Nutriphenomics in Rodent Models

C H A P T E R

40 Nutriphenomics in Rodent Models: Impact of Dietary Choices on Toxicological Biomarkers Michael A. Pellizzon, Matthew R. Ricci Research Diets, Inc., New Brunswick, NJ, United States

INTRODUCTION When designing an experiment involving animal models, there are many factors that will affect a given phenotype (i.e., observable or biochemical response), and these can be broken into two basic categories: the genotype of the animal and the environment. Rodent models such as mice and rats are the most commonly used animals in biomedical research because of their small size, low cost, the vast array of strains commercially available, and the ease of modifying their genetic background. There are many rodent models for studying chronic disease states such as metabolic disorders (i.e., obesity, nonalcoholic fatty liver disease (NAFLD)) or cancer, some which are driven by dietary means, genetic modification, or both. Therefore, many considerations need to be taken into account when choosing the proper rodent model for a given study. In some cases, phenotype is very predictable, but in others, rodents can have a variable response, including when presented with a dietary challenge (Enriori et al., 2007; Zhang et al., 2012). Like genotype, most environmental factors, such as light/dark cycle, temperature, humidity, and cage density, and type are typically well controlled, but diet (unless being directly studied) is usually a last consideration and is either not disclosed or is underreported in experimental studies. Most of the time, terms such as “a standard diet” or “a normal diet” are the commonly used “descriptors” when defining a diet in methods sections of publications, and in many of these cases, it is likely that the diet was not carefully considered. The importance of diet in toxicological studies was reviewed quite some time ago by toxicologists (Greenfield and Briggs, 1971; Wise, 1982), but some toxicologists still have not embraced this concept.

Biomarkers in Toxicology, Second Edition https://doi.org/10.1016/B978-0-12-814655-2.00040-2

As the researcher chooses a diet for their study, they should ask a number of questions. Is the formula “open” to the public? Do I have access to the exact composition of the diet? Is the diet variable from batch to batch? Can I easily modify the diet formula? Does the diet contain contaminants? By having an open and consistent formula that is easily modified as needed, it is then possible to effectively study how and why various dietary manipulations influence any given biological parameter and form valid conclusions from the data. The influence of dietary factors on an animal’s phenotype is called nutriphenomics and will occur under any experimental condition, whether diet is intentionally being altered to influence an animal’s phenotype or not. Although nutriphenomics is a term typically used to describe intentional diet-induced disease phenotypes, there are dietary factors that may affect certain toxicological biomarkers, which may not be noticed unless they are being directly studied. These factors include certain nutrients and non-nutrients that are found in commercially available diets. This chapter will provide an overview of dietary choices available, common diet-induced disease phenotypes, and factors in commonly used control diets that can affect nutriphenomics in rodent studies.

Dietary Choices Rodent diets can be broken down into two basic categories: grain-based (GB) or (cereal-based) diets or purified diets. A third category is chemically defined diets, which include ingredients that are entirely synthetic, but it is not something that is commonly used in research mainly because of their extreme expense and will not be discussed.

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40. RODENT DIETS AND NUTRIPHENOMICS

Grain-Based Diets GB diets are made with unrefined cereal grains or animal ingredients that contain multiple nutrients and non-nutrients (Fig. 40.1). GB diets typically include agricultural grade ingredients such as ground corn, ground wheat, wheat gluten, wheat middlings, barley, ground oats, soybean meal, alfalfa meal, and animal byproducts such as fish meal and porcine animal meal in varying proportions. Most GB diets are “closed formulas” or proprietary, and therefore the actual concentrations of these ingredients are not disclosed. Furthermore, GB diet companies will alter levels or sources of ingredients without disclosing these changes to researchers. These changes can be necessary to maintain a given nutrient concentration because nutrient levels in GB ingredients will vary with soil conditions, climate, and timing of harvest or sequence. However, and perhaps unwittingly, this can lead to changes in other nutrients and non-nutrients. For example, protein is typically monitored closely in GB diets, and a commonly used source of protein in these diets is soybean meal (around 50% protein). Besides protein, soybean meal also contains fiber, fat, minerals, and non-nutrients, such as phytoestrogens. Phytoestrogens, as their name implies, have similarities to the chemical structure of estrogen. Phytoestrogens in soybean meal are a complex mixture of isoflavones that are in several different chemical forms (daidzin, 600 -OAc daidzin, 600 -OMal daidzin, daidzein, genistin, 600 -OAc genistin, 600 -OMal genistin, genistein, glycitin, 600 -OMal glycitin, and glycitein), and each of these compounds is present either as b-glycosides (bound to glucose) or Purified Diet Ingredients Contain One Main Nutrient Casein L-Cystine Corn Starch Dextrose Sucrose

Protein

Carbohydrate

Fiber

Corn Oil Soybean Oil

Fat

FIGURE 40.1

Grain-Based Ingredients Contain Multiple Nutrients and Non-Nutrients Agricultural Products Soybean Meal Alfalfa Meal Ground Wheat Ground Oats Ground Corn Cane Molasses

Protein, Carbohydrate, Fiber, Fat, Minerals, Vitamins, Phytoestrogens *, Toxic Heavy Metals **

Agricultural By-Products

Cellulose Inulin

Vitamin Mix Mineral Mix Choline Bitartrate

as aglycones (not bound to glucose). Phytoestrogens in soybean meal are mainly in the chemical forms genistin and daidzin (b-glycosides) and the levels of these phytoestrogens can change significantly based on soy variety, location of harvest, and time of year (Eldridge and Kwolek, 1983; Brown and Setchell, 2001). Therefore, as soybean meal is altered intentionally in some GB diets to maintain protein, this intentional adjustment could cause unintentional changes to levels of phytoestrogens (Thigpen et al., 1999; Jensen and Ritskes-Hoitinga, 2007). Some GB diets are “open formulas,” and well-known examples of these include those developed by the National Institute of Health in the early 1970s (i.e., NIH-07, NIH-31). These “open” formulas will always contain a fixed level of ingredients, but it is difficult to maintain consistency in nutrient and non-nutrient contents of a given open- and fixed-formula GB diet from batch to batch as alluded to above (Rao and Knapka, 1987). GB diet producers also offer “phytoestrogen-free” diets by replacing soybean meal or both soybean meal and alfalfa meal (contains the phytoestrogen coumestrol) with casein (containing around 87% protein) or combinations of other plant protein sources. Although this reduces phytoestrogen levels (Jensen and Ritskes-Hoitinga, 2007), there are still grains in GB diets that contain smaller amounts of phytoestrogens including alfalfa, wheat, barley, corn, and oats (Farnsworth et al., 1975) and potentially other endocrine disruptors or confounders present in other ingredients that could mask the influence of a toxicological phenotype of interest (Heindel and vom Saal, 2008). In fact, several other potential contaminants exist, including

