Lesley Mills - Academia.edu (original) (raw)

Papers by Lesley Mills

Toxicology and Applied Pharmacology, 1994

Environmental Toxicology and Chemistry, Jul 1, 1998

This investigation evaluated polychlorinated biphenyl (PCB) accumulation, survival, and reproduct... more This investigation evaluated polychlorinated biphenyl (PCB) accumulation, survival, and reproduction in Fundulus heteroclitus from four stations along a gradient of increasing sediment contamination from West Island in Buzzards Bay, Massachusetts, USA, to the most contaminated area of the New Bedford Harbor, Massachusetts, USA, Superfund site. Fish collected during their natural spawning season were held in the laboratory for 5 weeks. Liver concentrations of non‐ortho‐ and mono‐ortho‐PCBs averaged 0.461, 9.48, 20.8, and 29.3 μg/g dry weight, with dioxin toxic equivalent concentrations (TEQs) of 0.006, 0.132, 0.543, and 1.56 ng/g; differences among stations were statistically significant. Females from two stations within the Superfund site had significantly greater mortality (30 and 23%) compared to those within West Island (0%), and growth was reduced. Progeny of fish from the most contaminated station exhibited significantly reduced survival (49%) and greater incidence of spinal abnormalities (26%) compared to those from West Island (70% survival, 7% spinal abnormalities). No differences in egg production or food consumption were observed. A significant residue‐effect relationship was found between TEQs of liver PCBs and female mortality, consistent with that determined previously from laboratory exposures and validating TEQ as an effects indicator. Embryo and larval survival were inversely related to maternal liver TEQ.

Carcinogenesis, 1991

The in vitro V79/metabolic cooperation assay measures the extent of gap-junctional transfer of me... more The in vitro V79/metabolic cooperation assay measures the extent of gap-junctional transfer of metabolites from wild-type to mutant V79 cells. The assay is currently being explored as a short-term test to screen for tumor promoting chemicals, many of which inhibit metabolic cooperation. In this study, the assay was used to determine whether chemical interactions affect detection of tumor promoters in mixtures and to investigate types of interactions that may occur between chemicals. Several two-chemical mixtures were examined. The effects of phorbol-12-myristate-13-acetate (PMA) and phorbol-12,13-dibutyrate, two inhibitors of metabolic cooperation that operate through the same receptor-mediated pathway, were additive at concentrations below the maximally effective concentrations of either. A summation effect was observed in mixtures of two other inhibitors of metabolic cooperation, the pesticide aldrin and the principal metabolite of sodium cyclamate, cyclohexylamine. Synergistic effects were noted when PMA was combined with either aldrin or cyclohexylamine, demonstrating that chemicals in a mixture may yield a much stronger response than expected based on individual chemical exposures. Interactions were also examined between PMA, aldrin, cyclohexylamine and 2,4-diaminotoluene, a chemical that appears to enhance metabolic cooperation. 2,4-Diaminotoluene reversed effects of all inhibiting chemicals to some extent, although the pattern of response was different for each combination. In the most dramatic case, the powerful tumor promoter PMA was completely masked by 2,4-diaminotoluene. These results suggest that the V79/metabolic cooperation assay must be applied with caution in mixture testing because detection of tumor promoting chemicals can depend on other chemicals present.

Environmental Health Perspectives, 2003

We thank C. Chichester, L. Meng, D. Nacci, J. Heltshe, and the anonymous reviewers for their crit... more We thank C. Chichester, L. Meng, D. Nacci, J. Heltshe, and the anonymous reviewers for their critical reviews of the manuscript. We also thank B. O'Neal and K. Kroll at the University of Florida for conducting vitellogenin analyses on cunner plasma samples. Although the research described in this article has been funded by the U.S. Environmental Protection Agency, it has not been subjected to agency-level review and does not necessarily reflect the views of the agency. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. This article represents contribution no.

Aquatic Toxicology, Apr 1, 2001

... Author , Ruth E. Gutjahr-Gobell, Romona A. Haebler, Doranne J. Borsay Horowitz, Saro Jayarama... more ... Author , Ruth E. Gutjahr-Gobell, Romona A. Haebler, Doranne J. Borsay Horowitz, Saro Jayaraman, Richard J. Pruell, Richard A. McKinney, George R ... In San Pedro Bay CA, which is the former site of a DDT manufacturing plant, white croaker have been found to be less fertile ...

Ecotoxicology and Environmental Safety, Feb 1, 2006

Endocrine-disrupting chemicals (EDCs) in the environment may alter the population dynamics of wil... more Endocrine-disrupting chemicals (EDCs) in the environment may alter the population dynamics of wildlife by affecting reproductive output. This study describes a matrix modeling approach to link laboratory studies on endocrine disruption with potential ecological effects. The experimental model used is cunner (Tautogolabrus adspersus), which inhabit estuarine and marine areas where sewage treatment and other discharges containing estrogenic EDCs are likely. To test the effects of estrogenic exposures on fecundity, reproductively active cunner were exposed in three separate experiments by implanting 17beta-estradiol, estrone, or 17alpha-ethynylestradiol subcutaneously in a slow-release matrix at 0.05, 0.5, and 2.5 mg/kg. Egg production per gram female and egg viability were determined daily for a 1-week preexposure period and then for a 2-week exposure period. The mean number of eggs produced per gram female and egg viability (%) were calculated for the initial preexposure period and the 2-week exposure period for each experiment. Significant changes were observed in egg production per gram female in the high-17beta-estradiol treatment (P = 0.07) and high-17alpha-ethynylestradiol treatment (P = 0.04). A significant increase was observed in egg viability (%) in the low-17alpha-ethynylestradiol treatment (39.0%; P < or = 0.05). Cunner population response was projected using an age-structured matrix population model parameterized with published survival and fecundity estimates. By incorporating reproductive response data from laboratory exposures, model projections were used to describe how reproductive changes by estrogen treatment could alter cunner population growth rate (lambda). Published by Elsevier Inc.

