Do changes in persistent organic pollutants after bariatric surgery cause endocrine disruption?

BACKGROUND: Bariatric surgery results in weight loss, marked endocrine changes and the release of persistent organic pollutants (POPs). The release of POPs might cause endocrine disruption. The study aimed to explore associations between POPs and adiponectin, leptin and ghrelin in subjects undergoing bariatric surgery. METHODS: The study included 63 subjects with severe obesity (men/women: 13/50), age (years): 45.0 (8.5), and BMI (kg/m2) 39.1 (3.4). Analyses of adiponectin, leptin and ghrelin and POPs (hexachlorobenzene (HCB), dichlorodiphenyldichloroethylene (p,p'-DDE), polychlorinated biphenyl (PCB) 118 (dioxin-like compound; dl), and sum 6 PCB (PCB 28, -52, -101, -138, -153, and -180) were performed before and 12 months after bariatric surgery. RESULTS: There were significant increases in adiponectin and all POPs and a fall in leptin after surgery. The main finding was the highly significant associations between adiponectin and all POPs. The increase in HCB explained 38% of the variation in adiponectin. CONCLUSIONS: If the POP-associated increase in adiponectin is a causal effect, the release of POPs might have important clinical consequences. Adiponectin has both positive and negative clinical effects exerted by essentially unknown mechanisms. The effects of released POPs on the metabolic functions in subjects undergoing bariatric surgery deserve further evaluation.

Effects of an environmentally relevant PFAS mixture on dopamine and steroid hormone levels in exposed mice.

In the present study, we investigated the dopaminergic and steroid hormone systems of A/J mice fed environmentally relevant concentrations of a perfluoroalkyl substance (PFAS) mixture over a period of 10 weeks. The PFAS mixture was chosen based on measured PFAS concentrations in earthworms at a Norwegian skiing area (Trondheim) and consisted of eight different PFAS. Dietary exposure to PFAS led to lower total brain dopamine (DA) concentrations in male mice, as compared to control. On the transcript level, brain tyrosine hydroxylase (th) of PFAS exposed males was reduced, compared to the control group. No significant differences were observed on the transcript levels of enzymes responsible for DA metabolism, namely - monoamine oxidase (maoa and maob) and catechol-O methyltransferase (comt). We detected increased transcript level for DA receptor 2 (dr2) in PFAS exposed females, while expression of DA receptor 1 (dr1), DA transporter (dat) and vesicular monoamine transporter (vmat) were not affected by PFAS exposure. Regarding the steroid hormones, plasma and muscle testosterone (T), 11-ketotestosterone (11-KT) and 17ß-estradiol (E2) levels, as well as transcripts for estrogen receptors (esr1 and esr2), gonadotropin releasing hormone (gnrh) and aromatase (cyp19) were unaltered by the PFAS treatment. These results indicate that exposure to PFAS doses, comparable to previous observation in earthworms at a Norwegian skiing area, may alter the dopaminergic system of mice with overt consequences for health, general physiology, cognitive behavior, reproduction and metabolism.

Alteration of neuro-dopamine and steroid hormone homeostasis in wild Bank voles in relation to tissue concentrations of PFAS at a Nordic skiing area.

Perfluoroalkyl substances (PFAS) are contaminants that are applied in a wide range of consumer products, including ski products. The present study investigated the neuro-dopamine (DA) and cellular steroid hormone homeostasis of wild Bank voles (Myodes glareolus) from a skiing area in Norway (Trondheim), in relation to tissue concentrations of PFAS. We found a positive association between brain DA concentrations and the concentration of several PFAS, while there was a negative association between PFAS and dopamine receptor 1 (dr1) mRNA. The ratio between DA and its metabolites (3,4-dihydroxyphenylacetic acid: DOPAC and homovanillic acid: HVA) showed a negative association between DOPAC/DA and several PFAS, suggesting that PFAS altered the metabolism of DA via monoamine oxidase (Mao). This assumption is supported by an observed negative association between mao mRNA and PFAS. Previous studies have shown that DA homeostasis can indirectly regulate cellular estrogen (E2) and testosterone (T) biosynthesis. We found no association between DA and steroid hormone levels, while there was a negative association between some PFAS and T concentrations, suggesting that PFAS might affect T through other mechanisms. The results from the current study indicate that PFAS may alter neuro-DA and steroid hormone homeostasis in Bank voles, with potential consequences on reproduction and general health.

