Regulatory and academic studies to derive reference values for human health: The case of bisphenol S.

The close structural analogy of bisphenol (BP) S with BPA, a recognized endocrine-disrupting chemical and a substance of very high concern in the European Union, highlights the need to assess the extent of similarities between the two compounds and carefully scrutinize BPS potential toxicity for human health. This analysis aimed to investigate human health toxicity data regarding BPS, to find a point of departure for the derivation of human guidance values. A systematic and transparent methodology was applied to determine whether European or international reference values have been established for BPS. In the absence of such values, the scientific literature on human health effects was evaluated by focusing on human epidemiological and animal experimental studies. The results were analyzed by target organ/system: male and female reproduction, mammary gland, neurobehavior, and metabolism/obesity. Academic experimental studies were analyzed and compared to regulatory data including subchronic studies and an extended one-generation and reproduction study. In contrast to the regulatory studies, which were performed at dose levels in the mg/kg bw/day range, the academic dataset on specific target organs or systems showed adverse effects for BPS at much lower doses (0.5-10 µg/kg bw/day). A large disparity between the lowest-observed-adverse-effect levels (LOAELs) derived from regulatory and academic studies was observed for BPS, as for BPA. Toxicokinetic data on BPS from animal and human studies were also analyzed and showed a 100-fold higher oral bioavailability compared to BPA in a pig model. The similarities and differences between the two bisphenols, in particular the higher bioavailability of BPS in its active (non-conjugated) form and its potential impact on human health, are discussed. Based on the available experimental data, and for a better human protection, we propose to derive human reference values for exposure to BPS from the N(L)OAELs determined in academic studies.

How to Differentiate General Toxicity-Related Endocrine Effects from Endocrine Disruption: Systematic Review of Carbon Disulfide Data.

This review provides an overview of the assessment of the endocrine disrupting (ED) properties of carbon disulfide (CS2), following the methodology used at the European level to identify endocrine disruptors. Relevant in vitro, in vivo studies and human data are analyzed. The assessment presented here focuses on one endocrine activity, i.e., thyroid disruption, and two main adverse effects, neurotoxicity and cardiotoxicity. The data available on the different ED or non-ED modes of action (MoA), known to trigger these adverse effects, are described and the strength of evidence of the different MoA is weighted. We conclude that the adverse effects could be due to systemic toxicity rather than endocrine-mediated toxicity. This assessment illustrates the scientific and regulatory challenges in differentiating a specific endocrine disruption from an indirect endocrine effect resulting from a non-ED mediated systemic toxicity. This issue of evaluating the ED properties of highly toxic and reactive substances has been insufficiently developed by European guidance so far and needs to be further addressed. Finally, this example also raises questions about the capacity of the technics available in toxicology to address such a complex issue with certainty.

Low-dose food contaminants trigger sex-specific, hepatic metabolic changes in the progeny of obese mice.

Environmental contaminants are suspected to be involved in the epidemic incidence of metabolic disorders, food ingestion being a primarily route of exposure. We hypothesized that life-long consumption of a high-fat diet that contains low doses of pollutants will aggravate metabolic disorders induced by obesity itself. Mice were challenged from preconception throughout life with a high-fat diet containing pollutants commonly present in food (2,3,7,8-tetrachlorodibenzo-p-dioxin, polychlorinated biphenyl 153, diethylhexyl phthalate, and bisphenol A), added at low doses in the tolerable daily intake range. We measured several blood parameters, glucose and insulin tolerance, hepatic lipid accumulation, and gene expression in adult mice. Pollutant-exposed mice exhibited significant sex-dependent metabolic disorders in the absence of toxicity and weight gain. In males, pollutants increased the expression of hepatic genes (from 36 to 88%) encoding proteins related to cholesterol biosynthesis and decreased (40%) hepatic total cholesterol levels. In females, there was a marked deterioration of glucose tolerance, which may be related to the 2-fold induction of estrogen sulfotransferase and reduced expression of estrogen receptor α (25%) and estrogen target genes (>34%). Because of the very low doses of pollutants used in the mixture, these findings may have strong implications in terms of understanding the potential role of environmental contaminants in food in the development of metabolic diseases.

