) (B) were measured by the tail-cuff method after 12-weeks PM2.5 exposure (A, two-tailed, unpaired t test with Welch’s correction, *P < 0.05 vs. control, n = 10; B, two-tailed, unpaired t test, *P < 0.05 vs. control, n = 10). (C and D) 24 h urine volume (C) and sodium excretion (D) were determined in the control and PM2.5-exposed SD rats after 12-week PM2.5 exposure (C and D): two-tailed, unpaired t test, *P < 0.05 vs. control, n = 10). (E) Differences of the SBP among vehicle- (control) and PM2.5-exposed SD rats aged 6-, 9-, 12-, 15- and 18-week-old (one-way ANOVA with Tukey’s post hoc test, *P < 0.05 vs. control, n = 10). (F) Weights of vehicle- (control) and PM2.5-exposed SD rats (two-tailed, unpaired t test, ns. P > 0.05 vs. control, n = 10).

Figure 2
Effect of PM2.5 exposure on the regulation of blood pressure and sodium excretion in SD rats

(A and B) Systolic blood pressure (SBP) (A) and diastolic blood pressure (DBP) (B) were measured by the tail-cuff method after 12-weeks PM2.5 exposure (A, two-tailed, unpaired t test with Welch’s correction, *P < 0.05 vs. control, n = 10; B, two-tailed, unpaired t test, *P < 0.05 vs. control, n = 10). (C and D) 24 h urine volume (C) and sodium excretion (D) were determined in the control and PM2.5-exposed SD rats after 12-week PM2.5 exposure (C and D): two-tailed, unpaired t test, *P < 0.05 vs. control, n = 10). (E) Differences of the SBP among vehicle- (control) and PM2.5-exposed SD rats aged 6-, 9-, 12-, 15- and 18-week-old (one-way ANOVA with Tukey’s post hoc test, *P < 0.05 vs. control, n = 10). (F) Weights of vehicle- (control) and PM2.5-exposed SD rats (two-tailed, unpaired t test, ns. P > 0.05 vs. control, n = 10).

Paternal PM2.5 exposure causes hypertension and impaired sodium excretion in male offspring rats

To show the effect of PM2.5 exposure on the blood pressure of male offspring rats, PM2.5 exposed-male SD rats were inbred with vehicle-treated female SD rats to get the offspring rats. Our results showed that SBP was higher in the offspring of PM2.5-treated paternal rats than the offspring of vehicle-treated control rats, which was in age-dependent manner (Figure 3A). The elevated SBP may be, at least in part, due to the impaired natriuresis because the 12-week-old offspring rats also showed decreased sodium excretion, determined by 24 h urine volume and sodium excretion (Figure 3B,C). It is noted that the renal structure (Figure 3D) and functions, determined by plasma urea nitrogen and creatinine concentrations, were normal, and there were no differences, regarding to body wight, heart rate, random plasma glucose level and kidney/weight ratio (Table 2), between PM2.5-offsprings and controls.

Effects of paternal PM2.5 exposure on the regulation of blood pressure and renal functions in offspring

Figure 3
Effects of paternal PM2.5 exposure on the regulation of blood pressure and renal functions in offspring

(A) Systolic blood pressure (SBP) in the different weeks old PM2.5 offspring (one-way ANOVA with Tukey’s post hoc test, *P < 0.05 vs. control offspring, n = 8). (B and C) 24 h urine volume (B) and sodium excretion (C) in the 12-week-old PM2.5 offspring (B and C, two-tailed, unpaired t test, *P < 0.05 vs. control offspring, n = 8). (D) Renal histopathology was examined by H&E staining in the 12-week-old PM2.5 offspring; magnification 200×. Control offspring: offspring of vehicle-exposed paternal SD rats; PM2.5 offspring: offspring of PM2.5-exposed paternal rats.

Figure 3
Effects of paternal PM2.5 exposure on the regulation of blood pressure and renal functions in offspring

(A) Systolic blood pressure (SBP) in the different weeks old PM2.5 offspring (one-way ANOVA with Tukey’s post hoc test, *P < 0.05 vs. control offspring, n = 8). (B and C) 24 h urine volume (B) and sodium excretion (C) in the 12-week-old PM2.5 offspring (B and C, two-tailed, unpaired t test, *P < 0.05 vs. control offspring, n = 8). (D) Renal histopathology was examined by H&E staining in the 12-week-old PM2.5 offspring; magnification 200×. Control offspring: offspring of vehicle-exposed paternal SD rats; PM2.5 offspring: offspring of PM2.5-exposed paternal rats.