Wheat Middlings Wheat Germ Beet Pulp

Protein, Fiber, Fat, Minerals, Vitamins

Animal By-Products Fish Meal Porcine Meat Meal

Essential Micronutrients

Protein, Fat, Minerals, Vitamins, Toxic Heavy Metals **

* Phytoestrogens mainly from soybean meal and alfalfa meal ** Toxic Heavy metals mainly from cereal grains and meat meals

Common ingredients in purified diets and GB diets and their nutrient/nonnutrient contributions.

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INTRODUCTION

heavy metals such as arsenic (Kozul et al., 2008; Mesnage et al., 2015), endotoxins (Hrncir et al., 2008; Schwarzer et al., 2017), and pesticides and pollutants (Mesnage et al., 2015). Often these contaminants are present at biologically relevant levels (Kozul et al., 2008; Thigpen et al., 2013; Mesnage et al., 2015; Schwarzer et al., 2017). There is evidence that the levels of contaminants in GB diets vary across batches of the same diet (Greenman et al., 1980; Jensen and Ritskes-Hoitinga, 2007; Thigpen et al., 2007), which could lead to different findings depending on the batch used. In addition to a diverse array of contaminants, GB diets contain both very high fiber contents and variable types of fiber because of the presence of multiple cereal grains. The diversity in the types of fibers present in GB diets has been described decades ago and showed that rat and mouse GB diets varied from 8% to 22% (total fiber) and proportions of different fiber types (i.e., pectin, hemicellulose, cellulose, and lignin) were highly variable among different diets (Wise and Gilburt, 1980). Therefore, GB diets contain fermentable fiber sources (i.e., soluble fibers such as pectin and to a partial degree from hemicellulose), which have the potential to modify the gut microbiome significantly. Thus, their use may limit our understanding of how microbiota affect overall health. Purified Diets Purified diets are open and fixed formulas made with refined ingredients, which contain one main nutrient and are commonly phytoestrogen-free, depending on the protein source. Given their open nature, the formulas are reportable and their nutrient contents are more easily defined than diets based on less refined grains and animal by-products. For example, casein is w87% protein (w11% moisture), corn starch is w88% carbohydrate (w11% moisture), soybean oil is 100% fat, cellulose is >99% insoluble fiber, and vitamin and mineral mixes are chemically defined ingredients. These ingredients contain minimal non-nutrients, and as such, it is possible to repeat a given nutrient composition of a particular diet from one lot to the next while limiting non-nutrients that can influence phenotype (Wise, 1982). Purified diets have been around since the 1920s and were used to prove the essentiality of vitamins and minerals (Knapka, 1988). Until the 1970s, researchers made their own purified diets in the lab, and it was not uncommon for the formulas to vary from one researcher to the next, or for essential nutrients to be missing or perhaps simply unreported (Greenfield and Briggs, 1971). These dietary differences among studies in a given area of toxicology (or other fields) led to confounding factors and reduced the ability of collaborating researchers to draw conclusions. In an effort to reduce what was the variable influence of diet

in toxicology studies, a committee of nutritional scientists known as the American Institute of Nutrition (AIN) set forth in 1973 to establish an open, fixed formula to meet requirements for growth, reproduction, and lactation of rats and mice (Bieri et al., 1977). Such a diet was considered important for toxicologists because it contained only a minimal level of non-nutrients that could influence the toxicological phenotype of a given rodent model. The initial formula, called the AIN-76, fulfilled the nutrient recommendations for rodents established in 1972 by the Committee on Animal Nutrition of the National Research Council (National Research Council, 1972). As researchers began using this diet, they noted that a high percentage of their rats were hemorrhaging either internally or externally; the problem was solved by adding 10-fold higher concentrations of menadione (vitamin K) (Roebuck et al., 1979). This revised formula was called the AIN-76A (Table 40.1), and additional suggestions to improve the formula were proposed in an editorial by Bieri in 1980 (Bieri, 1980). About a decade later, a new group of scientists formed another AIN committee over some of the nutritional concerns indicated by Bieri with the AIN76A diet. This committee developed a new set of diets, which would become the AIN-93 series diets (AIN-93G and AIN-93M, for growth and maintenance, respectively) (Reeves et al., 1993). Despite some improvements, studies with the AIN-93 series diets along with certain formulation issues, such as a low phosphorus mineral mix that relies on casein to supply part of the phosphorus requirement, have suggested that more improvements are required (Lien et al., 2001). That being said, these purified diets provide toxicologists and others a phytoestrogen-free formula that has a consistent nutrient composition from batch to batch, is easy to report, and is easily modified to the researcher’s advantage. TABLE 40.1