Toxicological Sciences, Aug 26, 2009

Atrazine (ATR) has recently been shown to activate the hypothalamic-pituitary-adrenal (HPA) axis ... more Atrazine (ATR) has recently been shown to activate the hypothalamic-pituitary-adrenal (HPA) axis in rodents. The current study investigated the effect of ATR and two of its chlorinated metabolites, desisopropylatrazine (DIA) and diaminos-chlorotriazine (DACT), on the HPA axis in the Long-Evans female rat. A single oral gavage administration of 75 mg/kg ATR or 60.2 mg/kg DIA (a dose equimolar to the applied ATR dose) during the morning of proestrus resulted in significant, acute increases in circulating adrenocorticotropic hormone (ACTH), corticosterone, and progesterone. Oral doses of ATR or DIA were given daily over the course of the 4-day ovarian cycle starting on the day of vaginal estrus, resulted in a similar, dose-responsive activation of the HPA axis. The increase in ACTH, corticosterone, and progesterone by these compounds was of a similar magnitude to that produced by 5-min restraint stress. Single or multiple oral exposures to DACT, on the other hand, did not significantly alter pituitary-adrenal hormone release. These results were observed despite plasma levels of DACT being higher than any other metabolite at the time of hormone measurement. Overall, circulating metabolite concentrations following equimolar dosing were much higher than those observed after ATR administration. Additional studies indicated that the activation of the HPA axis by oral exposure to ATR and DIA was not due simply to the stimulation of gastrointestinal afferents. Similar responses were observed in rats which received an oral dose of ATR following bilateral subdiaphramatic vagotomy and following intravenous administration of DIA in jugular vein catheterized animals. We conclude that ATR and the metabolite DIA significantly activate the HPA axis following oral exposure in the female rat. Activation of this endocrine axis by these chlorotriazines could contribute to the induced changes of female reproductive function reported previously.

This report has been reviewed by ERLN and approved for publication. Approval docs not signify tha... more This report has been reviewed by ERLN and approved for publication. Approval docs not signify that the contents reflect the view and policies of USEPA. The report has also been reviewed by PNSY, NORTHDIV, and NRaD. All data and information herein were presented at PNSY Technical Review Committee meetings and public workshops in Kittery, ME, and arc approved for public release. Mention of tradenames or commercial products does not constitute either endorsement or recommendation for use by the US Navy or USEPA. This is contribution number 1471 of ERLN and 286 of UNH Jackson Estuarine Laboratory.

Environmental toxicology and water quality, May 1, 1994

Four bioassays [MicrotoxTM, MutatoxTM, sister chromatid exchange (SCE), and metabolic cooperation... more Four bioassays [MicrotoxTM, MutatoxTM, sister chromatid exchange (SCE), and metabolic cooperation] were used to analyze marine sediment extracts fractionated by two different methods: silica gel column chromatography and acid–base fractionation. Results indicated that a sediment extract fractionated with different methods can lead to different conclusions about the same sediment.This research also further evaluated the new, mutagenic, bacterial bioassay Mutatox. Mutatox generally correlated with SCE and the Salmonella typhimurium assays. This rapid, operationally simple bioassay has potential as a screening bioassay to detect genotoxic agents. © 1994 by John Wiley & Sons, Inc..

Environmental Toxicology and Chemistry, Apr 1, 1999

A laboratory model was developed to predict exposure effects in the field. Accumulation of non‐or... more A laboratory model was developed to predict exposure effects in the field. Accumulation of non‐ortho‐ and mono‐ortho‐substituted PCBs in liver tissue and their effects on mummichogs (Fundulus heteroclitus) were investigated. An artificial diet spiked with a mixture of eight PCB congeners was fed to mummichogs in the laboratory. Ratios of the congeners were similar to those measured in livers of mummichogs indigenous to the PCB Superfund site, New Bedford Harbor, Massachusetts, USA. Nominal dietary concentrations were high (54.3 μg/g wet body weight), medium (10.9 μg/g), low (2.2 μg/g), and a control. Accumulation of PCBs was consistent with exposure; however, lower levels of congener 77 were detected in liver tissue (0.2–0.8% of total PCBs) than in the spiked diets (3.3–4.6%). Significant (p ≤ 0.05) mortality occurred in mummichogs fed high and medium doses relative to the control. Mortality was higher and growth was lower with increasing toxic equivalent concentration of dietary PCB concentration and accumulation of PCBs in liver tissue. Mummichogs exhibited an exposure response in congener accumulation and biological effects with increasing dietary PCB concentration. Unlike fish from New Bedford Harbor, clean fish exposed to PCBs appear to have either slower uptake or higher metabolism of congener 77, indicating possible adaptation of mummichogs inhabiting polluted environments.

