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Effects of elevated ammonia concentrations on survival, metabolic rates, and glutamine synthetase activity in the Antarctic pteropod mollusk limacina antarctica

Article in Polar Biology · July 2012 DOI: 10.1007/s00300-012-1158-7

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2

3 Effects of Elevated Ammonia Concentrations on Survival, Metabolic Rates and

4 Glutamine Synthetase Activity in the Antarctic Pteropod Mollusc

5 antarctica

6

7 Amy Maas1, 2, Brad A. Seibel1 and Patrick J. Walsh3

8

9 1 Department of Biological Sciences, University of Rhode Island, Kingston, RI 02881

10 2 Current address: Department of Biology, Woods Hole Oceanographic Institute, Woods

11 Hole, MA 02543

12 3Department of Biology, University of Ottawa, 30 Marie Curie, Ottawa, ON K1N 6N5

13 CANADA

14

15 Corresponding Author Contact Information:

16 P.J. Walsh

17 Dept. of Biology, University of Ottawa

18 30 Marie Curie

19 Ottawa, ON K1N 6N5 Canada

20 Email: [email protected]

21 Phone: 613-562-5800x6328

22 Fax: 613-562-5486 23

2 24 Abstract

25 Information on effects of elevated ammonia on invertebrates in general, and polar

26 Molluscs in particular, is scant. Questions of ammonia sensitivity are interesting for

27 several reasons, particularly since predicted global change scenarios include increases

28 in anthropogenic nitrogen and toxic ammonia. Furthermore, polar zooplankton species

29 are often rich in lipids, and authors have speculated that there is a linkage between

30 elevated levels of lipids/trimethylamine oxide (TMAO) and enhanced ammonia

31 tolerance. In the present study, we sought to examine ammonia tolerance and effects of

32 elevated exogenous ammonia on several key aspects of the physiology and

33 biochemistry of the pteropod mollusc, Clione antarctica limacina. We determined that the

34 96-hour LC50 value for this species is 7.465 mM total ammonia (Upper 95% CL = 8.498

35 mM and Lower 95% CL = 6.557 mM), or 0.51 mg/L as unionized ammonia (NH3) (at a

36 pH of 7.756). While comparative data for molluscs are limited, this value is at the lower

37 end of reported values for other species. When the effects of lower ammonia

38 concentrations (0.07 mM total ammonia) on oxygen consumption and ammonia

39 excretion rates were examined, no effects were noted. However, total ammonia levels as

40 low as 0.1 mM (or 0.007 mg/L NH3) elevated the activity of the ammonia detoxification

41 enzyme, glutamine synthetase, by approximately 1.5 fold. The values for LC50 and

42 observable effects on biochemistry for this one species are very close to permissible

43 marine ammonia concentrations, indicating a need to more broadly determine the

44 sensitivity of zooplankton to potential elevated ammonia levels in polar regions.

3 45 Key Words: global change, nitrogen pollution, Antarctica, pelagic molluscs, O:N ratio,

46 ammonia LC50 values, TMAO

47

4 48 Introduction

49 One of the more toxic forms of nitrogen to is ammonia. At least in

50 vertebrates, the mode of action of ammonia as a toxin is primarily through its effects on

51 the central nervous system (CNS). Ammonia CNS toxicity has been relatively well

52 documented in the medical literature (in association with the human disease hepatic

53 encephalopathy), and increases in plasma ammonia levels due to liver dysfunction

54 appear to affect glutamate receptors on neurons, as well as to cause swelling in

55 associated astrocytes (the nutritive and support cells of the vertebrate CNS) (Cooper

56 and Plum 1987; Butterworth 2001). The literature on ammonia toxicity in fish species is

57 smaller but growing, and so far indicates that, although overall mechanisms of toxicity

58 are similar to mammals, there are some important differences, notably: (1) astrocyte

59 swelling seems to be less pronounced in the brains of marine fish; (2) there are wide

60 species differences in the susceptibility of fish to ammonia, with some species showing

61 orders of magnitude greater ability to survive ammonia toxicity than can mammals

62 (Walsh et al. 2007).