The AIN-76A Rodent Diet

Ingredient

g

kcal

Casein

200

800

DL-Methionine

3

12

Corn Starch

150

600

Sucrose

500

2000

Cellulose

50

0

Corn Oil

50

450

Mineral Mix

35

0

Vitamin Mix

10

40

Choline Bitartrate

2

0

Total

1000

3902

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Diet-Induced Metabolic Disorders Much work has been done with respect to how diet influences disease phenotypes in rodent models, and purified diets have been crucial in this effort. In some cases, it is important to address the influence of an environmental toxicant or endocrine disruptor on a metabolic disorder. High-Fat Diets for Diet-Induced Obesity Models At the time of this writing, a Google Scholar search for “high-fat diet rat” and “high-fat diet mice” yielded over 359,000 articles, dating back to the 1940s. For much of this time, a high-fat diet (HFD) was made by adding various levels and types of fat to the available GB diet already in the animal facility. However, this is not ideal because (1) fat addition can lead to nutritional inadequacies (nutrient dilution) in the diet and (2) the use of GB diets has inherent drawbacks as discussed earlier (variable and unknown composition). As an example, phytoestrogens can reduce adiposity and improve insulin sensitivity in mice relative to diets with low phytoestrogens (Cederroth et al., 2007, 2008). Because purified diets allow for the easy formulation of an HFD without nutrient dilution, it is no surprise that in the last w20e25 years, purified ingredient HFDs have been widely used to study obesity and its associated comorbidities in rodents. There is a dosee response relationship between dietary fat and body weight and adiposity (Donovan et al., 2009; Jiang et al., 2009) and because animals fed a higher fat diet tend to gain more weight in a shorter period of time (which is often seen as cost savings to the researcher), the popularity of using diets containing 60% of calories from fat has grown as a standard method of promoting dietinduced obesity (DIO) in rodent models. Although most rodents tend to become obese on an HFD, there are variable responses in body weight gain, glucose tolerance, triglycerides (TG), and other parameters depending on the strain and gender (Levin et al., 1997; Rossmeisl et al., 2003) and type of dietary fat (Ikemoto et al., 1996; Wang et al., 2002; Buettner et al., 2006). Outbred SpragueeDawley and Wistar rats have a variable response to an HFD in that some animals become obese, whereas others remain as lean as lowefat diet fed rats (Farley et al., 2003). It is common to separate these rats (based on body weight gain) into DIO and diet-resistant (DR) groups (Chang et al., 1990; Farley et al., 2003; Levin and Dunn-Meynell, 2006). DIO and DR rats have been selectively bred over time such that the propensity to gain weight or resist obesity on an HFD is known in utero, allowing the researcher to look early in life (prior to the onset of obesity) for genetic traits that may later predispose them to their DIO or DR phenotypes (Levin et al., 1997; Ricci and Levin,

2003). Diet-induced obesity in SpragueeDawley and Wistar rats can induce glucose intolerance (Drake et al., 2005; Laurent et al., 2007), fatty liver (Ross et al., 2012), inflammation (De Souza et al., 2005; de La Serre et al., 2010), cardiac dysfunction (Burgmaier et al., 2010), and increased muscle lipid deposition (Storlien et al., 1991) and affect development of offspring when fed to pregnant rats (White et al., 2009). Mouse models of DIO are in more widespread use compared with those of rats, and the most commonly used mouse model of DIO is the C57BL/6 mouse, substrains of which are available from different breeders. Although it is rarely reported, there is some variability in weight gain in this strain, with one paper reporting that about 2/3 of the mice on an HFD became obese (Enriori et al., 2007). In C57BL/6 mice, HFDs induce obesity (Van Heek et al., 1997), cause insulin resistance (IR) (DeFuria et al., 2009), increase muscle triglyceride levels (Park et al., 2005), reduce glucose tolerance (Gallou-Kabani et al., 2007), cause inflammation (Weisberg et al., 2003), induce fatty liver (Ito et al., 2007a), change gut microflora populations (Ravussin et al., 2012), affect cognition (Pistell et al., 2010), and alter neurogenesis (Park et al., 2010), among other phenotypes. Other mouse strains such as the A/J or SWR/J are resistant to DIO (Surwit et al., 1995; Prpic et al., 2003). However, strains that may exhibit similar levels of obesity may have varied metabolic responses. For example, C57BL/6 mice are more glucose intolerant, compared with obese AKR mice that are more insulin resistant (Rossmeisl et al., 2003). Diet-Induced Atherosclerosis/ Hypercholesterolemia Models Western-type diets containing high levels of saturated fat and cholesterol are commonly used to “push” atherosclerosis risk factors (elevated total cholesterol [TC] and low-density lipoprotein cholesterol [LDL-C]) in certain rodent models such as mice, hamsters, and guinea pigs. Not surprisingly, different animal models require different diets. Mice and Rats Most wild-type mice and rats are not ideal models of cardiovascular disease research because they typically have very low levels of LDL-C and high levels of highdensity lipoprotein cholesterol (HDL-C). This is in contrast to humans in whom the reverse is true. Although diets containing high levels of cholesterol and saturated fat (w0.5% cholesterol, w40 kcal% fat) can increase TC, both LDL-C and HDL-C (Srivastava et al., 1991, 1992; Srivastava, 1994) increase, which limits atherosclerosis development (Getz and Reardon, 2006). The addition of the bile acid and cholic acid to diet (in combination with cholesterol) will increase LDL-C (Nishina et al.,

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1990, 1993; Zulet et al., 1999; Jeong et al., 2005; Yokozawa et al., 2006) by both facilitating fat and cholesterol absorption and reducing conversion of cholesterol to bile acids (Horton et al., 1995; Ando et al., 2005). However, cholic acid can also independently influence genes that regulate lipoprotein metabolism and inflammation and reduce plasma TG and HDL-C (Nishina et al., 1990; Ando et al., 2005; Getz and Reardon, 2006) and reduces body weight gain (without changing food intake), glucose intolerance, and plasma insulin either with or without the presence of cholesterol (Ikemoto et al., 1997). Therefore data from cholic acidecontaining diets should be interpreted carefully. Genetically modified mice such as those with mutations that slow the removal of cholesterol from the blood have led to more “human-like” phenotypes and can show significant elevations in circulating LDL-C and atherosclerotic lesions, especially when dietary cholesterol is added. Some of these knockout mouse models (such as the LDL receptor knockout and the apolipoprotein E knockout [apoE KO]) can be very responsive after 12 weeks on a high cholesterol diet (0.15%e1.25% cholesterol) (Lichtman et al., 1999; Collins et al., 2001; Joseph et al., 2002). Lesion development is very dramatic in apoE KO mice fed a Western-type diet, and beginning stages of atherosclerosis (i.e., fatty streak lesions) can be found at 6 weeks (Nakashima et al., 1994). A combination of multiple genetic modifications (e.g., apoE þ matrix metalloproteinase double KO) with a high-fat lard-based diet with cholesterol (0.15%) was found to increase plaque rupture after only 8 weeks (Johnson et al., 2005). With these mouse models, the main influence on atherosclerosis is dietary cholesterol rather than the level of fat (Davis et al., 2001; Wu et al., 2006), but certain threshold levels of dietary cholesterol may exist, at least within the context of a low-fat purified diet (Teupser et al., 2003). Very highefat diets (i.e., 60 kcal% fat) are capable of inducing some atherosclerosis (Subramanian et al., 2008; King et al., 2009), and the fatty acid profile and carbohydrate form (i.e., fructose, sucrose) can be manipulated to modify the atherosclerosis phenotype to the researchers advantage (Merat et al., 1999; Collins et al., 2001; Merkel et al., 2001). Hamsters Although hamsters typically have a high percentage of HDL-C when fed a low-fat/low-cholesterol diet (similar to rats and mice), dietary cholesterol alone will increase LDL-C, and like humans, saturated fat can increase these levels further (Otto et al., 1995; Alexaki et al., 2004). Diets containing high levels of saturated fat and cholesterol can drive the initial stages of atherosclerosis (fatty streaks, foam cells) in as little as 6 weeks (Kahlon et al., 1996). Even a diet high in saturated fat

