Paternal p,p'-DDE exposure and pre-pubertal high-fat diet increases the susceptibility to fertility impairment and sperm Igf2 DMR2 hypo-methylation in male offspring.

The hypothesis of paternal origins of health and disease (POHaD) indicates that paternal exposure to adverse environment could alter the epigenetic modification in germ line, increasing the disease susceptibility in offspring or even in subsequent generations. p,p'-Dichlorodiphenyldichloroethylene (p,p'-DDE) is an anti-androgenic chemical and male reproductive toxicant. Gestational p,p'-DDE exposure could impair reproductive development and fertility in male offspring. However, the effect of paternal p,p'-DDE exposure on fertility in male offspring remains uncovered. From postnatal day (PND) 35 to 119, male rats (F0) were given 10 mg/body weight (b.w.) p,p'-DDE or corn oil by gavage. Male rats were then mated with the control females to generate male offspring. On PND35, the male offspring were divided into 4 groups according whether to be given the high-fat diet (HF): corn oil treatment with control diet (C-C), p,p'-DDE treatment with control diet (DDE-C), corn oil treatment with high-fat diet (C-HF) or p,p'-DDE treatment with high-fat diet (DDE-HF) for 35 days. Our results indicated that paternal p,p'-DDE exposure did not affect the male fertility of male offspring directly, but decreased sperm quality and induced testicular apoptosis after the high-fat diet treatment. Further analysis demonstrated that paternal exposure to p,p'-DDE and pre-pubertal high-fat diet decreased sperm Igf2 DMR2 methylation and gene expression in male offspring. Hence, paternal exposure to p,p'-DDE and pre-pubertal high-fat diet increases the susceptibility to male fertility impairment and sperm Igf2 DMR2 hypo-methylation in male offspring, posing a significant implication in the disease etiology.

A multipollutant low-grade exposure regulates the expression of miR-30b, Let-7a and miR-223 in maternal sera: Evidence from the NEHO cohort.

There is growing evidence that environmental pollutants can induce epigenetic modifications altering the balance of miRNAs and inducing the onset of pathological conditions in animals. In this study, we measured the serum concentration of a suite of inorganic and organic pollutants (Cu, Zn, Se, Hg, HCB, p,p'-DDE, PCBs) and their association to serum miR-30b, miR-223 and Let-7a microRNA expression in 68 healthy pregnant women from the NEHO birth cohort sited in a highly industrialized area. The effects of the pollutants on the modulation of circulating miRNAs' expression were first investigated using linear continuous regression models with a single-compound approach showing that miR-223 expression was significantly associated with serum concentration of Se and Zn (pSe = 0.0336; pZn = 0.0225) and miR-30b was associated with Hg levels (pHg = 0.019). Furthermore, when contaminants were categorized into tertiles, miR-223 and miR-30b showed a positive association with higher tertiles of Zn, p,p'-DDE (pZn = 0.023; pDDE = 0.041) and Hg (pHg = 0.008), respectively. Moreover, Let-7a expression was exclusively influenced by medium tertiles levels of Se (low vs medium tertiles, p = 0.001). Simultaneous exposure to multi-pollutant mixture was approached by WQS regression model. Statistical analysis shows a driving effect of Zn, Se, Cu, Hg and HCB on significant increased expression of Let-7a (p = 0.045). Mercury and Se significantly amplified the expression for miR-30b (p = 0.038). Differently, the combined effect of p,p'-DDE, Zn and Se decreased miR-223 expression (p = 0.0001). The documented modified expression of circulating miRNAs in the serum of pregnant women, exposed to low-medium dose contaminants mixtures offers innovative early-warning approaches to human health risk assessment.

Protective effect of Pedro-Ximénez must against p,p'-DDE-induced liver damages in aged Mus spretus mice.

Aging is characterized by deterioration of biomolecules and impaired stress responses that make the elderly especially vulnerable to environmental pollutants. The pesticide p,p'-DDE is a DDT derivative that generates great concern because of its wide distribution and its harmful effects on both human health and the environment. We analyzed here the biological responses elicited by p,p'-DDE exposure in the liver of aged Mus spretus mice. Data demonstrate that the elderly constitute a population especially sensitive to this noxious environmental pollutant. We also demonstrated here that the daily consumption of sun-dried Pedro Ximénez (PX) white-grape must (PXM) protects the liver of aged mice from both the age and the damages caused by p,p'-DDE exposure. The PXM activity was exerted through the restoration of the hepatic metabolisms of lipids and carbohydrates and, probably, is a consequence of the ability of this polyphenol-rich mixture to avoid oxidative stress. Nutritional interventions including PXM, which ameliorates the effects of unavoidable exposure to pesticides in our food, are helpful tools that can help elderly populations to enjoy a healthy and expanded lifetime.