63 In contrast, much less is known about mechanisms of ammonia toxicity in

64 marine invertebrates in general and polar invertebrates and molluscs in particular. Data

65 exist on ammonia-induced mortality (e.g., standard Lethal Concentration 50, or LC50

66 values, the concentration that leads to mortality in 50% of a test population after a

67 standard time) for numerous freshwater and some marine invertebrate species,

68 including molluscs (e.g., Boardman et al 2004; USEPA 1989). Although toxic effects

69 leading to mortality are presumed to be primarily neuronal as in vertebrates, very little

5 70 is known. Furthermore, species considered to date have primarily been standard EPA

71 test indicator organisms, or organisms in inland waters that are predicted to be at risk

72 for exposure via close proximity to point sources (examined as part of mandated

73 environmental impact studies). With respect to polar invertebrates, we are not aware of

74 any studies examining ammonia-induced mortality or effects of ammonia on routine

75 physiological processes. In this regard, Seibel and Walsh (2002) previously reported that

76 Clione antarctica has high levels of trimethylamine oxide (TMAO) which is known to

77 counteract ammonia toxicity in some species (Kloiber et al. 1988; Minana et al. 1996).

78 This observation leads to a hypothesis that many polar zooplankton may show

79 enhanced ammonia tolerance because they have high lipid content for over-winter

80 survival and lipid formation is linked to TMAO levels (Seibel and Walsh 2002). It also

81 suggests that ammonia tolerance will depend to some extent on diet.

82 With this scant background in mind, in the present study we examined the

83 effects of ammonia on mortality, routine physiological processes (oxygen consumption

84 and nitrogen excretion), and the activity of an enzyme involved in ammonia

85 detoxification (glutamine synthetase) in the Antarctic pteropod, Clione limacina antarctica

86 in studies complementary to examination of the effects of acidification (Seibel et al.

87 submitted).

6 88 Materials and Methods

89 Collection, Maintenance and Ammonia Exposure of Animals

90 In January 2008, specimens of Clione limacina antarctica (Smith 1902) were collected

91 several meters offshore at Cape Royds (77° 34’ S, 166° 11’ E) on Ross Island near

92 McMurdo Station, Antarctica. Collectors wading in waters of approximately 1m depth

93 dipped animals out of the water using 1L beakers attached to 1 m poles. Organisms

94 were then gently poured into 500mL Nalgene bottles (to a density of 10-12 organisms

95 per bottle), placed in insulated coolers and returned to McMurdo Station by helicopter

96 within 6h of capture. Bottles were then placed in a cold room to maintain temperature

97 at -1.8 oC (also the temperature of all subsequent tests unless noted). Organisms

98 (ranging in body mass from 0.0429 to 0.3616 grams) were held in captivity without food

99 for a period of 24 hours to allow for gut clearance.

100 After initial range finder tests, C. limacina antarctica were exposed to ammonium

101 chloride concentrations of 0, 0.1, 0.5, 1.0, 2.5, 5, 7.5 and 10 mM by adding small volumes

102 of a 1M stock of ammonium chloride to 1L seawater in glass beakers. Seven C. limacina

103 antarctica were placed in each beaker/concentration (only one beaker was used for each

104 concentration) at the start of the experiment, and whether the animals were swimming

105 was monitored every 12h for 96h. Water was changed every 24h. If an organism ceased

106 a normal swimming pattern, it was gently prodded with a jet of seawater from a

107 Pasteur pipette to elicit a response. If no response was noted, revival was attempted in

108 seawater with no ammonium chloride. If no revival was evident, mortality was

109 recorded. At the end of 96h, only surviving animals were removed and briefly blotted

7 110 with a tissue, placed in individual pre-weighed cryovials, reweighed to obtain

111 mass, snap frozen in liquid nitrogen, stored at -80oC for several months (including

112 several days on dry ice in transit to Ottawa) prior to analysis of glutamine synthetase

113 activity (see below). Mortality data were subjected to a Trimmed Spearman-Karber

114 analysis, with trim level set at zero, using CETIS software in order to calculate a 96h

115 LC50 value (USEPA 2002). Software and documentation are available for download at

116 http://www.epa.gov/nerleerd/stat2.htm. Because most environmental regulatory

117 agencies set water quality criteria in mg/L of unionized ammonia (NH3), in several

118 places below we transform concentrations of total ammonia (mM) to these values.

119 Conversion of molar values to gram/volume values used the factor of 17.031

120 grams/mole. Calculation of fraction as NH3 used a rearrangement of the Henderson-

121 Hasselbalch equation with a pKa of 10.1483 (USEPA 1998; Bell et al 2007) and the

122 measured pH of seawater in our tests (7.756).

123

124 Measurement of Oxygen Consumption and Ammonia Excretion Rates.

125 Following results of ammonia toxicity testing, we sought to examine the effects of a

126 relatively modest increase in ammonia concentration on two physiological variables.

