Female immune system is protected from effects of prenatal exposure to mercury

Kayla L. Penta; Diego Altomare; Devon L. Shirley; Jennifer F. Nyland; Kayla L. Penta; Diego Altomare; Devon L. Shirley; Jennifer F. Nyland

doi:10.3934/environsci.2015.3.448

AIMS Environmental Science

2015, Volume 2, Issue 3: 448-463. doi: 10.3934/environsci.2015.3.448

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Female immune system is protected from effects of prenatal exposure to mercury

1.
Department of Pathology, Microbiology, and Immunology University of South Carolina, School of Medicine, Columbia, South Carolina, USA;
2.
Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA

Received: 29 October 2014 Accepted: 11 May 2015 Published: 08 June 2015

Mercury is a ubiquitous environmental toxicant which bioaccumulates and has many biological effects, including detrimental effects on the nervous and immune systems. Because mercury can cross the placenta and concentrates in the fetal compartment, the developing fetus is particularly vulnerable. We hypothesize that developmental exposure to mercury will cause immunological changes, leading to an increased susceptibility to, or exacerbation of, immune disorders later in life. To better understand these changes, we exposed pregnant female mice to low doses of mercury for a short duration and examined the genetic effects related to immune function in the adult offspring. Pregnant BALB/c mice were exposed to mercury (200 µg/kg HgCl₂ in PBS by subcutaneous injection) or vehicle control every other day from gestation day 5 to 15. Offspring remained with the dam until weaning and were euthanized at 8 weeks of age with no further exposures to mercury. Splenic RNA was isolated and gene expression changes examined by microarray in a non-random subset of samples and changes confirmed by quantitative PCR. Epigenetic changes were also examined in terms of miRNA levels in the spleen. Although male and female offspring were exposed to mercury in the same in utero environment, the effects on expression of immune-related genes and immune-regulatory epigenetic signals were different dependent upon the sex of the offspring with males, but not females, displaying up-regulation at least two-fold of arginase, interferon-γ, STAT1, vitronectin, and TNFSF18. Epigenetic changes in miRNA levels were differentially expressed in males and females with in utero mercury exposure; miR-191-5p was decreased in males, while miR-1188-3p was increased in females. These gene expression and gene regulation changes modulate the baseline immune response and may impact risks for autoimmunity later in life.
- prenatal exposure,
- mercury,
- epigenetic,
- miRNA,
- arginase,
- vitronectin
Citation: Kayla L. Penta, Diego Altomare, Devon L. Shirley, Jennifer F. Nyland. Female immune system is protected from effects of prenatal exposure to mercury[J]. AIMS Environmental Science, 2015, 2(3): 448-463. doi: 10.3934/environsci.2015.3.448

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Abstract

Mercury is a ubiquitous environmental toxicant which bioaccumulates and has many biological effects, including detrimental effects on the nervous and immune systems. Because mercury can cross the placenta and concentrates in the fetal compartment, the developing fetus is particularly vulnerable. We hypothesize that developmental exposure to mercury will cause immunological changes, leading to an increased susceptibility to, or exacerbation of, immune disorders later in life. To better understand these changes, we exposed pregnant female mice to low doses of mercury for a short duration and examined the genetic effects related to immune function in the adult offspring. Pregnant BALB/c mice were exposed to mercury (200 µg/kg HgCl₂ in PBS by subcutaneous injection) or vehicle control every other day from gestation day 5 to 15. Offspring remained with the dam until weaning and were euthanized at 8 weeks of age with no further exposures to mercury. Splenic RNA was isolated and gene expression changes examined by microarray in a non-random subset of samples and changes confirmed by quantitative PCR. Epigenetic changes were also examined in terms of miRNA levels in the spleen. Although male and female offspring were exposed to mercury in the same in utero environment, the effects on expression of immune-related genes and immune-regulatory epigenetic signals were different dependent upon the sex of the offspring with males, but not females, displaying up-regulation at least two-fold of arginase, interferon-γ, STAT1, vitronectin, and TNFSF18. Epigenetic changes in miRNA levels were differentially expressed in males and females with in utero mercury exposure; miR-191-5p was decreased in males, while miR-1188-3p was increased in females. These gene expression and gene regulation changes modulate the baseline immune response and may impact risks for autoimmunity later in life.