Decreased plasma levels of perfluoroalkylated substances one year after bariatric surgery.

Per- and polyfluoroalkylated substances (PFASs) are classified as persistent organic pollutants (POPs), and known to be protein bound. The aim of the present study was to determine the levels of 17 different PFASs before and one year after bariatric surgery, and to assess whether weight loss and changed serum protein concentrations could be influencing factors. Plasma samples from 63 patients were analyzed for nine perfluoroalkyl carboxylic acids (PFCAs), three perfluoroalkane sulfonic acids (PFSAs), and five perfluoroalkyl sulfonamide based substances (PASF) before and after surgery. Protein determination was performed in the corresponding serum samples. Mean weight loss one year after surgery was 32.1 kg. The plasma levels of all PFASs decreased with 4-34% compared to preoperative values, and included perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), and perfluorobutane sulfonate (PFBS), which have been identified with increasing levels in the general population during recent years. Serum protein concentrations also decreased with 7-8%. Although protein levels were positively correlated with PFOA, PFBS, PFHxS and PFOS, regression analysis revealed that neither weight loss nor reductions in concentrations of serum protein could explain the decreased PFAS levels. The type of surgical procedure did not influence the changes of PFAS levels between the two sample points. A reduced food intake and alterations in absorptions of nutrients after bariatric surgery may have influenced the observed decreasing plasma levels of PFASs.

Increased levels of persistent organic pollutants in serum one year after a great weight loss in humans: Are the levels exceeding health based guideline values?

BACKGROUND: With the growing prevalence of obesity, an increased number of bariatric surgeries are being performed. Lipophilic persistent organic pollutants (POPs) are stored in adipose tissue, and an increased release of lipophilic POPs into the blood circulation may occur following rapid weight loss such as after bariatric surgery. OBJECTIVES: To evaluate and compare POP levels in serum before and after bariatric surgery, and to assess if the POP levels exceeded health based guideline values, with particular focus on women of childbearing age (WCBA). METHODS: Serum samples from 63 patients before and one year after bariatric surgery were analysed for organochlorine pesticides (OCPs); polychlorinated biphenyls (PCBs); and brominated flame retardants (BFRs). RESULTS: Mean weight loss one year after surgery was 32.1kg. The levels of all the analysed POPs in serum increased during the study period. Median levels of dichlorodiphenyldichloroethylene (p,p'-DDE), hexachlorobenzen (HCB) and PCB-153 increased from 90.2ng/g lipid weight (lw) to 158.5ng/glw, from 21.1ng/glw to 36.4ng/glw and from 48.7ng/glw to 71.5ng/glw, respectively. The highest percentage increase was observed for PCB -138, with 83.1%. BFRs were detected in low sample numbers and at low levels. Guideline values for ΣPCB6 in serum were exceeded for 5% of the participants. CONCLUSIONS: Weight loss after bariatric surgery resulted in increases of POPs levels in serum between 46.7%-83.1%. Guideline values for ΣPCB6 in serum were exceeded for 5% of the participants. For WCBA, the possible transfer of comparable levels to infants warrants further attention.

Increased blood levels of persistent organic pollutants (POP) in obese individuals after weight loss-A review.

