Non-dioxin-like Polychlorinated Biphenyls Research Articles

Perspective on prenatal polychlorinated biphenyl exposure and the development of the progeny nervous system (Review).

The developmental origins of health and disease concept illustrates that exposure in early life to various factors may affect the offspring's long-term susceptibility to disease. During development, the nervous system is sensitive and vulnerable to the environmental insults. Polychlorinated biphenyls (PCBs), which are divided into dioxin-like (DL-PCBs) and non-dioxin-like PCBs (NDL-PCBs), are synthetic persistent environmental endocrine-disrupting chemicals. The toxicological mechanisms of DL-PCBs have been associated with the activation of the aryl hydrocarbon receptor and NDL-PCBs have been associated with ryanodine receptor-mediated calcium ion channels, which affect neuronal migration, promote dendritic growth and alter neuronal connectivity. In addition, PCB accumulation in the placenta destroys the fetal placental unit and affects endocrine function, particularly thyroid hormones and the dopaminergic system, leading to neuroendocrine disorders. However, epidemiological investigations have not achieved a consistent result in different study cohorts. The present review summarizes the epidemiological differences and possible mechanisms of the effects of intrauterine PCB exposure on neurological development.

Resistance to Cyp3a induction by polychlorinated biphenyls, including non-dioxin-like PCB153, in gills of killifish (Fundulus heteroclitus) from New Bedford Harbor

Previous reports suggested that non-dioxin-like (NDL) PCB153 effects on cytochrome P450 3A (Cyp3a) expression in Atlantic killifish (Fundulus heteroclitus) gills differed between F0 generation fish from a PCB site (New Bedford Harbor; NBH) and a reference site (Scorton Creek; SC). Here, we examined effects of PCB153, dioxin-like (DL) PCB126, or a mixture of both, on Cyp3a56 mRNA in killifish generations removed from the wild, without environmental PCB exposures. PCB126 effects in liver and gills differed between populations, as expected. Gill Cyp3a56 was not affected by either congener in NBH F2 generation fish, but was induced by PCB153 in SC F1 fish, with females showing a greater response. PCB153 did not affect Cyp3a56 in liver of either population. Results suggest a heritable resistance to NDL-PCBs in killifish from NBH, in addition to that reported for DL PCBs. Induction of Cyp3a56 in gills may be a biomarker of exposure to NDL PCBs in fish populations that are not resistant to PCBs.

Fish consumption is an indicator of exposure to non-dioxin like polychlorinated biphenyls in cumulative risk assessments based on a probabilistic and sensitive approach.

The health effects of non-dioxin like polychlorinated biphenyls (NDL-PCBs) include liver, immune, neurodevelopmental, and neurobehavioral effects in addition to hormone alteration. Among 209 PCB congeners, six indicator PCBs (ICES-6) account for about half of NDL-PCBs present in feed and food. The objectives of the current study were first to examine the levels of total PCBs, NDL-PCBs, and ICES-6 PCBs in 200 foods commonly consumed in Taiwan and, second, to estimate the cumulative health risks of NDL-PCB consumption. We suggest a risk management strategy that identifies foodstuffs with particularly high NDL-PCB content. In 200 food samples, which were grouped into 12 categories and 64 food types, 51 PCB congeners were detected. The concentrations of ICES-6 PCBs in all samples were lower than the maximum levels for NDL-PCBs in foodstuffs set by the European Union. PCB-153, PCB-138, and PCB-180 were the major congeners in all food, indicating that the food was contaminated in the past. ICES-6 PCBs contributed 42.2%-52.9% of total NDL-PCBs in all tested foodstuffs. The average estimated daily intake (EDI) of PCBs ranged from 1.22ng/kgbw/day to 2.89ng/kgbw/day in different age groups (95th quantile [P95]: 4.12-10.28ng/kgbw/day). The P95 EDI in 3-6-year-olds was higher than 10ng/kg/day. A qualitative sensitivity analysis in ICES-6 PCBs exposure showed that for the 3- to 6-year-old group, the highest sensitivity was how much fish they ate (37.6%) and its concentration (32.5%). The consumption of pork, eggs, fish, and other seafood accounts for over 90% of ICES-6 PCBs intake, and these foods should be highlighted in guidelines regarding NDL-PCB intake.