References

[1]	NRC (2000) Toxicological effects of methyl mercury. Washington, DC: National Academy Press.
[2]	Clarkson TW, Magos L, Myers GJ (2003) The toxicology of mercury--current exposures and clinical manifestations. N Engl J Med 349: 1731-1737. doi: 10.1056/NEJMra022471
[3]	Mergler D, Anderson HA, Chan LH, et al. (2007) Methylmercury exposure and health effects in humans: a worldwide concern. Ambio 36: 3-11. doi: 10.1579/0044-7447(2007)36[3:MEAHEI]2.0.CO;2
[4]	Langworth S, Elinder CG, Sundquist KG, et al. (1992) Renal and immunological effects of occupational exposure to inorganic mercury. Br J Ind Med 49: 394-401.
[5]	Grandjean P, White RF, Nielsen A, et al. (1999) Methylmercury neurotoxicity in Amazonian children downstream from gold mining. Environ Health Perspect 107: 587-591. doi: 10.1289/ehp.99107587
[6]	Grandjean P, Weihe P, White RF, et al. (1998) Cognitive performance of children prenatally exposed to "safe" levels of methylmercury. Environ Res 77: 165-172. doi: 10.1006/enrs.1997.3804
[7]	Myers GJ, Davidson PW, Cox C, et al. (1995) Neurodevelopmental outcomes of Seychellois children sixty-six months after in utero exposure to methylmercury from a maternal fish diet: pilot study. Neurotoxicology 16: 639-652.
[8]	Zahir F, Rizwi SJ, Haq SK, et al. (2005) Low dose mercury toxicity and human health. Environ Toxicol Pharmacol 20: 351-360. doi: 10.1016/j.etap.2005.03.007
[9]	Mahaffey KR, Clickner RP, Bodurow CC (2004) Blood organic mercury and dietary mercury intake: national health and nutrition examination survey, 1999 and 2000. Environ Health Perspect 112: 562-570.
[10]	Buchanan S, Anglen J, Turyk M (2015) Methyl mercury exposure in populations at risk: Analysis of NHANES 2011-2012. Environ Res 140: 56-64. doi: 10.1016/j.envres.2015.03.005
[11]	Gardner RM, Nyland JF, Evans SL, et al. (2009) Mercury induces an unopposed inflammatory response in human peripheral blood mononuclear cells in vitro. Environ Health Perspect 117: 1932-1938. doi: 10.1289/ehp.0900855
[12]	Gardner RM, Nyland JF, Silbergeld EK (2010) Differential immunotoxic effects of inorganic and organic mercury species in vitro. Toxicology Letters 198: 182-190. doi: 10.1016/j.toxlet.2010.06.015
[13]	Gardner RM, Nyland JF, Silva IA, et al. (2010) Mercury exposure, serum antinuclear/antinucleolar antibodies, and serum cytokine levels in mining populations in Amazonian Brazil: a cross-sectional study. Environ Res 110: 345-354. doi: 10.1016/j.envres.2010.02.001
[14]	Nyland JF, Fillion M, Barbosa Jr F, et al. (2011) Biomarkers of methyl mercury exposure immunotoxicity among fish consumers in Amazonian Brazil. Environ Health Perspect 119: 1733-1738. doi: 10.1289/ehp.1103741
[15]	Nyland JF, Fairweather D, Shirley DL, et al. (2012) Low-dose inorganic mercury increases severity and frequency of chronic coxsackievirus-induced autoimmune myocarditis in mice. Toxicol Sci 125: 134-143. doi: 10.1093/toxsci/kfr264
[16]	Penta KL, Fairweather D, Shirley DL, et al. (2014) Low dose inorganic mercury heightens early innate response to coxsackievirus infection in female mice. Inflammation Res 64: 31-40.
[17]	Harris HH, Pickering IJ, George GN (2003) The chemical form of mercury in fish. Science 301: 1203. doi: 10.1126/science.1085941
[18]	Silva IA, El Nabawi M, Hoover D, et al. (2005) Prenatal HgCl2 exposure in BALB/c mice: gender-specific effects on the ontogeny of the immune system. Dev Comp Immunol 29: 171-183. doi: 10.1016/j.dci.2004.05.008