Table 2
Basic characteristics of the male offspring from paternal rats with different treatments
CharacteristicsControlControl+tempolPM2.5PM2.5+tempol
Body weight (g) 263 ± 1.73 267 ± 3.53 264 ± 4.98 271 ± 4.49 
Kidney/weight (g/kg weight) 3.48 ± 0.07 3.57 ± 0.20 3.52 ± 0.05 3.37 ± 0.11 
Heart rate (beats/min) 337 ± 4 340 ± 6 342 ± 8 343 ± 7 
Plasma creatinine (mmol/l) 28.30 ± 0.87 28.47 ± 0.96 30.02 ± 1.13 28.68 ± 1.04 
Plasma urea nitrogen (mmol/l) 5.86 ± 0.26 5.49 ± 0.3 5.70 ± 0.24 5.67 ± 0.22 
Random plasma glucose (mmol/l) 7.14 ± 0.16 7.07 ± 0.12 6.98 ± 0.07 7.12 ± 0.15 
CharacteristicsControlControl+tempolPM2.5PM2.5+tempol
Body weight (g) 263 ± 1.73 267 ± 3.53 264 ± 4.98 271 ± 4.49 
Kidney/weight (g/kg weight) 3.48 ± 0.07 3.57 ± 0.20 3.52 ± 0.05 3.37 ± 0.11 
Heart rate (beats/min) 337 ± 4 340 ± 6 342 ± 8 343 ± 7 
Plasma creatinine (mmol/l) 28.30 ± 0.87 28.47 ± 0.96 30.02 ± 1.13 28.68 ± 1.04 
Plasma urea nitrogen (mmol/l) 5.86 ± 0.26 5.49 ± 0.3 5.70 ± 0.24 5.67 ± 0.22 
Random plasma glucose (mmol/l) 7.14 ± 0.16 7.07 ± 0.12 6.98 ± 0.07 7.12 ± 0.15 

These data were collected in 12-week-old male offspring of paternal rats with different treatments. Results are mean ± SEM, n = 8. Control group: offspring of vehicle-exposed- and vehicle-treated paternal rats; PM2.5 group: offspring of PM2.5- exposed- and vehicle-treated paternal rats; Control+tempol group: offspring of vehicle-exposed- and tempol-treated paternal rats; PM2.5+tempol group: offspring of PM2.5-exposed- and tempol-treated paternal rats.

Increased AT1R and GRK4 expression and function in the offspring of PM2.5-treated paternal rats

Renal AT1R, a G-protein–coupled receptor (GPCR), plays a vital role in the regulation of sodium balance and blood pressure [20]. To determine whether or not AT1R is involved in the paternal PM2.5 exposure-induced hypertension in offspring, the transcriptional and translational levels of AT1R were measured. We found that both renal AT1R mRNA and protein expressions were elevated in the 12-week-old male offspring of PM2.5-exposed paternal rats compared with the offspring of vehicle-treated paternal rats (Figure 4A,B). Then, losartan, an AT1R antagonist, was used to determine whether the aggravated expression of AT1R was reflected in its function. Results showed that treatment with losartan markedly decreased SBP in the offspring of PM2.5-exposed paternal rats as compared with the offspring of control rats (Figure 4C). We also found that treatment with losartan normalized the impaired 24 h urine volume and sodium excretion in the offspring of PM2.5-treated paternal rats; however, losartan had no natriuretic and diuretic effects in the offspring of control paternal rats (Figure 4D,E).

AT1R and GRK4 expression and function in the offspring of PM2.5-exposed paternal rats

Figure 4
AT1R and GRK4 expression and function in the offspring of PM2.5-exposed paternal rats

(A and B) The mRNA (A) and protein expression (B) of AT1R were determined by qt-PCR and immunoblotting in the 12-week-old PM2.5 offspring. AT1R mRNA level was normalized using GAPDH. The protein expression of AT1R was normalized using tubulin expression (A and B, two-tailed, unpaired t test, *P < 0.05 vs. control, n = 6). (C) Effect of losartan (20 mg/kg/d, 4 weeks) on the systolic blood pressure (SBP) in the PM2.5 offspring (two-way ANOVA with Tukey’s post hoc test, *P < 0.05 vs. P- offspring +losartan, n = 8; #P < 0.05 vs. C-offspring, n = 8). (D and E) Effect of losartan (20 mg/kg/d, 4 weeks) on the 24 h urine volume (D) and sodium excretion (E) in the PM2.5 offspring. (D and E, two-way ANOVA with Tukey’s post hoc test, *P < 0.05 vs. C-offspring, n = 8; #P < 0.05 vs. P-offspring, n = 8). (F and G) The mRNA (F) and protein expression (G) of GRK4 were determined by qt-PCR and immunoblotting in the 12-week-old PM2.5 offspring. AT1R mRNA level was normalized using GAPDH. The protein expressions of GRK4 were normalized using tubulin expression (F and G, two-tailed, unpaired t test, *P < 0.05 vs. C-offspring, n = 6). Control offspring (C or C-offspring): offspring of vehicle-exposed paternal SD rats; PM2.5 offspring (P or P-offspring): offspring of PM2.5-exposed paternal rats.

Figure 4
AT1R and GRK4 expression and function in the offspring of PM2.5-exposed paternal rats

(A and B) The mRNA (A) and protein expression (B) of AT1R were determined by qt-PCR and immunoblotting in the 12-week-old PM2.5 offspring. AT1R mRNA level was normalized using GAPDH. The protein expression of AT1R was normalized using tubulin expression (A and B, two-tailed, unpaired t test, *P < 0.05 vs. control, n = 6). (C) Effect of losartan (20 mg/kg/d, 4 weeks) on the systolic blood pressure (SBP) in the PM2.5 offspring (two-way ANOVA with Tukey’s post hoc test, *P < 0.05 vs. P- offspring +losartan, n = 8; #P < 0.05 vs. C-offspring, n = 8). (D and E) Effect of losartan (20 mg/kg/d, 4 weeks) on the 24 h urine volume (D) and sodium excretion (E) in the PM2.5 offspring. (D and E, two-way ANOVA with Tukey’s post hoc test, *P < 0.05 vs. C-offspring, n = 8; #P < 0.05 vs. P-offspring, n = 8). (F and G) The mRNA (F) and protein expression (G) of GRK4 were determined by qt-PCR and immunoblotting in the 12-week-old PM2.5 offspring. AT1R mRNA level was normalized using GAPDH. The protein expressions of GRK4 were normalized using tubulin expression (F and G, two-tailed, unpaired t test, *P < 0.05 vs. C-offspring, n = 6). Control offspring (C or C-offspring): offspring of vehicle-exposed paternal SD rats; PM2.5 offspring (P or P-offspring): offspring of PM2.5-exposed paternal rats.