Metabolic Impairments Caused by a "Chemical Cocktail" of DDE and Selenium in Mice Using Direct Infusion Triple Quadrupole Time-of-Flight and Gas Chromatography-Mass Spectrometry.

Among organic contaminants, pesticides are one of the most important groups of chemicals due to their persistent character and toxicity. However, the biological systems are exposed to a complex environment in which the contaminants can interact in a synergistic/antagonistic fashion, and for this reason, the study of "chemical cocktails" is of great interest to fully understand the final biological effect. In this way, selenium is known for its antagonistic action against several toxicants. In this paper, metabolic impairments caused by the joint exposure of p,p'-dichloro diphenyl trichloroethane (DDE) and selenium (Se) have been issued for the first time. A metabolomic workflow was applied to mice fed DDE and DDE with Se diet, on the basis of the complementary use of two organic mass spectrometric techniques, combining direct infusion mass spectrometry (DI-ESI-QqQ-TOF MS) and gas chromatography-mass spectrometry (GC-MS). The results show a good classification between the studied groups caused by about 70 altered metabolites in the liver, kidney, or brain, including the pathways of energy metabolism, degradation of phospholipidic membrane, ß-oxidation, and oxidative stress, which confirm the potential of combined metabolomic platforms in environmental studies.

Pectin reduces environmental pollutant-induced obesity in mice through regulating gut microbiota: A case study of p,p'-DDE.

BACKGROUND: The prevalence of obesity has raised global concerns. Environmental pollutants are one of the main causes of obesity. Many studies have demonstrated that dietary fiber could reduce obesity induced by high-fat diets, but whether environmental pollutant-induced obesity can be reversed is still unknown. OBJECTIVES: This study aimed to investigate the effects of pectin on obesity induced by a typical environmental pollutant p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) and explore the underlying mechanism by which pectin reversed p,p'-DDE-induced obesity. METHODS: p,p'-DDE was used to induce obesity in C57BL/6J mice and pectin was supplied during and after cessation of p,p'-DDE exposure. Body and fat weight gain, plasma lipid profile and insulin resistance of mice were assessed. Gut microbiota composition and the levels of short-chain fatty acids (SCFAs) as well as the receptor proteins and hormones in the SCFAs-related signaling pathway were analyzed. Moreover, p,p'-DDE levels in various tissues of mice were detected. RESULTS: Pectin supplementation reversed body and fat weight gain, dyslipidemia, hyperglycemia and insulin resistance in p,p'-DDE-exposed mice. Furthermore, pectin apparently altered the p,p'-DDE-induced microbial composition and then promoted the levels of SCFAs in colonic feces as well as the expression of G-protein coupled receptors and the concentration of hormone peptide YY (PYY) and glucagon like peptide-1 (GLP-1). Pectin treatment also significantly reduced p,p'-DDE accumulation in mice tissues during p,p'-DDE exposure but did not change p,p'-DDE metabolism after termination of p,p'-DDE exposure. CONCLUSIONS: Pectin had a good effect on reducing p,p'-DDE-induced obesity through regulating gut microbiota and provided a potential strategy for the treatment of environmental pollutant-caused health problems.

Dietary Se supplementation partially restores the REDOX proteomic map of M. spretus liver exposed to p,p'-DDE.

The toxicity of p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), a contaminant and metabolite derivative of DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] is partially mediated by reactive oxygen species. Protein cysteine-based regulatory switches and subsequent alterations of the overall hepatic metabolism are triggered by p,p'-DDE through the disruption of the cellular redox status. The consequences are reproductive impairment, metabolic disorders, diabetes, neurotoxicity and cancer. In recent years, the risk of p,p'-DDE exposure has increased worldwide, reflecting the rise of mosquito-borne diseases in tropical countries that produce and export contaminated foods. Selenium (Se) is an essential trace element in animal nutrition with antioxidant properties that protects against the toxicity of some xenobiotics. We analyzed the ability of diet Se-supplementation to prevent damages induced by p,p'-DDE in the liver of M. spretus mice, by using redox proteomics based on the determination of the redox status of protein Cys residues. Se selectively acted on specific target, restoring the redox status and functionality of some membrane proteins involved in mitochondrial functionality, protein transport, cell signaling and protein metabolism. However, the Se-enriched diet did not completely prevent the metabolic shift caused by p,p'-DDE exposure that leads to disturbed lipogenesis, hepatic steatosis and alterations in the synthesis of hormones and other cell signals.