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without added cholesterol can increase aortic cholesterol accumulation compared with a lower saturated fat diet with added cholesterol (Alexaki et al., 2004). The different response of the hamster (compared with the rat or mouse) to dietary cholesterol is related to different mechanisms of cholesterol processing by the liver (Dietschy et al., 1993; Horton et al., 1995; Khosla and Sundram, 1996). With the hamster, it is also important to consider the source of dietary protein because hamsters fed casein- and lactalbumin-based diets had higher levels of LDL-C and atherosclerosis than those fed an equal amount of soy protein, and like humans, males may be more susceptible than females (Blair et al., 2002). Guinea Pigs Unlike other wild-type rodents, guinea pigs have a similar cholesterol profile and lipoprotein metabolism to humans (more LDL-C vs. HDL-C) when maintained on a low-fat/low-cholesterol diet (Fernandez and Volek, 2006). Like hamsters, diets high in saturated fat can elevate TC and LDL-C levels and a diet with added cholesterol (at least up to 0.3%, w/w) can cause further elevations in LDL-C and induce atherosclerotic lesions (i.e., fatty streaks) after 12 weeks (Lin et al., 1994; Cos et al., 2001; Zern et al., 2003). Carbohydrate/fat ratio is also important to atherosclerosis development, as high-cholesterol diets that are high in carbohydrate and moderate in fat are more capable of promoting atherosclerosis (likely via increased number of smaller LDL particles) than those low in carbohydrate but very high in fat (Torres-Gonzalez et al., 2006). Also, plasma TC levels are higher with casein versus soy protein (Fernandez et al., 1999) and with sucrose versus starch (Fernandez et al., 1996), in the context of a cholesterolcontaining diet. The sensitivity of LDL-C to dietary manipulation with minimal change to HDL-C highlights the value of the guinea pig for studies examining the influence of drug therapies on lowering LDL-C (Conde et al., 1996; Aggarwal et al., 2005). High-Fructose/Sucrose Diets for Hypertriglyceridemia and Insulin Resistance In humans and rodents, the presence of higher levels of dietary carbohydrate as fructose or sucrose is capable of causing hypertriglyceridemia (hyperTG) and IR via increasing lipogenesis and glucose production in the liver (Daly et al., 1997; Basciano et al., 2005). Spraguee Dawley and Wistar rats are both established models of sucrose-induced IR and hyperTG (Pagliassotti et al., 1996, 2000), which can develop as quickly as 2 weeks in rats fed mostly sucrose (i.e., 68 kcal%) relative to corn starch (Pagliassotti et al., 1996). The fructose component of sucrose is largely responsible for the hyperTG and IR produced by high-sucrose diets (Sleder et al., 1980; Thorburn et al., 1989; Thresher et al., 2000).

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Although very high levels of sucrose or fructose are commonly used for driving IR in rodents, even lower levels of dietary sucrose (17% of energy) can cause this after chronic feeding periods (i.e., 30 weeks) (Pagliassotti and Prach, 1995). High-fructose diets can also raise liver TG levels and induce liver inflammation (Kawasaki et al., 2009) as well as adipose tissue and kidney inflammation (Oudot et al., 2013). Furthermore, gender is important in the development of sucroseinduced IR and hyperTG in rats as females (unlike males) are typically not responsive to elevations in dietary sucrose (Horton et al., 1997). Unlike HFD, high sucrose or fructose diets promote marginal weight gain in rats, and this typically requires a prolonged period of time and a significantly greater energy intake (Chicco et al., 2003). Similar to rats, hamsters are sensitive to metabolic alterations by high-fructose diets (w60% of energy) and quickly develop IR and hyperTG only after 2 weeks (Kasim-Karakas et al., 1996; Taghibiglou et al., 2000), but they may not be as sensitive to sucrose-induced hyperTG and IR (Kasim-Karakas et al., 1996), suggesting that the level of dietary fructose is important for this model. The addition of dietary cholesterol (0.25%) allows for the simultaneous development of hypercholesterolemia, greater IR, and hyperTG in this model compared to fructose alone (Basciano et al., 2009). The ability to induce these three metabolic disturbances together makes the hamster an attractive model for studying these conditions in one model without the need to alter background genetics. In contrast to rats and hamsters, mice are used less frequently as a model for sucrose/fructose-induced phenotypes, as the commonly used C57BL/6 strain either does not develop IR or develops the phenotype more slowly (Nagata et al., 2004; Sumiyoshi et al., 2006). For example, glucose intolerance (attributed to reduced pancreatic insulin secretion) develops in C57BL/6 mice fed a high-sucrose diet over the course of 10e55 weeks (Sumiyoshi et al., 2006). However, the mouse genome is much easier to manipulate than that of the rat and in certain cases can cause knockout models to have hyperTG with high dietary fructose (Hecker et al., 2012). Nonalcoholic Fatty Liver Disease NAFLD encompasses a spectrum of disease states, from steatosis (fatty liver) to nonalcoholic steatohepatitis (also called NASH; steatosis with inflammatory changes), which may be followed by progression to fibrosis, cirrhosis and hepatocellular carcinoma (Zafrani, 2004). There are several different dietary approaches to induce NAFLD. These different dietary approaches produce different severities of disease along the NAFLD spectrum and likely work by different mechanisms.