Our previous studies have shown that the expression and function of AT1R are mainly regulated by GRK4 [21,22]. Thus, we determined whether the increased expression and function of renal AT1R were regulated by GRK4 in the offspring of PM2.5-treated paternal rats. Results showed that compared with the offspring of vehicle-treated paternal rats, both renal GRK4 mRNA and protein expressions were elevated in the 12-weeks-old offspring of PM2.5-exposed paternal rats (Figure 4F,G). These suggested that the GRK4/AT1R pathway may be involved in the paternal PM2.5 exposure-induced hypertension in male offspring.

Role of oxidative stress in the paternal PM2.5 exposure-induced hypertension in the offspring

Our and other studies have shown that exposure to fine particulate matter causes increased systematic and local oxidative stress levels [23,24]. However, whether paternal oxidative stress is involved in the pathogenesis of their PM2.5 exposure-induced hypertension in the offspring is still unknown. Thus, we measured oxidative stress levels in the paternal PM2.5- and vehicle-treated rats. Results showed that levels of MDA, a lipid peroxidation product, were higher, whereas levels of SOD, an antioxidant, were lower in the kidney of PM2.5-treated paternal rats compared the kidney of control rats (Figure 5A,B), indicating that oxidative stress was increased in PM2.5-treated paternal rats.

Role of oxidative stress in the paternal PM2.5 exposure-induced hypertension in offspring

Figure 5
Role of oxidative stress in the paternal PM2.5 exposure-induced hypertension in offspring

(A and B) Renal MDA (A) and SOD (B) levels were measured in vehicle (control)- and PM2.5-treated paternal SD rats (A and B, two-tailed, unpaired t test, *P < 0.05 vs. control, n = 6). (C–E) Systolic blood pressure (SBP) (C), 24 h urine volume (D) and sodium excretion (E) were determined in the 12-week-old offspring of 12 weeks PM2.5-exposed- and 16 weeks tempol-treated paternal rats (C–E: two-way ANOVA with Tukey’s post hoc test, *P < 0.05 vs. control offspring, n = 8; #P < 0.05 vs. PM2.5 offspring, n = 8). (F and G) Protein expressions of AT1R (F) and GRK4 (G) were determined by Western blot in the kidney from the 12-week-old offspring of 12 weeks PM2.5-exposed- and 16 weeks tempol-treated paternal rats. AT1R or GRK4 protein expression was normalized using GAPDH expression (F and G, two-way ANOVA with Tukey’s post hoc test, *P < 0.05 vs. control, n = 6; #P < 0.05 vs. PM2.5, n = 6). Control: vehicle-exposed paternal rats; PM2.5: PM2.5-exposed-paternal rats; C-offspring: offspring of vehicle-exposed and vehicle-treated paternal rats; P-offspring: offspring of PM2.5-exposed and vehicle-treated paternal rats; C+Tempol-offspring: offspring of vehicle-exposed- and tempol-treated paternal rats; P+Tempol-offspring: offspring of PM2.5-exposed- and tempol-treated paternal rats.

Figure 5
Role of oxidative stress in the paternal PM2.5 exposure-induced hypertension in offspring

(A and B) Renal MDA (A) and SOD (B) levels were measured in vehicle (control)- and PM2.5-treated paternal SD rats (A and B, two-tailed, unpaired t test, *P < 0.05 vs. control, n = 6). (C–E) Systolic blood pressure (SBP) (C), 24 h urine volume (D) and sodium excretion (E) were determined in the 12-week-old offspring of 12 weeks PM2.5-exposed- and 16 weeks tempol-treated paternal rats (C–E: two-way ANOVA with Tukey’s post hoc test, *P < 0.05 vs. control offspring, n = 8; #P < 0.05 vs. PM2.5 offspring, n = 8). (F and G) Protein expressions of AT1R (F) and GRK4 (G) were determined by Western blot in the kidney from the 12-week-old offspring of 12 weeks PM2.5-exposed- and 16 weeks tempol-treated paternal rats. AT1R or GRK4 protein expression was normalized using GAPDH expression (F and G, two-way ANOVA with Tukey’s post hoc test, *P < 0.05 vs. control, n = 6; #P < 0.05 vs. PM2.5, n = 6). Control: vehicle-exposed paternal rats; PM2.5: PM2.5-exposed-paternal rats; C-offspring: offspring of vehicle-exposed and vehicle-treated paternal rats; P-offspring: offspring of PM2.5-exposed and vehicle-treated paternal rats; C+Tempol-offspring: offspring of vehicle-exposed- and tempol-treated paternal rats; P+Tempol-offspring: offspring of PM2.5-exposed- and tempol-treated paternal rats.

