Incorporating Transgenerational Epigenetic ... - ACS Publications

Subscriber access provided by UNIV OF NEWCASTLE

Critical Review

Incorporating transgenerational epigenetic inheritance into ecological risk assessment frameworks. Jennifer L.A. Shaw, Jonathan D Judy, Anupama Kumar, Paul Bertsch, Ming-Bo Wang, and Jason K. Kirby Environ. Sci. Technol., Just Accepted Manuscript • DOI: 10.1021/acs.est.7b01094 • Publication Date (Web): 26 Jul 2017 Downloaded from http://pubs.acs.org on July 31, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Environmental Science & Technology is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 38

Environmental Science & Technology

1

Incorporating transgenerational epigenetic inheritance into ecological risk

2

assessment frameworks.

3

Jennifer L.A. Shaw1*, Jonathan D. Judy1,3, Anupama Kumar1, Paul Bertsch2, Ming-Bo

4

Wang4, Jason, K. Kirby1.

5 6 7 8 9 10 11

1

12 13

*Corresponding author email: [email protected], tel: +61 8 8303 8438.

*Commonwealth Scientific and Industrial Research Organisation (CSIRO), Land and Water, Environmental Contaminant Mitigation and Technologies Research Program, Waite Road, Urrbrae, Adelaide, Australia, 5064. 2 Commonwealth Scientific and Industrial Research Organisation (CSIRO), Land and Water, Brisbane, Queensland, Australia, 4001. 3University of Florida, Soil and Water Sciences Department, 1692 McCarthy Drive, Gainesville, Florida, 32611. 4 Commonwealth Scientific and Industrial Research Organisation (CSIRO), Agriculture and Food Unit, Black Mountain, Canberra, ACT, Australia, 2601.

14 15

Abstract

16

Chronic exposure to environmental contaminants can induce heritable ‘transgenerational’

17

modifications to organisms, potentially affecting future ecosystem health and functionality.

18

Incorporating transgenerational epigenetic heritability into risk assessment procedures has

19

been previously suggested. However, a critical review of existing literature yielded numerous

20

studies claiming transgenerational impacts, with little compelling evidence. Therefore,

21

contaminant-induced epigenetic inheritance may be less common than is reported in the

ACS Paragon Plus Environment


22

literature. We identified a need for multi-generation epigenetic studies that extend beyond

23

what could be deemed ‘direct exposure’ to F1 and F2 gametes, which also include subsequent

24

multiple non-exposed generations to adequately evaluate transgenerational recovery times.

25

Also, increased experimental replication is required to account for the highly variable nature

26

of epigenetic responses and apparent irreproducibility of current studies. Further, epigenetic

27

endpoints need to be correlated with observable detrimental organism changes before a need

28

for risk management can be properly determined. We suggest that epigenetic-based

29

contaminant studies include concentrations lower than current ‘EC10-20’ or ‘Lowest

30

Observable Effect Concentrations’ for the organism’s most sensitive phenotypic endpoint, as

31

higher concentrations are likely to be already regulated. Finally, we propose a regulatory

32

framework and optimal experimental design that enables transgenerational epigenetic effects

33

to be assessed and incorporated into conventional ecotoxicological testing.

34

Key words: multigenerational | chronic contamination | ecotoxicology | DNA methylation |

35

gene expression | environment

36 37

1. Introduction

38

Contaminants can enter the environment via multiple pathways such as agricultural

39

production, urban runoff, manufacturing, waste disposal and mining. These contaminants can

40

have adverse effects on ecologically important organisms1–3 and ecosystem health.4,5 To

41

reduce environmental and health impacts, it is critical to understand contaminant-associated

42

risks, develop appropriate regulations, and implement appropriate risk management

43

strategies. Potential risks are assessed using specific frameworks that incorporate an

44

understanding of the biological and functional impacts caused by different exposure

45

concentrations and pathways.6–11 Assessments are made by measuring changes to various


Page 2 of 38

Page 3 of 38


46

biological and ecological endpoints in response to increasing concentrations of a

47

contaminant. Standard methods focus on organismal responses such as decreased biomass,

48

growth rates, reproductive fitness, increased mortality, or bioaccumulation of contaminant

49

residues, but sometimes also include molecular stress-biomarkers such as increases in

50

reactive oxygen species12,13, DNA damage14, and changes to hormonal and enzymatic

51

activities.15,16

52

More recently, epigenetic biomarkers have been highlighted as a potential future risk-

53

assessment tool.

54

code, which influence how an organism’s genes are expressed.20 These modifications can

55

change in response to a multitude of environmental factors, temporarily or permanently

56

altering expression of the DNA code and altering the organism’s phenotype as a result.21

57

Most importantly, epigenetic modifications can sometimes become inherited by offspring,22,23

58

potentially altering the evolutionary pathway of future generations. Therefore, there is

59

potential for transgenerational epigenetic analysis to be used for determining chronic risk to

60

future generations.17,24

61

We critically evaluate available literature on contaminant-induced transgenerational and

62

epigenetic changes, and explore key issues and gaps in current research that hinder our ability

63

to utilise these tools in risk assessment. We evaluate whether transgenerational epigenetics

64

could add value to existing ecological risk assessment frameworks, and propose a strategy for

65

developing useable transgenerational epigenetic endpoints for ecological risk assessment.

66

Finally, we propose a tiered assessment framework and experimental design, which

67

incorporate transgenerational, chronic risk into current risk assessment frameworks.