The PI3K/Akt and ERK pathways elevate thyroid hormone receptor ß1 and TRH receptor to decrease thyroid hormones after exposure to PCB153 and p,p'-DDE.

PCBs and DDT cause the disturbance of thyroid hormone (TH) homeostasis in humans and animals. To test the hypothesis that the PI3K/Akt and MAPK pathways would play significant roles in TH imbalance caused by PCBs and DDT, Sprague-Dawley rats were dosed with PCB153 and p,p'-DDE intraperitoneally for 5 consecutive days, and human thyroid follicular epithelial (Nthy-ori 3-1 cell line) were treated with PCB153 and p,p'-DDE for different time. Results showed that serum total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3) and thyroid stimulating hormone (TSH) were decreased, whereas serum free triiodothyronine (FT3) and thyrotropin releasing hormone (TRH) were not changed. The PI3K/Akt and ERK pathways were activated in vivo and in vitro after the treatment with PCB153 and p,p'-DDE. Moreover, TH receptor ß1 (TRß1) was elevated after the activation of the PI3K/Akt pathway and was depressed after the inhibition of the PI3K/Akt pathway; TRH receptor (TRHr) was increased after the activation of the ERK pathway and was decreased after the inhibition of the ERK pathway. Though TH receptor α1 (TRα1) level was increased in the hypothalamus, TRα1 and TSHr were not influenced by the status of signaling pathways in in vitro study. Taken together, after exposure to PCB153 and p,p'-DDE, activated PI3K/Akt and ERK pathways disrupt the hypothalamic-pituitary-thyroid (HPT) axis via TRß1 and TRHr and then decrease TH levels, and that would be a potential mechanism by which PCBs and DDT disturb TH homeostasis.

PCB153 and p,p'-DDE disorder thyroid hormones via thyroglobulin, deiodinase 2, transthyretin, hepatic enzymes and receptors.

Polychlorinated biphenyls (PCBs) and DDT are widespread environmental persistent organic pollutants that have various adverse effects on reproduction, development and endocrine function. In order to elucidate effects of PCBs and DDT on thyroid hormone homeostasis, Sprague-Dawley rats were dosed with PCB153 and p,p'-DDE intraperitoneally (ip) for five consecutive days and sacrificed within 24 h after the last dose. Results indicated that after combined exposure to PCB153 and p,p'-DDE, total thyroxine , free thyroxine, total triiodothyronine, and thyroid-stimulating hormone in serum were decreased, whereas free triiodothyronine and thyrotropin-releasing hormone were not affected. Thyroglobulin and transthyretin levels in serum were significantly reduced. mRNA expression of deiodinases 2 (D2) was also suppressed, while D1 and D3 levels were not significantly influenced after combined exposure. PCB153 and p,p'-DDE induced hepatic enzymes, UDPGTs, CYP1A1, CYP2B1, and CYP3A1 mRNA expressions being significantly elevated. Moreover, TRα1, TRß1, and TRHr expressions in the hypothalamus displayed increasing trends after combined exposure to PCB153 and p,p'-DDE. Taken together, observed results indicate that PCB153 and p,p'-DDE could disorder thyroid hormone homeostasis via thyroglobulin, deiodinase 2, transthyretin, hepatic enzymes, and hormone receptors.

Longitudinal association between early life socio-environmental factors and attention function at the age 11 years.

Prenatal and early-life exposures can affect the course of children's neuropsychological development well into pre-adolescence, given the vulnerability of the developing brain. However, it is unknown which socio-environmental factors at early childhood can influence specific cognitive processes like attention at a later age. In this study, we aim to determine social and environmental exposures in early childhood that may be associated with attention function of 11-year-olds. We measured attention function using the continuous performance test-II (CPT-II) on 393 11-year old children from the Menorca's birth-cohort within the INMA-project (Spain), and pre-selected a list of socio-environmental observations taken when they were up to 4 years of age. We found that earlier socio-environmental characteristics, such as parental social class, educational level and maternal mental health are associated with later inattentive and impulsive symptomatology through a higher rate of omission and commission errors. In addition, omission errors were higher in children with atopy and lower in those whose mothers took dietary supplementation with folic acid and vitamins during pregnancy. Breastfeeding played a protective role against commission errors, while higher DDE and PCBs levels at age 4 were associated with slow speed response. Our findings suggest that a number of life socio-environmental factors during prenatal life and early childhood, such as socio-demographic characteristics, breastfeeding, maternal nutritional supplementation with folic acid and vitamins and exposure to some organochlorine compounds may influence inattentive and hyperactive/impulsive symptomatology during pre-adolescence.

p,p'-DDE disturbs the homeostasis of thyroid hormones via thyroid hormone receptors, transthyretin, and hepatic enzymes.