Endocrine disrupting chemicals and metabolic disorders in the liver: What if we also looked at the female side?

Endocrine disrupting chemicals (EDCs) are linked to the worldwide epidemic incidence of metabolic disorders and fatty liver diseases, which affects quality of life and represents a high economic cost to society. Energy homeostasis exhibits strong sexual dimorphic traits, and metabolic organs respond to EDCs depending on sex, such as the liver, which orchestrates both drug elimination and glucose and lipid metabolism. In addition, fatty liver diseases show a strong sexual bias, which in part could also originate from sex differences observed in gut microbiota. The aim of this review is to highlight significant differences in endocrine and metabolic aspects of the liver, between males and females throughout development and into adulthood. It is also to illustrate how the male and female liver differently cope with exposure to various EDCs such as bisphenols, phthalates and persistent organic chemicals in order to draw attention to the need to include both sexes in experimental studies. Interesting data come from analyses of the composition and diversity of the gut microbiota in males exposed to the mentioned EDCs showing significant correlations with hepatic lipid accumulation and metabolic disorders but information on females is lacking or incomplete. As industrialization increases, the list of anthropogenic chemicals to which humans will be exposed will also likely increase. In addition to strengthening existing regulations, encouraging populations to protect themselves and promoting the substitution of harmful chemicals with safe products, innovative strategies based on sex differences in the gut microbiota and in the gut-liver axis could be optimistic outlook.

Impact of Estrogen Withdrawal and Replacement in Female Mice along the Intestinal Tract. Comparison of E2 Replacement with the Effect of a Mixture of Low Dose Pollutants.

Postmenopausal women represent a vulnerable population towards endocrine disruptors due to hormonal deficit. We previously demonstrated that chronic exposure of ovariectomized C57Bl6/J mice fed a high-fat, high-sucrose diet to a low-dose mixture of chemicals with one dioxin, one polychlorobiphenyl, one phthalate, and bisphenol A triggered metabolic alterations in the liver but the intestine was not explored. Yet, the gastrointestinal tract is the main route by which pollutants enter the body. In the present study, we investigated the metabolic consequences of ovarian withdrawal and E2 replacement on the various gut segments along with investigating the impact of the mixture of pollutants. We showed that genes encoding estrogen receptors (Esr1, Gper1 not Esr2), xenobiotic processing genes (e.g., Cyp3a11, Cyp2b10), and genes related to gut homeostasis in the jejunum (e.g., Cd36, Got2, Mmp7) and to bile acid biosynthesis in the gut (e.g., Fgf15, Slc10a2) and liver (e.g., Abcb11, Slc10a1) were under estrogen regulation. Exposure to pollutants mimicked some of the effects of E2 replacement, particularly in the ileum (e.g., Esr1, Nr1c1) suggesting that the mixture had estrogen-mimetic activities. The present findings have important implications for the understanding of estrogen-dependent metabolic alterations with regards to situations of loss of estrogens as observed after menopause.

Adipose-Tissue-Derived Mesenchymal Stem Cells Mediate PD-L1 Overexpression in the White Adipose Tissue of Obese Individuals, Resulting in T Cell Dysfunction.

The PD-L1/PD-1 immune checkpoint axis is the strongest T cell exhaustion inducer. As immune dysfunction occurs during obesity, we analyzed the impact of obesity on PD-L1/PD-1 expression in white adipose tissue (WAT) in mice and in human white adipocytes. We found that PD-L1 was overexpressed in WAT of diet-induced obese mice and was associated with increased expression of PD-1 in visceral but not subcutaneous WAT. Human in vitro cocultures with adipose-tissue-derived mesenchymal stem cells (ASC) and mononuclear cells demonstrated that the presence of ASC harvested from obese WAT (i) enhanced PD-L1 expression as compared with ASC from lean WAT, (ii) decreased Th1 cell cytokine secretion, and (iii) resulted in decreased cytolytic activity towards adipocytes. Moreover, (iv) the implication of PD-L1 in obese ASC-mediated T cell dysfunction was demonstrated through PD-L1 blockade. Finally, (v) conditioned media gathered from these cocultures enhanced PD-L1 expression in freshly differentiated adipocytes, depending on IFNγ. Altogether, our results suggest that PD-L1 is overexpressed in the WAT of obese individuals during IFNγ secretion, leading to T cell dysfunction and notably reduced cytolytic activity. Such a mechanism could shed light on why adipose-tissue-infiltrating viruses, such as SARS-CoV-2, can worsen disease in obese individuals.