[19]	Toomey CB, Cauvi DM, Hamel JC, et al. (2014) Cathepsin B regulates the appearance and severity of mercury-induced inflammation and autoimmunity. Toxicol Sci 142: 339-349. doi: 10.1093/toxsci/kfu189
[20]	Zhang Y, Bolivar VJ, Lawrence DA (2013) Maternal exposure to mercury chloride during pregnancy and lactation affects the immunity and social behavior of offspring. Toxicol Sci 133: 101-111. doi: 10.1093/toxsci/kft023
[21]	Ekstrand J, Nielsen JB, Havarinasab S, et al. (2010) Mercury toxicokinetics--dependency on strain and gender. Toxicol Appl Pharmacol 243: 283-291. doi: 10.1016/j.taap.2009.08.026
[22]	Clarkson TW (1997) The toxicology of mercury. Crit Rev Clin Lab Sci 34: 369-403. doi: 10.3109/10408369708998098
[23]	Thuvander A, Sundberg J, Oskarsson A (1996) Immunomodulating effects after perinatal exposure to methylmercury in mice. Toxicology 114: 163-175. doi: 10.1016/S0300-483X(96)03486-5
[24]	Virtanen JK, Rissanen TH, Voutilainen S, et al. (2007) Mercury as a risk factor for cardiovascular diseases. Journal of Nutritional Biochemistry 18: 75-85. doi: 10.1016/j.jnutbio.2006.05.001
[25]	Nielsen JB, Hultman P (2002) Mercury-induced autoimmunity in mice. Environ Health Perspect 110 Suppl 5: 877-881.
[26]	Pollard KM, Pearson DL, Hultman P, et al. (2001) Xenobiotic acceleration of idiopathic systemic autoimmunity in lupus- prone bxsb mice. Environ Health Perspect 109: 27-33. doi: 10.1289/ehp.01109s127
[27]	Martinez FO, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 6: 13.
[28]	Mantovani A, Sica A, Sozzani S, et al. (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25: 677-686. doi: 10.1016/j.it.2004.09.015
[29]	Chattopadhyay K, Ramagopal UA, Brenowitz M, et al. (2008) Evolution of GITRL immune function: murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily. Proc Natl Acad Sci U S A 105: 635-640. doi: 10.1073/pnas.0710529105
[30]	Zhou Z, Tone Y, Song X, et al. (2008) Structural basis for ligand-mediated mouse GITR activation. Proc Natl Acad Sci U S A 105: 641-645. doi: 10.1073/pnas.0711206105
[31]	Nocentini G, Ronchetti S, Cuzzocrea S, et al. (2007) GITR/GITRL: more than an effector T cell co-stimulatory system. Eur J Immunol 37: 1165-1169. doi: 10.1002/eji.200636933
[32]	Leavesley DI, Kashyap AS, Croll T, et al. (2013) Vitronectin--master controller or micromanager? IUBMB Life 65: 807-818.
[33]	Seiffert D, Geisterfer M, Gauldie J, et al. (1995) IL-6 stimulates vitronectin gene expression in vivo. J Immunol 155: 3180-3185.
[34]	Villanueva MBG, Koizumi S, Jonai H (2000) Cytokine production by human peripheral blood mononuclear cells after exposure to heavy metals. Journal of Health Science 46: 358-362. doi: 10.1248/jhs.46.358
[35]	Preissner KT (1991) Structure and biological role of vitronectin. Annu Rev Cell Biol 7: 275-310. doi: 10.1146/annurev.cb.07.110191.001423
[36]	Hezova R, Slaby O, Faltejskova P, et al. (2010) microRNA-342, microRNA-191 and microRNA-510 are differentially expressed in T regulatory cells of type 1 diabetic patients. Cell Immunol 260: 70-74. doi: 10.1016/j.cellimm.2009.10.012
[37]	Moore KW, de Waal Malefyt R, Coffman RL, et al. (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19: 683-765. doi: 10.1146/annurev.immunol.19.1.683
[38]	Saraiva M, O'Garra A (2010) The regulation of IL-10 production by immune cells. Nat Rev Immunol 10: 170-181. doi: 10.1038/nri2711

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