Dioxin-like and non-dioxin-like PCBs differentially regulate the hepatic proteome and modify diet-induced nonalcoholic fatty liver disease severity.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with metabolic disruption and non-alcoholic fatty liver disease (NAFLD). Based on their ability to activate the aryl hydrocarbon receptor (AhR), PCBs are subdivided into two classes: dioxin-like (DL) and non-dioxin-like (NDL) PCBs. Previously, we demonstrated that NDL PCBs compromised the liver to promote more severe diet-induced NAFLD. Here, the hepatic effects and potential mechanisms (by untargeted liver proteomics) of DL PCBs, NDL PCBs or co-exposure to both in diet-induced NAFLD are investigated. Male C57Bl/6 mice were fed a 42% fat diet and exposed to vehicle control; Aroclor1260 (20 mg/kg, NDL PCB mixture); PCB126 (20 μg/kg, DL PCB congener); or a mixture of Aroclor1260 (20 mg/kg)+PCB126 (20 μg/kg) for 12 weeks. Each exposure was associated with a distinct hepatic proteome. Phenotypic and proteomic analyses revealed increased hepatic inflammation and phosphoprotein signaling disruption by Aroclor1260. PCB126 decreased hepatic inflammation and fibrosis at the molecular level; while altering cytoskeletal remodeling, metal homeostasis, and intermediary/xenobiotic metabolism. PCB126 attenuated Aroclor1260-induced hepatic inflammation but increased hepatic free fatty acids in the co-exposure group. Aroclor1260+PCB126 exposure was strongly associated with multiple epigenetic processes, and these could potentially explain the observed non-additive effects of the exposures on the hepatic proteome. Taken together, the results demonstrated that PCB exposures differentially regulated the hepatic proteome and the histologic severity of diet-induced NAFLD. Future research is warranted to determine the AhR-dependence of the observed effects including metal homeostasis and the epigenetic regulation of gene expression.

Prenatal exposure to organic pollutants in northwestern Spain using non-invasive matrices (placenta and meconium)

Human exposure to environmental organic pollutants (OPs) begins in the uterine life period by trans-placental transfer. Epidemiological studies have consistently demonstrated the vulnerability of human fetuses and infants to the effects of OPs because of their rapid growth and organ development, cell differentiation, and immaturity of metabolism. The aim of the present study was to evaluate the prenatal exposure to OPs characterized by different physicochemical properties using non-invasive biological samples (meconium and placenta). A total of 88 placenta and 53 meconium samples were collected in Ourense, a city located in northwestern Spain, at the delivery and after birth from mothers and their infants from the University Hospital of Ourense, respectively. Selective pressurized liquid extraction (SPLE) methodologies were used to determine the targeted OPs in the selected biological samples. Cleanup of extracts was performed by solid-phase extraction (SPE) using EZ-POP cartridges and detection by gas chromatography (GC) coupled to tandem mass spectrometry (QqQ-MS/MS). The targeted OPs were detected with the following mean level total concentration order polycyclic aromatic hydrocarbons (PAHs) > organophosphorus pesticides (OPPs) > non-dioxin like polychlorinated biphenyls (NDLPCBs) > pyrethroids (PYRs) > polybrominated diphenyl ethers (PBDEs) > dioxin like polychlorinated biphenyls (DLPCBs) > organochlorine pesticides (OCPs) for placenta and ΣNDLPCBs > ΣPAHs > ΣOCPs > ΣPYRs > ΣOPPs > ΣDLPCBs > ΣPBDEs for meconium, respectively. Significant correlations (p < .050) between the socio-demographic characteristics of the selected population (mother's parity, age, weight increase during pregnancy, place of living and smoking habits) and log transformed concentration of some of the targeted OPs (OCPs, PBDEs, PYRs, OPPs and PAHs) were detected. The results obtained shown the complementary information given by both biological samples selected. Nevertheless, additional research will be needed to gain an understanding of the trans-placental transfer of OPs, to choose the best biological matrix to evaluate the prenatal exposure to OPs in a correct way and to know their health implications.