Lipophilic persistent organic pollutants (POP) are stored in adipose tissue. Following rapid weight loss such as when induced by bariatric surgery, an increased release of potential harmful lipophilic compounds into the blood circulation may occur. Weight reduction is recommended for overweight and obese individuals in order to decrease risk of weight-related health problems. However, in cases of significant weight reduction POP become mobilized chemicals and consequently may adversely affect health, including endocrine disruption. The objective of the present investigation was to estimate quantitatively the level of mobilization of POP following weight loss over time. According to literature search criteria, 17 studies were identified with 2061 participants. Data from 5 of the studies with 270 participants were used to assess the change in blood levels of POP in percent per kilogram weight loss. Weight loss in the included studies varied from 4.4 to 64.8 kg. In all studies, the majority of POP concentrations in blood were found to rise following weight reduction. Blood concentrations following weight reduction were elevated by 2-4% per kilogram weight loss for most POP examined. The increased POP levels were still elevated 12 mo after intervention. Most research in this field, including animal studies, is carried out on a single compound or group of selected compounds, not taking the "cocktail effect" into consideration. This does not reflect the true range of POP to which humans are actually exposed. Few chronic investigations have been published and, in particular, few studies were available that compared the increase in POP concentrations with clinical consequences as individuals lost weight. These limitations call for caution in interpreting results. The benefits of losing weight still far outweigh the potential adverse health risks. However, further studies are recommended to determine the clinical significance of increased blood levels of POPs following rapid and excessive weight loss, particularly for women attending weight reduction treatment before pregnancy.

Transcriptional profiling in burbot (Lota lota) from Lake Mjøsa--a Norwegian Lake contaminated by several organic pollutants.

Lake Mjøsa is the largest freshwater repository in Norway, receiving runoff from a wide surrounding region of urban country. As a result of industrial activity, large quantities of persistent organic pollutants (POPs) have been discharged into Lake Mjøsa during the last century. The levels of PCBs, DDTs and PBDEs in burbot from Lake Mjøsa (study population) exceed the corresponding levels in burbot from Lake Losna (reference) by a factor of 3, 6 and 113, respectively. We used shotgun and suppression subtraction hybridization (SSH) cDNA libraries followed by 454 FLX sequencing (957 303 reads sequenced in total) and RT-qPCR to study the effects of POPs in burbot from Lake Mjøsa. The gene list of putatively higher or lower expressed genes in liver of burbot from Lake Mjøsa compared to liver of burbot from Lake Losna, generated from the SSH cDNA libraries, suggest that mechanisms associated with drug metabolism and oxidative stress are enriched in burbot from Lake Mjøsa (Ingenuity Pathway Analysis (IPA) top networks). According to the IPA analyses, the top toxicity list ranking was "LXR/RXR activation", "Negative/Positive acute phase response proteins", "LPS/IL-1-mediated inhibition of RXR function" and "FXR/RXR activation". Functional analyses further identified PPAR, HNF4A, dexamethasone and ß-estradiol as potential upstream key regulator factors. Overall, the study shows that SSH cDNA libraries coupled to next-generation sequencing (RNA-Seq) may be a valuable supplement or alternative to microarray technology in toxicogenomic discovery of environmental samples.

Parental exposure to natural mixtures of POPs reduced embryo production and altered gene transcription in zebrafish embryos.

Determination of toxicity of complex mixtures has been proposed to be one of the most important challenges for modern toxicology. In this study we performed genome wide transcriptome profiling to assess potential toxicant induced changes in gene regulation in zebrafish embryos following parental exposure to two natural mixtures of persistent organic pollutants (POPs). The mixtures used were extracted from burbot (Lota lota) liver originating from two lakes (Lake Mjøsa and Lake Losna) belonging to the same freshwater system in Norway. The dominating groups of contaminants were polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane metabolites (DDTs). Because both mixtures used in the present study induced similar effects, it is likely that the same toxicants are involved. The Mjøsa mixture contains high levels of PBDEs while this group of pollutants is low in the Losna mixture. However, both mixtures contain substantial concentrations of PCB and DDT suggesting these contaminants as the predominant contributors to the toxicity observed. The observed effects included phenotypic traits, like embryo production and survival, and gene transcription changes corresponding with disease and biological functions such as cancer, reproductive system disease, cardiovascular disease, lipid and protein metabolism, small molecule biochemistry and cell cycle. The changes in gene transcription included genes regulated by HNF4A, insulin, LH, FSH and NF-κB which are known to be central regulators of endocrine signaling, metabolism, metabolic homeostasis, immune functions, cancer development and reproduction. The results suggest that relative low concentrations of the natural mixtures of POPs used in the present study might pose a threat to wild freshwater fish living in the lakes from which the POPs mixtures originated.