Of the dietary approaches discussed here, methionineecholine deficient (MCD) diets produce the most severe phenotype in the shortest timeframe. Used for over 40 years, MCD diets will quickly induce measurable hepatic steatosis (mainly macrovesicular) in rodents by 2e4 weeks, and this progresses to inflammation and fibrosis shortly thereafter (Weltman et al., 1996; Sahai et al., 2004). Fat levels in MCD diets can vary, though they typically contain about 20% fat by energy (most “control” diets, purified ingredient or grain based, tend to be w10% by energy). The mechanism for steatosis includes increased hepatic fatty acid uptake, impaired very low density lipoprotein secretion (due to lack of phosphatidyl choline synthesis), and increased fatty acid transport proteins (Kulinski et al., 2004; Rinella and Green, 2004). MCD dieteinduced NASH is reversible in rats by switching to a diet with sufficient methionine and choline (Mu et al., 2010). The disadvantage of using MCD diets is that they induce rapid weight loss (due to a vastly lower caloric intake) and the rodents do not become insulin resistant (Kirsch et al., 2003; Rinella and Green, 2004), unlike the typical obese, insulin-resistant human NAFLD patient. Similar to MCD diets, choline deficient (CD) diets also tend to contain higher levels of fat, though it is often difficult to know the specifics because, unfortunately, authors rarely publish the details of the diets. CD diets induce steatosis, inflammation, and fibrosis over 10 weeks without any difference in body weight compared with the control group (Fujita et al., 2010). This lack of weight loss makes CD diets more appealing to some researchers. If weight gain is desired, a CD HFD (i.e., 45 kcal% fat) can increase body weight of C57BL/6 mice further than a matched low-fat diet (10 kcal% fat) with or without choline after 8 weeks, but mice remain glucose tolerant (Raubenheimer et al., 2006). Even longer feeding periods of up to 1 year have found that a CD 45 kcal% fat diet (same as Raubenheimer et al.) can drive hepatocarcinoma in mice relative to those simply fed a choline-sufficient 45 kcal% fat diet (Wolf et al., 2014). The mechanisms involved with liver fat accumulation may be different from those at work during MCD diet feeding (Kulinski et al., 2004). When both CD and MCD diets were fed to rats for 7 weeks, the MCD diet group had higher scores of liver inflammation and steatosis than the CD group. However, the CD fed rats gained weight, were insulin resistant, and had higher plasma lipids than the MCD group (Vetela¨inen et al., 2007). As discussed earlier, HFDs are well known to increase body weight and body fat and induce IR in rodent models. HFD (with sufficient methionine and choline) can also increase liver fat levels quite rapidly (within days) as well as hepatic IR before significant

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INTRODUCTION

increases in peripheral fat deposition occur (Samuel et al., 2004). Chronically, HFDs-induced liver fat accumulation may not follow a linear progression and liver fat levels may actually decrease and then increase again during prolonged HFDs feeding (Gauthier et al., 2006). When fed for equal lengths of time, HFD feeding results in 10-fold lower liver fat levels compared to what accumulates on an MCD diet (Romestaing et al., 2007). In general, HFD feeding does not produce liver fibrosis but only mild steatosis as compared with MCD diets (Anstee and Goldin, 2006), thus highlighting an important difference between these dietary regimes. It is important to remember that the term “HFDs” encompasses a wide variety of diet formulas that can be expected to alter the liver phenotype in various ways. In a dietary combination approach, Matsumoto et al. (2013) used a high fat (60% of energy), CD diet containing only 0.1% methionine by weight (most purified ingredient diets based on casein contain 5e8 times this amount). Fatty liver, markers of liver injury, and inflammation were increased after 1e3 weeks, and after an initial loss of body weight, the C57BL/6 mice gained weight at a trajectory similar to control animals (Matsumoto et al., 2013). In contrast, A/J mice exhibited reduced weight and inflammation with no evidence of fibrosis (Matsumoto et al., 2013). Increasing methionine from 0.1% to 0.2% in the context of a 45 kcal% fat diet increased body weight gain and still allowed for NASH to develop after 12 weeks in C57BL/6 mice (Chiba et al., 2016). Thus it seems that HFDs containing lower than normal levels of methionine and choline allow for the development of NASH without massive weight loss. This idea of modifying so-called “standard” HFDs is powerful because it allows the researcher to “fine-tune” the phenotype to meet their needs. Combination HFDs with 40 kcal% fat using a vegetable-based shortening (combination of palm oil and partially hydrogenated soybean oil), 2% cholesterol, and 20% as fructose source have been used often by those interested in developing both NASH and metabolic disease. Both lard or the shortening were capable of increasing intrahepatic lipid levels in ob/ob knockout mice, which are genetically obese and already have a higher intrahepatic lipid level on a low-fat diet, and a similar effect was found in C57BL/6 mice, but the shortening was found to elevate the lipid level even more than lard in both these mouse models after 12 (for ob/ ob) and 16 (for C57BL/6) weeks (Trevaskis et al., 2012). To develop more advanced NASH including fibrosis, it is necessary to feed C57BL/6 mice up to 30 weeks (Trevaskis et al., 2012). Therefore, prolonged feeding is necessary to drive a combination of fibrosis with metabolic disorders in wild-type mice.

