Laurence Huc

French National Institute for Agriculture, Food, and Environment (INRAE) | INRAE · LISIS

Non-alcoholic fatty liver disease (NAFLD) is a worldwide epidemic for which environmental contaminants are increasingly recognized as important etiological factors. Among them, the combination of benzo[a]pyrene (B[a]P), a potent environmental carcinogen, with ethanol, was shown to induce the transition of steatosis toward steatohepatitis. However,...

Regulating chemicals: Science and decisionmaking, slowness and confusion The regulation of chemicals has a noteworthy place in the complex relations between science, society and public decision-making. Through examples about the carcinogenicity of chemical substances, endocrine disruption and the concept of an exposome, the relations between scienc...

The risk assessment of pesticides: Between regulatory know-how and academic science Since the mid-20th century, pesticides have come under regulation. The marketing of this category of products is now subject to administrative authorizations based on an assessment of their efficiency and risks to human health and the environment. Light is shed on t...

To investigate environmental impacts upon colorectal carcinogenesis (CRC) by diet, we assessed two western diet food contaminants: 4-hydroxynonenal (HNE), a major lipid peroxidation product neoformed during digestion, and a mixture of pesticides. We used human colonic cell lines ectopically eliciting varied genetic susceptibilities to CRC: the non-...

Succinate dehydrogenase (SDH) inhibitors (SDHIs) are used worldwide to limit the proliferation of molds on plants and plant products. However, as SDH, also known as respiratory chain (RC) complex II, is a universal component of mitochondria from living organisms, highly conserved through evolution, the specificity of these inhibitors toward fungi w...

Résumé Les maladies métaboliques représentent un problème croissant en termes de santé publique. De nombreux polluants ou contaminants alimentaires sont suspectés de participer à l’émergence de ces pathologies par leur action en tant que perturbateurs endocriniens ou obésogènes. Dans cette revue, nous décrirons les nombreuses voies d’entrée de ces...

Despite the improvement of diagnostic methods and anticancer therapeutics, the human population is still facing an increasing incidence of several types of cancers. According to the World Health Organization, this growing trend would be partly linked to our environment, with around 20% of cancers stemming from exposure to environmental contaminants...

Background The World Health Organization classified processed and red meat consumption as “carcinogenic” and “probably carcinogenic”, respectively, to humans. Haem iron from meat plays a role in the promotion of colorectal cancer in rodent models, in association with enhanced luminal lipoperoxidation and subsequent formation of aldehydes. Here, we...

L’appel à projets annoncé par le gouvernement le 9 mai ne suffira pas à couvrir l’ensemble des problématiques liées à l’utilisation des pesticides, déplore un collectif de près de 260 scientifiques, qui prônent une gestion plus ambitieuse « au nom du bien commun ».

Metabolic diseases are a growing public health issue. Many pollutants or food contaminants are suspected of contributing to the emergence of these diseases through their action as endocrine disrupters or as obesogens. In this review, we will describe the many pathways of entry of these xenobiotics, from production to food consumption, as well as th...

Polycyclic aromatic hydrocarbons (PAHs) are widely distributed environmental contaminants, known to affect T lymphocytes. However, the molecular targets and pathways involved in their immunotoxic effects in human T lymphocytes remain unknown. Here, we analyzed the gene expression profile of primary human T lymphocytes treated with the prototypical...

54. Congress of the European-Societies-of-Toxicology (EUROTOX) -Toxicology Out of the Box

Even if the comet assay has been widely used for decades, there is still a need for controlled studies and good mathematical models to assess the variability of the different versions of this assay and in particular to assess potential intra‐experimental variability of the high‐throughput comet assay. To address this point, we further validate a hi...

Most tumors undergo metabolic reprogramming towards glycolysis, the so-called Warburg effect, to support growth and survival. Overexpression of IF1, the physiological inhibitor of the F0F1ATPase, has been related to this phenomenon and appears to be a relevant marker in cancer. Environmental contributions to cancer development are now widely accept...