127 We chose 70 µM total ammonia as an exposure concentration that would clearly be well

128 below lethal limits (some 1/100th the LC50, see ‘Results’ and only 3.5 to 15 fold above

129 current background levels of 5-20 µM in seawater), but one which has shown biological

130 effects in fish species in simulated global change studies (Linton et al 1998). For these

131 tests we randomly selected C. limacina antarctica that had been held in captivity between

8 132 24 and 36 hours and placed them in air-tight glass syringes with a known volume of 0.2

133 micron-filtered and well aerated seawater. Ammonium chloride was added to half of

134 the trials to achieve a 70 µM total ammonia concentration. A blank syringe containing

135 no organism was set up for every 1-2 experimental syringes and allowed to incubate

136 simultaneously to monitor background (presumably microbial/bacterial) respiration.

137 After a 20-28 hour period we measured the O2 concentration in the glass syringes by

138 drawing a water sample using a Hamilton gas tight syringe (500 μL) and then injecting

139 the sample through a water-jacketed Clarke-type microcathode oxygen electrode

140 (Strathkelvin Instruments, North Lanarkshire, United Kingdom; Marsh and Manahan

141 1999). We then removed the animals from their syringe, gently blotted them dry and

142 weighed them on an analytical balance. This method has been used successfully to

143 determine effects of body mass, feeding, temperature and carbon dioxide on pteropod

144 metabolism (Seibel and Dierssen 2003; Seibel et al 2007; Maas et al 2011; Seibel et al

145 submitted).

146 At the termination of the respiration measurements, a water sample was

147 analyzed for ammonia concentration by the phenol-hypochlorite method (Ivancic and

148 Degobbis 1984). Notably, in preliminary experiments, no urea excretion was detected

149 using a standard colorimetric method (Rahmatullah and Boyd 1980).

150

151 Measurement of Glutamine Synthetase Activity.

152 Glutamine Synthetase (GS; L-glutamate:ammomnia ligase (ADP forming), E.C. 6.3.1.2)

153 activity was measured using the glutamyl transferase assay as previously applied to

9 154 fish tissues (e.g., Walsh 1996). Individual pteropods were homogenized on ice in 5

155 volumes per weight in 50 mM Hepes, pH 7.5 using a Fisher Powergen 125 with a 5 mm

156 tip, and then centrifuged at 16,100 x g for 5 min at 4oC in an Eppendorf 5415D

157 microcentrifuge. An aliquot of 50 µl of the supernatant was added to a 1.5 ml

158 microcentrifuge tube with 1 ml of a reaction cocktail containing (in mM): glutamine

159 (60), hydroxylamine (15), ADP (0.4), KH2AsO4 (20), MnCl2 (3), Hepes (50) (pH 6.7), and

160 the reaction proceeded for 20 min at 20oC. The reaction was terminated and color

161 developed by addition of 0.3 ml Ferric Chloride reagent (containing equal parts 50%

162 HCl : 24% Trichloroacetic acid : 10% FeCl3 in 0.2 N HCl). The reaction mixture was

163 then centrifuged and 200 µL of the supernatant was read for absorbance at 540 nm in a

164 Molecular Devices Spertra Max Plus microtitre plate spectrophotometer. A time zero

165 blank absorbance (Ferric Chloride reagent added before addition of supernatant) was

166 subtracted from the measured sample absorbance and then the concentration of product

167 was calculated from a standard curve (absorbance vs. concentration) of gamma

168 glutamyl monohydroxamate reacted with the Ferric Chloride reagent. Using

169 micromoles of product, time of reaction, body mass, and homogenization dilution

170 factors, enzyme activities were calculated in µmols Substrate  Product min-1 g wet

171 mass-1.

172

173 Results

174 The 96h LC50 value for C. limacina antarctica exposed to ammonium chloride was 7.465

175 mM (Upper 95% CL = 8.498 mM and Lower 95% CL = 6.557 mM). Since most

10 176 comparisons of ammonia toxicity data are compared in the literature as mg/L

177 unionized ammonia available (NH3), the above 96h LC50 value converts to 0.51 mg/L

178 NH3. Notably the mortality curve yielding this value was rather steep with no deaths

179 occurring up to 5 mM, 3 out of 7 animals dying at 7.5 mM, and all animals dying at 10

180 mM.

181 Oxygen consumption and nitrogen excretion rates fit well to standard mass-

182 scaling equations (Table 1), and there were no significant effects of ammonia on either

183 rate or on the O:N ratio (Figure 1).