Environmental Toxicology and Chemistry, 1999

A laboratory model was developed to predict exposure effects in the field. Accumulation of non‐or... more A laboratory model was developed to predict exposure effects in the field. Accumulation of non‐ortho‐ and mono‐ortho‐substituted PCBs in liver tissue and their effects on mummichogs (Fundulus heteroclitus) were investigated. An artificial diet spiked with a mixture of eight PCB congeners was fed to mummichogs in the laboratory. Ratios of the congeners were similar to those measured in livers of mummichogs indigenous to the PCB Superfund site, New Bedford Harbor, Massachusetts, USA. Nominal dietary concentrations were high (54.3 μg/g wet body weight), medium (10.9 μg/g), low (2.2 μg/g), and a control. Accumulation of PCBs was consistent with exposure; however, lower levels of congener 77 were detected in liver tissue (0.2–0.8% of total PCBs) than in the spiked diets (3.3–4.6%). Significant (p ≤ 0.05) mortality occurred in mummichogs fed high and medium doses relative to the control. Mortality was higher and growth was lower with increasing toxic equivalent concentration of dietary PCB concentration and accumulation of PCBs in liver tissue. Mummichogs exhibited an exposure response in congener accumulation and biological effects with increasing dietary PCB concentration. Unlike fish from New Bedford Harbor, clean fish exposed to PCBs appear to have either slower uptake or higher metabolism of congener 77, indicating possible adaptation of mummichogs inhabiting polluted environments.

Environmental Toxicology and Chemistry, 1998

This investigation evaluated polychlorinated biphenyl (PCB) accumulation, survival, and reproduct... more This investigation evaluated polychlorinated biphenyl (PCB) accumulation, survival, and reproduction in Fundulus heteroclitus from four stations along a gradient of increasing sediment contamination from West Island in Buzzards Bay, Massachusetts, USA, to the most contaminated area of the New Bedford Harbor, Massachusetts, USA, Superfund site. Fish collected during their natural spawning season were held in the laboratory for 5 weeks. Liver concentrations of non‐ortho‐ and mono‐ortho‐PCBs averaged 0.461, 9.48, 20.8, and 29.3 μg/g dry weight, with dioxin toxic equivalent concentrations (TEQs) of 0.006, 0.132, 0.543, and 1.56 ng/g; differences among stations were statistically significant. Females from two stations within the Superfund site had significantly greater mortality (30 and 23%) compared to those within West Island (0%), and growth was reduced. Progeny of fish from the most contaminated station exhibited significantly reduced survival (49%) and greater incidence of spinal abnormalities (26%) compared to those from West Island (70% survival, 7% spinal abnormalities). No differences in egg production or food consumption were observed. A significant residue‐effect relationship was found between TEQs of liver PCBs and female mortality, consistent with that determined previously from laboratory exposures and validating TEQ as an effects indicator. Embryo and larval survival were inversely related to maternal liver TEQ.

Environmental Toxicology and Chemistry, Feb 1, 2002

In ecotoxicological testing, there are few studies that report on reproductive output (egg produc... more In ecotoxicological testing, there are few studies that report on reproductive output (egg production) of marine or estuarine fish. Cunner (Tautogolabrus adspersus) were studied as a potential model species to evaluate the impact of pollutants with estrogenic activity on reproduction in estuarine fish populations. Cunner inhabit marine and estuarine areas where contaminant discharges are likely. Baseline values for cunner gonadosomatic index (GSI), hepatosomatic index (HSI), and plasma vitellogenin (VTG) were determined in a field reference site (April 1999-December 1999). Male and female GSI indicated that cunner spawning is synchronized. Female HSI and VTG increased prior to GSI. From our laboratory observations, cunner are suitable for conducting experiments with reproductive endpoints indicative of both exposure (vitellogenin levels) and effects (egg production). However, cunner are not sexually dimorphic and stripping ripe fish is the only method to distinguish sex. In preparation for laboratory exposure studies with cunner, we designed a laboratory experimental holding system to accommodate cunner's reproductive behavior, a vertical spawning run to the water surface. Cunner were successfully acclimated from overwintering torpor to spawning condition in the laboratory by gradually changing the environmental conditions of fish held at winter conditions (4ЊC and 9:15-h light:dark photoperiod) to spawning condition (18ЊC and 15:9-h light:dark photoperiod). Our results show that cunner successfully spawned daily in the laboratory. They produced fertile eggs in our experimental system designed to accommodate cunner's vertical spawning runs, demonstrating that male and female reproductive behavior was synchronized in the laboratory. Our observations indicate that cunner would be a useful model species for evaluating reproductive effects of environmental contaminants in laboratory studies.