To confirm the role of oxidative stress in the paternal PM2.5 exposure-induced hypertension in the offspring, a SOD mimetic tempol, as an antioxidant, was administered in combination with fine particulate matter to paternal rats. Results showed that administration with tempol for 16 weeks in PM2.5-treated paternal rats restored the increased SBP in their male offspring, which was accompanied with elevated 24 h urine volume and sodium excretion (Figure 5C–E). Furthermore, treatment with tempol in PM2.5-treated paternal rats also reversed the enhanced expressions of renal AT1R and GRK4 in their male offspring (Figure 5F,G).

It is well established that the maternal nutrition and lifestyle during the periconceptional period impact offspring’s long-term health [25,26]. However, in recent years, studies have focused on exploring the influence that paternal exposures, including nutrition, lifestyle, drug and environment can have on the development of their offspring [27,28]. For example, paternal low protein diet attenuates vascular dysfunction, impairs glucose tolerance and elevates circulating TNF-α level in adult offspring [29]. Paternal healthy lifestyles such as exercise suppress the effects of paternal high-fat diet on offspring, including reversing the impairment in glucose tolerance, decreasing the percentage of fat mass, and increasing glucose uptake in skeletal muscles [30]. Streptozotocin-induced paternal hyperglycemia in SD rats exacerbates the development of obesity in offspring [31]. These suggest that paternal exposures have significant effects on offspring development and life-long health.

Among maternal environmental stimulus, air pollution has attracted more attentions on its adverse effects on the development of cardiovascular diseases such as hypertension in adult offspring [32,33]. Our and other studies have shown that in utero exposure to air pollution causes hypertension in offspring [14,15,34]. But there are few studies reporting the effect of paternal adverse environmental exposure in offspring. Chen et al. reported that paternal concentrated ambient PM2.5 exposure resulted in significant hypophagia and weight loss in male offspring [35]. Another study showed that paternal and maternal collective exposure, not only paternal exposure, to concentrated ambient PM2.5 caused a significant decrease in the body weight of adult male offspring [36]. In addition, paternal O3 exposure has a direct effect on offspring hay fever [37]. All these studies did not observe the perinatal outcomes such as fetal biometrics, mortality or pre-term birth in the offspring. Thus, until now, whether or not paternal particulate matter exposure has any significant perinatal outcomes remains still unknown. Moreover, whether or not paternal PM2.5 exposure leads to the increased blood pressure in offspring remains unknown. Our present study showed that compared with the offspring of vehicle-treated rats, the offspring of paternal rats with long-term PM2.5 exposure had higher SBP, which was accompanied with the decreased 24 h urine volume and sodium excretion. These suggested that paternal long-term exposure to fine particulate matter causes hypertension in their offspring, which may be associated with the impaired renal functions.

The renin–angiotensin system (RAS) principal effector peptide Ang II, via its receptors, exerts its physiological functions [20]. The vast majority of actions of Ang II are transmitted via AT1R, including elevation of sodium reabsorption and vasoconstriction [20,38,39]. In our present study, we found that compared with the offspring of vehicle-treated paternal rats, the expression and anti-natriuretic function of renal AT1R were aggravated in the offspring of PM2.5-exposed paternal rats, which was accompanied by increased expression of its upstream GRK4 [22,40]. Further study showed increased oxidative stress, one of the fundamental mechanisms responsible for the development of hypertension [41,42], in paternal rats may be involved in it because administration with an antioxidant tempol for 16 weeks in paternal PM2.5-treated rats restored the increased SBP and impaired sodium excretion, reversed the increased renal AT1R and GRK4 expression in offspring.

It is still unknown how elevated oxidative stress in paternal PM2.5-treated rats causes increases the expressions of renal GRK4 and AT1R in offspring. In fact, the mechanisms underlying the effects of paternal exposures on offspring phenotype are only beginning to be elucidated, but many factors are hypothesized to be involved. There are at least two mechanisms involved in it: genetic impacts and epigenetic changes [43,44]. Paternal genetic information provides roughly half of their offspring’s nuclear DNA. Thus, paternal environmental exposures directly impact offspring genotype and phenotype via inducing DNA damage and de novo genetic mutations in the male germline [45]. However, although paternal genetic changes are assumed as a mechanism for adverse effects in offspring, current reports do not often provide enough evidence for an exposure-related mutagenic effect. An increasing number of experiments have shown that paternal sperm epigenetic alterations induced by environmental exposures influence epigenetic profiles of offspring such as DNA methylation, chromatin modifications and non-coding RNAs, thereby impact their health status [43,46]. In our present study, we found increased oxidative stress level in paternal rats, which has been reported to cause epigenetic alterations [47,48]. Thus, although we cannot exclude the paternal genetic changes, we presume that oxidative stress-induced epigenetic changes may, at least in part, be involved in the increased renal GRK4 and AT1R expression and subsequently hypertension in offspring. However, it is should be noted that compared with prenatal exposure, more studies have been focused on the mechanisms of maternal and placental exposures, including impaired nephrogenesis, epigenetic reprograming, increased oxidative stress, over-activation of RAS, dysregulation of the immune system and hypothalamic–pituitary–adrenal axis [49,50].

