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PGC-1 α. Mitochondrion. (i). ( ii ). ( iii ). Decreased placental mitochondrial DNA-content in response to air pollution during in utero life

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Introduction

PGC-1α

Mitochondrion

(i)

(ii)

(iii)

  • Decreased placental mitochondrial DNA-content in response to air pollution during in uterolife

  • Bram Janssen1, Nicky Pieters1, Elke Munters1, Karen Smeets1, Ann Cuypers1, Joris Penders2, Jaco Vangronsveld1, Wilfried Gyselaers2, Tim Nawrot11Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium2 Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium

Endothelialdysfunction

PPARγ

ΔPlacentaldevelopment

Vasoconstriction

Hypoxia

Nutrientdeprivation

Mitochondrialdysregulation

ETC

ENERGY COMPENSATION

Environmentalcomponents

(PM, toxic metals)

mtDNAcn

Mitochondrialabundance

mtDNAmutation

Lack of histones

Insufficient DNA repair

Feedback mechanism

ROS

ROS

ROS

BIO-ENERGETIC DECLINE

mtDNAcn

Mitochondrialabundance

A

B

Introduction

Recent studies have emphasized the importance of PM, and its associated metal components, in the formation of reactive oxygen species (ROS) and inflammation. Mitochondria are the major intracellular sources and primary targets of ROS. Mitochondrial DNA (mtDNA) is particularly vulnerable to ROS-induced damage, resulting in a higher mutation rate that impacts mitochondrial function. Given its multiple essential roles in metabolic pathways, mitochondrial dysfunction (i.e. change in mtDNA-content) is important in fetal development. In uteroexposure to environmental factors may influence mitochondrial function which may comprise a mechanism of earlier onset of multifactorial disease such as cardiovascular disease in later life1.

r = -0.40

p < 0.0001

n = 174

r = -0.46

p < 0.0001

n = 174

Objective

In this cross-sectional study, we investigated the influence of PM10 exposure during pregnancy on the mtDNA-content, an established marker of mitochondrial damage and dysfunction2,3.

  • Results

  • The study consisted of 82 male and 96 female newborns and mean maternal age was 29.1 (± 4.92).

  • The mean mtDNA-content was 1.028 (IQR: 0.64 - 1.63) in placentas and 1.019 (IQR: 0.75 - 1.30) in cord blood.

  • Average levels of PM10 exposure varied between 9 – 39 µg/m3 with a geometric mean of 28.07 µg/m3 during whole pregnancy.

  • We found a significant association between placental mtDNA-content and exposure to PM10 during the last period of pregnancy [Panel A to C].

  • After adjustment, we showed that each 10 µg/m3 increase in PM10 exposure during the third trimester of pregnancy was associated with a decrease in placental mtDNA/nDNA ratio by 31 % (95 % CI: 19.5 % to 41.0 %, p < 0.0001) [Panel D].

  • Furthermore, we found that each doubling in distance was associated with an increase in placental mtDNA/nDNA ratio by 5.8 % (95 % CI: 0.2 % to 6.5 %, p = 0.0447).

  • No association between mtDNA-content in cord blood and PM10 exposure was found.

  • Methods

  • 178 mother-newborn pairs were recruited from ZiekenhuisOost-Limburg in Genk.

  • We quantified mtDNA and nDNA copy numbers in placental tissue and leukocytes of umbilical cord blood using real-time PCR.

  • mtDNA-content was determined by amplification of two mitochondrial genes (MTF3212/R3319 and ND-1) and adjusted for three single-copy nuclear control genes (36B4, β-act and HBG-1).

  • PM10 exposure was calculated during whole pregnancy using a model that provided interpolated PM10 values from the Belgian telemetric air quality networks in 4 km by 4 km grids.

  • Distances from home addresses to major roads were calculated through geocoding.

C

D

r = -0.34

p < 0.0001

n = 174

Effect size was calculated for each 10 µg/m3 increase in PM10 exposure at each participants residence during the corresponding period.

The model was adjusted for maternal age, infant’s sex, parity, gestational age, ethnicity, smoking status, season period and apparent week temperature.

Hypothesized mechanisms of mitochondrial dysregulationby environmental components

Conclusions

PM exposure during fetal life is associated with mitochondrial damage as exemplified by mtDNA copy number. Damaged mitochondria intensify oxidative stress production. The potential health consequences of decreased mitochondrial copy number in early life must be further elucidated.

  • References

  • 1 Yang et al. Mutation research, 2007

  • 2Sahin et al. Nature, 2011

  • 3Hou et al. Environmental Health, 2010

  • Acknowledgment

  • FondsvoorWetenschappelijkOnderzoek (FWO-kredietaannavorsers)

  • tUL-Impuls (Transnational University Limburg, Hasselt-Maastricht Impuls Financing)

  • IRCEL


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