Aquatic Toxicology, Sep 1, 2001

The intent of this study was to compare histopathologically the effect of 17β-estradiol (E2), o,p... more The intent of this study was to compare histopathologically the effect of 17β-estradiol (E2), o,p′-DDT, octylphenol and p,p′-DDE on gonadal development and liver and kidney condition in sexually immature (juvenile) summer flounder (Paralichthys dentatus). The dorsal sinus of 2-year-old juvenile male summer flounder was injected with the appropriate amount of chemical incorporated in coconut oil. A second identical injection was

Aquatic Toxicology, Feb 1, 2014

The steroidogenic enzyme aromatase catalyzes the conversion of androgens to estrogens and therefo... more The steroidogenic enzyme aromatase catalyzes the conversion of androgens to estrogens and therefore plays a central role in reproduction. In contrast to most vertebrates, teleost fish have two distinct forms of aromatase. Because brain aromatase activity in fish is up to 1000 times that in mammals, fish may be especially susceptible to negative effects from environmental endocrine-disrupting chemicals (EDCs) that impact aromatase activity. In this study, the effects of estradiol (E 2), ethynylestradiol (EE 2), octylphenol (OP), and androstatrienedione (ATD) on reproduction and aromatase activity in brains and gonads from the marine fish cunner (Tautogolabrus adspersus) was investigated. The purpose of the study was to explore the relationship between changes in aromatase activity and reproductive output in a marine fish, as well as compare aromatase activity to two commonly used indicators of EDC exposure, plasma vitellogenin (VTG) and gonadosomatic index (GSI). Results with E 2 , EE 2 , and ATD indicate that aromatase activity in cunner brain and ovary are affected differently by exposure to these EDCs. In the case of E 2 and EE 2 , male brain aromatase activity was signficantly increased by these treatments, female brain aromatase activity was unaffected, and ovarian aromatase activity was significantly decreased. Treatment with the aromatase inhibitor ATD resulted in significantly decreased aromatase activity in male and female brain, but had no significant impact on ovarian aromatase activity. Regardless of test chemical, a decrease or an increase in male brain aromatase activity relative to controls was associated with decreased egg production in cunner and was also correlated with significant changes in GSI in both sexes. E 2 and EE 2 significantly elevated plasma VTG in males and females, while ATD had no significant effect. Treatment of cunner with OP had no significant effect on any measured endpoint. Overall, results with these exposures indicate EDCs that impact aromatase activity also affect reproductive output in spawning cunner.

Environmental Toxicology, Aug 25, 2015

Tamoxifen is an endocrine-active pharmaceutical (EAP) that is used world-wide. Because tamoxifen ... more Tamoxifen is an endocrine-active pharmaceutical (EAP) that is used world-wide. Because tamoxifen is a ubiquitous pharmaceutical and interacts with estrogen receptors, a case study was conducted with this compound to (1) determine effects on reproductive endpoints in a nontarget species (i.e., a fish), (2) compare biologically-active metabolites across species, (3) assess whether in vitro assays predict in vivo results, and (4) investigate metabolomic profiles in tamoxifen-treated fish to better understand the biological mechanisms of tamoxifen toxicity. In reproductive assays, tamoxifen exposure caused a significant reduction in egg production and significantly increased ovarian aromatase activity in spawning adult cunner fish (Tautogolabrus adspersus). In plasma from tamoxifen-exposed cunner, the predominant metabolite was 4-hydroxytamoxifen, while in rats it was N-desmethyltamoxifen. Because 4-hydroxytamoxifen is a more biologically active metabolite than N-desmethyltamoxifen, this difference could result in a different level of risk for the two species. The results of in vitro assays with fish hepatic microsomes to assess tamoxifen metabolism did not match in vivo results, indicating probable differences in excretion of tamoxifen metabolites in fish compared with rats. For the first time, a complete in vitro characterization of the metabolism of tamoxifen using fish microsomes is presented. Furthermore, a metabolomic investigation of cunner gonad extracts demonstrates that tamoxifen alters the biochemical profile in this nontarget species. Understanding the consequence of tamoxifen exposure in nontarget species, and assessing the discrepancies between sex- and species-mediated endpoints, is a step toward understanding how to accurately assess the risks posed by EAPs, such as tamoxifen, in the aquatic environment. © 2015 Wiley Periodicals, Inc. Environ Toxicol, 2015.

Biochemistry (Moscow), 2004

We have studied the effect of polycyclic aromatic hydrocarbons (PAH) on gap junction intercellula... more We have studied the effect of polycyclic aromatic hydrocarbons (PAH) on gap junction intercellular communica tions (GJIC) in culture of hepatoma cells Hep G2 and G27. Carcinogenic PAH inhibited GJIC in both cultures in contrast to non carcinogenic PAH. We showed that both constitutive and inducible expressions of mRNAs of Ah receptor and cytochrome P4501A1 (the main isoform involved in PAH metabolism) were absent in hepatoma G27 cells. We concluded that the initial, non metabolized molecules of carcinogenic PAH are responsible for changes in GJIC through interaction with an unknown factor in the cellular membrane.

An ecological risk assessment framework was applied to assess the ecological risk of the operatio... more An ecological risk assessment framework was applied to assess the ecological risk of the operations of the Portsmouth Naval Shipyard (PNSY) in Kittery, ME, on the Piscataqua River and Great Bay Estuary located in NH and ME. Measures of contamination and biological impact were ...

Environmental Toxicology & Water Quality, 1994

... Science Applications International Corporation, 27 Tarzwell Drive, Narragansett, Rhode Island... more ... Science Applications International Corporation, 27 Tarzwell Drive, Narragansett, Rhode Island 02882 A. Russell Malcolm US Environmental Protection Agency, Environmental Research Laboratory, Narragansett, 27 Tarzwell Drive, Narragansett, Rhode Island 02882 ...