1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (p, p'-dichlorodiphenyldichloroethylene, p, p'-DDE), the major metabolite of 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT), is a known persistent organic pollutant and endocrine disrupting toxicant. In recent years, it has attracted many attentions on account of its disturbing effects on thyroid and thyroid hormones (THs). However, the mechanisms by which the p, p'-DDE exposure influences THs still remain uncertain. To elucidate the possible mechanisms, 20 male rats are administered with different doses of p, p'-DDE (0, 20, 60, 100 mg/kg body wt) every other day by intraperitoneal injection for 10 days. The results indicate that after the p, p'-DDE exposure, serum total thyroxine (TT4) and free thyroxine (FT4) are significantly reduced and other THs changed only little. Transthyretin (TTR) declines in serum and thyroid hormone receptors (TRα1 and TRß1) mRNA expressions elevate in hypothalamus. The hepatic enzymes CYP1A1 (EROD), CYP2B1 (PROD), and UDPGTs are significantly upregulated, but CYP1A2 (MROD) does not show significant change. Taken together, the observed effects in the present study show that p, p'-DDE could disturb the homeostasis of THs via TRs increase, TTR decrease, and hepatic enzymes induction.

Species-specific regulation of PXR/CAR/ER-target genes in the mouse and rat liver elicited by o, p'-DDT.

BACKGROUND: Dichlorodiphenyltrichloroethane (DDT) is a persistent estrogenic organochlorine pesticide that is a rodent hepatic tumor promoter, with inconclusive carcinogenicity in humans. We have previously reported that o, p'-DDT elicits primarily PXR/CAR-mediated activity, rather than ER-mediated hepatic responses, and suggested that CAR-mediated effects, as opposed to ER-mediated effects, may be more important in tumor promotion in the rat liver. To further characterize species-specific hepatic responses, gene expression analysis, with complementary histopathology and tissue level analyses were investigated in immature, ovariectomized C57BL/6 mice treated with 300 mg/kg o, p'-DDT, and compared to Sprague-Dawley rat data. RESULTS: Rats and mice exhibited negligible histopathology with rapid o, p'-DDT metabolism. Gene expression profiles were also similar, exhibiting PXR/CAR regulation with the characteristic induction of Cyp2b10 and Cyp3a11. However, PXR-specific target genes such as Apoa4 or Insig2 exhibited more pronounced induction compared to CAR-specific genes in the mouse. In addition, mouse Car mRNA levels decreased, possibly contributing to the preferential activation of mouse PXR. ER-regulated genes Cyp17a1 and Cyp7b1 were also induced, suggesting o, p'-DDT also elicits ER-mediated gene expression in the mouse, while ER-mediated effects were negligible in the rat, possibly due to the inhibitory effects of CAR on ER activities. In addition, o, p'-DDT induced Gadd45a, Gadd45b and Cdkn1, suggesting DNA damage may be an additional risk factor. Furthermore, elevated blood DHEA-S levels at 12 h after treatment in the mouse may also contribute to the endocrine-related effects of o, p'-DDT. CONCLUSION: Although DDT is known to cause rodent hepatic tumors, the marked species differences in PXR/CAR structure, expression patterns and ligand preference as well as significant species-specific differences in steroidogenesis, especially CYP17A1 expression and activity, confound the extrapolation of these results to humans. Nevertheless, the identification of potential modes of action as well as species-specific responses may assist in the selection and further development of more appropriate models for assessing the toxicity of DDT to humans and wildlife.

[Environmental pollutants in maternal milk and cryptorchidism]. / Polluants environnementaux dans le lait maternel et cryptorchidie.