17–19

Epigenetics describes chemical modifications that exist along a DNA

68 69

2. Contaminant-induced epigenetic changes



70

Numerous environmental contaminants have been shown to induce epigenetic changes to a

71

wide range of ecologically relevant organisms (Table 1), such as mammals22,25, plants26–28,

72

insects29,30, fish31–33, nematode worms34, molluscs35, and reptiles36,37. Several of these studies

73

have cited contaminant-induced hypermethylation of specific genes, suggesting that

74

epigenetic alterations vary with contaminant type. For example, studies have demonstrated

75

that regions of the rat (Rattus norvegicus) genome are differentially methylated in response to

76

exposure from different contaminants including dioxins38, plastics39, and pesticides.40

77

Vandegehuchte et al. (2010) found that water fleas (Daphnia magna) exposed to different

78

contaminants (7.4 mg/L 5-azacytidine, 4.4 mg/L genistein, and 3.6 mg/L vinclozolin) had

79

alternative methylation profiles.41 And in plants, Aina et al., (2004) found that exposure to

80

different heavy metals (25 and 100 mg/kg Ni2+, 25 and 100 mg/kg Cd2+, and 25 and 50 mg/kg

81

Cr6+) induced site-specific DNA methylation.42 Another study examining plant responses

82

found that 100 mg/L concentration of various nanoparticles (ZnO, TiO2, and fullerene soot)

83

induced statistically different gene expression profiles 43, and Nair and Chung (2014) found

84

that specific genes (mismatch repair MMR and AtPCNA associated genes) were significantly

85

up-regulated in plants when exposed to Ag nanoparticles (0.2, 0.5, 1 mg/kg) but not Ag ions

86

at equivalent concentrations.44

87

Other researchers have argued that these contaminant-induced epigenetic responses are

88

simply stochastic in nature. For example, a study by Takiguchi et al. (2003) demonstrated

89

that 2.5 µM cadmium reduced genome methylation by interfering with methyltransferase

90

molecules.45 Valinuck et al. (2004) similarly demonstrated that metal induced oxidative stress

91

interferes with the ability of methyltransferases to interact with DNA46, which could result in

92

generalised (stochastic) changes to methylation patterns. These studies confirmed that for

93

some contaminants DNA methylation changes occur as a by-product of enzymatic

94

inhibition47 and therefore, contaminant-induced methylation effects may not be reproducible.


Page 4 of 38

Page 5 of 38


95

Examining the effect of stressors on an organism’s epigenome has become a relatively

96

common research subject in recent years. However, the critical question of whether these

97

changes can become permanent or semi-permanent across multiple generations is still under-

98

studied. In a transgenerational scenario it is hypothesised that an initial exposure to a

99

contaminant can result in adverse phenotypic (and epigenetic) outcomes not only for the

100

directly exposed parent (P0) and offspring (F1 generation as developing gametes within the

101

P0 organism), but also the F2, F3 and later, non-directly exposed generations.22 This

102

transgenerational hypothesis assumes that epigenetic modifications can be sustained through

103

multiple generations, even in the absence of persistent exposure, and could lead to a chronic

104

accumulation of changes to an organisms’ phenotype if exposure does persist. In the next

105

section we discuss ecotoxicological studies that have assessed multiple generations.



106

Page 6 of 38

Table 1. Studies demonstrating links between epigenetic modifications and environmental contaminants. Organism

Contaminant

Molecular method

Physiological impact

Molecular impact

Length of

identified

identified

exposure (time)

N/A

DNA methylation

45 days

Author, Year

Aquatic vertebrates European Eel

Cadmium (0.4 and 4µg/L-1)

(Anguilla anguilla)

ELISA assay/ methylation sensitive

significantly higher in

PCR

two genes (1.4 – 1.7

Pierron et al. 201348

fold higher). Rainbow trout

Atrazine*

Gene expression

Elevated cortisol,

Gene expression

(Oncorhynchus

(2.3, 18, 59, 555 µg/L)

microarray

decreased lymphocytes.

changes (653 – 845

mykiss) Zebrafish (Danio

4 days

Shelley et al. 201231

genes p < 0.05) BPA* (5, 10, 20µg/L)

rerio)

RT-qPCR, and Chromatin

Promoted apoptosis of

Down-regulated oocyte

ImmunoPrecipitation

reproductive follicles

maturation-promoting

(ChIP) analysis

3 weeks

Santangeli et al. 201632

signals, likely through changes in the chromatin structure mediated by histone modifications.

Invertebrates Water flea (Daphnia magna)

Zinc (388µg/L)

cDNA microarray of gene

N/A

expression

Common genes similarly up or down regulated for two generations (15% of genes).


< 24hrs

Vandegehucht e et al. 201030

Page 7 of 38


Tiger Mosquito

Phytoestrogen (Genistein*

Global DNA methylation

Decrease in insecticide

Changes to global

(Aedes albopictus)

5mg/L) and fungicide

(UHPLC-MS/MS

sensitivity in unexposed

DNA methylation in P0

(vinclozolin* 3mg/L)

analysis)

offspring.

generation (74%

8 days

Oppold et al. 201529

Genistein and 82% Vinclozolin). Nematode worm

Arsenic (sodium arsenite

Affymetrix expression

Survival assay curves

Dose dependant

(Caenorhabditis

media 0.03 and 0.003%

microarrays

significantly different

differential expression

elegans)

w/v)

(P2-fold gene

7 days

201243

expression difference

(100 mg/L)

Landa et al.

(p=< 0.05) in genes associated with cell organization, biogenesis, translation, nucleosome assembly, stress response genes.

Maize (Zea Mays L.)

Zinc (5, 10, 20, 40 mM)

DNA methylation

Decreases in specific

Dose dependent

7 days (seedling

Erturk et al.,

(restriction enzymes) and

hormones with

increases in

germination)

201526

damage

increasing Zinc

methylation levels with

concentrations (p=
3)

•Determine LC/LD50 •Hours - days

exposure

relationship and ECx

•Applied during gamete

values for sub-acute

development/gestation

•Two generation +

ECx for transgenerational

effects

periods

•Weeks - months

effects

•Days – weeks

•Two generation •Determine ECx values for reproductive impairment •Weeks

•Epigenetic analyses of P0 generation (and F1 generation if modifications are observed at low concentrations)

•Determine dose-response and

•Long term, chronic exposure •Treatments focused around lower concentrations •Determine prevalence of epigenetic memory •Determine recovery time (no. of generations to recover)



375

5. Tier 5 experimental design details

376

If warranted by lower tier assessment results, then tier 5 risk assessment can be initiated. The

377

experimental design for a Tier 5 transgenerational assessment (Table 3) must be adequate to

378

determine long-term persistence of any transgenerationally transferred phenotypic alterations

379

(Figure 2). First a sufficient number of generations (both exposed and non-exposed) must be

380

considered to eliminate the confounding effects of direct exposure to gametes (i.e. the F1

381

generation exposed as developing gametes). Further, multiple exposed generations followed

382

by multiple non-exposed generations must be assessed, as several studies have suggested that

383

multiple generations must be exposed before transgenerational inheritance occurs.51,56 Note

384

that careful selection of model organisms with short generation times and well-characterised,

385

small genomes would also be critical for minimising time and costs if a tier 5 assessment is

386

required.