Toxicology and Applied Pharmacology, 1994

Environmental Toxicology and Chemistry, Jul 1, 1998

This investigation evaluated polychlorinated biphenyl (PCB) accumulation, survival, and reproduct... more This investigation evaluated polychlorinated biphenyl (PCB) accumulation, survival, and reproduction in Fundulus heteroclitus from four stations along a gradient of increasing sediment contamination from West Island in Buzzards Bay, Massachusetts, USA, to the most contaminated area of the New Bedford Harbor, Massachusetts, USA, Superfund site. Fish collected during their natural spawning season were held in the laboratory for 5 weeks. Liver concentrations of non‐ortho‐ and mono‐ortho‐PCBs averaged 0.461, 9.48, 20.8, and 29.3 μg/g dry weight, with dioxin toxic equivalent concentrations (TEQs) of 0.006, 0.132, 0.543, and 1.56 ng/g; differences among stations were statistically significant. Females from two stations within the Superfund site had significantly greater mortality (30 and 23%) compared to those within West Island (0%), and growth was reduced. Progeny of fish from the most contaminated station exhibited significantly reduced survival (49%) and greater incidence of spinal abnormalities (26%) compared to those from West Island (70% survival, 7% spinal abnormalities). No differences in egg production or food consumption were observed. A significant residue‐effect relationship was found between TEQs of liver PCBs and female mortality, consistent with that determined previously from laboratory exposures and validating TEQ as an effects indicator. Embryo and larval survival were inversely related to maternal liver TEQ.

Carcinogenesis, 1991

The in vitro V79/metabolic cooperation assay measures the extent of gap-junctional transfer of me... more The in vitro V79/metabolic cooperation assay measures the extent of gap-junctional transfer of metabolites from wild-type to mutant V79 cells. The assay is currently being explored as a short-term test to screen for tumor promoting chemicals, many of which inhibit metabolic cooperation. In this study, the assay was used to determine whether chemical interactions affect detection of tumor promoters in mixtures and to investigate types of interactions that may occur between chemicals. Several two-chemical mixtures were examined. The effects of phorbol-12-myristate-13-acetate (PMA) and phorbol-12,13-dibutyrate, two inhibitors of metabolic cooperation that operate through the same receptor-mediated pathway, were additive at concentrations below the maximally effective concentrations of either. A summation effect was observed in mixtures of two other inhibitors of metabolic cooperation, the pesticide aldrin and the principal metabolite of sodium cyclamate, cyclohexylamine. Synergistic effects were noted when PMA was combined with either aldrin or cyclohexylamine, demonstrating that chemicals in a mixture may yield a much stronger response than expected based on individual chemical exposures. Interactions were also examined between PMA, aldrin, cyclohexylamine and 2,4-diaminotoluene, a chemical that appears to enhance metabolic cooperation. 2,4-Diaminotoluene reversed effects of all inhibiting chemicals to some extent, although the pattern of response was different for each combination. In the most dramatic case, the powerful tumor promoter PMA was completely masked by 2,4-diaminotoluene. These results suggest that the V79/metabolic cooperation assay must be applied with caution in mixture testing because detection of tumor promoting chemicals can depend on other chemicals present.

Environmental Health Perspectives, 2003

We thank C. Chichester, L. Meng, D. Nacci, J. Heltshe, and the anonymous reviewers for their crit... more We thank C. Chichester, L. Meng, D. Nacci, J. Heltshe, and the anonymous reviewers for their critical reviews of the manuscript. We also thank B. O'Neal and K. Kroll at the University of Florida for conducting vitellogenin analyses on cunner plasma samples. Although the research described in this article has been funded by the U.S. Environmental Protection Agency, it has not been subjected to agency-level review and does not necessarily reflect the views of the agency. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. This article represents contribution no.

Aquatic Toxicology, Apr 1, 2001

... Author , Ruth E. Gutjahr-Gobell, Romona A. Haebler, Doranne J. Borsay Horowitz, Saro Jayarama... more ... Author , Ruth E. Gutjahr-Gobell, Romona A. Haebler, Doranne J. Borsay Horowitz, Saro Jayaraman, Richard J. Pruell, Richard A. McKinney, George R ... In San Pedro Bay CA, which is the former site of a DDT manufacturing plant, white croaker have been found to be less fertile ...

Ecotoxicology and Environmental Safety, Feb 1, 2006

Endocrine-disrupting chemicals (EDCs) in the environment may alter the population dynamics of wil... more Endocrine-disrupting chemicals (EDCs) in the environment may alter the population dynamics of wildlife by affecting reproductive output. This study describes a matrix modeling approach to link laboratory studies on endocrine disruption with potential ecological effects. The experimental model used is cunner (Tautogolabrus adspersus), which inhabit estuarine and marine areas where sewage treatment and other discharges containing estrogenic EDCs are likely. To test the effects of estrogenic exposures on fecundity, reproductively active cunner were exposed in three separate experiments by implanting 17beta-estradiol, estrone, or 17alpha-ethynylestradiol subcutaneously in a slow-release matrix at 0.05, 0.5, and 2.5 mg/kg. Egg production per gram female and egg viability were determined daily for a 1-week preexposure period and then for a 2-week exposure period. The mean number of eggs produced per gram female and egg viability (%) were calculated for the initial preexposure period and the 2-week exposure period for each experiment. Significant changes were observed in egg production per gram female in the high-17beta-estradiol treatment (P = 0.07) and high-17alpha-ethynylestradiol treatment (P = 0.04). A significant increase was observed in egg viability (%) in the low-17alpha-ethynylestradiol treatment (39.0%; P < or = 0.05). Cunner population response was projected using an age-structured matrix population model parameterized with published survival and fecundity estimates. By incorporating reproductive response data from laboratory exposures, model projections were used to describe how reproductive changes by estrogen treatment could alter cunner population growth rate (lambda). Published by Elsevier Inc.