There is a limitation in our present study. To avoid the influence of estrogen on the blood pressure [51,52], we only used male offspring. It should be noted that there may be different between male and female offspring after paternal exposures. For example, paternal high-fat diet leads to glucose intolerance due to impairment of pancreatic insulin secretion in female offspring [53] but causes a growth defect, impaired adipogenesis and decreased muscle growth in male offspring [54]. Paternal ambient PM2.5 exposure causes hypophagia and weight loss in male, but not female, offspring [35]. Paternal bisphenol A exposure causes impaired glucose tolerance in female, not male, offspring [55]. Thus, whether or not paternal long-term PM2.5 exposure causes hypertension as well as impaired renal functions in offspring with a sex-specific manner needs to be studied in the future.

In summary, we have demonstrated that paternal PM2.5 exposure leads to hypertension in male offspring, which is, at least in part, due to the decreased urine volume and sodium excretion. PM2.5 exposure-associated oxidative stress increases the level of renal GRK4, leading to the enhanced AT1R expression and its-mediated urinary sodium retention, and consequently causes hypertension in the offspring of PM2.5-exposed paternal rats (Figure 6).

Schematic diagram of the effect of paternal long-term PM2.5 exposure on renal AT1R function and blood pressure in offspring

Figure 6
Schematic diagram of the effect of paternal long-term PM2.5 exposure on renal AT1R function and blood pressure in offspring

Paternal PM2.5 exposure, via increased oxidative stress, elevates renal expressions of GRK4 and its downstream target AT1R in their offspring, which leads to the enhanced AT1R-mediated urinary sodium retention, and ultimately hypertension.

Figure 6
Schematic diagram of the effect of paternal long-term PM2.5 exposure on renal AT1R function and blood pressure in offspring

Paternal PM2.5 exposure, via increased oxidative stress, elevates renal expressions of GRK4 and its downstream target AT1R in their offspring, which leads to the enhanced AT1R-mediated urinary sodium retention, and ultimately hypertension.

  • Our and other studies have shown that in utero exposure to air pollution causes hypertension in offspring. However, whether or not paternal PM2.5 exposure leads to the increased blood pressure in offspring still remains unknown.

  • Long-term PM2.5 exposure to paternal rats causes hypertension in male offspring. The mechanism may be involved that paternal PM2.5 exposure-associated oxidative stress induces the increased renal GRK4 expression, causing the elevated AT1R level and its-mediated sodium retention, consequently leads to hypertension in male offspring.

  • Exploring the pathogenesis of hypertension in early life development will provide new strategies for its prevention and treatment.

All supporting data are included within the main article.

The authors declare that there are no competing interests associated with the manuscript.

These studies were supported in part by grants from the National Natural Science Foundation of China [grant numbers 31730043 and 81700375]; Postdoctoral Science Special Foundation of Chongqing; National Key R&D Program of China [grant number 2018YFC1312700]; Program of Innovative Research Team by National Natural Science Foundation [grant number 81721001].

Cuimei Hu: Data curation, Investigation, Methodology and Writing—original draft. Yu Tao: Data curation, Investigation and Methodology. Yi Deng: Investigation and Methodology. Qi Cai: Investigation and Methodology. Hongmei Ren: Investigation and Methodology. Cheng Yu: Investigation and Methodology. Shuo Zheng: Investigation and Methodology. Jian Yang: Supervision, Investigation, Methodology, Writing—review & editing. Chunyu Zeng: Supervision, Investigation, Methodology, Project administration and Writing—review & editing.