Exposure to pollutants altered glucocorticoid signaling and clock gene expression in female mice. Evidence of tissue- and sex-specificity.

Environmental pollutants suspected of disrupting the endocrine system are considered etiologic factors in the epidemic of metabolic disorders. As regulation of energy metabolism relies on the integrated action of a large number of hormones, we hypothesized that certain chemicals could trigger changes in glucocorticoid signaling. To this end, we exposed C57Bl6/J female and male mice between 5 and 20 weeks of age to a mixture of 2,3,7,8- tetrachlorodibenzo-p-dioxin (20 pg/kg body weight/day [bw/d]), polychlorobiphenyl 153 (200 ng/kg bw/d), di-[2-ethylhexyl]-phthalate (500 µg/kg bw/d) and bisphenol A (40 µg/kg bw/d). In female mice fed a standard diet (ST), we observed a decrease in plasma levels of leptin as well as a reduced expression of corticoid receptors Nr3c1 and Nr3c2, of leptin and of various canonical genes related to the circadian clock machinery in visceral (VAT) but not subcutaneous (SAT) adipose tissue. However, Nr3c1 and Nr3c2 mRNA levels did not change in high-fat-fed females exposed to pollutants. In ST-fed males, pollutants caused the same decrease of Nr3c1 mRNA levels in VAT observed in ST-fed females but levels of Nr3c2 and other clock-related genes found to be down-regulated in female VAT were enhanced in male SAT and not affected in male VAT. The expression of corticoid receptors was not affected in the livers of both sexes in response to pollutants. In summary, exposure to a mixture of pollutants at doses lower than the no-observed adverse effect levels (NoAELs) resulted in sex-dependent glucocorticoid signaling disturbances and clock-related gene expression modifications in the adipose tissue of ST-fed mice.

Adipose Tissue and Endocrine-Disrupting Chemicals: Does Sex Matter?

Obesity and metabolic-related diseases, among which diabetes, are prominent public health challenges of the 21st century. It is now well acknowledged that pollutants are a part of the equation, especially endocrine-disrupting chemicals (EDCs) that interfere with the hormonal aspect. The aim of the review is to focus on adipose tissue, a central regulator of energy balance and metabolic homeostasis, and to highlight the significant differences in the endocrine and metabolic aspects of adipose tissue between males and females which likely underlie the differences of the response to exposure to EDCs between the sexes. Moreover, the study also presents an overview of several mechanisms of action by which pollutants could cause adipose tissue dysfunction. Indeed, a better understanding of the mechanism by which environmental chemicals target adipose tissue and cause metabolic disturbances, and how these mechanisms interact and sex specificities are essential for developing mitigating and sex-specific strategies against metabolic diseases of chemical origin. In particular, considering that a scenario without pollutant exposure is not a realistic option in our current societies, attenuating the deleterious effects of exposure to pollutants by acting on the gut-adipose tissue axis may constitute a new direction of research.

Estrogen withdrawal and replacement differentially target liver and adipose tissues in female mice fed a high-fat high-sucrose diet: impact of a chronic exposure to a low-dose pollutant mixture☆.