Toxicological Sciences, Aug 26, 2009

Atrazine (ATR) has recently been shown to activate the hypothalamic-pituitary-adrenal (HPA) axis ... more Atrazine (ATR) has recently been shown to activate the hypothalamic-pituitary-adrenal (HPA) axis in rodents. The current study investigated the effect of ATR and two of its chlorinated metabolites, desisopropylatrazine (DIA) and diaminos-chlorotriazine (DACT), on the HPA axis in the Long-Evans female rat. A single oral gavage administration of 75 mg/kg ATR or 60.2 mg/kg DIA (a dose equimolar to the applied ATR dose) during the morning of proestrus resulted in significant, acute increases in circulating adrenocorticotropic hormone (ACTH), corticosterone, and progesterone. Oral doses of ATR or DIA were given daily over the course of the 4-day ovarian cycle starting on the day of vaginal estrus, resulted in a similar, dose-responsive activation of the HPA axis. The increase in ACTH, corticosterone, and progesterone by these compounds was of a similar magnitude to that produced by 5-min restraint stress. Single or multiple oral exposures to DACT, on the other hand, did not significantly alter pituitary-adrenal hormone release. These results were observed despite plasma levels of DACT being higher than any other metabolite at the time of hormone measurement. Overall, circulating metabolite concentrations following equimolar dosing were much higher than those observed after ATR administration. Additional studies indicated that the activation of the HPA axis by oral exposure to ATR and DIA was not due simply to the stimulation of gastrointestinal afferents. Similar responses were observed in rats which received an oral dose of ATR following bilateral subdiaphramatic vagotomy and following intravenous administration of DIA in jugular vein catheterized animals. We conclude that ATR and the metabolite DIA significantly activate the HPA axis following oral exposure in the female rat. Activation of this endocrine axis by these chlorotriazines could contribute to the induced changes of female reproductive function reported previously.

This report has been reviewed by ERLN and approved for publication. Approval docs not signify tha... more This report has been reviewed by ERLN and approved for publication. Approval docs not signify that the contents reflect the view and policies of USEPA. The report has also been reviewed by PNSY, NORTHDIV, and NRaD. All data and information herein were presented at PNSY Technical Review Committee meetings and public workshops in Kittery, ME, and arc approved for public release. Mention of tradenames or commercial products does not constitute either endorsement or recommendation for use by the US Navy or USEPA. This is contribution number 1471 of ERLN and 286 of UNH Jackson Estuarine Laboratory.

Environmental toxicology and water quality, May 1, 1994

Four bioassays [MicrotoxTM, MutatoxTM, sister chromatid exchange (SCE), and metabolic cooperation... more Four bioassays [MicrotoxTM, MutatoxTM, sister chromatid exchange (SCE), and metabolic cooperation] were used to analyze marine sediment extracts fractionated by two different methods: silica gel column chromatography and acid–base fractionation. Results indicated that a sediment extract fractionated with different methods can lead to different conclusions about the same sediment.This research also further evaluated the new, mutagenic, bacterial bioassay Mutatox. Mutatox generally correlated with SCE and the Salmonella typhimurium assays. This rapid, operationally simple bioassay has potential as a screening bioassay to detect genotoxic agents. © 1994 by John Wiley & Sons, Inc..

Environmental Toxicology and Chemistry, Apr 1, 1999

A laboratory model was developed to predict exposure effects in the field. Accumulation of non‐or... more A laboratory model was developed to predict exposure effects in the field. Accumulation of non‐ortho‐ and mono‐ortho‐substituted PCBs in liver tissue and their effects on mummichogs (Fundulus heteroclitus) were investigated. An artificial diet spiked with a mixture of eight PCB congeners was fed to mummichogs in the laboratory. Ratios of the congeners were similar to those measured in livers of mummichogs indigenous to the PCB Superfund site, New Bedford Harbor, Massachusetts, USA. Nominal dietary concentrations were high (54.3 μg/g wet body weight), medium (10.9 μg/g), low (2.2 μg/g), and a control. Accumulation of PCBs was consistent with exposure; however, lower levels of congener 77 were detected in liver tissue (0.2–0.8% of total PCBs) than in the spiked diets (3.3–4.6%). Significant (p ≤ 0.05) mortality occurred in mummichogs fed high and medium doses relative to the control. Mortality was higher and growth was lower with increasing toxic equivalent concentration of dietary PCB concentration and accumulation of PCBs in liver tissue. Mummichogs exhibited an exposure response in congener accumulation and biological effects with increasing dietary PCB concentration. Unlike fish from New Bedford Harbor, clean fish exposed to PCBs appear to have either slower uptake or higher metabolism of congener 77, indicating possible adaptation of mummichogs inhabiting polluted environments.