     
  • AT1R

    angiotensin II type 1 receptor

  •  
  • DBP

    diastolic blood pressure

  •  
  • DOHaD

    developmental origins of health and disease

  •  
  • GPCR

    G-protein–coupled receptor

  •  
  • GRK4

    G-protein–coupled receptor kinase type 4

  •  
  • H&E

    hematoxylin and eosin

  •  
  • MDA

    malondialdehyde

  •  
  • PM2.5

    fine particulate matter

  •  
  • RAS

    renin–angiotensin system

  •  
  • SBP

    systolic blood pressure

  •  
  • SD rat

    Sprague–Dawley rat

  •  
  • SOD

    superoxide dismutase

1.
Virani
S.S.
,
Alonso
A.
,
Aparicio
H.J.
,
Benjamin
E.J.
,
Bittencourt
M.S.
,
Callaway
C.W.
et al.
(
2021
)
Heart disease and stroke statistics-2021 update: a report from the American Heart Association
.
Circulation
143
,
e254
e743
[PubMed]
2.
Kawarazaki
W.
and
Fujita
T.
(
2021
)
Kidney and epigenetic mechanisms of salt-sensitive hypertension
.
Nat. Rev. Nephrol.
17
,
350
363
[PubMed]
3.
Seidel
E.
and
Scholl
U.I.
(
2017
)
Genetic mechanisms of human hypertension and their implications for blood pressure physiology
.
Physiol. Genomics
49
,
630
652
[PubMed]
4.
Fuks
K.B.
,
Weinmayr
G.
,
Basagaña
X.
,
Gruzieva
O.
,
Hampel
R.
,
Oftedal
B.
et al.
(
2017
)
Long-term exposure to ambient air pollution and traffic noise and incident hypertension in seven cohorts of the European study of cohorts for air pollution effects (ESCAPE)
.
Eur. Heart J.
38
,
983
990
[PubMed]
5.
Arima
Y.
and
Fukuoka
H.
(
2020
)
Developmental origins of health and disease theory in cardiology
.
J. Cardiol.
76
,
14
17
[PubMed]
6.
Briffa
J.F.
,
Wlodek
M.E.
and
Moritz
K.M.
(
2020
)
Transgenerational programming of nephron deficits and hypertension
.
Semin. Cell Dev. Biol.
103
,
94
103
[PubMed]
7.
Chen
K.
,
Sun
D.
,
Qu
S.
,
Chen
Y.
,
Wang
J.
,
Zhou
L.
et al.
(
2019
)
Prenatal cold exposure causes hypertension in offspring by hyperactivity of the sympathetic nervous system
.
Clin. Sci. (Lond.)
133
,
1097
1113
[PubMed]
8.
Wang
X.
,
Wang
J.
,
Luo
H.
,
Chen
C.
,
Pei
F.
,
Cai
Y.
et al.
(
2015
)
Prenatal lipopolysaccharide exposure causes mesenteric vascular dysfunction through the nitric oxide and cyclic guanosine monophosphate pathway in offspring
.
Free Radic. Biol. Med.
86
,
322
330
[PubMed]
9.
Luo
H.
,
Chen
C.
,
Guo
L.
,
Xu
Z.
,
Peng
X.
,
Wang
X.
et al.
(
2018
)
Exposure to maternal diabetes mellitus causes renal dopamine D1 receptor dysfunction and hypertension in adult rat offspring
.
Hypertension
72
,
962
970
[PubMed]
10.
Chersich
M.F.
,
Pham
M.D.
,
Areal
A.
,
Haghighi
M.M.
,
Manyuchi
A.
,
Swift
C.P.
et al.
(
2020
)
Climate change and heat-health study group. Associations between high temperatures in pregnancy and risk of preterm birth, low birth weight, and stillbirths: systematic review and meta-analysis
.
BMJ
371
,
m3811
[PubMed]
11.
Bu
X.
,
Xie
Z.
,
Liu
J.
,
Wei
L.
,
Wang
X.
,
Chen
M.
et al.
(
2021
)
Global PM2.5-attributable health burden from 1990 to 2017: estimates from the global burden of disease study 2017
.
Environ. Res.
197
,
111123
[PubMed]
12.
Coogan
P.F.
,
White
L.F.
,
Yu
J.
,
Brook
R.D.
,
Burnett
R.T.
,
Marshall
J.D.
et al.
(
2017
)
Long-term exposure to NO2 and Ozone and hypertension incidence in the black women's health study
.
Am. J. Hypertens.
30
,
367
372
[PubMed]
13.
Qin
G.
,
Xia
J.
,
Zhang
Y.
,
Guo
L.
,
Chen
R.
and
Sang
N.
(
2018
)
Ambient fine particulate matter exposure induces reversible cardiac dysfunction and fibrosis in juvenile and older female mice
.
Part. Fibre Toxicol.
15
,
27
[PubMed]
14.
Ye
Z.
,
Lu
X.
,
Deng
Y.
,
Wang
X.
,
Zheng
S.
,
Ren
H.
et al.
(
2018
)
In utero exposure to fine particulate causes hypertension due to impaired renal dopamine D1 receptor in offspring
.
Cell. Physiol. Biochem.
46
,
148
159
[PubMed]
15.
Ni
Y.
,
Szpiro
A.A.
,
Young
M.T.
,
Loftus
C.T.
,
Bush
N.R.
,
LeWinn
K.Z.
et al.
(
2021
)
Associations of pre- and postnatal air pollution exposures with child blood pressure and modification by maternal nutrition: a prospective study in the CANDLE cohort
.
Environ. Health Perspect.
129
,
47004
[PubMed]
16.
Lu
X.
,
Ye
Z.
,
Zheng
S.
,
Ren
H.
,
Zeng
J.
,
Wang
X.
et al.
(
2018
)
Long-term exposure of fine particulate matter causes hypertension by impaired renal D1 receptor-mediated sodium excretion via upregulation of G-protein-coupled receptor kinase type 4 expression in Sprague-Dawley rats
