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«Effects of Periconception Cadmium and Mercury Co-Administration to Mice on Indices of Chronic Disease in Male Offspring at Maturity Cagri Camsari, ...»

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Effects of Periconception Cadmium and Mercury

Co-Administration to Mice on Indices of Chronic

Disease in Male Offspring at Maturity

Cagri Camsari, Joseph K. Folger, Devin McGee,

Steven J. Bursian, Hongbing Wang, Jason G. Knott,

and George W. Smith

http://dx.doi.org/10.1289/EHP481 Received: 9 May 2016 Revised: 17 October 2016 Accepted: 18 October 2016 Published: 4 November 2016 Note to readers with disabilities: EHP will provide a 508-conformant version of this article upon final publication. If you require a 508-conformant version before then, please contact ehponline@niehs.nih.gov. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

Environ Health Perspect DOI: 10.1289/EHP481 Advance Publication: Not Copyedited Effects of Periconception Cadmium and Mercury Co- Administration to Mice on Indices of Chronic Disease in Male Offspring at Maturity Cagri Camsari1,3, Joseph K. Folger1,3, Devin McGee1,3, Steven J. Bursian3, Hongbing Wang4,5, Jason G. Knott2,3, and George W. Smith1,3 1 Laboratory of Mammalian Reproductive Biology and Genomics, Michigan State University, East Lansing, Michigan 48824.

2 Developmental Epigenetics Laboratory, Michigan State University, East Lansing, Michigan 48824.

3 Department of Animal Science, Michigan State University, East Lansing, Michigan 48824.

4 Department of Physiology, Michigan State University, East Lansing, Michigan 48824.

5 Neuroscience Program, Michigan State University, East Lansing, Michigan 48824.

Running Title: Developmental Programming Effects of Heavy Metals Corresponding Author: George W. Smith, PhD 446 W. Circle Drive, Room 109 East Lansing, MI 48824-1225 517 355 0123 (phone) 517 353 5406 (fax) smithge7@msu.edu 1 Environ Health Perspect DOI: 10.1289/EHP481 Advance Publication: Not Copyedited Funding Information This work was supported by Michigan State University AgBioResearch.

Acknowledgements We thank Callie Swanepoel for her excellent technical assistance with animal experiments.

A Competing Financial Interests Declaration The authors declare they have no competing financial interests.

2 Environ Health Perspect DOI: 10.1289/EHP481 Advance Publication: Not Copyedited Abstract Background: Long-term exposure to the heavy metals cadmium (Cd) and mercury (Hg) is known to increase risk of chronic diseases. However, to our knowledge, exposure to Cd and Hg beginning at the periconception period has not been studied to date.

Objective: The effect of co-administration of Cd and Hg during early development on indices of chronic diseases at adulthood was examined.

Methods: Adult female CD1 mice were subcutaneously administered a combination of cadmium chloride (CdCl2) and methylmercury (II) chloride (CH3HgCl; 0, 0.125, 0.5 or 2.0 mg/kg body weight each) four days before and four days after conception (8 days total). Indices of anxietylike behavior, glucose homeostasis, endocrine and molecular markers of insulin resistance and organ weights were examined in adult male offspring.

Results: Increased anxiety-like behavior, impaired glucose homeostasis, and higher body weight and abdominal adipose tissue weight were observed in male offspring of treated females compared to controls. Significantly increased serum leptin and insulin concentrations and impaired insulin tolerance in the male offspring of dams treated with 2.0 mg/kg body weight of Cd and Hg suggested insulin resistance. Altered mRNA abundance for genes associated with glucose and lipid homeostasis (GLUT4, IRS1, FASN, ACACA, FATP2, CD36, G6PC) in liver and abdominal adipose tissues as well as increased IRS1 phosphorylation in liver (Ser 307) provided further evidence of insulin resistance.