387

Figure 2 depicts a suggested framework for an optimal transgenerational experimental design,

388

covering a number of different experimental circumstances. For clarity this figure only

389

extends to the F3 generation; however, more generations would likely need to be considered.

390

This is a crucial step toward differentiating between true transgenerational modifications and

391

repeated direct exposures. However, it is understandable that an experiment of this scale may

392

be beyond the spatial and/or financial means of many studies, in which case some sections of

393

the design/scheme may be omitted or modified as the experiment progresses. For example,

394

section (lineage) A (Figure 3), which assesses continuous re-exposure with zero non-exposed

395

progenies, would ideally be omitted in favour of lineage B, D, or H, which includes a number

396

of subsequent non-exposed generations after multiple exposed generations. Further,

397

epigenetic assessment would not have to occur in every treatment level, instead epigenetic

398

testing could be reserved for samples which show a culmination of observable morphological

399

detrimental impacts in the F3+ progeny.


Page 24 of 38

Page 25 of 38


400

If a transgenerational effect, resulting from multiple-generation chemical exposure, is found

401

to persist in subsequent multiple non-exposed generations then it may be necessary to lower

402

the current guideline maximum allowable concentrations for that chemical. It would also be

403

critical, for research purposes, at this stage to link epigenetic changes with any

404

transgenerational morphological or functional changes occurring in later generations. Finally,

405

it may also be important to explore the concept of resistance and resilience at this stage (e.g.

406

lineage type C, E, F, or G; Figure 3).51,56,105 It may be that the organism has inherited an

407

epigenetic profile that enables it to be resilient to the contaminant related stress, in which case

408

it must be determined whether these inherited modifications are desirable or not (e.g. in the

409

case of economically or functionally important species). If the morphological change does

410

not affect the mortality, fecundity or function of the organism or ecosystem, then guidelines

411

would not need to be changed.

412

It must also be noted that it is critical to adhere to the main principles of sound

413

ecotoxicology106 if we are to be able to put transgenerational results into any kind of

414

environmental context. These principles include: 1) adequate planning and design of study

415

(see figure 2), 2) defining the baseline of what is ‘normal’ for that endpoint in an unexposed

416

organism, 3) including an appropriate number of controls, 4) using appropriate exposure

417

routes and environmentally realistic exposures, 5) measure the exposure (don’t rely on

418

hypothetical/theoretical exposure measurements), 6) minimise variability by having a good

419

understanding of the biology and background of the organisms used and also the

420

methods/tools used, 7) consider statistical analysis prior to beginning the experiment, 8)

421

consider if the number of concentrations will be substantial enough for a dose-response (at

422

least three concentrations excluding the controls are needed for reporting dose-responses, and

423

unusual patterns need further justification/experimentation), 9) the experiment conclusions

424

must be repeatable or validated independently, 10) consider potential confounding factors,



425

11) results should be compared with previous studies, 12) do not over-extrapolate or over-

426

hype a result with low significance and report negative as well as positive findings.

427

Carrying out transgenerational epigenetic assessments in a standardised manner such as this,

428

would allow a more robust body of literature to accumulate. This would assist us with a

429

clearer understanding of the prevalence of epigenetic transgenerational inheritance in the

430

environment. Over time clear pathways or biomarkers of heritable epigenetic alteration may

431

become apparent, which may enable risk assessors to predict the likelihood of heritable

432

contamination-induced epigenetic changes. If the likelihood of occurrence could be predicted

433

with a reasonable level of confidence within the first few generations, then fewer generations

434

would need to be tested, reducing both financial and time costs for assessments. However,

435

until more robust experimental designs are adopted, any such patterns will remain obscured.


Page 26 of 38

Page 27 of 38


436 437

Figure 2. Schematic of robust experimental design, with lineages including multiple

438

generations of exposed organisms, followed by multiple generations of non-exposed

439

organisms.

440



441

6. Conclusions

442

Contaminant-induced transgenerational epigenetics has received much scientific attention in

443

the last decade, but there remains little clarity as to how heritable epigenetic changes might

444

be incorporated into ecotoxicological assessments. In part this is due to studies lacking

445

sufficient replication, an insufficient number of exposed and non-exposed generations, and

446

technological difficulties obtaining appropriate and detailed genetic coverage in organisms

447

with complex genomes. For transgenerational epigenetics to be effectively incorporated into

448

ecotoxicological risk assessment, a number of issues and gaps must be resolved. Firstly, an

449

adequate number of re-exposed and non-exposed progenies are needed to provide evidence of

450

transgenerational effects beyond what could be deemed ‘direct exposure’ to gametes. In

451

addition to this, greater levels of replication are needed to account for stochastic variability in

452

epigenomes across individuals. And also, more relevant dose ranges should be tested, such as

453

ranges overlapping the contaminant EC10-20, or LOEC and NOEC concentration levels for the

454

organism’s most sensitive phenotypic endpoint. Finally, and perhaps most crucially, more

455

attention needs to be paid to the definition of transgenerational inheritance, as some studies

456

have reported contaminant-induced transgenerational impacts, when the effect may be caused

457

by direct exposure to developing gametes, causing confusion in the body of literature. These

458

processes along with the frameworks suggested in this review will assist in developing useful

459

transgenerational risk biomarkers for low-level chronic contamination in current risk

460

assessment frameworks.

461

462

Funding and image sources: All funding for this work was provided by CSIRO. All images

463

were created by- or belong to- the authors on this manuscript.