OBJECTIVE: Numerous maternal lipophilic compounds are eliminated into milk during lactation, their concentrations reflecting fetal in utero exposure. Some of them are endocrine disruptors. Their role in the occurrence of genital malformation, dysfunction or cancer has been suggested. We wanted to study the exposure of our population and its potential association with cryptorchidism, as few clinical studies are available. PATIENTS AND METHODS: Over three years, we screened for cryptorchidism all boys born alive at or above 34 weeks of gestational age, in two maternity wards (CHU Nice, CHG Grasse). Cryptorchid boys were matched with two controls. Nursing mothers provided a colostrum sample that was screened for 15 compounds known for their antiandrogenic and/or anti estrogenic properties, including dichloro-diphenyl-trichloro-ethylene (DDE), polychlorinated biphenyls (PCBs), dibutylphthalate (DBP) (& metabolite monobutylphthalate-mBP) and hexachlorobenzene (HCB). RESULTS: Out of 6246 boys, 102 were cryptorchid (1.6%). All available colostrums (56 for cryptorchid and 69 for controls) were contaminated. Median concentrations of DDE, PCBs, HCB and phthalates were higher though not significantly in cryptorchid versus controls. Cryptorchid boys were more likely to be classified in the most contaminated groups for DDE and SigmaPCBs, with a trend for mBP. Odds ratio (OR) for cryptorchidism was increased for the highest score of SigmaPCB, with a trend only for DDE versus the lowest score of those components. Our results are similar to those of a Scandinavian study with comparable design. DISCUSSION AND CONCLUSIONS: Our results show the universal contamination of milk with endocrine disruptors in our area, and support the association between congenital cryptorchidism and fetal exposure to PCBs and possibly DDE, alone or in association with other chemicals.

Environmental antiandrogens: developmental effects, molecular mechanisms, and clinical implications.

Industrial chemicals and environmental pollutants can disrupt reproductive development in wildlife and humans by mimicking or inhibiting the action of the gonadal steroid hormones, estradiol and testosterone. The toxicity of these so-called environmental endocrine disruptors is especially insidious during sex differentiation and development due to the crucial role of gonadal steroid hormones in regulating these processes. This review describes the mechanism of toxicity and clinical implications of a new class of environmental chemicals that inhibit androgen-mediated sex development. For several of these chemicals, including the agricultural fungicide vinclozolin and the ubiquitous and persistent 1,1,1-trichloro-2,2-bis (p-chlorophenyl)ethane metabolite, 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene, the molecular mechanism of action and the adverse developmental effects on male sex differentiation have been elucidated and are used as examples. Environmental chemicals with antiandrogenic activity offer profound implications with regard to recent clinical observations that suggest an increasing incidence of human male genital tract malformations, male infertility, and female breast cancer. Finally, in light of increasing concern over the potential endocrine disrupting effects of environmental pollutants, an in vitro/in vivo investigational strategy is presented which has proved useful in identifying chemicals with antiandrogen activity and their mechanism of action.

Effects of mercury, selenium, and organochlorine contaminants on reproduction of Forster's terns and black skimmers nesting in a contaminated Texas Bay.

Mean mercury (0.40 micrograms/g), and geometric mean DDE (1.6 micrograms/g) and polychlorinated biphenyl (PCB) (2.3 micrograms/g) concentrations in Forster's tern (Sterna forsteri) eggs from Lavaca Bay were higher than those in tern eggs from a reference area in San Antonio Bay, but residues were not correlated with hatching success. Nest success was similar between bays. Selenium levels in Lavaca Bay tern eggs (0.71 micrograms/g) were also comparable to those in eggs from the reference area (0.68 micrograms/g). Clutch size (3.1 to 3.4) of Lavaca Bay black skimmers (Rynchops niger) was no different than that (3.4) at a reference colony near Laguna Vista. Nest success was similar among three Lavaca Bay colonies, but success was lower at one Lavaca Bay colony (40%) than at Laguna Vista (65%). Mean mercury (0.46 micrograms/g) and selenium (0.75 micrograms/g) concentrations in skimmer eggs from Lavaca Bay were higher than those (0.19, 0.33 micrograms/g) from Laguna Vista; however, concentrations of neither contaminant were related to hatching success. DDE concentrations in Lavaca Bay skimmer eggs (3.4 micrograms/g) were similar to those from Laguna Vista (3.2 micrograms/g) and DDE was negatively correlated with hatching success. PCBs were higher in eggs from Lavaca Bay (1.3 micrograms/g) than Laguna Vista (0.8 micrograms/g). Organochlorine and metal contaminants in most eggs were below embryotoxic levels. Eggshell thinning in Forster's terns (7%) and black skimmers (5%) was below that associated with lowered reproduction. DDE and PCBs were detected in 9 Caspian tern (S. caspia) eggs; maximum concentrations were 4.7 and 5.4 micrograms/g. Caspian tern and least tern (S. albifrons) eggs contained low (less than or equal to 0.9 micrograms/g) concentrations of mercury and selenium.