184 The sub-lethal exposure concentrations used in the mortality experiment had

185 significant effects on the activity of GS (Figure 2) with a pronounced 1.5-fold increase in

186 GS activity at even the lowest concentration employed (0.1 mM) and then declining

187 activities at higher concentrations until there was no significant difference from controls

188 (nominal 0 mM).

189

190

11 191 Discussion

192 Studies of ammonia toxicity effects on marine organisms are rather scant, certainly in

193 comparison to the body of information for freshwater organisms (Boardman et al. 2004;

194 USEPA 1989; 1998), and this is understandable since most significant ammonia

195 pollution point sources are freshwater or estuarine. From the data on marine

196 invertebrates available, marine molluscs can be among the more ammonia tolerant

197 invertebrate species, showing for example 96h LC50 values in quahog clams (Mercenaria

198 mercenaria) of up to 36.3 mg/L NH3 (Boardman et al 2004). Thus the 96h LC50 value we

199 obtained for C. limacina antarctica at 0.51 mg/L NH3 is considerably lower and indicates

200 a high sensitivity to ammonia (see below). Noting this low LC50 value, it does not

201 appear that high levels of lipids and TMAO confer ammonia tolerance to at least this

202 species of polar zooplankton as initially hypothesized.

203 The measured O:N ratios and underlying rates were in line with previously

204 reported data for this species (Maas et al 2011), and more generally indicate that

205 metabolism in C. limacina antarctica is being fueled exclusively by proteins/amino acids;

206 Mayzaud and Conover (1988) point out that O:N ratios of 3 to 16 are indicative of pure

207 protein catabolism in zooplankton. At more realistic concentrations of ammonia, we

208 observed no effects on the processes of oxygen consumption and nitrogen excretion.

209 The lack of effect on ammonia excretion rates is somewhat surprising in light of what is

210 known about mechanisms of ammonia excretion in aquatic organisms in general. At

211 least in fish, ammonia excretion is now known to take place largely through ammonia

212 channels in gill/respiratory surfaces, the so-called Rhesus (or Rh) glycoproteins

12 213 (Weihrauch et al 2009; Wright and Wood 2009) and is largely a facilitated diffusion

214 process determined by the numbers/density of transporters and the partial pressure

215 gradients of dissolved ammonia gas from the internal to seawater compartments.

216 Raising external ammonia concentrations even slightly often causes fish to show a net

217 uptake of ammonia from the environment, albeit usually briefly (e.g., for up to 24h),

218 until an outwardly directed gradient is re-established and ammonia excretion can

219 resume (see reviews by Weihrauch et al 2009; Wright and Wood 2009). Excretion

220 pathways in invertebrates, while appearing also to rely on Rh glycoproteins, may be

221 more complicated, with possible mechanisms in crustaceans involving initial

222 sequestration of ammonia in gill vesicles (Weihrauch et al 2009). The fact that ammonia

223 excretion could continue without change at the elevated test concentrations used in the

224 present study (Figure 1) perhaps reflects that these potential specialized mechanisms

225 exist in molluscs, or that the 24h measurement period was sufficient for gradients and

226 total excretion rates to be reestablished.

227 In this study, we also wished to examine a biochemical process or endpoint that

228 might show greater sensitivity to low concentrations of environmental ammonia,

229 namely activity of the ammonia detoxification/metabolism enzyme glutamine

230 synthetase. Even the lowest test concentration used, 0.1 mM total ammonia or 0.007

231 mg/L NH3 led to a significant increase in the activity of this enzyme in C. limacina

232 antarctica (Fig. 2). Several environmental regulatory agencies have set water quality

233 levels very close to both this concentration and the LC50 value we measured. For

234 example, the US EPA has set Criteria Continuous Concentration water quality levels for

13 235 ammonia in seawater at 0.019-0.030 mg/L NH3 (at 0oC, 30 ppt and representative

236 seawater pHs of 7.8 to 8.0) (USEPA 1989). Similarly, the UK Environment Agency has

237 proposed a short-term (96h) PNEC (predicted no effect concentration) for ammonia in

238 seawater under similar conditions at 0.0057 mg/L NH3 (UK Environment Agency 2007).