464


Page 28 of 38

Page 29 of 38


465

7. References

466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512

(1)

(2)

(3) (4) (5) (6)

(7)

(8)

(9)

(10) (11) (12) (13)

(14) (15)

(16)

Alkio, M.; Tabuchi, T. M.; Wang, X.; Colón-Carmona, A. Stress responses to polycyclic aromatic hydrocarbons in Arabidopsis include growth inhibition and hypersensitive response-like symptoms. J. Exp. Bot. 2005, 56 (421), 2983–2994 DOI: 10.1093/jxb/eri295. Harries, J. E.; Runnalls, T.; Hill, E.; Harris, C. A.; Maddix, S.; Sumpter, J. P.; Tyler, C. R. Development of a Reproductive Performance Test for Endocrine Disrupting Chemicals Using Pair-Breeding Fathead Minnows (Pimephales promelas). Environ. Sci. Technol. 2000, 34 (14), 3003–3011 DOI: 10.1021/es991292a. Kakkar, P.; Jaffery, F. N. Biological markers for metal toxicity. Environ. Toxicol. Pharmacol. 2005, 19 (2), 335–349 DOI: 10.1016/j.etap.2004.09.003. Depledge, M. H.; Billinghurst, Z. Ecological Significance of Endocrine Disruption in Marine Invertebrates. Mar. Pollut. Bull. 1999, 39 (1–12), 32–38. Hewitt, J. E.; Anderson, M. J.; Thrush, S. F. Assessing and Monitoring Ecological Community Health in Marine Systems. Ecol. Appl. 2005, 15 (3), 942–953 DOI: 10.1890/04-0732. ANZECC; NHMRC. Australian and New Zealand Guidelines for the Assessment and Management of Contaminated sites; Australian and New Zealand Environment and Conservation Council, and National Health and Medical Research Council, 1992. ANZECC; ARMCANZ. NATIONAL WATER QUALITY MANAGEMENT STRATEGY: Australian and New Zealand Guidelines for Fresh and Marine Water Quality.; Australian and New Zealand Environment and Conservation Council, and Resource Management Council of Australia and New Zealand, 2000. European Commission. Guidance on data requirement for active substances and biocidal products. Technical guidance document in support of the directive 98/8/EC concerning the placing of biocidal products on the market.; Eurpean Commision. Ispra (IT): European Chemicals Bureau., 2000. European Commission. Technical guuidance document on risk assessment in support of Commission Directive 93/67/EEC on Risk assessment to new notified substances and commission regulation (EC) No 1488/94 on risk assessment for existing substances and Directive 98/8/EC of the European parliment and the council concerning the placing of biocidal products on the market.; European Commision. Ispra (IT): European Chemicals Bureau.; p 1009. US EPA. Framework for ecological Risk Assessment; United States Environmental Protection Agency: Washington DC, USA., 1992. US EPA. Guidelines for Ecological Risk Assessment.; United States Environmental Protection Agency: Washington DC, USA., 1998. Ali, S. .; LeBel, C. .; Bondy, S. . Reactive oxygen species formation as a biomarker of methylmercury and trimethyltin neurotoxicity. Neurotoxicology 1991, 13 (3), 637–648. Bruskov, V. I.; Malakhova, L. V.; Masalimov, Z. K.; Chernikov, A. V. Heat-induced formation of reactive oxygen species and 8-oxoguanine, a biomarker of damage to DNA. Nucleic Acids Res. 2002, 30 (6), 1354–1363. Wogan, G. N. Molecular epidemiology in cancer risk assessment and prevention: recent progress and avenues for future research. Environ. Health Perspect. 1992, 98, 167–178. Champoux, L.; Rodrigue, J.; DesGranges, J.-L.; Trudeau, S.; Hontela, A.; Boily, M.; Spear, P. Assessment of Contamination and Biomarker Responses in Two Species of Herons on the St. Lawrence River. Environ. Monit. Assess. 79 (2), 193–215 DOI: 10.1023/A:1020289425542. Oliveira, M.; Pacheco, M.; Santos, M. A. Fish thyroidal and stress responses in contamination monitoring—An integrated biomarker approach. Ecotoxicol. Environ. Saf. 2011, 74 (5), 1265–1270 DOI: 10.1016/j.ecoenv.2011.03.001.



513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563

(17)

(18) (19) (20) (21) (22) (23)

(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33)

Alyea, R. A.; Gollapudi, B. B.; Rasoulpour, R. J. Are we ready to consider transgenerational epigenetic effects in human health risk assessment? Environ. Mol. Mutagen. 2014, 55 (3), 292–298 DOI: 10.1002/em.21831. Vandegehuchte, M. B.; Janssen, C. R. Epigenetics in an ecotoxicological context. Mutat. Res. Toxicol. Environ. Mutagen. 2014, 764–765, 36–45 DOI: 10.1016/j.mrgentox.2013.08.008. Vandegehuchte, M. B.; Janssen, C. R. Epigenetics and its implications for ecotoxicology. Ecotoxicology 2011, 20 (3), 607–624 DOI: 10.1007/s10646-011-0634-0. Bae, J.-B. Perspectives of International Human Epigenome Consortium. Genomics Inform. 2013, 11 (1), 7 DOI: 10.5808/GI.2013.11.1.7. Jaenisch, R.; Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 2003, 33, 245–254 DOI: 10.1038/ng1089. Anway, M. D.; Cupp, A. S.; Uzumcu, M.; Skinner, M. K. Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility. Science 2005, 308 (5727), 1466–1469. Anway, M. D.; Skinner, M. K. Epigenetic programming of the germ line: effects of endocrine disruptors on the development of transgenerational disease. Reprod. Biomed. Online 2008, 16 (1), 23–25 DOI: 10.1016/S1472-6483(10)60553-6. Ray, P. D.; Yosim, A.; Fry, R. C. Incorporating epigenetic data into the risk assessment process for the toxic metals arsenic, cadmium, chromium, lead, and mercury: strategies and challenges. Epigenomics Epigenetics 2014, 5, 201 DOI: 10.3389/fgene.2014.00201. Byun, H.; Benachour, N.; Zalko, D.; Frisardi, M. C.; Colicino, E.; Takser, L.; Baccarelli, A. A. Epigenetic effects of low perinatal doses of flame retardant BDE-47 on mitochondrial and nuclear genes in rat offspring. Toxicology 2015, 328 (3), 152–159. Erturk, F. A.; Agar, G.; Arslan, E.; Nardemir, G. Analysis of genetic and epigenetic effects of maize seeds in response to heavy metal (Zn) stress. Environ. Sci. Pollut. Res. 2015, 22 (13), 10291–10297 DOI: 10.1007/s11356-014-3886-4. Erturk, F. A.; Aydin, M.; Sigmaz, B.; Taspinar, M. S.; Arslan, E.; Agar, G.; Yagci, S. Effects of As2O3 on DNA methylation, genomic instability, and LTR retrotransposon polymorphism in Zea mays. Environ. Sci. Pollut. Res. 2015, 22 (23), 18601–18606 DOI: 10.1007/s11356-0155426-2. Wang, H.; He, L.; Song, J.; Cui, W.; Zhang, Y.; Jia, C.; Francis, D.; Rogers, H. J.; Sun, L.; Tai, P.; et al. Cadmium-induced genomic instability in Arabidopsis: Molecular toxicological biomarkers for early diagnosis of cadmium stress. Chemosphere 2016, 150, 258–265 DOI: 10.1016/j.chemosphere.2016.02.042. Oppold, A.; Kreß, A.; Vanden Bussche, J.; Diogo, J. B.; Kuch, U.; Oehlmann, J.; Vandegehuchte, M. B.; Müller, R. Epigenetic alterations and decreasing insecticide sensitivity of the Asian tiger mosquito Aedes albopictus. Ecotoxicol. Environ. Saf. 2015, 122, 45–53 DOI: 10.1016/j.ecoenv.2015.06.036. Vandegehuchte, M. B.; De Coninck, D.; Vandenbrouck, T.; De Coen, W. M.; Janssen, C. R. Gene transcription profiles, global DNA methylation and potential transgenerational epigenetic effects related to Zn exposure history in Daphnia magna. Environ. Pollut. 2010, 158 (10), 3323–3329 DOI: 10.1016/j.envpol.2010.07.023. Shelley, L. K.; Ross, P. S.; Miller, K. M.; Kaukinen, K. H.; Kennedy, C. J. Toxicity of atrazine and nonylphenol in juvenile rainbow trout (Oncorhynchus mykiss): Effects on general health, disease susceptibility and gene expression. Aquat. Toxicol. 2012, 124–125, 217–226 DOI: 10.1016/j.aquatox.2012.08.007. Santangeli, S.; Maradonna, F.; Gioacchini, G.; Cobellis, G.; Piccinetti, C. C.; Dalla Valle, L.; Carnevali, O. BPA-Induced Deregulation Of Epigenetic Patterns: Effects On Female Zebrafish Reproduction. Sci. Rep. 2016, 6 DOI: 10.1038/srep21982. Baer, C. E.; Ippolito, D. L.; Hussainzada, N.; Lewis, J. A.; Jackson, D. A.; Stallings, J. D. Genome-wide gene expression profiling of acute metal exposures in male zebrafish. Genomics Data 2014, 2, 363–365.