Dioxins and PCBs – Environment impact on freshwater fish contamination and risk to consumers

This paper reports polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/F) and polychlorinated biphenyls (PCB) concentrations in sediment and fish collected from Polish rivers in agricultural and urban areas and the associated risk for fish consumers. Total TEQ concentrations in fish muscles were in the range 0.29–7.25 pg WHO-TEQ g−1 wet weight (w.w.). Generally, levels in sediment and fish muscles were low except for in the Vistula River in Cracow. In this fishery, total TEQ concentrations in sediments were high at 7.84 ± 1.73 pg WHO-TEQ g−1 dry matter and fish were non-compliant with Commission Regulation (EU) 1259/2011/EU (3.5 pg WHO-TEQ g−1 w.w. for PCDD/F and 6.5 pg WHO-TEQ g−1 w.w. for total TEQ). Dioxin congener profiles in sediments were dominated by OCDD, and in the most contaminated fisheries in Cracow additionally by OCDF and 1,2,3,4,7,8-HxCDF. The most accumulated PCDD/Fs congeners in fish were 2,3,7,8-TCDF and 2,3,4,7,8-PeCDF except in Cracow, where 1,2,3,4,7,8-HxCDF dominated. The most abundant dioxin-like PCB (DL-PCB) and non-dioxin-like PCB (NDL-PCB) congeners were PCB 118 and PCB 153, respectively, both in sediment and fish muscles. The levels and profiles of contaminants in fish reflected the pollution of their environment. To characterize the potential health risk associated with dioxin and DL-PCB intake, doses ingested in two 100g portions of fish by adults and children were calculated and expressed as percentages of Tolerable Weekly Intake (TWI). Both values of TWI – that of 14 pg WHO-TEQ kg−1 b.w. and the newer value of 2 pg WHO-TEQ kg−1 b.w. established by the EFSA in November 2018 – were taken into account.It appears that regular consumption of some species could pose a health risk, especially those from urban areas.

Informal e-waste recycling and plasma levels of non-dioxin-like polychlorinated biphenyls (NDL-PCBs) – A cross-sectional study at Agbogbloshie, Ghana

Informal e-waste recycling leads to a contamination of the workers with several hazardous substances, in particular heavy metals and persistent organic pollutants (POPs). Polychlorinated biphenyls (PCBs) belong to the group of POPs and are suspected to be associated with adverse health effects. In particular lower chlorinated PCBs, such as the congeners PCB 28 and PCB 52 are a marker of occupational exposure. The aim of our study was to assess the occupational PCB exposure in e-waste workers in relation to their specific recycling task (e.g. dismantling, burning). Altogether, n = 88 e-waste workers and n = 196 control subjects have been included in this study. All plasma participant's samples were evaluated for the PCB congeners PCB 28, 52, 101, 138, 153, 180 and sum of NDL-indicator congeners by human biomonitoring. A significant difference could be detected for the lower chlorinated PCB congeners (PCB 28, 52, and 101) for e-waste workers in comparison to the control group. Analyzing specific recycling tasks, workers who dismantle and those who burn e-waste showed the highest plasma levels of PCB 28 and 52. In conclusion, e-waste workers showed occupational related elevated PCB levels. Although those levels did not exceed the BAT value, workers were contaminated with PCBs during their task. Occupational health and safety measure are therefore necessary to protect the worker's health.

The developmental neurotoxicity of legacy vs. contemporary polychlorinated biphenyls (PCBs): similarities and differences.

Although banned from production for decades, PCBs remain a significant risk to human health. A primary target of concern is the developing brain. Epidemiological studies link PCB exposures in utero or during infancy to increased risk of neuropsychiatric deficits in children. Nonclinical studies of legacy congeners found in PCB mixtures synthesized prior to the ban on PCB production suggest that non-dioxin-like (NDL) congeners are predominantly responsible for the developmental neurotoxicity associated with PCB exposures. Mechanistic studies suggest that NDL PCBs alter neurodevelopment via ryanodine receptor-dependent effects on dendritic arborization. Lightly chlorinated congeners, which were not present in the industrial mixtures synthesized prior to the ban on PCB production, have emerged as contemporary environmental contaminants, but there is a paucity of data regarding their potential developmental neurotoxicity. PCB 11, a prevalent contemporary congener, is found in the serum of children and their mothers, as well as in the serum of pregnant women at increased risk for having a child diagnosed with a neurodevelopmental disorder (NDD). Recent data demonstrates that PCB 11 modulates neuronal morphogenesis via mechanisms that are convergent with and divergent from those implicated in the developmental neurotoxicity of legacy NDL PCBs. This review summarizes these data and discusses their relevance to adverse neurodevelopmental outcomes in humans.