Environmental Toxicology and Chemistry, 1999

A laboratory model was developed to predict exposure effects in the field. Accumulation of non‐or... more A laboratory model was developed to predict exposure effects in the field. Accumulation of non‐ortho‐ and mono‐ortho‐substituted PCBs in liver tissue and their effects on mummichogs (Fundulus heteroclitus) were investigated. An artificial diet spiked with a mixture of eight PCB congeners was fed to mummichogs in the laboratory. Ratios of the congeners were similar to those measured in livers of mummichogs indigenous to the PCB Superfund site, New Bedford Harbor, Massachusetts, USA. Nominal dietary concentrations were high (54.3 μg/g wet body weight), medium (10.9 μg/g), low (2.2 μg/g), and a control. Accumulation of PCBs was consistent with exposure; however, lower levels of congener 77 were detected in liver tissue (0.2–0.8% of total PCBs) than in the spiked diets (3.3–4.6%). Significant (p ≤ 0.05) mortality occurred in mummichogs fed high and medium doses relative to the control. Mortality was higher and growth was lower with increasing toxic equivalent concentration of dietary PCB concentration and accumulation of PCBs in liver tissue. Mummichogs exhibited an exposure response in congener accumulation and biological effects with increasing dietary PCB concentration. Unlike fish from New Bedford Harbor, clean fish exposed to PCBs appear to have either slower uptake or higher metabolism of congener 77, indicating possible adaptation of mummichogs inhabiting polluted environments.

Environmental Toxicology and Chemistry, 1998

This investigation evaluated polychlorinated biphenyl (PCB) accumulation, survival, and reproduct... more This investigation evaluated polychlorinated biphenyl (PCB) accumulation, survival, and reproduction in Fundulus heteroclitus from four stations along a gradient of increasing sediment contamination from West Island in Buzzards Bay, Massachusetts, USA, to the most contaminated area of the New Bedford Harbor, Massachusetts, USA, Superfund site. Fish collected during their natural spawning season were held in the laboratory for 5 weeks. Liver concentrations of non‐ortho‐ and mono‐ortho‐PCBs averaged 0.461, 9.48, 20.8, and 29.3 μg/g dry weight, with dioxin toxic equivalent concentrations (TEQs) of 0.006, 0.132, 0.543, and 1.56 ng/g; differences among stations were statistically significant. Females from two stations within the Superfund site had significantly greater mortality (30 and 23%) compared to those within West Island (0%), and growth was reduced. Progeny of fish from the most contaminated station exhibited significantly reduced survival (49%) and greater incidence of spinal abnormalities (26%) compared to those from West Island (70% survival, 7% spinal abnormalities). No differences in egg production or food consumption were observed. A significant residue‐effect relationship was found between TEQs of liver PCBs and female mortality, consistent with that determined previously from laboratory exposures and validating TEQ as an effects indicator. Embryo and larval survival were inversely related to maternal liver TEQ.

Environmental Toxicology and Chemistry, Feb 1, 2002

In ecotoxicological testing, there are few studies that report on reproductive output (egg produc... more In ecotoxicological testing, there are few studies that report on reproductive output (egg production) of marine or estuarine fish. Cunner (Tautogolabrus adspersus) were studied as a potential model species to evaluate the impact of pollutants with estrogenic activity on reproduction in estuarine fish populations. Cunner inhabit marine and estuarine areas where contaminant discharges are likely. Baseline values for cunner gonadosomatic index (GSI), hepatosomatic index (HSI), and plasma vitellogenin (VTG) were determined in a field reference site (April 1999-December 1999). Male and female GSI indicated that cunner spawning is synchronized. Female HSI and VTG increased prior to GSI. From our laboratory observations, cunner are suitable for conducting experiments with reproductive endpoints indicative of both exposure (vitellogenin levels) and effects (egg production). However, cunner are not sexually dimorphic and stripping ripe fish is the only method to distinguish sex. In preparation for laboratory exposure studies with cunner, we designed a laboratory experimental holding system to accommodate cunner's reproductive behavior, a vertical spawning run to the water surface. Cunner were successfully acclimated from overwintering torpor to spawning condition in the laboratory by gradually changing the environmental conditions of fish held at winter conditions (4ЊC and 9:15-h light:dark photoperiod) to spawning condition (18ЊC and 15:9-h light:dark photoperiod). Our results show that cunner successfully spawned daily in the laboratory. They produced fertile eggs in our experimental system designed to accommodate cunner's vertical spawning runs, demonstrating that male and female reproductive behavior was synchronized in the laboratory. Our observations indicate that cunner would be a useful model species for evaluating reproductive effects of environmental contaminants in laboratory studies.