Postmenopausal women may be at particular risk when exposed to chemicals especially endocrine disruptors because of hormonal deficit. To get more insight, ovariectomized C57Bl6/J mice fed a high-fat high-sucrose diet were chronically exposed from 5 to 20 weeks of age to a low-dose mixture of chemicals with one dioxin, one polychlorobiphenyl, one phthalate and bisphenol A. Part of the mice received as well E2 implants to explore the potential estrogenic dependency of the metabolic alterations. With this model, estrogen loss resulted in glucose but not lipid metabolism impairment, and E2 replacement normalized the enhanced body and fat pad weight, and the glucose intolerance and insulin resistance linked to ovariectomy. It also altered cholesterol metabolism in the liver concurrently with enhanced estrogen receptor Esr1 mRNA level. In addition, fat depots responded differently to estrogen withdrawal (e.g., selective mRNA enhancement of adipogenesis markers in subcutaneous and of inflammation in visceral fat pads) and replacement challenges. Importantly, the pollutant mixture impacted lipid deposition and mRNA expression of several genes related to lipid metabolism but not Esr1 in the liver. Adiponectin levels were altered as well. In addition, the mRNA abundance of the various estrogen receptors was regionally impacted in fat tissues. Besides, xenobiotic processing genes did not change in response to the pollutant mixture in the liver. The present findings bring new light on estrogen-dependent metabolic alterations with regards to situations of loss of estrogens as observed after menopause.

Chronic exposure to a pollutant mixture at low doses led to tissue-specific metabolic alterations in male mice fed standard and high-fat high-sucrose diet.

Excessive consumption of industrialized food and beverages is a major etiologic factor in the epidemics of obesity and associated metabolic diseases because these products are rich in fat and sugar. In addition, they contain food contact materials and environmental pollutants identified as metabolism disrupting chemicals. To evaluate the metabolic impact of these dietary threats (individually or combined), we used a male mouse model of chronic exposure to a mixture of low-dose archetypal food-contaminating chemicals that was added in standard or high-fat, high-sucrose (HFHS) diet. Specifically, the mixture contained bisphenol A, diethylhexylphthalate, 2,3,7,8-tetrachlorodibenzo-p-dioxine and polychlorinated biphenyl 153. Exposure lasted from 5 to 20 weeks of age. Metabolic exploration was conducted setting the basis of candidate gene expression mRNA analyses in liver, jejunum and adipose tissue depots from 20 week-old mice. Strong metabolic deleterious effects of the HFHS diet were demonstrated in line with obesity-associated metabolic features and insulin resistance. Pollutant exposure resulted in significant changes on plasma triglyceride levels and on the expression levels of genes mainly encoding xenobiotic processing in jejunum; estrogen receptors, regulators of lipoprotein lipase and inflammatory markers in jejunum and adipose tissues as well as adipogenesis markers. Importantly, the impact of pollutants was principally evidenced under standard diet. In addition, depending on nutritional conditions and on the metabolic tissue considered, the impact of pollutants could mimic or oppose the HFHS effects. Collectively, the present study extends the cocktail effect concept of a low-dosed pollutant mixture and originally points to tissue-specificity responsiveness especially in jejunum and adipose tissues.

A comprehensive survey of the laminins and collagens type IV expressed in mouse Leydig cells and their regulation by LH/hCG.

Extracellular matrix (ECM) proteins have been shown to alter Leydig cell steroidogenesis in vitro, substantiating the hypothesis that Leydig cell steroidogenic activity and matrix environment are interdependent events. However, the nature of the ECM components synthesized by Leydig cells and their regulation by LH/human chorionic gonadotropin (hCG) remain unknown. Here, we examine the occurrence of the 11 laminin subunits and the 6 alpha chains of collagen IV (COL4A1-6) by RT-PCR in Leydig cells cultured with or without LH/hCG. Leydig cells were a tumor Leydig cell line (mLTC-1) or 8-week-old mice Leydig cells. Based on PCR data, it is suggested that normal Leydig cells may synthesize a maximum of 11 laminin heterotrimers and the 6 alpha chains of collagen IV. They also may synthesize various proteases and inhibitors of the metzincin family. The mLTC-1 cells have a limited repertoire as compared with normal Leydig cells. Interestingly, none of the ten proteases and inhibitors monitored is under LH-hCG regulation whereas every protease and inhibitor of the serine protease family yet identified in Leydig cells is under gonadotropin regulation. In addition, a few laminin and collagen subunit genes are regulated by LH/hCG. These are laminins alpha3 and gamma3 (Lama3 and Lamc3), Col4a3, and Col4a6, which are negatively regulated by LH/hCG in both Leydig cell types, and Col4a4, which was downregulated in primary cultures but not in mLTC-1 cells. Collectively, the present study suggests that Leydig cells modulate in a selective fashion their matrix environment in response to their trophic hormone. This may alter the steroidogenic outcome of Leydig cells.

