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Persistent organic pollutants (POPs) are ubiquitously distributed among the U.S. population and adversely impact human reproduction. These compounds have been detected in human ovarian follicular fluid (FF), where they directly contact a developing oocyte. As a pilot investigation, we measured 43 polychlorinated biphenyl (PCB) congeners, p,p'-dichlorodiphenyltrichloroethane (DDT), and its persistent metabolite p,p'-dichlorodiphenyldichloroethylene (DDE) in residual FF collected from 32 women undergoing in vitro fertilization (IVF). We identified significant inverse associations between higher levels of PCB congeners and indicators of ovarian reserve (e.g., antral follicle count), follicular response to administered gonadotropins (e.g., peak estradiol, number of oocytes retrieved, endometrial thickness), intermediate IVF endpoints (e.g., oocyte fertilization and embryo quality), and clinical IVF outcomes (e.g., embryo implantation and live birth), after adjusting for body mass index, cigarette smoking, race, and age. Our results suggest that ongoing exposure to POPs impacts IVF and merit confirmation in a larger and more definitive future study., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The aim of this study was to evaluate the association between persistent organic pollutants (POPs) and thyroid hormones in an aging population. Forty-eight women and 66 men, aged 55-74 years and living in upper Hudson River communities completed a questionnaire and provided blood specimens. Serum was analyzed for thyrotropin (thyroid stimulating hormone, TSH), free (fT4) and total thyroxine (T4), total triiodothyronine (T3), and for POPs. POPs included 39 polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) determined by gas chromatography with electron capture detection (GC-ECD), and nine polybrominated diphenyl ethers (PBDEs) determined by high-resolution gas chromatography with high-resolution mass spectrometry detection (HRGC-HRMS). Multivariable linear regression analysis was used to evaluate associations between thyroid hormones and sums of POPs, adjusted for covariates and stratified by sex. Effects were expressed as differences in thyroid hormone levels associated with a doubling in the level of exposure. Among women, DDT+DDE increased T4 by 0.34μg/dL (P=0.04) and T3 by 2.78ng/dL (P=0.05). Also in women, sums of PCBs in conjunction with PBDEs elicited increases of 24.39-80.85ng/dL T3 (P<0.05), and sums of PCBs in conjunction with DDT+DDE elicited increases of 0.18-0.31μg/dL T4 (P<0.05). For men estrogenic PCBs were associated with a 19.82ng/dL T3 decrease (P=0.003), and the sum of estrogenic PCBs in conjunction with DDT+DDE elicited an 18.02ng/dL T3 decrease (P=0.04). Given age-related declines in physiologic reserve, the influence of POPs on thyroid hormones in aging populations may have clinical implications and merits further investigation., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Background: Love Canal, in Niagara Falls, NY is among the earliest and most significant hazardous waste sites in the USA, but no study has ever measured chemical body burdens in nearby residents to document that human exposure occurred. This study measured concentrations of selected organochlorines and chlorinated benzenes in archived serum samples collected from former Love Canal residents., Methods: We analyzed serum samples collected from 373 former residents in 1978-1979 for compounds disposed of at Love Canal, and we compared their concentrations according to surrogate indicators of exposure such as residential proximity, adjusting for potential confounders., Results: Three compounds were detectable in the serum of most participants: 1,2,4-trichlorobenzene (1,2,4-TCB), beta-hexachlorocyclohexane (beta-HCH) and 1,2-dichlorobenzene (1,2-DCB). Concentrations of 1,2,4-TCB and 1,2-DCB were 2-14 times greater among persons who at the time their blood was collected lived closest to the Canal compared to those living further away. We found no consistent trends for beta-HCH with respect to any exposure definition., Conclusions: These results provide evidence that residential proximity to Love Canal contributed to the body burden of certain contaminants, and helps validate the use of surrogate exposure measures in health effect studies. Further surveillance of the Love Canal cohort is warranted., ((c) 2009 Elsevier Inc. All rights reserved.)

Background: Polychlorinated biphenyls (PCBs) may accelerate the cognitive and motor dysfunction found in normal aging, but few studies have examined these outcomes and PCB exposure among older adults., Objective: We evaluated neuropsychological status and low-level PCB exposure among older adults living along contaminated portions of the upper Hudson River in New York., Methods: A total of 253 persons between 55 and 74 years of age were recruited and interviewed, and provided blood samples for congener-specific PCB analysis. Participants also underwent a neuropsychological battery consisting of 34 tests capable of detecting subtle deficits in cognition, motor function, affective state, and olfactory function., Results: After adjustment for potential confounders, the results indicated that an increase in serum total PCB concentration from 250 to 500 ppb (lipid basis) was associated with a 6.2% decrease in verbal learning, as measured by California Verbal Learning Test trial 1 score (p = 0.035), and with a 19.2% increase in depressive symptoms, as measured by the Beck Depression Inventory (p = 0.007)., Conclusions: The results suggest that exposure to PCBs may be associated with some measures of memory and learning and depression among adults 55-74 years of age whose current body burdens are similar to those of the general population. Although the results are useful in delineating the neuropsychological effects of low-level exposure to PCBs, further studies of whether older men and women are a sensitive subpopulation are needed.

The upper Hudson River has been heavily contaminated with polychlorinated biphenyls (PCBs) due to discharges from former electrical capacitor plants in Hudson Falls and Fort Edward, NY. An epidemiologic study was conducted to assess the impact of dietary and residential exposure on PCB body burden among older, long-term, non-occupationally exposed adults living in the vicinity of these former capacitor plants. The study population consisted of 133 persons 55-74 years of age who had lived in Hudson Falls or Fort Edward for 25 years or more. The comparison group consisted of 120 persons from Glens Falls, which is upriver. Both groups were interviewed, and blood samples were obtained for congener-specific PCB analysis. Persons from the study area reported greater past consumption of Hudson River fish than did the comparison area, but current rates were very low in both areas. The geometric mean serum PCB concentrations for the study and comparison populations did not differ significantly (3.07 ppb wet weight and 3.23 ppb, respectively, for total PCB). Serum PCB concentrations increased with cumulative lifetime exposure to PCBs from Hudson River fish consumption (p<0.10). Persons who lived within 800 m of the river did not have significantly greater serum PCB concentrations than the control population, nor did persons who lived downwind and within 800 m of a PCB-contaminated site. The results indicate no detectable differences in serum PCB levels according to proximity or wind direction relative to local point sources, but lifetime consumption of Hudson River fish was positively associated with serum PCB concentrations.

We used adult rat hepatocytes in primary culture (HPC) as a model system to study the hepatic phase II metabolism of the anticoagulant warfarin. Hepatocytes were isolated by a collagenase perfusion technique and maintained for 24 hr in Waymouth's medium containing 0.1 mM (R)-warfarin. When HPC medium was analyzed by reverse phase high performance liquid chromatography with diode-array detection, 4'-, 6-, and 7-hydroxywarfarin were identified. Several putative conjugates were observed eluting between 13 and 18 min. Treatment of hepatocyte medium with beta-glucuronidase and sulfatase resulted in the loss of five putative conjugates and concomitant increases in 4'-, 6-, and 7-hydroxywarfarin and warfarin, suggesting that these metabolites and warfarin were conjugated. Use of the beta-glucuronidase inhibitor saccharic acid 1,4-lactone enabled the determination of the relative extents of conjugation of each metabolite by glucuronic acid and sulfate. Glucuronidation was the predominant pathway for 4'-hydroxywarfarin, whereas 6-hydroxywarfarin and warfarin occurred mainly as sulfate conjugates. In contrast, 7-hydroxywarfarin was converted to both glucuronide and sulfate conjugates. Exposure of HPC to phenobarbital resulted in a decrease in cytochrome P-450-mediated production of hydroxylated warfarin metabolites; however, an increase in the production of 8-hydroxywarfarin was observed when HPC were exposed to beta-naphthoflavone. Unique conjugation patterns were found when hydroxylated warfarins were substituted for warfarin in HPC medium. Both 7- and 8-hydroxywarfarin were converted to one sulfate and two glucuronide conjugates, whereas 4'-hydroxywarfarin was converted to a single glucuronide conjugate. A spectral library of these conjugates was used to identify the major conjugates of warfarin formed by rat HPC.

Histone gene expression was studied during the cell cycle of continuously dividing HeLa S3-cells and following stimulation of confluent monolayers of WI-38 human diploid fibroblasts to proliferate. The presence of histone messenger RNA (mRNA) sequences was assayed by hybridization to a 3H-labeled single-stranded DNA complementary to histone mRNA's. In HeLa S3-cells, histone mRNA sequences were found in the nucleus and associated with polyribosomes during S phase but not during G1. Transcripts of S-phase chromatin contained histone mRNA sequences but those of G1 chromatin did not. Similarly, in WI-38 cells association of histone mRNA sequences with polyribosomes and transcription of histone mRNA sequences from chromatin parallel DNA replication. Together these results suggest that the regulation of histone gene expression resides, at least in part, at the transcriptional level. Chromatin reconstitution studies provide evidence that nonhistone chromosomal proteins play a key role in activation of histone gene transcription during the period of the cell cycle when DNA is replicated. Phosphate groups associated with the S-phase nonhistone chromosomal proteins appear to be functionally involved in the control of histone gene readout. Although WI-38 human diploid fibroblasts transformed by SV40 exhibit morphological and biochemical modifications characteristic of neoplastic cells, transcription of histone mRNA sequences remains unaltered.

Histone-gene expression was studied during the cell cycle of continuously dividing HeLa S3 cells and after stimulation of confluent monolayers of WI-38 human diploid fibroblasts to proliferate. The presence of histone-mRNA sequences was assayed by hybridization to a 3H-labelled single-stranded DNA complementary to histone-mRNA molecules. In HeLa S3 cells histone mRNA sequences were found in the nucleus and associated with polyribosomes during S-phase, but not during G1-phase. Transcripts of S-phase chromatin contained histone-mRNA sequences, but those of G1-phase chromatin did not. Similarly, in WI-38 cells association of histone-mRNA sequences with polyribosomes and transcription of histone-mRNA sequences from chromatin parallel DNA replication. Taken together these results suggest that the regulation of histone-gene expression resides, at least in part, at the transcriptional level. Chromatin-reconstitution studies provide evidence that non-histone chromosomal proteins play a key role in activation of histone-gene transcription during the period of the cell cycle when DNA is replicated. Phosphate groups associated with the S-phase non-histone chromosomal proteins appear to be functionally involved in the control of histone-gene readout.

The regulation of histone gene expression was examined after confluent, nondividing WI-38 human diploid fibroblasts were stimulated to proliferate. Histone mRNA sequences were assayed by hybrid formation with an 3H-labeled single-stranded DNA complementary to histone mRNAs. Histone mRNA became associated with polyribosomes concomitant with the activation of DNA synthesis. The ability of chromatin from WI-38 cells to serve as a template for in vitro transcription of histone mRNA sequences parallels the onset of DNA replication. A role for nonhistone chromosomal proteins in the control of histone gene readout is suggested because, when chromatin from confluent WI-38 cells was dissociated and then reconstituted in the presence of S phase nonhistone chromosomal proteins, a 500-fold activation of histone mRNA sequence transcription was observed.

The induction of aryl hydrocarbon hydroxylase (AHH) by Aroclor 1254, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other polychlorinated organic compounds was examined in primary cultures of adult rat hepatocytes isolated by a collagenase perfusion technique. Following exposure of fresh hepatocyte cultures to 1 microgram/ml Aroclor 1254, AHH induction was undetected for 48 hr and then increased dramatically up to 96 hr. Cultures maintained in control medium for either 24, 48, or 72 hr prior to a 24-hr exposure to Aroclor 1254 displayed significant inducible AHH which was sustained to 96 hr. AHH induction was extremely sensitive to two planar polyaromatic hydrocarbons, 2,3,7,8-TCDD and 2,3,7,8-tetrachlorodibenzofuran, and the PCB congener 3,4,3',4'-tetrachlorobiphenyl, but insensitive to 2,6-dichlorodibenzofuran, 2,5,2',5'-tetrachlorobiphenyl, 2,4,5,2',4',5'-hexachlorobiphenyl, and hexachlorobenzene. The induction of AHH activity in primary cultures of adult rat hepatocytes may represent a useful bioassay for screening extracts of foodstuffs, biological fluids, or environmental samples for dioxin-like activity.

The representation of mRNA sequences in normal and SV40-transformed WI-38 human diploid fibroblasts was examined. Variations in the hybridization of polysomal RNAs to 3H-labeled DNAs complementary to poly A+ mRNA of normal and SV40-transformed cells suggest differences in the mRNA populations. a comparison of the representation of histone RNA sequences of normal and SV40-transformed human diploid cells did not reveal significant differences.