Page 30 of 38

Page 31 of 38

564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614


(34)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

(44)

(45)

(46)

(47) (48)

Sahu, S. N.; Lewis, J.; Patel, I.; Bozdag, S.; Lee, J. H.; Sprando, R.; Cinar, H. N. Genomic Analysis of Stress Response against Arsenic in Caenorhabditis elegans. PLOS ONE 2013, 8 (7), e66431 DOI: 10.1371/journal.pone.0066431. Zhang, H.; Zhai, Y.; Yao, L.; Jiang, Y.; Li, F. Discovery of genes associated with cadmium accumulation from gill of scallop Chlamys farreri based on high-throughput sequencing. Genes Genomics 2016, 38 (5), 439–445 DOI: 10.1007/s13258-016-0391-9. Matsumoto, Y.; Hannigan, B.; Crews, D. Embryonic PCB Exposure Alters Phenotypic, Genetic, and Epigenetic Profiles in Turtle Sex Determination, a Biomarker of Environmental Contamination. Endocrinology 2014, 155 (11), 4168–4177 DOI: 10.1210/en.2014-1404. Nilsen, F. M.; Parrott, B. B.; Bowden, J. A.; Kassim, B. L.; Somerville, S. E.; Bryan, T. A.; Bryan, C. E.; Lange, T. R.; Delaney, J. P.; Brunell, A. M.; et al. Global DNA methylation loss associated with mercury contamination and aging in the American alligator (Alligator mississippiensis). Sci. Total Environ. 2016, 545–546, 389–397 DOI: 10.1016/j.scitotenv.2015.12.059. Manikkam, M.; Tracey, R.; Guerrero-Bosagna, C.; Skinner, M. K. Dioxin (TCDD) Induces Epigenetic Transgenerational Inheritance of Adult Onset Disease and Sperm Epimutations. PLOS ONE 2012, 7 (9), e46249 DOI: 10.1371/journal.pone.0046249. Manikkam, M.; Tracey, R.; Guerrero-Bosagna, C.; Skinner, M. K. Plastics Derived Endocrine Disruptors (BPA, DEHP and DBP) Induce Epigenetic Transgenerational Inheritance of Obesity, Reproductive Disease and Sperm Epimutations. PLOS ONE 2013, 8 (1), e55387 DOI: 10.1371/journal.pone.0055387. Manikkam, M.; Tracey, R.; Guerrero-Bosagna, C.; Skinner, M. K. Pesticide and insect repellent mixture (permethrin and DEET) induces epigenetic transgenerational inheritance of disease and sperm epimutations. Reprod. Toxicol. 2012, 34 (4), 708–719 DOI: 10.1016/j.reprotox.2012.08.010. Vandegehuchte, M. B.; Lemière, F.; Vanhaecke, L.; Vanden Berghe, W.; Janssen, C. R. Direct and transgenerational impact on Daphnia magna of chemicals with a known effect on DNA methylation. Comp. Biochem. Physiol. Part C Toxicol. Pharmacol. 2010, 151 (3), 278–285 DOI: 10.1016/j.cbpc.2009.11.007. Aina, R.; Sgorbati, S.; Santagostino, A.; Labra, M.; Ghiani, A.; Citterio, S. Specific hypomethylation of DNA is induced by heavy metals in white clover and industrial hemp. Physiol. Plant. 2004, 121 (3), 472–480 DOI: 10.1111/j.1399-3054.2004.00343.x. Landa, P.; Vankova, R.; Andrlova, J.; Hodek, J.; Marsik, P.; Storchova, H.; White, J. C.; Vanek, T. Nanoparticle-specific changes in Arabidopsis thaliana gene expression after exposure to ZnO, TiO2, and fullerene soot. J. Hazard. Mater. 2012, 241–242, 55–62 DOI: 10.1016/j.jhazmat.2012.08.059. Nair, P. M. G.; Chung, I. M. Assessment of silver nanoparticle-induced physiological and molecular changes in Arabidopsis thaliana. Environ. Sci. Pollut. Res. 2014, 21 (14), 8858– 8869 DOI: 10.1007/s11356-014-2822-y. Takiguchi, M.; Achanzar, W. E.; Qu, W.; Li, G.; Waalkes, M. P. Effects of cadmium on DNA(Cytosine-5) methyltransferase activity and DNA methylation status during cadmiuminduced cellular transformation. Exp. Cell Res. 2003, 286 (2), 355–365 DOI: 10.1016/S00144827(03)00062-4. Valinluck, V.; Tsai, H.-H.; Rogstad, D. K.; Burdzy, A.; Bird, A.; Sowers, L. C. Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2). Nucleic Acids Res. 2004, 32 (14), 4100–4108 DOI: 10.1093/nar/gkh739. Valko, M.; Morris, H.; Cronin, M. T. D. Metals, Toxicity and Oxidative Stress. Curr. Med. Chem. 2005, 12 (10), 1161–1208 DOI: 10.2174/0929867053764635. Pierron, F.; Baillon, L.; Sow, M.; Gotreau, S.; Gonzalez, P. Effect of Low-Dose Cadmium Exposure on DNA Methylation in the Endangered European Eel. Environ. Sci. Technol. 2014, 48 (1), 797–803 DOI: 10.1021/es4048347.