High prevalence of infections and pathological changes in burbot (Lota lota) from a polluted lake (Lake Mjøsa, Norway).

The aim of the present study was to investigate whether exposure to high levels of persistent organic pollutants (POPs) affected a fish population in Lake Mjøsa. Lake Mjøsa is known to be contaminated by polybrominated diphenyl ethers (PBDEs), a subgroup of brominated flame retardants from local industrial activities. Fish from Lake Losna, a less contaminated lake located close to Lake Mjøsa, was used as reference (control). The sampling of burbot (Lota lota) was carried out between 2005 and 2008. Hepatic levels of POPs were analysed in burbot from the two lakes, and the fish were examined for bacterial- and parasite infection and histopathological changes. The levels of polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethanes (DDTs), and PBDEs were about 10, 15 and 300 times higher in fish from Lake Mjøsa compared to fish from Lake Losna. Mycobacterium salmoniphilum was present in 7% and 35% of the fish from Lake Losna and Lake Mjøsa respectively. Significantly higher number of external and visceral macroscopic lesions, histopathological diffuse changes and granulomas were seen in fish from Lake Mjøsa compared to Lake Losna. Furthermore the parasite infection was higher and the hepatic lipid content was significantly lower in burbot from Lake Mjøsa. The results of the present study suggest that the high level of contamination in Lake Mjøsa could have a negative impact on the health status of wild fish inhabiting the lake.

Policy relevant results from an expert elicitation on the human health risks of decabromodiphenyl ether (decaBDE) and hexabromocyclododecane (HBCD).

AIM: Apply a recently developed expert elicitation procedure to evaluate the state of the current knowledge of the two brominated flame retardants (BFRs) most commonly used today; decabromo-diphenyl ether (decaBDE) and hexabromocyclododecane (HBCD) and their potential impact on human health in order to support policy considerations. This expert elicitation was organized by the HENVINET (Health and Environment Network) Consortium. METHOD: The HENVINET expert elicitation procedure that was used in the evaluations of decaBDE and HBCD is a rapid assessment tool aimed at highlighting areas of agreement and areas of disagreement on knowledge-related key issues for environment and health policy decision making. RESULTS: The outcome of the expert consultation on BFRs was concrete expert advice for policy makers with specific priorities for further action made clear for both stakeholders and policy makers. The experts were not in agreement whether or not the knowledge currently available on decaBDE or HBCD is sufficient to justify policy actions, but most experts considered that enough data already exists to support a ban or restriction on the use of these compounds. All experts agreed on the necessity of more research on the compounds. Priority issues for further research were, among others:• more studies on the extent of human exposure to the compounds.• more studies on the fate and concentration in the human body of the compounds.

Mycobacterium salmoniphilum infection in burbot Lota lota.

Burbot Lota lota sampled from lakes Mjosa and Losna in southeastern Norway between 2005 and 2008 were found to be infected with Mycobacterium salmoniphilum at a culture-positive prevalence of 18.6 and 3.3%, respectively. The condition factor (CF) of mycobacteria-affected fish sampled from Mjøsa in 2008 was lower than the average CF of total sampled fish the same year. Externally visible pathological changes included skin ulceration, petechiae, exopthalmia and cataract. Internally, the infections were associated with capsulated, centrally necrotic granulomas, containing large numbers of acid-fast bacilli, found mainly in the mesenteries, spleen, heart and swim bladder. Mycobacterial isolates recovered on Middlebrook 7H10 agar were confirmed as M. salmoniphilum by phenotypical investigation and by partial sequencing of the 16S rRNA, rpoB and Hsp65genes as well as the internal transcribed spacer (ITS1) locus. This study adds burbot to the list of fish species susceptible to piscine mycobacteriosis and describes M. salmoniphilum infection in a non-salmonid fish for the first time.

Natural mixtures of POPs affected body weight gain and induced transcription of genes involved in weight regulation and insulin signaling.