.
J. Am. Heart Assoc.
7
,
e007185
[PubMed]
17.
Wang
J.
,
Deng
Y.
,
Zou
X.
,
Luo
H.
,
Jose
P.A.
,
Fu
C.
et al.
(
2019
)
Long-term low salt diet increases blood pressure by activation of the renin-angiotensin and sympathetic nervous systems
.
Clin. Exp. Hypertens.
41
,
739
746
[PubMed]
18.
Wang
S.
,
Tan
X.
,
Chen
P.
,
Zheng
S.
,
Ren
H.
,
Cai
J.
et al.
(
2019
)
Role of thioredoxin 1 in impaired renal sodium excretion of hD5R F173L transgenic mice
.
J. Am. Heart Assoc.
8
,
e012192
[PubMed]
19.
Zhang
Y.
,
Wang
S.
,
Huang
H.
,
Zeng
A.
,
Han
Y.
,
Zeng
C.
et al.
(
2020
)
GRK4-mediated adiponectin receptor-1 phosphorylative desensitization as a novel mechanism of reduced renal sodium excretion in hypertension
.
Clin. Sci. (Lond.)
134
,
2453
2467
[PubMed]
20.
Paz
O.M.
,
Riquelme
J.A.
,
García
L.
,
Jalil
J.E.
,
Chiong
M.
,
Santos
R.A.S.
et al.
(
2020
)
Counter-regulatory renin-angiotensin system in cardiovascular disease
.
Nat. Rev. Cardiol.
17
,
116
129
[PubMed]
21.
Wang
Z.
,
Zeng
C.
,
Villar
V.A.
,
Chen
S.Y.
,
Konkalmatt
P.
,
Wang
X.
et al.
(
2016
)
Human GRK4γ142V variant promotes angiotensin II type I receptor-mediated hypertension via renal histone deacetylase type 1 inhibition
.
Hypertension
67
,
325
334
[PubMed]
22.
Chen
K.
,
Fu
C.
,
Chen
C.
,
Liu
L.
,
Ren
H.
,
Han
Y.
et al.
(
2014
)
Role of GRK4 in the regulation of arterial AT1 receptor in hypertension
.
Hypertension
63
,
289
296
[PubMed]
23.
Xu
M.
,
Ge
C.
,
Qin
Y.
,
Gu
T.
,
Lou
D.
,
Li
Q.
et al.
(
2019
)
Prolonged PM2.5 exposure elevates risk of oxidative stress-driven nonalcoholic fatty liver disease by triggering increase of dyslipidemia
.
Free Radic. Biol. Med.
130
,
542
556
[PubMed]
24.
Haberzettl
P.
,
Conklin
D.J.
,
Abplanalp
W.T.
,
Bhatnagar
A.
and
O'Toole
T.E.
(
2018
)
Inhalation of fine particulate matter impairs endothelial progenitor cell function via pulmonary oxidative stress
.
Arterioscler. Thromb. Vasc. Biol.
38
,
131
142
[PubMed]
25.
Baird
J.
,
Jacob
C.
,
Barker
M.
,
Fall
C.H.
,
Hanson
M.
,
Harvey
N.C.
et al.
(
2017
)
Developmental origins of health and disease: a lifecourse approach to the prevention of non-communicable diseases
.
Healthcare (Basel)
5
,
14
[PubMed]
26.
Deng
Y.
,
Song
L.
,
Nie
X.
,
Shou
W.
and
Li
X.
(
2018
)
Prenatal inflammation exposure-programmed cardiovascular diseases and potential prevention
.
Pharmacol. Ther.
190
,
159
172
[PubMed]
27.
Morkve Knudsen
G.T.
,
Rezwan
F.I.
,
Johannessen
A.
et al.
(
2019
)
Epigenome-wide association of father’s smoking with offspring DNA methylation: a hypothesis-generating study
.
Environ. Epigenet.
5
,
dvz023
[PubMed]
28.
de Castro Barbosa
T.
,
Alm
P.S.
,
Krook
A.
,
Barres
R.
and
Zierath
J.R.
(
2019
)
Paternal high-fat diet transgenerationally impacts hepatic immunometabolism
.
FASEB J.
33
,
6269
6280
[PubMed]
29.
Watkins
A.J.
and
Sinclair
K.D.
(
2014
)
Paternal low protein diet affects adult offspring cardiovascular and metabolic function in mice
.
Am. J. Physiol. Heart Circ. Physiol.
306
,
H1444
H1452
[PubMed]
30.
Stanford
K.I.
,
Rasmussen
M.
,
Baer
L.A.
,
Lehnig
A.C.
,
Rowland
L.A.
,
White
J.D.
et al.
(
2018
)
Paternal exercise improves glucose metabolism in adult offspring
.
Diabetes
67
,
2530
2540
[PubMed]
31.
Shi
X.
,
Li
X.
,
Hou
Y.
,
Cao
X.
,
Zhang
Y.
,
Wang
H.
et al.
(
2017
)
Paternal hyperglycemia in rats exacerbates the development of obesity in offspring
.
J. Endocrinol.
234
,
175
186
[PubMed]
32.
Weldy
C.S.
,
Liu
Y.
,
Liggitt
H.D.
and
Chin
M.T.
(
2014
)
In utero exposure to diesel exhaust air pollution promotes adverse intrauterine conditions, resulting in weight gain, altered blood pressure, and increased susceptibility to heart failure in adult mice
.
PLoS ONE
9
,
e88582
[PubMed]
33.
Zhang
B.
,
Liang
S.
,
Zhao
J.
,
Qian
Z.
,
Bassig
B.A.
,
Yang
R.
et al.
(
2016
)
Maternal exposure to air pollutant PM2.5 and PM10 during pregnancy and risk of congenital heart defects
.
J. Expo. Sci. Environ. Epidemiol.
26
,
422
427
[PubMed]
34.
Warembourg
C.
,
Maitre
L.
,
Tamayo-Uria
I.
,
Fossati
S.
,
Roumeliotaki
T.
,
Aasvang
G.M.
et al.
(
2019
)
Early-life environmental exposures and blood pressure in children
.
J. Am. Coll. Cardiol.
74
,