Resveratrol (RES), a polyphenol found in natural foods, displays anti-oxidant, anti-inflammatory and anti-proliferative properties potentially beneficial in cancers, in particular in the prevention of tumor growth. However, the rapid metabolism of resveratrol strongly limits its bioavailability. The molecular mechanisms sustaining the potential bio...

Beside their crucial role in xenobiotic biotransformation, AhR and Nrf2 are involved in the regulation of energetic metabolism. Nrf2, as a cytoprotective transcription factor, supply energy for detoxification and antioxidant response. AhR is ligand-activated transcriptional factor implicated in several physiological function. Following pollutant ex...

Following exposure to xenobiotics, cellular mechanisms will take place to prevent damages relative to i) DNA, to maintain genome integrity, ii) proteins, to maintain their activities, iii) lipids, to limit peroxidation. This system of cellular defence and resistance is energetically costly. In this commentary review, we discuss the impact of DNA da...

According to the World Health Organization, around 20% of all cancers would be due to environmental factors. Among these factors, several chemicals are indeed well recognized carcinogens. The widespread contaminant benzo[a]pyrene (B[a]P), an often used model carcinogen of the polycyclic aromatic hydrocarbons’ family, has been suggested to target mo...

Cancer cells display alterations in many cellular processes. One core hallmark of cancer is the Warburg effect which is a glycolytic reprogramming that allows cells to survive and proliferate. Although the contributions of environmental contaminants to cancer development are widely accepted, the underlying mechanisms have to be clarified. Benzo[a]p...

The composition of the human microbiota influences tumorigenesis, notably in colorectal cancer (CRC). Pathogenic Escherichia coli possesses a variety of virulent factors, among them the Cytolethal Distending Toxin (CDT). CDT displays dual DNase and phosphatase activities and induces DNA double strand breaks, cell cycle arrest and apoptosis in a bro...

Epidemiological studies have associated red meat intake with risk of colorectal cancer. Experimental studies explain this positive association by the oxidative properties of heme iron released in the colon. This latter is a potent catalyst for lipid peroxidation, resulting in the neoformation of deleterious aldehydes in the fecal water of heme-fed...

Benzo[a]pyrene (B[a]P), the prototype molecule of polycyclic aromatic hydrocarbons, exhibits genotoxic and carcinogenic effects, which has led the International Agency for Research on Cancer to recognize it as a human carcinogen. Besides the well-known apoptotic signals triggered by B[a]P, survival signals have also been suggested to occur, both si...

Bisphenol A (BPA) is a suspected endocrine disruptor highly prevalent in our environment since it is used as monomer of polycarbonate plastics and epoxy resins. Recent epidemiological and animal studies have suggested that BPA exposure may influence the development of obesity and related pathologies such as type 2 diabetes and cardiovascular diseas...

During the last three decades, 4-hydroxy-2-nonenal (HNE), a major α,β-unsaturated aldehyde product of n-6 fatty acid oxidation, has been shown to be involved in a great number of pathologies such as metabolic diseases, neurodegenerative diseases and cancers. These multiple pathologies can be explained by the fact that HNE is a potent modulator of n...

Key points Acid extrusion from ventricular myocytes typically occurs via Na ⁺ /H ⁺ exchange (NHE1) and Na ⁺ –HCO 3 ⁻ co‐transporters (NBC). This maintains intracellular pH at ∼7.2: The membrane distribution of these transporters is uncertain. Immunofluorescence indicates that: NBC isoforms are located in lateral sarcolemma, intercalated discs and t...

F1F0-ATPase was initially believed to be strictly expressed in the mitochondrial membrane. Interestingly, recent reports have shown that the F1 complex can serve as a cell surface receptor for apparently unrelated ligands. Here, we show for the first time the presence of the F1-ATPase at the cell surface of normal or cancerous colonic epithelial ce...

Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (B[a]P), are ubiquitous toxic environmental pollutants capable of inducing cell death. Intracellular pH plays a key role in the regulation of cell survival and death. Our previous works have demonstrated that intracellular alkalinization mediated by Na(+)/H(+) exchanger 1 (NHE-1) is a...

Bisphenol A (BPA) is an endocrine-disrupting chemical that leaches from polycarbonate plastics that consequently leads to low-dose human exposure. In addition to its known xenoendocrine action, BPA exerts a wide variety of metabolic effects, but no data are available on its actions on the functions of liver mitochondrial. To assess these effects, H...

The early apoptotic events induced by environmental pollutants with carcinogenic properties are poorly understood. Here, we focus on the early cytotoxic effects of benzo[a]pyrene (B[a]P). In F258 rat hepatic epithelial cells, B[a]P induces intrinsic apoptosis via a mitochondrial dysfunction characterized by the release of hexokinase II (HKII) from...

Animal and epidemiological studies suggest that dietary heme iron would promote colorectal cancer. Oxidative properties of heme could lead to the formation of cytotoxic and genotoxic secondary lipid oxidation products, such as 4-hydroxy-2(E)-nonenal (HNE). This compound is more cytotoxic to mouse wild-type colon cells than to isogenic cells with a...

The formation of reactive oxygen species (ROS) and the change of the intracellular pH (pH(i)) are common phenomena during apoptosis. How they are interconnected, however, is poorly understood. Here we show that numerous anticancer drugs and cytokines such as Fas ligand and tumour necrosis factor α provoke intracellular acidification and cause the f...

Acidic extracellular pH is now well recognized as being a common feature of solid tumors, due to a change in the way cells produce their energy. This change in extracellular pH is not just a consequence of tumor development since this parameter plays an important role per se in the tumorigenesis process by acting at different levels. This chapter w...

Background / Purpose: Subunits of mitochondrial complex II function as tumour suppressor genes and are involved in apoptosis. However, the underlying mechanisms, notably in response to anticancer agents, are not fully deciphered. The formation of reactive oxygen species and the change of the intracellular pH (pHi) are common phenomena when cell h...

Oxidative stress and resulting lipid peroxidation is involved in various and numerous pathological states including inflammation, atherosclerosis, neurodegenerative diseases and cancer. This review is focused on recent advances concerning the formation, metabolism and reactivity towards macromolecules of lipid peroxidation breakdown products, some...

Metabolomics experiments seldom achieve their aim of comprehensively covering the entire metabolome. However, important information can be gleaned even from sparse datasets, which can be facilitated by placing the results within the context of known metabolic networks. Here we present a method that allows the automatic assignment of identified meta...

Benzo[alpha]pyrene (B[alpha]P) often serves as a model for mutagenic and carcinogenic polycyclic aromatic hydrocarbons (PAHs). Our previous work suggested a role of membrane fluidity in B[alpha]P-induced apoptotic process. In this study, we report that B[alpha]P modifies the composition of cholesterol-rich microdomains (lipid rafts) in rat liver F2...

NHE-1 is a ubiquitous, mitogen-activatable, mammalian Na+/H+ exchanger that maintains cytosolic pH and regulates cell volume. We have previously shown that the kinetics of NHE-1 positive cooperative activation by intracellular acidifications fit best with a Monod-Wyman-Changeux mechanism, in which a dimeric NHE-1 oscillates between a low- and a hig...

The Na+/H+ exchanger 1, which plays an essential role in intracellular pH regulation in most tissues, is also known to be a key actor in both proliferative and apoptotic processes. Its activation by H+ is best described by the Monod-Wyman-Changeux model: the dimeric NHE-1 oscillates between a low and a high affinity conformation, the balance betwee...

While lysosomal disruption seems to be a late step of necrosis, a moderate lysosomal destabilization has been suggested to participate early in the apoptotic cascade. The origin of lysosomal dysfunction and its precise role in apoptosis or apoptosis-like process still needs to be clarified, especially upon carcinogen exposure. In this study, we foc...