Influence of the geographical origin on substance concentrations in herring as basis for dietary exposure assessments.

Previous investigations on agricultural products showed that geographical origin influences concentrations of selected undesirable substances and ultimately dietary exposure assessment. This could also be relevant for fish from different catching areas, as substance concentrations have been found to vary between catching areas. Herring was chosen as an example. Norwegian and German data on consumption and substance concentrations were considered. To investigate if concentrations of substances are different in Norway and Germany, monitoring data between 2012 and 2017 were used. Norway provided data of commercial catching areas from the Norwegian Spring Spawning (NSS) herring stock, while Germany had market data available. Concentrations of cadmium, mercury and selenium tended to be higher in herring from Norway, while lead concentrations were higher in Germany. Polychlorinated dibenzo‐p‐dioxins/polychlorinated dibenzofurans (PCDD/Fs), dioxin‐like polychlorinated biphenyls (DL‐PCBs) and non‐dioxin‐like PCBs (NDL‐PCBs) tended to have higher concentrations in Germany, while perfluorinated alkylated substances (PFAS) were mostly below quantifiable levels in the two countries. These differences could be attributed to different herring stocks available on the market in Germany and Norway. Country‐specific data on consumption and substance concentrations give a basis for a refined exposure assessment covering both the Norwegian and the German situation. This is of special importance if European risk assessments are carried out combining concentration data recorded in several countries without taking origin into account.

Associations of peri-pubertal serum dioxins and polychlorinated biphenyls with growth and body composition among Russian boys in a longitudinal cohort.

Childhood exposure to organochlorines has been associated with alterations in somatic growth. We evaluated the associations of peri-pubertal serum levels of dioxin-like compounds (DLCs) and nondioxin-like polychlorinated biphenyls (NDL-PCBs), with adolescent growth, body composition, and near adult height (NAH) in a longitudinal cohort study of Russian boys. 473 8-9 year-old boys had serum DLCs and associated toxic equivalents (TEQs) and NDL-PCBs concentrations measured. Physical examinations were performed at enrollment between 2003 and 2005, and annually over 11 years to 2016; annual bio-electric impedance analysis (BIA) of body composition began in 2006. We used mixed effects models to evaluate associations of quartiles of serum chemical concentrations with longitudinal measurements through age 19 of body mass index (BMI-Z) and height (HT-Z) z-scores, annual height velocity (HV), and BIA-derived height-adjusted fat (FMi) and fat-free mass (FFMi) indexes. Potential modification by age of the associations of chemical exposures with growth was evaluated. NAH (defined as HV < 1 cm/year) and age at NAH attainment were estimated using parametric survival models accounting for right censoring. The medians of serum ∑TEQs, ∑DLCs, and ∑NDL-PCBs were 21.1 pg TEQ/g lipid, 362 pg/g lipid, and 250 ng/g lipid, respectively. In multivariable models, higher serum concentrations of peri-pubertal ∑TEQs, ∑DLCs, and ∑NDL-PCBs were associated with significantly lower BMI-Z, FMi, and FFMi over 11 years of follow-up. The differences in FFMi for boys with higher versus lower ΣTEQs and ΣNDL-PCBs increased with age. In multivariable models, higher ∑NDL-PCBs were associated with lower HT-Z, with attenuation of the association with age (interaction p < 0.001). The highest versus the lowest quartiles of ∑NDL-PCBs were not associated with differences in NAH, but were associated with an average of 6 months later attainment of NAH. Our findings suggest that dioxin and NDL-PCB exposures during childhood are associated with alterations in body composition and subsequent somatic growth.

High intake of persistent organic pollutants generated by a municipal waste incinerator by breastfed infants