Environmental Pollutants and Metabolic Disorders: The Multi-Exposure Scenario of Life.

Obesity and diabetes have reached epidemic proportions the past few decades and continue to progress worldwide with no clear sign of decline of the epidemic. Obesity is of high concern because it is the main risk factor for a number of non-communicable diseases such as cardiovascular diseases and type 2 diabetes. Metabolic diseases constitute a major challenge as they are associated with an overall reduced quality of life and impose a heavy economic burden on countries. These are multifactorial diseases and it is now recognized that environmental exposure to man-made chemical pollutants is part of the equation. Yet, risk assessment procedures are based on a one-by-one chemical evaluation which does not meet the specificities of the multi-exposure scenario of life, e.g., a combined and long-term exposure to even the smallest amounts of chemicals. Indeed, it is assumed that environmental exposure to chemicals will be negligible based on the low potency of each chemical and that they do not interact. Within this mini-review, strong evidences are brought that exposure to low levels of multiple chemicals especially those shown to interfere with hormonal action, the so-called endocrine disrupting compounds do trigger metabolic disturbances in conditions in which no effect was expected if considering the concentration of each individual chemical in the mixture. This is known as the cocktail effect. It means that risk assessment procedures are not protective enough and thus that it should be revisited for the sake of Public Health.

Effects of bisphenol A on metabolism and evidences of a mode of action mediated through endocrine disruption.

Based on rodent studies after prenatal and/or perinatal or adult exposure, there is now evidence that BPA may increase metabolic disturbances eventually leading to type-2 diabetes development via an ED MoA. In particular, BPA has been shown to alter insulin synthesis and/or release by pancreatic ß-cells, and insulin signaling within insulin-sensitive organs (i.e., liver, muscle, adipose tissues). This resulted in variations in the expression of specific hepatic or adipose tissue markers, which are indicative of a state of insulin resistance. These effects are considered by experts to be hallmarks of adverse hormonal effects, each leading to insulin resistance within the different insulin-sensitive tissues. Although epidemiological studies are inconclusive, these effects are considered relevant for humans, because similarities exist in homeostatic regulation of insulin production and sensitivity between rodents and humans and because evidence was also shown through in vitro experimental data using human cells or tissues.

Evidence for estrogeno-mimetic effects of a mixture of low-dose pollutants in a model of ovariectomized mice.

We recently hypothesized that a mixture of low-dosed dioxin, polychlorobiphenyl, phthalate and bisphenol may induce estrogeno-mimetic activities in a model of lifelong-exposed female mice. Herein, we evaluated the impact of this mixture in estrogen deficiency conditions. Based on the protective effects of estrogens against metabolic disorders, we reasoned that exposure to pollutants should attenuate the deleterious metabolic effects induced by ovariectomy. In line with the hypothesis, exposure to pollutants was found to reduce the impact of ovariectomy on glucose intolerance and insulin resistance, to enhance the expression levels of the hepatic estrogen receptor α and to attenuate the ovariectomy-induced enhancement of the chemokine MCP-1/CCL2 considered as an indicator of estrogen signalling. Because of the very low doses of pollutants used in mixture, these findings may have strong implications in terms of understanding the potential role of environmental contaminants in the development of metabolic diseases, specifically in females during menopausal transition.

Regulatory identification of BPA as an endocrine disruptor: Context and methodology.