Obesity is reaching epidemic proportions worldwide, and is associated with chronic illnesses such as diabetes, cardiovascular disease, hypertension and dyslipidemias (metabolic syndrome). Commonly held causes of obesity are overeating coupled with a sedentary lifestyle. However, it has also been postulated that exposure to endocrine disrupting chemicals (EDCs) may be related to the significant increase in the prevalence of obesity and associated diseases. In the present study, developmental and reproductive effects of lifelong exposure to environmentally relevant concentrations of two natural mixtures of persistent organic pollutants (POPs) were investigated using classical and molecular methods in a controlled zebrafish model. The mixtures used were extracted from burbot (Lota lota) liver originating from freshwater systems in Norway (Lake Mjøsa and Lake Losna). The concentration of POPs in the zebrafish ranged from levels detected in wild fish (Lake Mjøsa and Lake Losna), to concentrations reported in human and wildlife populations. Phenotypic effects observed in both exposure groups included (1) earlier onset of puberty, (2) elevated male/female sex ratio, and (3) increased body weight at 5 months of age. Interestingly, genome-wide transcription profiling identified functional networks of genes, in which key regulators of weight homeostasis (PPARs, glucocoricoids, CEBPs, estradiol), steroid hormone functions (glucocoricoids, estradiol, NCOA3) and insulin signaling (HNF4A, CEBPs, PPARG) occupied central positions. The increased weight and the regulation of genes associated with weight homeostasis and insulin signaling observed in the present study suggest that environmental pollution may affect the endocrine regulation of the metabolism, possibly leading to increased weight gain and obesity.

Effects of long-term maternal exposure to low doses of PCB126 and PCB153 on the reproductive system and related hormones of young male goats.

In this study, female goats were orally exposed to PCB126 or PCB153, at 49 ng/kg body weight per day and 98 microg/kg body weight per day respectively, from gestational day 60 until delivery at approximately day 150. Exposure of the offspring continued via lactation until postnatal day 40. Reproductive toxicity in the male offspring was studied by the evaluation of conventional reproductive endpoints as well as flow cytometric analyses of spermatogenesis and sperm chromatin structure. PCB153-treated animals showed a significant smaller testis diameter in comparison to the control group. Neither of the treated groups showed differences for plasma FSH in comparison to controls. PCB153-treated animals differed significantly from the control group with respect to plasma LH and testosterone levels, whereas PCB126-treated animals only differed from the controls in plasma testosterone concentrations. Neither the PCB126 nor the PCB153 group differed from the controls with respect to the conventional sperm parameters or testis histology. A significant lower ratio of interstitium area to seminiferous tubules area and proportion of diploid testis cells were observed for the PCB153 group. Sperm from PCB153-treated animals showed a significantly higher percentage of sperm with damaged DNA. From the results of the present study it was concluded that PCB153 was able to induce alterations in reproductive endpoints related to the hypothalamic-pituitary-axis as well as to the testis. The effects observed in male kids after a long-term maternal exposure to PCB153 support the concept that exposure to endocrine-disrupting compounds during foetal development may lead to adverse reproductive effects in adult life.

Effects of gestational and lactational exposure to low doses of PCBs 126 and 153 on anterior pituitary and gonadal hormones and on puberty in female goats.

The aim of the present study was to investigate if environmental doses of PCB 153 and PCB 126 could produce effects in a controlled animal model. Possible adverse effects on the hypothalamic-pitutitary-gonadal axis were examined by measuring gonadotrophins and gonadal steroid hormone concentrations in goat kids exposed during gestation and lactation. The concentrations of PCB 153 and PCB 126 in adipose tissue in the goat kids 9 months post-partum were 5800 ng/g (fat-weight, range; 2900-12700 ng/g) and 0.49 ng/g (fat-weight, range; 0.28-0.80 ng/g), respectively. The pre- and post-pubertal plasma concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (Prl) and progesterone (P4) were analysed. LH, FSH, Prl, and P4 were also measured during an induced oestrus cycle. The prepubertal LH concentration was significantly lower, the puberty was delayed and the P4 level during the luteal phase of an estrous cycle was higher in the group exposed to PCB 153. No significant effect of PCB 153 exposure was found on Prl and FSH. PCB 126 did not produce any effects at the exposure level tested in this study. In conclusion, perinatal exposure to PCB 153 affected the reproductive function and the puberty maturation in goats.