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Diets High in Sodium (and Fructose) for Hypertension Diet-induced hypertension is possible in both rats and mice though there are more published papers using rats, perhaps because of their larger size, the amount of physiological data available, and robust blood pressure response that some strains present. The main dietary contributor to diet-induced hypertension is the level of NaCl. Levels of NaCl well above what are normally found in purified (w0.1%) or GB diets (w0.3e0.4%) are required to raise blood pressure in most rodent models. The Dahl salt-sensitive (SS) rat shows a significant rise in blood pressure within 2e4 weeks after being fed a purified diet containing 8% NaCl (Ogihara et al., 2002; Karmakar et al., 2011), though lower levels of NaCl (4%) will still raise blood pressure (Konda et al., 2006) albeit more slowly (Owens, 2006). This rise in blood pressure can be attenuated by supplementing the diet with extra potassium (Ogihara et al., 2002). Aside from the NaCl level itself, the background diet can also affect the hypertension phenotype. When either low (0.4%) or high (4%) NaCl was added to both a GB diet and a purified diet, Dahl SS rats that were fed the purified diet had higher blood pressure and more renal damage compared with GB dietefed rats (Mattson et al., 2004). Given the many differences between GB and purified diets, it is difficult to know exactly which components were responsible. The possibilities include the source of protein (Nevala et al., 2000), carbohydrate (Bun˜ag et al., 1983), fat (Zhang et al., 1999), fiber (Preuss et al., 1995), and/or the level of minerals such as potassium (Ogihara et al., 2002), all of which can greatly differ between GB and purified diets. Aside from salt-sensitive rats, outbred rat strains such as the SpragueeDawley (which are in widespread use for obesity research) can develop hypertension. When fed an 8% NaCl diet, hypertension develops, but this usually occurs over a longer time period and to a lesser magnitude compared with Dahl SS rats (Thierry-Palmer et al., 2010). SpragueeDawley rats can also develop hypertension as they become obese on an HFD (Dobrian et al., 2000). Diets high in fructose (around 60% of calories) but with normal levels of NaCl (0.1%) can induce metabolic abnormalities, including increased blood pressure (Vasudevan et al., 2005; Sa´nchez-Lozada et al., 2007) and kidney damage in both Spraguee Dawley and Wistar rats (Hwang et al., 1987; Vasudevan et al., 2005; Sa´nchez-Lozada et al., 2007). The IR induced by such high-fructose diets (Hwang et al., 1987) is believed to play a causal role in the development of hypertension (DeFronzo, 1981). Even in a spontaneous rat model of hypertension (such as the spontaneously hypertensive rat [SHR],

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which will develop hypertension on a variety of diets), diet can be used to modify the onset or degree of this disease. For example, dietary supplementation with antioxidants (such as vitamins E and C) can lower blood pressure in stroke-prone SHR (Noguchi et al., 2004), as can dietary calcium supplementation (Sallinen et al., 1996). As mentioned earlier, the mouse is not as widely used for the study of diet-induced hypertension. Inbred mice such as the C57BL/6 can develop elevated blood pressure on purified diets high in NaCl (8%), though this appears to be on the order of several months (Yu et al., 2004). Although C57BL/6 mice are sensitive to diet-induced obesity when fed an HFD, mean arterial blood pressure was slightly, but significantly increased relative to a lowfat diet (around 3 mm Hg) after 7 days of feeding a very HFD (i.e., 60 kcal% fat, mainly lard). The addition of 5% NaCl to the HFD increased blood pressure by 4.5 mm Hg compared to baseline measures on an HFD with normal NaCl levels (i.e., 0.3%) and was also increased (by 2.1 mm Hg) compared to those fed a low-fat diet with similar 5% NaCl levels (Nizar et al., 2016). From a mechanism standpoint, they observed that after being exposed to an acute NaCl load, high fat feeding reduced sodium excretion compared with low fat feeding. Metabolic Disease Development and the Importance of Fiber Type Although increasing dietary fat in the diet is a major factor affecting weight gain and metabolic disease development in rodents, the underlying agents that may be key to driving these effects are the type of fiber and the gut microbiome. Over 2000 years ago, Hippocrates proposed a link between gut health and disease development (“All disease starts in the gut”), and recent studies in rodent models have shown that there is merit to this blanket statement when it comes to metabolic disease and possibly other diseases. The presence of the 100 trillion bacteria in our lower gastrointestinal tract (made up of 500e1000 different species) has important implications in this link between the gut and metabolic disease development. These bacteria are “fed” with the fiber present in our diets, in particular, soluble fiber (i.e., prebiotic fibers), and in turn this fiber can affect bacterial composition rapidly, leading to changes in gut health. Replacement of cellulose (i.e., insoluble fiber typically used in purified diets) with soluble fibers (such as inulin) in a HFD has been found to have a dramatic effect on gut health, including reduced adiposity, improved gut morphology, improved insulin sensitivity, better glucose tolerance, increased beneficial bacteria and SCFAs, and reduced gap junctions between enterocytes, the latter of which reduces permeability and slows transfer of bacterial substances such as lipopolysaccharides thus limiting low-grade inflammation. All of these

effects are preceded by changes in gut microbiota (Chassaing et al., 2015, 2017; Zou et al., 2017). These effects by inulin on gut and metabolic health were found to be mediated by interleukin (IL)-22 rather than changes in short-chain fatty acids in one study (Zou et al., 2017). IL-22 is produced by immune cells to promote both epithelial cell proliferation and induce antimicrobials, which provides a direct link to how fiberinduced changes in gut microbiota influence low-grade inflammation and metabolic disease risk (Zou et al., 2017). However, the particular diet may play some role in this process as Brooks et al. reported that shortchain fatty acid production was important to the beneficial influence of soluble fiber on reducing adiposity and liver triglyceride levels when animals were fed a lower level of inulin (7.5 g%) in the context of a high-fat (21 g % as milk fat)/high- sucrose (34 g%) diet (Brooks et al., 2017). Therefore, it’s important to consider the diet background when forming conclusions regarding how fiber is mediating its effect. Know Your Control Diet The choice of the control diet used in a diet-induced metabolic disease study can profoundly affect data interpretation. When a study is performed using a GB diet as a “control” diet for a purified HFD, it is not possible to know whether the differences between the HFD and the GB diet are driven by the higher level of fat or because of the other factors that differ between the diets. To know that the observed differences are due to the high fat content, it is important to have a low-fat diet that matches the nutrient sources in the HFD (except for the fat and carbohydrate levels). This is easy to do with purified ingredients because each ingredient contains one main nutrient. However, all too often do we find that a GB diet has been used as the “control” diet for a purified HFD (Warden and Fisler, 2008; Pellizzon and Ricci, 2018). Using a GB diet as a comparator diet can lead to a severe misinterpretation of how a purified HFD influences the gut morphology and microbiota. This was highlighted in recent studies that demonstrated that mice fed a high-fat purified diet (i.e., 60 kcal% fat, mainly lard) had a reduced cecum and colon size relative to those from mice fed a GB diet, whereas there was no difference in gut morphology in the matched low-fat purified diet (10 kcal% fat, increased carbohydrate in place of lard) (Chassaing et al., 2015; Dalby et al., 2017). Furthermore, the same high-fat purified diet altered ileal and cecal microbiota profiles significantly from those fed the GB diet, whereas those fed a matched low-fat purified diet were similar to the high-fat fed group (Dalby et al., 2017). Although fat level is an important variable for driving adiposity, fiber type can mediate effects on gut morphology and microbiota in rodents, which can in turn alter metabolic

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INTRODUCTION

disease development by an HFD. Therefore, it is important to choose the control diet carefully and consider the fiber type when designing any metabolic disease studies (Pellizzon and Ricci, 2018).