BPA is one of the most investigated substances for its endocrine disruptor (ED) properties and it is at the same time in the center of many ED-related controversies. The analysis on how BPA fits to the regulatory identification as an ED is a challenge in terms of methodology. It is also a great opportunity to test the regulatory framework with a uniquely data-rich substance and learn valuable lessons for future cases. From this extensive database, it was considered important to engage in a detailed analysis so as to provide specific and strong evidences of ED while reflecting accurately the complexity of the response as well the multiplicity of adverse effects. An appropriate delineation of the scope of the analysis was therefore critical. Four effects namely, alterations of estrous cyclicity, mammary gland development, brain development and memory function, and metabolism, were considered to provide solid evidence of ED-mediated effects of BPA.

Endocrine disrupting chemicals in mixture and obesity, diabetes and related metabolic disorders.

Obesity and associated metabolic disorders represent a major societal challenge in health and quality of life with large psychological consequences in addition to physical disabilities. They are also one of the leading causes of morbidity and mortality. Although, different etiologic factors including excessive food intake and reduced physical activity have been well identified, they cannot explain the kinetics of epidemic evolution of obesity and diabetes with prevalence rates reaching pandemic proportions. Interestingly, convincing data have shown that environmental pollutants, specifically those endowed with endocrine disrupting activities, could contribute to the etiology of these multifactorial metabolic disorders. Within this review, we will recapitulate characteristics of endocrine disruption. We will demonstrate that metabolic disorders could originate from endocrine disruption with a particular focus on convincing data from the literature. Eventually, we will present how handling an original mouse model of chronic exposition to a mixture of pollutants allowed demonstrating that a mixture of pollutants each at doses beyond their active dose could induce substantial deleterious effects on several metabolic end-points. This proof-of-concept study, as well as other studies on mixtures of pollutants, stresses the needs for revisiting the current threshold model used in risk assessment which does not take into account potential effects of mixtures containing pollutants at environmental doses, e.g., the real life exposure. Certainly, more studies are necessary to better determine the nature of the chemicals to which humans are exposed and at which level, and their health impact. As well, research studies on substitute products are essential to identify harmless molecules.

Low-dose pollutant mixture triggers metabolic disturbances in female mice leading to common and specific features as compared to a high-fat diet.

Environmental pollutants are potential etiologic factors of obesity and diabetes that reach epidemic proportions worldwide. However, it is important to determine if pollutants could exert metabolic defects without directly inducing obesity. The metabolic disturbances triggered in nonobese mice lifelong exposed to a mixture of low-dose pollutants (2,3,7,8-tetrachlorodibenzo-p-dioxine, polychlorinated biphenyl 153, diethylhexyl-phthalate, and bisphenol A) were compared with changes provoked by a high-fat high-sucrose (HFHS) diet not containing the pollutant mixture. Interestingly, females exposed to pollutants exhibited modifications in lipid homeostasis including a significant increase of hepatic triglycerides but also distinct features from those observed in diet-induced obese mice. For example, they did not gain weight nor was glucose tolerance impacted. To get more insight, a transcriptomic analysis was performed in liver for comparison. We observed that in addition to the xenobiotic/drug metabolism pathway, analysis of the hepatic signature illustrated that the steroid/cholesterol, fatty acid/lipid and circadian clock metabolic pathways were targeted in response to pollutants as observed in the diet-induced obese mice. However, the specific sets of dysregulated annotated genes (>1300) did not overlap more than 40% between both challenges with some genes specifically altered only in response to pollutant exposure. Collectively, results show that pollutants and HFHS affect common metabolic pathways, but by different, albeit overlapping, mechanisms. This is highly relevant for understanding the synergistic effects between pollutants and the obesogenic diet reported in the literature.

The mouse testis is the source of various serine proteases and serine proteinase inhibitors (SERPINs): Serine proteases and SERPINs identified in Leydig cells are under gonadotropin regulation.