To monitor the body burden of persistent organic pollutants in mothers and infants living in proximity to a 10-year-old municipal waste incinerator (MWI), levels of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) in the breast milk of mothers were evaluated, and the estimated daily intake (EDI) level of these pollutants in infants was assessed. In total, 14 mothers from the exposure area and 18 mothers from a control area were recruited for this study. In addition, the levels of 17 PCDD/F congeners and 18 PCB congeners in the breast milk of the mothers were estimated, and risk assessment for their infants by calculating their EDI levels was performed. The mean levels of ΣPCDD/Fs and TEQ-ΣPCDD/Fs in the breast milk of the exposure group were significantly greater than those of the control group (3.36 vs. 1.47 pg/g wet weight; and 0.24 vs. 0.12 pg TEQ/g wet weight, respectively; p < 0.05). With respect to PCBs, the mean levels of the total PCBs (ΣPCBs) and non-dioxin like-PCBs (ΣNDL-PCBs) in the exposure group were significantly greater than those in the control group (269 vs. 141 pg/g wet weight; 230 vs. 115 pg/g wet weight, respectively; p < 0.05). The mean levels of ΣPCDD/Fs and TEQ-ΣPCDD/Fs were positively correlated with the inhabit time of the exposure group (r = 0.636, r = 0.629, p < 0.05, respectively). The mean EDI level of the exposure group in infants was significantly greater than that of the control group (22.0 vs. 13.0 pg TEQ/kg bw day; p < 0.05). In conclusion, mothers and their breast-fed infants living in proximity to the 10-year-old MWI located in the Zhejiang Province of China exhibited a significantly higher body burden of PCDD/Fs and PCBs compared to those living in the control area.

A relationship between environmental pollutants and enteric viruses in mussels(Mytilus galloprovincialis)

Mussels can be affected by environmental contaminants, as non-dioxin-like polychlorinated biphenyls (NDL-PCBs), polycyclic aromatic hydrocarbons (PAHs) and cadmium (Cd). Moreover, mussels may concentrate human enteric viruses, like noroviruses (NoVGI/GII), astrovirus (AsV) and rotavirus (RV). Herein, to establish a relationship between environmental and viral contamination, with the aim to ensure human food safety, both chemical and microbiological analysis were carried out in mussels Mytilus galloprovincialis, farmed in Campania region (Italy). Chemical analysis revealed ranges below the European maximum limits, and were: ∑6 NDL-PCBs (28, 52, 101, 138, 153, 180) 0.579–16.857 ng g−1 wet weight (ww); BaP LOQ (<0.2 µg kg−1)− 2.9 µg kg−1 ww, and ∑4 PAHs (BaA, CHR, BbFA, BaP) 0.7–23.7 µg kg−1 ww; Cd LOQ (<0.005 mg kg−1)− 0.078 mg kg−1 ww. In addition, mussels exhibited a prevalence of NoVGI (18%), NoVGII (43%), AsV (40%), RV (30%) and the presence of more than one viruses resulted in about 35%. Overall, a simultaneous contamination, both chemical and viral, was found in 62% of samples. Interestingly, virus-positive mussels showed levels of chemicals higher than negative ones.

Polychlorinated biphenyl exposures differentially regulate hepatic metabolism and pancreatic function: Implications for nonalcoholic steatohepatitis and diabetes

The endocrine disrupting chemicals, polychlorinated biphenyls (PCBs), have been associated with nonalcoholic steatohepatitis (NASH) and diabetes. However, an integrative analysis of the effects of PCBs on the liver and pancreas has never been performed for the two major PCB subtypes, dioxin-like (DL) and nondioxin-like (NDL), and a mixture of NDL/DL PCBs. Therefore, male C57BL/6 J mice fed a control synthetic diet were treated with either a NDL PCB mixture, Aroclor 1260 (20 mg/kg); a single DL PCB congener, PCB 126 (20 μg/kg); a NDL/DL mixture, Aroclor 1260 plus PCB 126; or vehicle control for 2 weeks. PCB126 had the greatest impact on hepatic lipid metabolism. It caused steatosis due to increased hepatic lipid import with associated hypolipidemia. However, all PCB exposures impacted expression of hepatic lipid metabolism genes in different manners. The ‘NASH gene’, Pnpla3, was elevated by Aroclor 1260, but decreased by all other exposures. The expression of hepatokines implicated in metabolic syndrome (Fgf21, Igf1, and betatrophin) were differentially regulated. The NDL/DL PCB mixture had the greatest effects on pancreatic histology, including acinar cell atrophy, mild steatosis, and fibrosis without ductal changes or immune cell infiltration. It decreased expression of insulin and altered the expression of genes regulating islet identity. None of these exposures was associated with altered HOMA-IR or HOMA-B. In summary, PCB exposures differentially regulated liver and pancreas structure and function. Novel mechanisms for PCB-induced endocrine/metabolic disruption included altered hepatokines and Pnpla3 as well as ‘PCB pancreatopathy’ that was associated with altered expression of pancreatic islet identity factors. More research is required to understand fully these findings in the context of human NASH and diabetes.