Potential Effects of Grain-Based Diets and Low-Fat Purified Diets on the Rodent Phenotype Similar to the importance of choosing the proper control diet, choosing the diet in any study should not be overlooked as this may lead to significant misinterpretation of data. Like mice with a certain genetic background, each diet background is unique and there is no such thing as a “standard chow”, a common reference made for the diet used in methods sections of publications. In fact, this vague term and the lack of reporting about the particular diet being fed suggest a general lack of consideration for the diet background in most studies, which is perplexing, given how dietary factors have been shown to alter study outcomes in so many cases. Both GB and purified low-fat diets (such as the AIN diets) can alter an animal’s health status (either unfavorably or favorably) and interact with, attenuate, or completely mask the influence of a toxicological compound of interest on a given phenotype. Therefore, the details of the diet used (i.e., diet number, formulation, if available) should be reported in any study for the scientific community to critically evaluate the validity of the findings. Grain-Based Diets Phytoestrogens and Development/Maturation As discussed previously, GB diets can contain soybean and alfalfa meals, which are known to contain biologically relevant and variable levels of phytoestrogens including genistin, daidzin, glyceitin, genistein, daidzein, and coumestrol. In contrast, purified diets such as the AIN-76A and AIN-93 series diets contain no phytoestrogens. When ingested, these phytoestrogens undergo biotransformation into more absorbable forms such that genistin and daidzin are converted into the isoflavones genistein and daidzein. Daidzein can undergo further metabolism by resident bacteria to S-(-) equol and enter the circulation. This latter form, equol, is found in highest concentrations in the serum and urine of adult rats and mice consuming soybean meale containing GB diets, and it remains high in newborn pups after in utero exposure to these diets (Brown and Setchell, 2001). As mentioned earlier, different GB diet batches (i.e., same diet, but different mill dates) can vary in isoflavone concentrations three- to fourfold, and this can have a concentration-dependent influence on circulating phytoestrogens levels (Thigpen et al., 2004). However, these circulating levels can differ significantly in mice fed different GB diets, even when dietary

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isoflavones levels are similar (Brown and Setchell, 2001) suggesting that it is difficult to predict circulating isoflavone levels based on the concentration in the diet. Once in the circulation, these phytoestrogens are free to target estrogen receptors, in particular estrogen receptor b, but with a lower affinity compared to estradiol (Oseni et al., 2008). The effects can be either pro- or antiestrogenic, depending on the stage of life. Examples of a proestrogenic effect are found during development and maturation and include a dose-dependent reduction in timing of vaginal opening (VO) and an increase in uterine weights when rats and mice have prepubertal exposure to phytoestrogens (Thigpen et al., 2002, 2007; Heindel and vom Saal, 2008). Examples of antiestrogenic effects include the antagonistic effect of soy isoflavones on endogenous estrogens in certain cancers as discussed in the next section. The levels of phytoestrogens in GB diets are also high enough to negate effects of endogenously administered endocrine disruptors (such as bisphenol A) on DNA methylation and oocyte development, and their variability may contribute to inconsistencies in data where such compounds are studied during earlier stages of life (Thigpen et al., 2013). Phytoestrogens and Cancer Aside from altering pubertal onset, GB diets have the potential to inhibit carcinogenesis, and the presence of many plant-based compounds such as phytoestrogens is likely key to the reduced frequency and slower onset of tumors in certain cancer models relative to phytoestrogen-free diets such as the AIN-76A (Fullerton et al., 1991, 1992). There can be several mechanisms by which phytoestrogens play a role in carcinogenesis, but one is likely through their ability to bind estrogen receptors (Nikov et al., 2000). Their action may be either pro- or anticarcinogenic depending on age, mode of cancer induction, phytoestrogen dose, and rodent model being studied (Bouker and Hilakivi-Clarke, 2000). Genistein can dose-dependently increase mammary tumor area in estrogen-sensitive ovariectomized mice (Allred et al., 2001), but in contrast, early life (gestation and lactation) exposure to genistein can dosedependently reduce tumor formation in a carcinogeninduced mammary cancer model with intact ovaries (Fritz et al., 1998). In a prostate cancer mouse model (transgenic mice with prostatic adenocarcinoma), genistein at levels found in GB diets can reduce prostate weight of mice with adenomas and improve survival (Mentor-Marcel et al., 2005). Phytoestrogens can, depending on the dose, either inhibit or promote the efficacy of drugs called selective estrogen receptor modulators (SERMs). For example, in a transgenic mouse model of mammary carcinogenesis, lower doses of isoflavones (211 mg/kg diet) abrogated tamoxifen’s ability to reduce carcinogenesis relative to either

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higher concentrations of isoflavones (491 mg/kg) or phytoestrogen-free diets (GB diet or purified) based on casein (Liu et al., 2005). Therefore in studies evaluating the influence of SERMs on tumors, it is important to eliminate exposure to phytoestrogens or any other compounds in diets that can bind estrogen receptors. GB diets that contain low levels of phytoestrogens are available but it is not possible to truly control other factors within these GB diets, given each ingredient contains multiple nutrients and non-nutrients. Aside from offering a clean background and consistent composition that is phytoestrogen free, the refined nature of the ingredients in purified diets allows for easy customizations, which provide researchers an additional advantage in the cancer field. Making select changes to various nutrients such as increasing the level of fat calories in place of carbohydrate, reducing fiber, and certain vitamins (i.e., lower folate) and minerals (i.e., lower calcium) can increase tumor incidence in wild-type mice without carcinogen exposure given a long enough timeframe (Newmark et al., 2001; Yang et al., 2008). Therefore, purified diets allow the researcher to conduct studies with animals that may be more relevant to humans in addition to minimizing the presence of estrogenic compounds that can influence carcinogenesis.

