Environmental factors including diet, sedentary lifestyle and exposure to pollutants largely influence human health throughout life. Cellular and molecular events triggered by an exposure to environmental pollutants are extremely variable and depend on the age, the chronicity and the doses of exposure. Only a fraction of all relevant mechanisms involved in the onset and progression of pathologies in response to toxicants has probably been identified. Mitochondria are central hubs of metabolic and cell signaling responsible for a large variety of biochemical processes, including oxidative stress, metabolite production, energy transduction, hormone synthesis, and apoptosis. Growing evidence highlights mitochondrial dysfunction as a major hallmark of environmental insults. Here, we present mitochondria as crucial organelles for healthy metabolic homeostasis and whose dysfunction induces critical adverse effects. Then, we review the multiple mechanisms of action of pollutants causing mitochondrial toxicity in link with chronic diseases. We propose the Aryl hydrocarbon Receptor (AhR) as a model of “exposome receptor”, whose activation by environmental pollutants leads to various toxic events through mitochondrial dysfunction. Finally, we provide some remarks related to mitotoxicity and risk assessment.

Objective There is growing evidence that maternal mortality in pregnant women with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is lower than that in available data. In order to evaluate this hypothesis, we collected data of pregnancies in women with PAH-CHD. Methods Women with PAH-CHD followed in seven French referral centres were retrospectively included from 1997 to 2015. All pregnancies were recorded. We collected data on maternal, obstetrical and neonatal outcomes. Results 28 pregnancies in 20 women (26±6 years old) with PAH-CHD were managed during this period. There were 18 complete pregnancies (≥20 weeks’ gestation (WG)), 8 abortions and 2 miscarriages. Six (33%, 95% CI (11.9 to 54.3)) patients experienced severe cardiac events. The concerned women had lower resting oxygen saturation (79.6±4.1% vs 89.3±3.8%, p<0.01). The most common cardiac complications during the complete pregnancies were heart failure (n=4) and severe hypoxaemia (n=5). Heart failure was overall severe, requiring inotropic treatment in three patients, mechanical circulatory support in one and led to one maternal death (mortality=5.0% 95% CI (0.1 to 24.9)). Obstetrical complications occurred in 25% of pregnancies. Small for gestational age was diagnosed in 39% (7/18) of fetuses. 12/18 (67%) pregnancies were delivered by caesarean section, of which 10 in emergency for obstetrical reason. Prematurity was frequent (78%), but no neonatal death occurred. Conclusions Outcome of pregnancy in women with PAH-CHD is better than previously reported, with only 5% maternal mortality in our cohort. However, because of the severity of heart failure and the high rate of neonatal complications, patients should still be advised against pregnancy.

Adverse outcome pathways (AOPs) are formalized and structured linear concepts that connect one molecular initiating event (MIE) to an adverse outcome (AO) via different key events (KE) through key event relationships (KER). They are mainly used in eco-toxicology toxicology, and regulatory health issues. AOPs must respond to specific guidelines from the Organization for Economic Co-operation and Development (OECD) to weight the evidence between each KE. Breast cancer is the deadliest cancer in women with a poor prognosis in case of metastatic breast cancer. The role of the environments in the formation of metastasis has been suggested. We hypothesized that activation of the AhR (MIE), a xenobiotic receptor, could lead to breast cancer related death (AO), through different KEs, constituting a new AOP. An artificial intelligence tool (AOP-helpfinder), which screens the available literature, was used to collect all existing scientific abstracts to build a novel AOP, using a list of key words. Four hundred and seven abstracts were found containing at least a word from our MIE list and either one word from our AO or KE list. A manual curation retained 113 pertinent articles, which were also screened using PubTator. From these analyses, an AOP was created linking the activation of the AhR to breast cancer related death through decreased apoptosis, inflammation, endothelial cell migration, angiogenesis, and invasion. These KEs promote an increased tumor growth, angiogenesis and migration which leads to breast cancer metastasis and breast cancer related death. The evidence of the proposed AOP was weighted using the tailored Bradford Hill criteria and the OECD guidelines. The confidence in our AOP was considered strong. An in vitro validation must be carried out, but our review proposes a strong relationship between AhR activation and breast cancer-related death with an innovative use of an artificial intelligence literature search.

Breast cancer (BC) is frequent with a poor prognosis in case of metastasis. The role of the environment has been poorly evaluated in its progression. We searched to assess whether a mixture of pollutants could be responsible of BC aggressiveness. Patients undergoing surgery for their BC were prospectively included in the METAPOP cohort. Forty-two POPs were extracted, among them 17 dioxins (PCDD/F), 16 polychlorobiphenyls (PCB), 8 polybromodiphenylethers (PBDE) and 2,2',4,4',5,5'-hexabromobiphenyl (PBB153) were measured in the adipose tissue surrounding the tumor. BC aggressiveness was defined using tumor size and metastasis (distant or lymph nodes). Two complementary models were used to evaluate the impact of the mixture of pollutants: the BKMR (Bayesian Kernel machine regression) and WQS (weighted quantile sum regression) models. The WQS estimates the weight (positive or negative) of a certain chemical based on its quantile and the BKMR model applies a kernel-based approach to estimate posterior inclusion probabilities. The sub-group of patients with a body mass index (BMI) > 22 kg/ m² was also analyzed. Ninety-one patients were included. Of these, 38 patients presented a metastasis, and the mean tumor size was 25.4 mm. The mean BMI was 24.5 kg/m² (+/- 4.1). No statistical association was found in the general population. However, in patients with a BMI > 22 kg/ m², our mixture was positively associated with tumor size (OR: 9.73 95 %CI: 1.30-18.15) and metastasis (OR = 3.98 95 %CI = 1.09-17.53) using the WQS model. Moreover, using the BKMR model on chemical families, dioxin like chemicals and PCDD were associated with a higher risk of metastasis. These novel findings identified a mixture associated with breast cancer aggressiveness in patients with a BMI > 22 kg/ m².