239 Again, data on GS activation by elevated ammonia in marine molluscs have not been

240 previously reported, so it is difficult to compare our data to other species, and to know

241 whether the elevation of GS activity by low ammonia concentrations is sufficient to

242 protect the organism from neuronal/behavioral impairment at sub-lethal

243 concentrations. Clione limacina (the northern congener) has been used extensively as a

244 model for the neural basis of behavior and these studies indicate that elements of the

245 feeding system of this species are activated by the neurotransmitter gamma amino

246 butyric acid (GABA) (Arshavsky et al 1993). In mammalian models, some of the

247 symptoms of hepatic encephalopathy are believed to be the result of imbalances

248 between GABA- vs. glutamate-mediated neuronal pathways (Cooper and Plum 1987;

249 Butterworth 2001). In this regard, it would be instructive to examine effects of modest

250 ammonia concentrations on feeding behavior in Clione sp.

251 Interestingly, while anthropogenic ammonia point sources in Antarctic waters

252 are certainly rare, potential naturally occurring sources of ammonia might exist in

253 runoff from the substantial guano mounds associated with penguin rookeries. It would

254 be informative to obtain information on nearshore ammonia concentrations adjacent to

255 these rookeries. Furthermore, in examining the potential effects of global change

256 scenarios on polar marine organisms, investigators have largely focused on increased

14 257 temperature and carbon dioxide (and resulting acidification) as important variables

258 (Orr et al 2005; Trathan et al 2007; McNeil and Matear 2008; Moline et al 2008).

259 However, nitrogen loading (notably as potentially toxic ammonia and nitrite) in the

260 marine environment is also expected to increase, primarily due to anthropogenic

261 sources such as fertilizers and sewerage (Vitousek et al 2009), all with potential

262 disruptions to the natural nitrogen cycle (Canfield et al 2010). While most polar regions

263 are currently relatively shielded from direct anthropogenic point sources of nitrogenous

264 pollution, eventually, any increase in background oceanic levels could potentially reach

265 polar oceans and species, and therefore it would be prudent to obtain additional

266 information on the effects of toxic nitrogenous molecules on polar organisms. One

267 study has shown that GS mRNA transcript levels in Crassostrea virginica are elevated by

268 pesticides, hydrocarbons and hypoxia (Tanguy et al 2005). Our enzymatic data indicate

269 that GS could potentially be used as one important bioindicator of environmental

270 degradation/exposure in polar mollusc species. Certainly, the high sensitivity of this

271 one species to ammonia toxicity warrants additional study of the effects of elevated

272 nitrogen on the physiology of polar zooplankton.

273

274 Acknowledgements

275 This research was supported by a US National Science Foundation grant (OPP#

276 0538479) to BAS and VJ Fabry, and by a Discovery Grant from the Natural Sciences and

277 Engineering Council of Canada to PJW, who is also supported by the Canada Research

278 Chair Program. The authors wish to thank Drs. Martin Grosell and Andrew Esbaugh of

15 279 the University of Miami Rosenstiel School for advice on calculation of LC50 values.

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363

364

20 365 Fig 1: Effect of ammonia on oxygen consumption and nitrogen excretion rates of Clione

366 limacina antarctica. There is no statistical difference between the oxygen consumption

367 rate (A, p = 0.77), ammonia excretion rate (B, p = 0.25) and O:N ratio (C, p = 0.50) for

368 organisms exposed to nominal 0 µM ammonia (white circles) and 70 µM ammonia

369 (black circles).

370

371

21 372 Fig. 2: Effect of 96h exposure to variable levels of ammonium chloride on Glutamine

373 Synthetase Activity (µmols S  P min-1 g-1) for Clione limacina antarctica. Values are

374 means + 1 S.E.M. and N = 7 for all treatments except 0 mM where N = 14. Total

375 ammonia concentration has a significant effect on the Glutamine Synthetase Activity

376 (ANOVA, F6,49 = 3.1, p = 0.011) and bars with common letters are not significantly

377 different.

378 379 380 381

22 382 Table 1: Mean oxygen consumption and ammonia excretion rates and O:N ratio of Clione

383 limacina antarctica exposed to 0 µM vs. 70 µM ammonia. P values calculated using a

384 Welch’s t-test. Regression constants are in the form of Y=aXb where oxygen consumption or

385 ammonia excretion rate = Y and organismal mass = X.

386

O2 NH3 O:N

0 uM 70 uM 0 uM 70 uM 0 uM 70 uM

Mean 1.31 1.28 0.42 0.33 8.18 9.25

Std Error 0.09 0.08 0.06 0.04 1.17 1.07 p 0.77 0.25 0.5

a 0.54 -0.50 0.22 0.22

b 0.71 -0.30 -0.28 -0.14 R 0.83 0.64 0.31 0.11

387

23