615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664

(49)

(50)

(51)

(52)

(53)

(54)

(55)

(56)

(57)

(58)

(59) (60) (61) (62)

(63) (64)

Zhao, C. Q.; Young, M. R.; Diwan, B. A.; Coogan, T. P.; Waalkes, M. P. Association of arsenicinduced malignant transformation with DNA hypomethylation and aberrant gene expression. Proc. Natl. Acad. Sci. 1997, 94 (20), 10907–10912 DOI: 10.1073/pnas.94.20.10907. Jablonka, E.; Raz, G. Transgenerational Epigenetic Inheritance: Prevalence, Mechanisms, and Implications for the Study of Heredity and Evolution. Q. Rev. Biol. 2009, 84 (2), 131–176 DOI: 10.1086/598822. Schultz, C. L.; Wamucho, A.; Tsyusko, O. V.; Unrine, J. M.; Crossley, A.; Svendsen, C.; Spurgeon, D. J. Multigenerational exposure to silver ions and silver nanoparticles reveals heightened sensitivity and epigenetic memory in Caenorhabditis elegans. Proc R Soc B 2016, 283 (1832), 20152911 DOI: 10.1098/rspb.2015.2911. Jobson, M. A.; Jordan, J. M.; Sandrof, M. A.; Hibshman, J. D.; Lennox, A. L.; Baugh, L. R. Transgenerational Effects of Early Life Starvation on Growth, Reproduction, and Stress Resistance in Caenorhabditis elegans. Genetics 2015, 201 (1), 201–212 DOI: 10.1534/genetics.115.178699. Yu, Z.; Chen, X.; Zhang, J.; Wang, R.; Yin, D. Transgenerational effects of heavy metals on L3 larva of Caenorhabditis elegans with greater behavior and growth inhibitions in the progeny. Ecotoxicol. Environ. Saf. 2013, 88, 178–184 DOI: 10.1016/j.ecoenv.2012.11.012. Olsvik, P. A.; Williams, T. D.; Tung, H.; Mirbahai, L.; Sanden, M.; Skjaerven, K. H.; Ellingsen, S. Impacts of TCDD and MeHg on DNA methylation in zebrafish (Danio rerio) across two generations. Comp. Biochem. Physiol. Part C Toxicol. Pharmacol. 2014, 165, 17–27 DOI: 10.1016/j.cbpc.2014.05.004. Plautz, S. C.; Guest, T.; Funkhouser, M. A.; Salice, C. J. Transgenerational cross-tolerance to stress: parental exposure to predators increases offspring contaminant tolerance. Ecotoxicology 2013, 22 (5), 854–861 DOI: 10.1007/s10646-013-1056-y. Reza Rahavi, M.; Migicovsky, Z. D.; Titov, V.; Kovalchuk, I. Transgenerational adaptation to heavy metal salts in Arabidopsis. Plant Genet. Genomics 2011, 2, 91 DOI: 10.3389/fpls.2011.00091. Kou, H. P.; Li, Y.; Song, X. X.; Ou, X. F.; Xing, S. C.; Ma, J.; Von Wettstein, D.; Liu, B. Heritable alteration in DNA methylation induced by nitrogen-deficiency stress accompanies enhanced tolerance by progenies to the stress in rice (Oryza sativa L.). J. Plant Physiol. 2011, 168 (14), 1685–1693 DOI: 10.1016/j.jplph.2011.03.017. Ou, X.; Zhang, Y.; Xu, C.; Lin, X.; Zang, Q.; Zhuang, T.; Jiang, L.; Wettstein, D. von; Liu, B. Transgenerational Inheritance of Modified DNA Methylation Patterns and Enhanced Tolerance Induced by Heavy Metal Stress in Rice ( Oryza sativa L.). PLOS ONE 2012, 7 (9), e41143 DOI: 10.1371/journal.pone.0041143. Roemer, I.; Reik, W.; Dean, W.; Klose, J. Epigenetic inheritance in the mouse. Curr. Biol. 1997, 7 (4), 277–280 DOI: 10.1016/S0960-9822(06)00124-2. Morgan, H. D.; Sutherland, H. G. E.; Martin, D. I. K.; Whitelaw, E. Epigenetic inheritance at the agouti locus in the mouse. Nat. Genet. 1999, 23 (3), 314–318 DOI: 10.1038/15490. Anway, M. D.; Leathers, C.; Skinner, M. K. Endocrine Disruptor Vinclozolin Induced Epigenetic Transgenerational Adult-Onset Disease. Endocrinology 2006, 147 (12). Anway, M. D.; Memon, M. A.; Uzumcu, M.; Skinner, M. K. Transgenerational Effect of the Endocrine Disruptor Vinclozolin on Male Spermatogenesis. J. Androl. 2006, 27 (6), 868–879 DOI: 10.2164/jandrol.106.000349. Anway, M. D.; Skinner, M. K. Epigenetic Transgenerational Actions of Endocrine Disruptors. Endocrinology 2006, 147 (6), s43–s49 DOI: 10.1210/en.2005-1058. Anway, M. D.; Skinner, M. K. Transgenerational effects of the endocrine disruptor vinclozolin on the prostate transcriptome and adult onset disease. The Prostate 2008, 68 (5), 517–529 DOI: 10.1002/pros.20724.