Environmental Exposures to PCDDs, PCDFs, and PCBs and Mechanism of Steatohepatitis in the Anniston Community Health Survey II

PCDDs, PCDFs, and some PCBs activate the aryl hydrocarbon receptor (AhR); but non-dioxin like (NDL) PCBs do not. We previously reported a high prevalence of suspected nonalcoholic steatohepatitis (NASH) associated with PCB exposures in the Anniston Community Health Survey (ACHS). Here, we determine if dioxins and NDL PCB exposures were associated with serologic biomarkers of NASH in the subgroup of ACHS-II participants with suspected liver disease. The total dioxin toxic equivalency (TEQ) was determined by summing the TEQs for serum PCBs, PCDDs, and PCDFs using WHO toxic equivalency factors. Disease biomarkers were measured by ELISA or Milliplex. Subjects were categorized as having suspected liver disease if serum cytokeratin 18 was elevated. Linear regression models examined associations between TEQ or &amp;#931;NDL PCBs with NASH biomarkers in the suspected liver disease subgroup. In 345 adult participants, the prevalence of suspected liver disease was 62%. These subjects were at risk for NASH due to a high prevalence of overweight/obesity and diabetes. Suspected liver disease was significantly associated with male sex, non-Hispanic White race/ethnicity, increased liver enzymes, and a trend towards increased diabetes. Both TEQ and &amp;#931;NDL PCBs were associated with altered intermediary metabolism biomarkers (increased LDL, VLDL, phospholipids; and decreased HOMA-IR). TEQ was also associated with decreased HOMA-B. TEQ was associated with increased TNF&amp;#945;, IL-12 and CXCL11; while &amp;#931;NDL PCBs was associated with increased IL-13. Both TEQ and &amp;#931;NDL PCBs were positively associated with TGF&amp;#946;. Neither exposure biomarker was positively associated with either CK18 or transaminases. In ACHS-II participants with suspected liver disease we found associations with altered biomarkers of liver intermediary metabolism, inflammation, fibrosis, and synthetic function; but not cell death. The potential role of the AhR, dioxins, and NDL PCBs in NASH progression warrants further investigation.

Occurrence of Polychlorinated Dibenzo-p-Dioxins and Dibenzofurans and Polychlorinated Biphenyls in Fruit and Vegetables from the "Land of Fires" Area of Southern Italy.

The concentrations of polychlorinated dibenzo-p-concentrations dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) (PCDD/Fs), and polychlorinated biphenyls (PCBs) were determined in fruit and vegetables collected in farms located in the well-known “Land of Fires” area of Southern Italy, in an effort to learn more about the environmental pollution of this high-risk area due to illegal waste dumping and uncontrolled burning near cultivated fields. Concentrations were in the range 0.011–2.26 ng g−1 for the six “indicator” non-dioxin-like PCBs (NDL-PCBs), and 0.0009–0.096 pg WHO toxic equivalent (TEQ) g−1 for the sum of dioxin-like PCBs (DL-PCBs) and PCDD/Fs. Lacking maximum limits for these contaminants in fruit and vegetables, the concentration values found were compared with the action levels set out in the EU Recommendations. These levels were never exceeded in the examined samples. In the present study, the highest mean value for PCDD/Fs + DL-PCB corresponded to apricots, olives, and nuts, while the lowest values were observed in endive and green beans. The results showed also that NDL-PCB levels in apricots were much higher than in any other food, suggesting that they can accumulate PCBs: this fruit might be proposed as a “sentinel” of the presence of these contaminants in the environment.

Skeletal and dental effects on rats following in utero/lactational exposure to the non-dioxin-like polychlorinated biphenyl PCB 180.