Conclusions: Results suggest administration of cadmium and mercury to female mice during early development of their offspring (which in this study is the periconception period) was associated with anxiety-like behavior, altered glucose metabolism and insulin resistance in male

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Environ Health Perspect DOI: 10.1289/EHP481 Advance Publication: Not Copyedited Introduction The in utero environment, including maternal nutrition, stress, and exposure to chemicals, can influence susceptibility of offspring to chronic diseases at adulthood (Rosenfeld 2012). The impact of environmental influences during early life on developmental programming of diseases in adulthood has been previously demonstrated in both human and animal studies (Barker et al. 2002; Ronco et al. 2011) and is linked to numerous conditions including obesity, type-2 diabetes, and hypertension (Barker 1997). During the last decade, much of the emphasis in developmental programming research has been placed on the impact of nutritional insults, endocrine disruptors and pesticides during pregnancy (Manikkam et al. 2012; Seet et al. 2015).

Less attention has been placed on in utero developmental programming effects of exposure to environmental contaminants such as heavy metals, cadmium (Cd) and mercury (Hg).

Previous epidemiological studies demonstrated an association between chronic Cd or Hg exposure through the diet or smoking during pregnancy and high diastolic blood pressure (Thurston et al. 2007), insulin resistance (Thiering et al. 2011), increased brain-derived neurotrophic factor concentration in cord serum (Spulber et al. 2010) and attention deficit hyperactivity disorder in children (Sagiv et al. 2012). Pronounced phenotypic effects at adulthood have also been reported in rodent studies in response to maternal and lactational Cd or Hg exposure. Gestational Cd exposure has effects on behavior (Desi et al. 1998), and indicators of semen quality of offspring at adulthood (Petrochelli Banzato et al. 2012). Likewise, chronic maternal exposure to Hg caused altered immune and neurologic functions (Pilones et al. 2009) and behavioral effects (Onishchenko et al. 2007) in offspring.

Current data in the literature on developmental programming effects of Cd and Hg are

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Environ Health Perspect DOI: 10.1289/EHP481 Advance Publication: Not Copyedited pregnancy and/or lactation. But, in actuality, exposure to multiple toxic chemicals may occur simultaneously from several different sources. Furthermore, due to increased public consciousness, women may change their lifestyle after becoming aware of their pregnancy to reduce potential exposures. Therefore, administration of environmental contaminants during the very early stages of pregnancy, and even before conception, is relevant to understanding the long-term effects of adverse maternal conditions on subsequent offspring health. Evidence suggests the periconception period (comprising the time immediately before and after conception) is a critical time for developmental programming (Gardebjer et al. 2015). However, the majority of data demonstrating developmental programming during the periconception period are derived from studies that manipulated the maternal diet (Watkins et al. 2011). Studies of periconception developmental programming are of increasing importance because approximately 50% of pregnancies are unplanned in the United States, which greatly increases the chances of exposure of developing germ cells/embryo to potential unfavorable conditions during this critical time (Rayburn and Brennan 2011).

In the present study, we hypothesized that maternal administration of a combination of Cd and Hg during the periconception period would increase indices of chronic disease in offspring at adulthood. Depending on the tissue and body burden, half-lives of Cd and Hg in mice are variable (Fair et al. 1987; Feldman et al. 1978; Magos and Butler 1976). Available studies for gestational Cd or Hg exposure at varying doses during the entire pregnancy or prior to parturition suggest accumulation of these heavy metals mainly in maternal tissues and placenta (Baranski et al. 1982; Lau et al. 1998). In contrast, only small amounts of Cd or Hg were detected in fetal organs (Hazelhoff Roelfzema et al. 1988; Lau et al. 1998). Given long half-lives

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Environ Health Perspect DOI: 10.1289/EHP481 Advance Publication: Not Copyedited dams. In addition, some direct exposure of offspring via placental transfer and lactation is also possible. Therefore, although the present study evaluated the effects of administration of Cd and Hg during the periconception period, exposure may have extended beyond this period.

Materials and Methods Animals Eight-week-old CD1 mice were obtained from Charles River Breeding Laboratories and acclimatized to local conditions for two weeks prior to initiation of experiments. Animals were maintained in a controlled environment with 12h light: dark cycle and 22±1 °C room temperature with food and water provided ad libitum. Four animals per cage were housed in standard ventilated caging system made of polysulfone where each cage was provided with autoclaved aspen-chip bedding. All animals received a commercial irradiated laboratory rodent diet (Teklad Diet 7913; Harlan Laboratories, Madison, WI). Animals were treated humanely and with regard to alleviation of suffering. All experimental procedures were approved by the Michigan State University Institutional Animal Care and Use Committee (IACUC).