The present study compares and elucidates possible mechanisms why B[a]P induces different cell signals and triggers apparently different apoptotic pathways in two rather similar cell lines (hepatic epithelial cells of rodents). The rate and maximal capacity of metabolic activation, as measured by the formation of B[a]P-tetrols and B[a]P-DNA adducts...

Regulation of the balance between survival, proliferation, and apoptosis on carcinogenic polycyclic aromatic hydrocarbon (PAH) exposure is still poorly understood and more particularly the role of physiologic variables, including intracellular pH (pH(i)). Although the involvement of the ubiquitous pH(i) regulator Na(+)/H(+) exchanger isoform 1 (NHE...

Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) is a potential anticancer agent that induces apoptosis in cancer cells but not in most normal cells. How tumor physiology, particularly acidic extracellular pH (pH(e)), would modify sensitivity of cancer cells to TRAIL-induced cell death is not known. We have previously shown tha...

Polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]yrene (B[a]P) constitute a widely distributed class of environmental pollutants, responsible for highly toxic effects. Elucidating the intracellular mechanisms of this cytotoxicity thus remains a major challenge. Besides the activation of the p53 apoptotic pathway, we have previously found in...

Exogenous treatment with monosialoganglioside GM1 has been described to afford protection against different apoptotic insults. However, the underlying mechanisms remain to be determined. In this study, we focused on the effect of GM1 on the apoptotic cascade induced by benzo[a]pyrene (B[a]P) in rat hepatic F258 epithelial cells. We first demonstrat...

Polycyclic aromatic hydrocarbons (PAH), such as benzo[a]pyrene (B[a]P), are ubiquitous genotoxic environmental pollutants. Their DNA-damaging effects lead to apoptosis induction, through similar pathways to those identified after exposure to other DNA-damaging stimuli with activation of p53-related genes and the involvement of the intrinsic apoptot...

How tumor microenvironment, more specifically low extracellular pH (6.5), alters cell response to TNF-related apoptosis-inducing ligand (TRAIL)-based cancer therapy has yet to be determined. The aim of the current work was to test the effect of acidic extracellular pH on TRAIL-induced cell death in human HT29 colon carcinoma and HepG2 hepatocarcino...

The relationship between bulk membrane fluidizing effect of ethanol and its toxicity due to oxidative stress is still unknown. To elucidate this issue, membrane fluidity of primary rat hepatocytes was studied by measuring order parameter after inhibition of ethanol-induced oxidative stress. We showed that pretreating cells with either 4-methyl-pyra...

Intracellular pH (pHi) has an important role in the maintenance of normal cell function, and hence this parameter has to be tightly controlled within a narrow range, largely through the activity of transporters located at the plasma membrane. These transporters can be modulated by endogenous or exogenous molecules as well as, in some pathological s...

We examined the effects of amiloride derivatives, especially 5-(N-ethyl-N-isopropyl)amiloride (EIPA), on the activity of cytochrome P450 (CYP) 1 isoforms, known to metabolize carcinogenic polycyclic aromatic hydrocarbons (PAHs), such as benzo(a)pyrene (BP), into mutagenic metabolites and whose cellular expression can be induced through interaction...

The ubiquitous environmental pollutants polycyclic aromatic hydrocarbons are responsible for important carcinogenic and apoptotic effects, whose mechanisms are still poorly understood, owing to the multiplicity of possible cellular targets. Among these mechanisms, alterations of ionic homeostasis have been suggested. In this work, the effects of be...

How pH(i) changes, more specifically alkalinization, affect the apoptotic cascade has yet to be determined. The aim of the present work was to test the involvement of mitochondria in the apoptotic cascade triggered by benzo(a)pyrene [B(a)P] and to determine the role of pH(i) changes and p53 relative to mitochondria. Our results indicate that B(a)P-...