Page 32 of 38

Page 33 of 38

665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715


(65)

(66)

(67)

(68)

(69)

(70)

(71)

(72)

(73)

(74)

(75)

(76)

(77)

(78)

(79)

(80)

Manikkam, M.; Guerrero-Bosagna, C.; Tracey, R.; Haque, M. M.; Skinner, M. K. Transgenerational Actions of Environmental Compounds on Reproductive Disease and Identification of Epigenetic Biomarkers of Ancestral Exposures. PLoS ONE 2012, 7 (2), e31901 DOI: 10.1371/journal.pone.0031901. Manikkam, M.; Guerrero-Bosagna, C.; Tracey, R.; Haque, M. M.; Skinner, M. K. Transgenerational Actions of Environmental Compounds on Reproductive Disease and Identification of Epigenetic Biomarkers of Ancestral Exposures. PLOS ONE 2012, 7 (2), e31901 DOI: 10.1371/journal.pone.0031901. Bruner-Tran, K. L.; Osteen, K. G. Developmental exposure to TCDD reduces fertility and negatively affects pregnancy outcomes across multiple generations. Reprod. Toxicol. 2011, 31 (3), 344–350. Bruner-Tran, K. L.; Resuehr, D.; Ding, T.; Lucas, J. A.; Osteen, K. G. The Role of Endocrine Disruptors in the Epigenetics of Reproductive Disease and Dysfunction: Potential Relevance to Humans. Curr. Obstet. Gynecol. Rep. 2012, 1 (3), 116–123 DOI: 10.1007/s13669-0120014-7. McCarrey, J. R.; Lehle, J. D.; Raju, S. S.; Wang, Y.; Nilsson, E. E.; Skinner, M. K. Tertiary Epimutations – A Novel Aspect of Epigenetic Transgenerational Inheritance Promoting Genome Instability. PLOS ONE 2016, 11 (12), e0168038 DOI: 10.1371/journal.pone.0168038. Murphey, P.; Yamazaki, Y.; McMahan, C. A.; Walter, C. A.; Yanagimachi, R.; McCarrey, J. R. Epigenetic regulation of genetic integrity is reprogrammed during cloning. Proc. Natl. Acad. Sci. 2009, 106 (12), 4731–4735 DOI: 10.1073/pnas.0900687106. Sved, J.; Bird, A. The expected equilibrium of the CpG dinucleotide in vertebrate genomes under a mutation model. Proc. Natl. Acad. Sci. 1990, 87 (12), 4692–4696 DOI: 10.1073/pnas.87.12.4692. Lutsenko, E.; Bhagwat, A. S. Principal causes of hot spots for cytosine to thymine mutations at sites of cytosine methylation in growing cells: A model, its experimental support and implications. Mutat. Res. Mutat. Res. 1999, 437 (1), 11–20 DOI: 10.1016/S13835742(99)00065-4. Collins, D. W.; Jukes, T. H. Rates of Transition and Transversion in Coding Sequences since the Human-Rodent Divergence. Genomics 1994, 20 (3), 386–396 DOI: 10.1006/geno.1994.1192. Dwan, K.; Altman, D. G.; Arnaiz, J. .; Bloom, J.; Chan, A.-W.; Cronin, E.; Decullier, E.; Easterbrook, P.; Elm, E. V.; Gamble, C.; et al. Systematic Review of the Empirical Evidence of Study Publication Bias and Outcome Reporting Bias. PLoS ONE 2008, 3 (8), e3081. Wang, Q.; Ebbs, S. D.; Chen, Y.; Ma, X. Trans-generational impact of cerium oxide nanoparticles on tomato plants. Metallomics 2013, 5 (6), 753–759 DOI: 10.1039/C3MT00033H. Yi, H.; Richards, E. J. Gene Duplication and Hypermutation of the Pathogen Resistance Gene SNC1 in the Arabidopsis bal Variant. Genetics 2009, 183 (4), 1227–1234 DOI: 10.1534/genetics.109.105569. Waterland, R. A.; Travisano, M.; Tahiliani, K. G. Diet-induced hypermethylation at agouti viable yellow is not inherited transgenerationally through the female. FASEB J. 2007, 21 (12), 3380–3385 DOI: 10.1096/fj.07-8229com. Cropley, J. E.; Suter, C. M.; Beckman, K. B.; Martin, D. I. K. Germ-line epigenetic modification of the murine Avy allele by nutritional supplementation. Proc. Natl. Acad. Sci. 2006, 103 (46), 17308–17312 DOI: 10.1073/pnas.0607090103. Pecinka, A.; Rosa, M.; Schikora, A.; Berlinger, M.; Hirt, H.; Luschnig, C.; Scheid, O. M. Transgenerational Stress Memory Is Not a General Response in Arabidopsis. PLOS ONE 2009, 4 (4), e5202 DOI: 10.1371/journal.pone.0005202. Molinier, J.; Ries, G.; Zipfel, C.; Hohn, B. Transgeneration memory of stress in plants. Nature 2006, 442 (7106), 1046–1049 DOI: 10.1038/nature05022.



716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765

(81)

(82)

(83) (84) (85)

(86)

(87)

(88)

(89)

(90) (91)

(92)

(93)

(94)

(95) (96) (97)