Research Design Experiment 1 Individually caged 10-week-old female CD1 mice were administered a combination of cadmium chloride (CdCl2) and methylmercury(II) chloride (CH3HgCl) at daily subcutaneous (sc) doses of 0.125, 0.5 or 2.0 mg of Cd and Hg each or vehicle (0.9% NaCl) for four days before injected females were placed with age-matched naïve males for mating (n=4 litters per

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Environ Health Perspect DOI: 10.1289/EHP481 Advance Publication: Not Copyedited amounts of Cd and Hg administered, but we acknowledge such approach is less environmentally relevant. In previous studies, administration of 0.5 mg/kg body weight of Cd (ip injection) in mice during 13-17 days of gestation (Ji et al. 2011), 2 mg/kg body weight of Cd (sc administration) in mice during 7-9 days of gestation (Paniagua-Castro et al. 2007), 2 mg/kg body weight of Hg (oral gavage) in rats during 6-9 days of gestation (Fredriksson et al. 1993), 0.5 and 2 mg/kg body weight of Hg (oral gavage) in rats during gestational day 5 until parturition (Gandhi et al. 2014) as well as 2 mg/kg body weight of Hg administration in mice at gestational day 8 (Hughes and Annau 1976) resulted in developmental programming effects in offspring.

Thus dose range of 0.125-2 mg/kg body weight of Cd and Hg was selected for the current studies. Presence of a vaginal plug at embryonic day 0.5 was considered confirmation of conception, and males were separated from females. Plug-positive females were dosed as above for the four days following mating. Administration of Cd and Hg were performed between Zeitgeber Time (ZT; ZT 0 corresponds to lights on and ZT 12 corresponds to lights off in a 12h light: dark cycle) 4 and ZT5. Duration of adminstration of Cd plus Hg to assess developmental programming effects (4 days prior and 4 days post conception) was based on a regime used in prior studies of periconception nutritional insults (Gardebjer et al. 2015). After completion of periconception heavy metal administration, no further Cd and Hg treatment was performed and the duration of gestation was recorded.

After delivery, birth weights were determined for all pups, and litter size was standardized to eight by randomly selecting four males and four females from each litter.

Offspring were individually housed with their dams until weaning at 28 days of age. At weaning, offspring from the same litter were then group-housed together based on sex (n=4

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Environ Health Perspect DOI: 10.1289/EHP481 Advance Publication: Not Copyedited Assessments of phenotypic effects of periconception Cd and Hg administration was initiated when offspring were eight weeks of age. Endocrine and molecular indices of metabolic syndrome only were investigated in male offspring since impaired glucose homeostasis and increased abdominal adiposity were displayed together by the male, but not female offspring (described in results). Therefore, in the current study results for male offspring are emphasized.

Behavioral Tests Anxiety-like behavior of male offspring was assessed by performing elevated plus maze and open field tests (Bailey et al. 2007; Rex et al. 2004). For the behavioral analyses, two males per litter were chosen randomly (n=8 males per treatment). A week before the experiment, animals were individually caged and subjected to behavioral analyses at eight weeks of age. All behavioral tests were performed between ZT4 and ZT10 (Hostetter 2013). Each animal was assigned to use only once for behavioral tests, either for elevated plus maze or open field test.

The investigators were blinded to treatment status of offspring.

1. Elevated Plus Maze Test (EPM) The maze consisted of a central component two opposing open arms and two opposing closed arms. Each session lasted 30 min and was videotaped. Lighting conditions and temperature of the test room were maintained constant during the entire experiment. Animals were situated individually at the center of the maze. Increased number of entries in the open arms was used for the assessment of anxiety-like behavior.

8 Environ Health Perspect DOI: 10.1289/EHP481 Advance Publication: Not Copyedited

2. Open Field Test (OFT) Animals were located at the center of a mouse activity monitoring cage to determine open-field activity during 30 min sessions using the TruScan Photo Beam Activity System (Coulbourn Instruments, Whitehall, PA, USA), which is equipped with sensor rings that detect the movement of individually placed animals in every direction. The data were analyzed using TruScan 99 software. Decreased movement time and reduced entries to the center area as well as increased movement time in the margins and altered locomotor activity were used to assess the anxiety-like behavior.

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