Aquatic Toxicology, Sep 1, 2001

The intent of this study was to compare histopathologically the effect of 17β-estradiol (E2), o,p... more The intent of this study was to compare histopathologically the effect of 17β-estradiol (E2), o,p′-DDT, octylphenol and p,p′-DDE on gonadal development and liver and kidney condition in sexually immature (juvenile) summer flounder (Paralichthys dentatus). The dorsal sinus of 2-year-old juvenile male summer flounder was injected with the appropriate amount of chemical incorporated in coconut oil. A second identical injection was

Aquatic Toxicology, Feb 1, 2014

The steroidogenic enzyme aromatase catalyzes the conversion of androgens to estrogens and therefo... more The steroidogenic enzyme aromatase catalyzes the conversion of androgens to estrogens and therefore plays a central role in reproduction. In contrast to most vertebrates, teleost fish have two distinct forms of aromatase. Because brain aromatase activity in fish is up to 1000 times that in mammals, fish may be especially susceptible to negative effects from environmental endocrine-disrupting chemicals (EDCs) that impact aromatase activity. In this study, the effects of estradiol (E 2), ethynylestradiol (EE 2), octylphenol (OP), and androstatrienedione (ATD) on reproduction and aromatase activity in brains and gonads from the marine fish cunner (Tautogolabrus adspersus) was investigated. The purpose of the study was to explore the relationship between changes in aromatase activity and reproductive output in a marine fish, as well as compare aromatase activity to two commonly used indicators of EDC exposure, plasma vitellogenin (VTG) and gonadosomatic index (GSI). Results with E 2 , EE 2 , and ATD indicate that aromatase activity in cunner brain and ovary are affected differently by exposure to these EDCs. In the case of E 2 and EE 2 , male brain aromatase activity was signficantly increased by these treatments, female brain aromatase activity was unaffected, and ovarian aromatase activity was significantly decreased. Treatment with the aromatase inhibitor ATD resulted in significantly decreased aromatase activity in male and female brain, but had no significant impact on ovarian aromatase activity. Regardless of test chemical, a decrease or an increase in male brain aromatase activity relative to controls was associated with decreased egg production in cunner and was also correlated with significant changes in GSI in both sexes. E 2 and EE 2 significantly elevated plasma VTG in males and females, while ATD had no significant effect. Treatment of cunner with OP had no significant effect on any measured endpoint. Overall, results with these exposures indicate EDCs that impact aromatase activity also affect reproductive output in spawning cunner.

Environmental Toxicology, Aug 25, 2015

Tamoxifen is an endocrine-active pharmaceutical (EAP) that is used world-wide. Because tamoxifen ... more Tamoxifen is an endocrine-active pharmaceutical (EAP) that is used world-wide. Because tamoxifen is a ubiquitous pharmaceutical and interacts with estrogen receptors, a case study was conducted with this compound to (1) determine effects on reproductive endpoints in a nontarget species (i.e., a fish), (2) compare biologically-active metabolites across species, (3) assess whether in vitro assays predict in vivo results, and (4) investigate metabolomic profiles in tamoxifen-treated fish to better understand the biological mechanisms of tamoxifen toxicity. In reproductive assays, tamoxifen exposure caused a significant reduction in egg production and significantly increased ovarian aromatase activity in spawning adult cunner fish (Tautogolabrus adspersus). In plasma from tamoxifen-exposed cunner, the predominant metabolite was 4-hydroxytamoxifen, while in rats it was N-desmethyltamoxifen. Because 4-hydroxytamoxifen is a more biologically active metabolite than N-desmethyltamoxifen, this difference could result in a different level of risk for the two species. The results of in vitro assays with fish hepatic microsomes to assess tamoxifen metabolism did not match in vivo results, indicating probable differences in excretion of tamoxifen metabolites in fish compared with rats. For the first time, a complete in vitro characterization of the metabolism of tamoxifen using fish microsomes is presented. Furthermore, a metabolomic investigation of cunner gonad extracts demonstrates that tamoxifen alters the biochemical profile in this nontarget species. Understanding the consequence of tamoxifen exposure in nontarget species, and assessing the discrepancies between sex- and species-mediated endpoints, is a step toward understanding how to accurately assess the risks posed by EAPs, such as tamoxifen, in the aquatic environment. © 2015 Wiley Periodicals, Inc. Environ Toxicol, 2015.

Biochemistry (Moscow), 2004

We have studied the effect of polycyclic aromatic hydrocarbons (PAH) on gap junction intercellula... more We have studied the effect of polycyclic aromatic hydrocarbons (PAH) on gap junction intercellular communica tions (GJIC) in culture of hepatoma cells Hep G2 and G27. Carcinogenic PAH inhibited GJIC in both cultures in contrast to non carcinogenic PAH. We showed that both constitutive and inducible expressions of mRNAs of Ah receptor and cytochrome P4501A1 (the main isoform involved in PAH metabolism) were absent in hepatoma G27 cells. We concluded that the initial, non metabolized molecules of carcinogenic PAH are responsible for changes in GJIC through interaction with an unknown factor in the cellular membrane.

An ecological risk assessment framework was applied to assess the ecological risk of the operatio... more An ecological risk assessment framework was applied to assess the ecological risk of the operations of the Portsmouth Naval Shipyard (PNSY) in Kittery, ME, on the Piscataqua River and Great Bay Estuary located in NH and ME. Measures of contamination and biological impact were ...

Environmental Toxicology & Water Quality, 1994

... Science Applications International Corporation, 27 Tarzwell Drive, Narragansett, Rhode Island... more ... Science Applications International Corporation, 27 Tarzwell Drive, Narragansett, Rhode Island 02882 A. Russell Malcolm US Environmental Protection Agency, Environmental Research Laboratory, Narragansett, 27 Tarzwell Drive, Narragansett, Rhode Island 02882 ...