Polychlorinated biphenyls (PCBs) are a large class of persistent organic pollutants that are potentially harmful to human and wildlife health. Although a small number of dioxin-like (DL) PCBs are well characterized, the majority of PCBs have non-dioxin-like (NDL) modes of action and biological effects that are less understood. We conducted a dose-response study of the skeletal and dental effects of in utero/lactational exposure to 2,2',3,4,4',5,5'-heptachlorobiphenyl (PCB 180), a NDL PCB congener that is abundantly present in the environment and foods, including mother’s milk. In a sample of 35- and 84-day-old male and female offspring from pregnant rats exposed to different doses of PCB 180 (0, 10, 30, 100, 300, and 1000 mg/kg bw), we measured the three-dimensional (3D) coordinates of 27 landmarks on the craniofacial skeleton with a Microscribe G2X system, the buccolingual width of all molars with digital sliding calipers, and a variety of tibial parameters with peripheral quantitative computed tomography (pQCT) and a biomechanical testing apparatus. The landmark coordinates were analyzed for variation in size, shape, and fluctuating asymmetry (FA) using MorphoJ software, showing no effects on cranial size, on FA in females only (i.e., decreased asymmetry), and on shape in both sexes (i.e., decreased facial length and shift in the palatal suture). In the maxillary teeth, females in the highest dose group showed a significant decrease of 0.1 mm (p = 0.033) of the second molar only, whereas males in most dose groups showed average increases of 0.1 mm (p = 0.006–0.044) in all three molars. In the mandibular teeth, the only significant response to PCB 180 exposure was the average increase of 0.1 mm (p = 0.001–0.025) in the third molars of males only. Males also shower greater sensitivity in postcranial effects of increased tibial length and decreased cortical bone mass density, although only females showed significant effects on tibial bone area and thickness. These results demonstrate marked sex differences in effects of PCB 180, which can be attributed to differences in their underlying biological mechanisms of toxicity. Furthermore, although tooth and bone development are targets of both DL and NDL compounds, this study shows that there are marked differences in their mechanisms and effects.

Polychlorinated biphenyl 19 blocks the most common form of store-operated Ca2+ entry through Orai.

PCB19, a 2,2',6-trichlorinated biphenyl, is one of many non-dioxin-like polychlorinated biphenyls (NDL-PCBs), which are ubiquitous pollutants. NDL-PCBs affect cytosolic Ca2+ signaling by promoting Ca2+ release from ryanodine receptor-sensitive Ca2+ pools and inhibiting store-operated Ca2+ entry (SOCE) from the extracellular space. However, NDL-PCB-mediated SOCE inhibition has only been demonstrated in PC12 cells, in which SOCE is thought to be mainly mediated by TRPC family channels. Here, we investigated the effect of PCB19 on SOCE using human embryonic kidney 293 (HEK293) cells, human leukemia T cell line Jurkat-T cells and human promyelocytoma HL-60 cells which are the cell lines that are previously demonstrated to mediate the most common form of SOCE solely by the intrinsic Orai channels. PCB19 reduced thapsigargin-induced Ca2+ influx after Ca2+ pool depletion in HEK293 cells. SOCEs in HEK293, Jurkat T, HL-60 and PC12 cells showed distinct sensitivities to SOCE inhibitors such as Gd3+ and ML-9; however, PCB19 also showed a common effect of inhibiting SOCEs in all cell lines. PCB19-mediated SOCE inhibition was confirmed by demonstrating the ability of PCB19 to inhibit the SOCE current but not the TRPM7 current. These results imply that PCB19 inhibits not only TRPC-mediated SOCE as in PC12 cells but also Orai-mediated SOCE as in many other cells including HEK293, Jurkat T and HL-60 cells.

Organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) in human breast milk and associated health risks to nursing infants in Northern Tanzania

This is the first study to report organochlorines (OCs), including chlorinated pesticides (OCPs) and polychlorinated biphenyls (PCBs) in human milk from Tanzania. The main aims of this study were to assess the level of contamination and the possible health risks related to OC exposure in nursing infants from the Northern parts of Tanzania. Ninety-five healthy mother-infant couples attending Mount Meru Regional Referral Hospital (MMRRH), Arusha, Tanzania, were assessed for associations between maternal/infant characteristics, i.e. mother's age, BMI, gestational weight gain, occupation, residence and fetal growth parameters and breast milk levels of OCPs, such as dichlorodiphenyltrichloroethane (DDT) and its metabolites, dieldrin and PCBs. p,p′-DDE and p,p′-DDT were detected in 100% and 75% of the breast milk samples, respectively, and ranged between 24 and 2400ng/g lipid weight (lw) and <LOD and 133ng/g lw, respectively. Dieldrin was detected in 66% of the samples in levels up to 937ng/g lw. ∑7PCBs ranged between <LOD and 157ng/g lw. Other OCPs were detected in low levels. For assessment of health risks, the Hazard Quotient (HQ) was calculated by comparing estimated daily intakes of OCPs and PCBs with health based guidance values. The estimated daily intake (ng/kg body weight/day) of ∑DDTs, dieldrin and nondioxin-like PCBs (∑6PCBs) exceeded the provisional tolerable daily intake (PTDI) in two, six and forty-eight of the nursing infants, respectively, suggesting potential health risks. In addition, head circumference were negatively associated with p,p´-DDE in female infants, suggesting that OC exposure during pregnancy may influence fetal growth.