1317
1328
[PubMed]
35.
Chen
M.J.
,
Xu
Y.Y.
,
Wang
W.J.
,
Wang
X.K.
,
Qiu
L.L.
,
Chen
S.F.
et al.
(
2021
)
Paternal exposure to PM2.5 programs offspring's energy homeostasis
.
Environ. Sci. Technol.
55
,
6097
6106
[PubMed]
36.
Tanwar
V.
,
Adelstein
J.M.
,
Grimmer
J.A.
,
Youtz
D.J.
,
Katapadi
A.
,
Sugar
B.P.
et al.
(
2018
)
Preconception exposure to fine particulate matter leads to cardiac dysfunction in adult male offspring
.
J. Am. Heart Assoc.
7
,
e010797
[PubMed]
37.
Kuiper
I.N.
,
Markevych
I.
,
Accordini
S.
,
Bertelsen
R.J.
,
Bråbäck
L.
,
Christensen
J.H.
et al.
(
2020
)
Associations of preconception exposure to air pollution and greenness with offspring asthma and hay fever
.
Int. J. Environ. Res. Public Health
17
,
5828
[PubMed]
38.
Wu
C.H.
,
Mohammadmoradi
S.
,
Chen
J.Z.
,
Sawada
H.
,
Daugherty
A.
and
Lu
H.S.
(
2018
)
Renin-angiotensin system and cardiovascular Functions
.
Arterioscler. Thromb. Vasc. Biol.
38
,
e108
e116
[PubMed]
39.
Crowley
S.D.
,
Gurley
S.B.
and
Coffman
T.M.
(
2007
)
AT(1) receptors and control of blood pressure: the kidney and more
.
Trends Cardiovasc. Med.
17
,
30
34
[PubMed]
40.
Yang
J.
,
Villar
V.A.
,
Jones
J.E.
,
Jose
P.A.
and
Zeng
C.
(
2015
)
G protein-coupled receptor kinase 4: role in hypertension
.
Hypertension
65
,
1148
1155
[PubMed]
41.
Griendling
K.K.
,
Camargo
L.L.
,
Rios
F.J.
,
Alves-Lopes
R.
,
Montezano
A.C.
and
Touyz
R.M.
(
2021
)
Oxidative stress and hypertension
.
Circ. Res.
128
,
993
1020
[PubMed]
42.
Pinheiro
L.C.
and
Oliveira-Paula
G.H.
(
2020
)
Sources and effects of oxidative stress in hypertension
.
Curr. Hypertens. Rev.
16
,
166
180
[PubMed]
43.
Li
J.
,
Tsuprykov
O.
,
Yang
X.
and
Hocher
B.
(
2016
)
Paternal programming of offspring cardiometabolic diseases in later life
.
J. Hypertens.
34
,
2111
2126
[PubMed]
44.
Houfflyn
S.
,
Matthys
C.
and
Soubry
A.
(
2017
)
Male obesity: epigenetic origin and effects in sperm and offspring
.
Curr. Mol. Biol. Rep.
3
,
288
296
[PubMed]
45.
Beal
M.A.
,
Yauk
C.L.
and
Marchetti
F.
(
2017
)
From sperm to offspring: assessing the heritable genetic consequences of paternal smoking and potential public health impacts
.
Mutat. Res. Rev. Mutat. Res.
773
,
26
50
[PubMed]
46.
Sharp
G.C.
and
Lawlor
D.A.
(
2019
)
Paternal impact on the life course development of obesity and type 2 diabetes in the offspring
.
Diabetologia
62
,
1802
1810
[PubMed]
47.
Wyck
S.
,
Herrera
C.
,
Requena
C.E.
,
Bittner
L.
,
Hajkova
P.
,
Bollwein
H.
et al.
(
2018
)
Oxidative stress in sperm affects the epigenetic reprogramming in early embryonic development
.
Epigenetics Chromatin
11
,
60
[PubMed]
48.
Feng
B.
,
Ruiz
M.A.
and
Chakrabarti
S.
(
2013
)
Oxidative-stress-induced epigenetic changes in chronic diabetic complications
.
Can. J. Physiol. Pharmacol.
91
,
213
220
[PubMed]
49.
Morton
J.S.
,
Cooke
C.L.
and
Davidge
S.T.
(
2016
)
In utero origins of hypertension: mechanisms and targets for therapy
.
Physiol. Rev.
96
,
549
603
[PubMed]
50.
Burton
G.J.
,
Fowden
A.L.
and
Thornburg
K.L.
(
2016
)
Placental origins of chronic disease
.
Physiol. Rev.
96
,
1509
1565
[PubMed]
51.
Colafella
K.M.M.
and
Denton
K.M.
(
2018
)
Sex-specific differences in hypertension and associated cardiovascular disease
.
Nat. Rev. Nephrol.
14
,
185
201
[PubMed]
52.
O'Donnell
E.
,
Harvey
P.J.
,
Goodman
J.M.
and
De Souza
M.J.
(
2007
)
Long-term estrogen deficiency lowers regional blood flow, resting systolic blood pressure, and heart rate in exercising premenopausal women
.
Am. J. Physiol. Endocrinol. Metab.
292
,
E1401
E1409
[PubMed]
53.
Ng
S.F.
,
Lin
R.C.
,
Laybutt
D.R.
,
Barres
R.
,
Owens
J.A.
and
Morris
M.J.
(
2010
)
Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring
.
Nature
467
,
963
966
[PubMed]
54.
Lecomte
V.
,
Maloney
C.A.
,
Wang
K.W.
and
Morris
M.J.
(
2017
)
Effects of paternal obesity on growth and adiposity of male rat offspring
.
Am. J. Physiol. Endocrinol. Metab.
312
,
E117
E125
[PubMed]
55.
Rashid
C.S.
,
Bansal
A.
,
Mesaros
C.
,
Bartolomei
M.S.
and
Simmons
R.A.
(
2020
)
Paternal bisphenol A exposure in mice impairs glucose tolerance in female offspring
.
Food Chem. Toxicol.
145
,
111716
[PubMed]

Author notes

*

These authors contributed equally to this work.

This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND).