DDE and PCB serum concentration in maternal blood and their adult female offspring.

BACKGROUND: Dichlorodiphenyl dichloroethylene (DDE) and polychlorinated biphenyls (PCBs) can be passed from mother to offspring through placental transfer or breastfeeding. Unknown is whether maternal levels can predict concentrations in adult offspring. OBJECTIVES: To test the association between maternal blood levels of DDE and PCBs and adult female offspring levels of these compounds using data from the Michigan Fisheaters'Cohort. METHODS: DDE and PCB concentrations were determined in 132 adult daughters from 84 mothers. Prenatal exposures were estimated based on maternal DDE and PCB serum levels measured between 1973 and 1991. Levels in adult daughters were regressed on maternal and estimated prenatal exposure levels, adjusting for potential confounders using linear mixed models. Confounders included daughter's age, birth order, birth weight, number of pregnancies, the length of time the daughter was breast-fed, the length of time the daughter breast-fed her own children, last year fish-eating status, body mass index, and lipid weight. RESULTS: The median age of the participants was 40.4 years (range 18.4-65.4, 5-95 percentiles 22.5-54.6%, respectively). Controlling for confounders and intra-familial associations, DDE and PCB concentrations in adult daughters were significantly positively associated with estimated prenatal levels and with maternal concentrations. The proportion of variance in the adult daughters' organochlorine concentrations explained by the maternal exposure levels is approximately 23% for DDE and 43% for PCBs. The equivalent of a median of 3.67 µg/L prenatal DDE and a median of 2.56 µg/L PCBs were 15.64 and 10.49 years of fish consumption, respectively. When controlling for effects of the shared environment (e.g., fish diet) by using a subsample of paternal levels measured during the same time frames (n=53 and n=37), we determined that the direct maternal transfer remains important. CONCLUSIONS: Estimated intra-uterine DDE and PCB levels predicted concentrations in adult female offspring 40 years later. Interpretation of adverse health effects from intra-uterine exposures of persistent pollutants may need to consider the sustained impact of maternal DDE and PCB levels found in their offspring.

Prenatal and concurrent exposure to halogenated organic compounds and gene expression of CYP17A1, CYP19A1, and oestrogen receptor alpha and beta genes.

OBJECTIVE: To determine whether prenatal exposure to dichlorodiphenyl ethylene (DDE) and polychlorinated biphenyls (PCBs) and concurrent exposure to DDE, PCBs and polybrominated diphenylethers (PBDEs) affect gene expression of aromatase (CYP19A1), 17-α-hydroxylase (CYP17A1), and oestrogen receptors α and ß (ESR 1 and ESR2). METHODS: Based on maternal PCB and DDE levels in the parent generation of the Michigan Fisheater Cohort determined between 1973 and 1991, individual prenatal exposures were estimated and have been published. In 2007, female adult offspring of this cohort were examined. Gene expression and concurrent lipid-adjusted exposures to DDE, PCBs and PBDEs were measured in blood and serum, respectively. Using mixed models and path analyses, gene-expression data were regressed on prenatal and concurrent exposures controlling for confounders. RESULTS: 139 daughters of Michigan fisheaters (65.3%) participated in the investigation. While prenatal PCB levels were statistically significantly associated with decreased expression of the aromatase and 17-α-hydroxylase genes, prenatal DDE levels were significantly related to increased gene expression of aromatase but not of 17-α-hydroxylase. The DDE association seems to be mediated by concurrent lipid-adjusted p,p'-DDE serum levels. Prenatal and concurrent exposure of both PCBs and DDE had comparable effects. No association was found for PBDEs or for the gene expression of ESR 1 and ESR2. CONCLUSIONS: A 40-year antecedent prenatal exposure and concurrent levels of PCBs and DDE are associated with the expression of aromatase and 17-α-hydroxylase genes. Prenatal exposures to organochlorines may instigate long-term alterations of gene expression. Mechanisms of prenatal induction of persistent gene-expression alterations are speculated to be epigenetic in nature.

Common classification schemes for PCB congeners and the gene expression of CYP17, CYP19, ESR1 and ESR2.

BACKGROUND: Reliable techniques to measure polychlorinated biphenyl (PCB) congeners make the clearer definition of their effects on human health possible. Given that PCBs are classified as endocrine disrupters, we sought to explore the expression of some key genes involved in sex steroid metabolism. OBJECTIVES: To examine common classification schemes of PCB congeners and determine whether exposure to groups classified by mechanism of action alter the gene expression (GE) of CYP17, CYP19, and ESR1 and ESR2. METHODS: GE and exposure to various classifications of lipid-adjusted PCB congeners were examined in 139 daughters of the Michigan Fisheaters' Cohort. Using mixed models analyses and adjusting for age, menopausal status, and current use of oral contraceptives and hormone replacement therapy, GE data were regressed on exposure to PCB congener groupings based on mechanism of action. RESULTS: Three novel findings are elucidated: first, that up-regulation of CYP19 expression is associated with exposure to PCB groupings containing dioxin-like, potentially anti-estrogenic, immunotoxic congeners, including PCB IUPAC #74, #105, #118, #138, #156, #157, #158, #167, and #170 from this cohort. Second, that exposure to similar congeners (PCB IUPAC #105, #156, #157, #158, and #167 in this cohort) but using a classification based solely on hormonal mechanisms of action is associated with increased expression of ESR2. Third, that increased expression of CYP17 is of borderline significance when associated with exposure to PCB IUPAC #118, #138, and #156. CONCLUSIONS: These findings are both counter-intuitive and intriguing. Rather than exhibiting anti-estrogenic effects alone, they suggest that these congeners up-regulate the major enzyme involved in estrogen synthesis and tend to confirm previous findings of links between AhR and ER signaling pathways. Replication of these findings, expansion of the number of genes examined, exploration of mixtures of environmental chemicals, and subsequent study of health outcomes in a larger cohort are future priorities.

Reactive oxygen species generation is independent of de novo sphingolipids in apoptotic photosensitized cells.

Our recent studies have shown that the de novo sphingolipids play a role in apoptosis of photosensitized cells. To elucidate the involvement of the de novo sphingolipids in reactive oxygen species (ROS) production and mitochondrial depolarization during apoptosis, the stress inducer photodynamic therapy (PDT) with the photosensitizer Pc 4 was used. In Jurkat cells PDT-triggered ROS production or mitochondrial membrane potential (deltapsi(m)) loss was not prevented by the de novo sphingolipid synthesis inhibitor ISP-1. However, PDT + C16-ceramide led to enhanced mitochondrial depolarization and DEVDase activation. The superoxide dismutase mimic manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) protected Jurkat cells from ROS generation and apoptosis, but not from deltapsi(m) reduction. Sphinganine or C16-ceramide counteracted MnTBAP-induced protection from apoptosis in Jurkat, as well as CHO cells. In LY-B cells, CHO-derived mutants deficient in serine palmitoyltransferase (SPT) activity and the de novo sphingolipid synthesis, mitochondrial depolarization, but not ROS generation, was suppressed post-PDT. In LY-B cells transfected with the SPT component LCB1, deltapsi(m) collapse post-PDT was restored. The data support the following hypotheses: MnTBAP protects against apoptosis via steps downstream of deltapsi(m) loss; de novo sphingolipids are not required for ROS generation, but can play a role in deltapsi(m) dissipation in photosensitized apoptotic cells.