Basu, N.; Head, J.; Nam, D.-H.; Pilsner, J. R.; Carvan, M. J.; Chan, H. M.; Goetz, F. W.; Murphy, C. A.; Rouvinen-Watt, K.; Scheuhammer, A. M. Effects of methylmercury on epigenetic markers in three model species: Mink, chicken and yellow perch. Comp. Biochem. Physiol. Part C Toxicol. Pharmacol. 2013, 157 (3), 322–327 DOI: 10.1016/j.cbpc.2013.02.004. Burdge, G. C.; Lillycrop, K. A.; Jackson, A. A. Nutrition in early life, and risk of cancer and metabolic disease: alternative endings in an epigenetic tale? Br. J. Nutr. 2008, 101 (5), 619– 630 DOI: 10.1017/S0007114508145883. Jirtle, R. L.; Skinner, M. K. Environmental epigenomics and disease susceptibility. Nat. Rev. Genet. 2007, 8 (4), 253–262 DOI: 10.1038/nrg2045. Suter II, G. W. Ecological risk assessment; CRC press, 1992. Ankley, G. T.; Bennett, R. S.; Erickson, R. J.; Hoff, D. J.; Hornung, M. W.; Johnson, R. D.; Mount, D. R.; Nichols, J. W.; Russom, C. L.; Schmieder, P. K.; et al. Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment. Environ. Toxicol. Chem. 2010, 29 (3), 730–741 DOI: 10.1002/etc.34. van der Oost, R.; Beyer, J.; Vermeulen, N. P. E. Fish bioaccumulation and biomarkers in environmental risk assessment: a review. Environ. Toxicol. Pharmacol. 2003, 13 (2), 57–149 DOI: 10.1016/S1382-6689(02)00126-6. Kavlock, R. J.; Daston, G. P.; DeRosa, C.; Fenner-Crisp, P.; Gray, L. E.; Kaattari, S.; Lucier, G.; Luster, M.; Mac, M. J.; Maczka, C.; et al. Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the U.S. EPA-sponsored workshop. Environ. Health Perspect. 1996, 104 (Suppl 4), 715–740. Damalas, C. A.; Eleftherohorinos, I. G. Pesticide Exposure, Safety Issues, and Risk Assessment Indicators. Int. J. Environ. Res. Public. Health 2011, 8 (5), 1402–1419 DOI: 10.3390/ijerph8051402. US EPA, O. Technical Overview of Ecological Risk Assessment - Analysis Phase: Ecological Effects Characterization https://www.epa.gov/pesticide-science-and-assessing-pesticiderisks/technical-overview-ecological-risk-assessment-0 (accessed Jan 9, 2017). Suter, G. W.; Tsao, C. L. Toxicological Benchmarks for Screening Potential Contaminants of Concern for Effects on Aquatic Biota. Risk Assess. Programme US Dep. Energy 1996. Alyea, R. A.; Moore, N. P.; LeBaron, M. J.; Gollapudi, B. B.; Rasoulpour, R. J. Is the current product safety assessment paradigm protective for epigenetic mechanisms? J. Pharmacol. Toxicol. Methods 2012, 66 (3), 207–214. National Toxicology Program. NTP Toxicology and Carcinogenesis Studies of 1,3-Butadiene (CAS No. 106-99-0) in B6C3F1 Mice (Inhalation Studies). Natl. Toxicol. Program Tech. Rep. Ser. 1984, 288, 1–111. National Toxicology Program. NTP Toxicology and Carcinogenesis Studies of 1,3-Butadiene (CAS No. 106-99-0) in B6C3F1 Mice (Inhalation Studies). Natl. Toxicol. Program Tech. Rep. Ser. 1993, 434, 1–389. Koturbash, I.; Scherhag, A.; Sorrentino, J.; Sexton, K.; Bodnar, W.; Tryndyak, V.; Latendresse, J. R.; Swenberg, J. A.; Beland, F. A.; Pogribny, I. P.; et al. Epigenetic Alterations in Liver of C57BL/6J Mice after Short-Term Inhalational Exposure to 1,3-Butadiene. Environ. Health Perspect. 2011, 119 (5), 635–640. Wetterstrand, K. A. DNA Sequencing Costs: Data from the NHGRI Genome Sequencing Program (GSP) https://www.genome.gov/sequencingcostsdata (accessed Feb 21, 2017). Mardis, E. R. A decade/’s perspective on DNA sequencing technology. Nature 2011, 470 (7333), 198–203 DOI: 10.1038/nature09796. Broos, K.; Macdonald, L. M.; J. Warne, M. S.; Heemsbergen, D. A.; Barnes, M. B.; Bell, M.; McLaughlin, M. J. Limitations of soil microbial biomass carbon as an indicator of soil pollution in the field. Soil Biol. Biochem. 2007, 39 (10), 2693–2695 DOI: 10.1016/j.soilbio.2007.05.014.


Page 34 of 38

Page 35 of 38

766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788


(98) (99) (100) (101) (102)

(103) (104)

(105)

(106)

Warne, M. S. J.; van Dam, R. NOEC and LOEC Data Should No Longer Be Generated or Used. Australas. J. Ecotoxicol. 2008, 14 (1), 1. US EPA. Technical Support Document for Water Quality-Based Toxics Control; EPA 505/2-90001; US EPA (United States Environmental Protection Agency): Washington DC, USA., 1991. Hoekstra, J. a.; van Ewijk, P. h. Alternatives for the no-observed-effect level. Environ. Toxicol. Chem. 1993, 12 (1), 187–194 DOI: 10.1002/etc.5620120119. Moore, D. R. J.; Caux, P.-Y. Estimating low toxic effects. Environ. Toxicol. Chem. 1997, 16 (4), 794–801 DOI: 10.1002/etc.5620160425. Fox, D. R.; Landis, W. G. Don’t be fooled—A no-observed-effect concentration is no substitute for a poor concentration–response experiment. Environ. Toxicol. Chem. 2016, 35 (9), 2141–2148 DOI: 10.1002/etc.3459. Warne, M. S. J.; van Dam, R. NOEC and LOEC Data Should No Longer Be Generated or Used. Australas. J. Ecotoxicol. 2008, 14 (1), 1. Broos, K.; Macdonald, L. M.; J. Warne, M. S.; Heemsbergen, D. A.; Barnes, M. B.; Bell, M.; McLaughlin, M. J. Limitations of soil microbial biomass carbon as an indicator of soil pollution in the field. Soil Biol. Biochem. 2007, 39 (10), 2693–2695 DOI: 10.1016/j.soilbio.2007.05.014. Plautz, S. C.; Guest, T.; Funkhouser, M. A.; Salice, C. J. Transgenerational cross-tolerance to stress: parental exposure to predators increases offspring contaminant tolerance. Ecotoxicology 2013, 22 (5), 854–861 DOI: 10.1007/s10646-013-1056-y. Harris, C. A.; Scott, A. P.; Johnson, A. C.; Panter, G. H.; Sheahan, D.; Roberts, M.; Sumpter, J. P. Principles of Sound Ecotoxicology. Environ. Sci. Technol. 2014, 48 (6), 3100–3111 DOI: 10.1021/es4047507.

789


Environmental Science & Technology Page 36 of 38


Page 37 of 38




Figure 2. Schematic of robust experimental design, with lineages including multiple generations of exposed organisms, followed by multiple generations of non-exposed organisms. 218x257mm (300 x 300 DPI)


Page 38 of 38

Incorporating Transgenerational Epigenetic ... - ACS Publications

Recommend Documents