The occurrence of various serine proteinases and serine proteinases inhibitors (SERPINs) was investigated by RT-PCR in whole testes of 1-, 3-, and 8-wk-old mice in crude and enriched germ cell fractions, mouse Leydig tumor cells (mLTC-1), and primary cultures of 3- and 8-wk-old enriched fractions of Leydig cells and 3-wk-old Sertoli cells. New members were identified in the testis protease repertoire. Within the Leydig repertoire, a PCR product was found for plasminogen activators urokinase plasminogen activator (uPA) and tissue plasminogen activator (8-wk-old cells), matriptase-2 (mLTC-1), kallikrein-21, SERPINA5, SERPINB2 (primary cultures), and serine peptidase inhibitor Kunitz type 2 (SPINT2). The gonadotropin regulation was explored by semiquantitative RT-PCR, using steroidogenic acute regulatory protein (StAR) as a positive control. Matriptase-2, kallikrein-21, SPINT2, and SERPINA5 were down-regulated, whereas uPA and its receptor were up-regulated by human chorionic gonadotropin (hCG) via cAMP in the mLTC-1 cells. Positive effects were observed transiently after 1-8 h of hCG exposure, and negative effects, first evidenced after 6 h, lasted 48 h. The hCG-induced effects were confirmed in primary cultures. In addition, SERPINB2 was augmented by hCG in primary cultures. Addition of either trypsin or protease inhibitors did not alter the hCG-induced surge of StAR. Because hCG regulated proteases and SERPINs (whereas testosterone did not), it could alter the proteolytic balance of Leydig cells and consequently the metabolism of extracellular matrix components. Therefore, even though a direct interplay between the early hCG-induced surge of uPA and StAR is unlikely, our data together with the literature suggest that extracellular matrix proteins alter Leydig cell steroidogenesis.

Lack of effect on rat testicular organogenesis after in utero exposure to 3-monochloropropane-1,2-diol (3-MCPD).

3-Monochloropropane-1,2-diol (3-MCPD) is a food-born contaminant known to display toxic effects on male reproduction, producing infertility in rats and humans. Using the rat as a model, we investigated whether or not testicular organogenesis, which, in the rat species, occurs during the second half of gestation, was at particular risk regarding 3-MCPD toxicity. Pregnant rats were given daily doses of 5, 10 or 25 mg/kg BW of 3-MCPD from days 11.5-18.5 postcoitum (dpc). On 19.5 dpc, testes were removed from fetuses for histological examination and testosterone analysis. Eight genes were selected among the differentiation markers of testicular cell lineages, and their expression was studied by RT-PCR. The levels of 3-MCPD and its main metabolite, beta-chlorolactic acid, were assayed in fetal tissues and dam plasma. Our results show a statistically significant decrease in the mean body weight gain of pregnant rats treated with 10 and 25 mg/kg BW of 3-MCPD. Fetal testes exposed to 3-MCPD exhibited normal histology and produced testosterone at levels that were similar to controls. In addition, 3-MCPD did not alter gene expression in the fetal testes. This lack of effect occurred under conditions where 3-MCPD and beta-chlorolactic acid were found to readily cross the placental barrier and diffuse throughout the fetal tissues. Our findings indicate that 3-MCPD has minimal effect on rat testicular organogenesis.

[Impact of in utero exposure to pollutants on metabolic health in adults]. / Exposition maternelle aux polluants et altération de la santé métabolique à l'âge adulte.

Obesity is a major public health problem because it is a risk factor for metabolic disorders including type 2 diabetes and cardiovascular disorders. Notably, pollutants endowed with endocrine disrupting activities have been charged to contribute to the etiology of obesity and type 2 diabetes, especially if exposure occurs during the early life shown to be a highly vulnerable window of time. An overview on endocrine disrupters in relation with the obesogen and metabolic disruption hypothesis is presented. Convincing data support the plausibility of such hypothesis. They also highlight the limits of the current threshold model used in risk assessment which focused on single chemicals and does not take into account potential effects of mixtures containing pollutants at environmental doses, e.g. the real life exposure. Certainly, the principle of precaution should guide the making of decisions especially when considering early life exposure.