From the Cover: BDE-47 and BDE-49 Inhibit Axonal Growth in Primary Rat Hippocampal Neuron-Glia Co-Cultures via Ryanodine Receptor-Dependent Mechanisms.

Polybrominated diphenyl ethers (PBDEs) are widespread environmental contaminants associated with adverse neurodevelopmental outcomes in children and preclinical models; however, the mechanisms by which PBDEs cause developmental neurotoxicity remain speculative. The structural similarity between PBDEs and nondioxin-like (NDL) polychlorinated biphenyls (PCBs) suggests shared toxicological properties. Consistent with this, both NDL PCBs and PBDEs have been shown to stabilize ryanodine receptors (RyRs) in the open configuration. NDL PCB effects on RyR activity are causally linked to increased dendritic arborization, but whether PBDEs similarly enhance dendritic growth is not known. In this study, we quantified the effects of individual PBDE congeners on not only dendritic but also axonal growth since both are regulated by RyR-dependent mechanisms, and both are critical determinants of neuronal connectivity. Neuronal-glial co-cultures dissociated from the neonatal rat hippocampus were exposed to BDE-47 or BDE-49 in the culture medium. At concentrations ranging from 20 pM to 2 µM, neither PBDE congener altered dendritic arborization. In contrast, at concentrations ≥ 200 pM, both congeners delayed neuronal polarization resulting in significant inhibition of axonal outgrowth during the first few days in vitro. The axon inhibitory effects of these PBDE congeners occurred independent of cytotoxicity, and were blocked by pharmacological antagonism of RyR or siRNA knockdown of RyR2. These results demonstrate that the molecular and cellular mechanisms by which PBDEs interfere with neurodevelopment overlap with but are distinct from those of NDL PCBs, and suggest that altered patterns of neuronal connectivity may contribute to the developmental neurotoxicity of PBDEs.

Reaching Nutritional Adequacy Does Not Necessarily Increase Exposure to Food Contaminants: Evidence from a Whole-Diet Modeling Approach

Dietary guidelines are designed to help meet nutritional requirements, but they do not explicitly or quantitatively account for food contaminant exposures. In this study, we aimed to test whether dietary changes needed to achieve nutritional adequacy were compatible with acceptable exposure to food contaminants. Data from the French national dietary survey were linked with food contaminant data from the French Total Diet Study to estimate the mean intake of 204 representative food items and mean exposure to 27 contaminants, including pesticides, heavy metals, mycotoxins, nondioxin-like polychlorinated biphenyls (NDL-PCBs) and dioxin-like compounds. For each sex, 2 modeled diets that departed the least from the observed diet were designed: 1) a diet respecting only nutritional recommendations (NUT model), and 2) a diet that met nutritional recommendations without exceeding Toxicological Reference Values (TRVs) and observed contaminant exposures (NUTOX model). Food, nutrient, and contaminant contents in observed diets and NUT and NUTOX diets were compared with the use of paired t tests. Mean observed diets did not meet all nutritional recommendations, but no contaminant was over 48% of its TRV. Achieving all the nutrient recommendations through the NUT model mainly required increases in fruit, vegetable, and fish intake and decreases in meat, cheese, and animal fat intake. These changes were associated with significantly increased dietary exposure to some contaminants, but without exceeding 57% of TRVs. The highest increases were found for NDL-PCBs (from 26% to 57% of TRV for women). Reaching nutritional adequacy without exceeding observed contaminant exposure (NUTOX model) was possible but required further departure from observed food quantities. Based on a broad range of nutrients and contaminants, this first assessment of compatibility between nutritional adequacy and toxicological exposure showed that reaching nutritional adequacy might increase exposure to food contaminants, but within tolerable levels. However, there are some food combinations that can meet nutritional recommendations without exceeding observed exposures.