type II metabolism genes (cytochrome P450 enzymes, involved in xenobiotic metabolism) as well as inflammatory genes were found in liver and lung of GB diete fed mice with or without arsenic in water (10 or 100 ppb). In contrast clear differences in gene expression were found between dosed or control mice fed the AIN-76A (Kozul et al., 2008). Although arsenic in GB diet was at 4 to 40 times the level being studied and was likely to blame for the lack of expressional changes, it could be also that other factors in the diet were masking the effects. Follow-up studies suggest that arsenic levels much lower than those found in GB diets can significantly influence an animal’s phenotype. For example, 100-ppb arsenic in the water consumed by mice fed a purified diet can impair inflammatory factor activation and the immune response to infection (Kozul et al., 2009a,b). When these same investigators wanted to see how arsenic exposure early in life (i.e., during gestation and lactation) influenced the immune response in these mice, profound reductions in postnatal growth and development were observed with only 10-ppb arsenic, which was likely attributed to reduced energy from milk (i.e., lower fat content) of lactating dams fed arsenic (Kozul-Horvath et al., 2012).

Arsenic and Heavy Metals GB diets are commonly based on cereal grains such as ground wheat, ground corn, and ground oats and meat meals such as fish meal, all of which can contain varying levels of toxic heavy metals (Newberne, 1975; Greenman et al., 1980; Wise, 1982). It has been suggested that the levels of these heavy metals in rodent GB diets are not high enough to affect animals from a disease standpoint (Greenman et al., 1980). However, some toxic heavy metals such as arsenic can be found in these diets at biologically relevant levels, and it is critical to consider potential dietary contributions especially when determining the effect of lower doses of heavy metals on the phenotype of rodent models. One study found that arsenic levels were quite high (390 ppb) and other heavy metals (i.e., cadmium, lead, nickel, and vanadium) were also present in a GB dietd all of which were virtually absent in the purified AIN-76A diet (Kozul et al., 2008). Of the 390-ppb arsenic, 56 ppb was considered inorganic arsenic, whereas none was detectable in the AIN-76A. This level of inorganic arsenic in this particular GB diet was higher than what is designated by the Enviromental Protection Agency as safe in drinking water (National Research Council, 1999, 2001), and therefore can severely compromise data from studies using GB diets to evaluate the influence of lower doses (i.e., 10e100 ppb) of arsenic (or other heavy metals). In fact, similar gene expression levels in both type I and

Other Compounds or Contaminants A list of phytoestrogens and toxic heavy metals in GB diets and how they may influence phenotypes are summarized in Fig. 40.2. In addition to these contaminants, other compounds that may be present in GB diets at varying concentrations include mycotoxins (zearalenone), herbicide and pesticide residues, polychlorinated dibenzo-p-dioxins (PCDDs), and dibenzofurans, which can influence various toxicological phenotypes by targeting estrogen receptors and the aryl hydrocarbon receptor (AhR) (Rao and Knapka, 1987; Schecter et al., 1996; Thigpen et al., 2004). These factors may work alone or together (additively or synergistically) with other contaminants previously discussed (i.e., phytoestrogens, heavy metals) to influence phenotype. For example, GB diets were found to activate AhR of cells that modulate immunity defense and detoxification in the intestine and throughout the body in mice (Ito et al., 2007b; Li et al., 2011). Although it is unknown what ligand(s) in GB diets affected the AhR, a similar effect on the AhR was found when mice were fed a purified diet containing a high concentration of a known ligand of the AhR (indole-3carbinol) found in cruciferous vegetables. Although GB diets do not contain cruciferous vegetable sources, it may be that other known ligands of this receptor such as isoflavones and PCDDs known to be present in these diets could very well be responsible for these effects (Amakura et al., 2003).

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INTRODUCTION

Grain-Based Diet Ingredients Soybean & Alfalfa Meal

Fish & Meat Meals Cereal Grains

FIGURE 40.2

Contaminants

Known Phenotypes Affected

Genistin, Genistein, Daidzin, Daidzein, Glycetin, Glycetein, Coumestrol

Maturation, Cancer, Heart Disease, Bone Health, Obesity, Insulin Sensitivity, Xenobiotic Metabolism

Arsenic and Other Toxic Heavy Metals, Pesticides, PCDDs

Maturation, Immune Function, Xenobiotic Metabolism

GB diet contaminants that can influence various phenotypes in rodents.

Purified Low-Fat Diets and Health Status of Rodents As pointed out earlier, purified diets have been used in laboratory animal research since the 1920s and were essential for determining nutrient recommendations because researchers were able to remove specific vitamins and minerals to determine requirements. However, there are phenotypical responses to purified diets that may not be favorable, and in some cases, they have led to unfavorable health outcomes. Research has pointed out where the potential flaws may lie, which have led to improvements in the purified diet formulas in use today. Kidney Calcinosis The AIN-76A diet has a long history of use since its initial conception in 1976, but along the way, it has come under criticism with good reason. One initial observation found with feeding the AIN-76A was that it promoted nephrocalcinosis (or kidney calcinosis (KC)), particularly in rats. Nephrocalcinosis is an abnormal condition of the kidney in which deposits of calcium (Ca) form in the filtering units. This may reduce kidney function and eventually lead to significant damage and kidney stone formation. Although calcium and phosphorus levels were in the recommended range for rodents, studies done carefully were able to determine that a low Ca to phosphorus (P) molar ratio (0.75) in the AIN-76A was the culprit for KC in weanling female rats (Cockell et al., 2002; Cockell and Belonje, 2004). This phenotype develops very quickly (i.e., 2e4 weeks) and is irreversible in these rats (Ritskes-Hoitinga et al.,

1989; Peterson et al., 1996; Matsuzaki et al., 2002; Cockell and Belonje, 2004). Other factors that may affect development of KC within this diet include the type of carbohydrate, fiber, and sulfur-containing amino acid (AA) supplementdspecifically, fructose (Bergstra et al., 1993), insoluble fiber cellulose (Anderson et al., 1985), and DL-methionine (Reeves et al., 1993b). That said, it is important to point out also that the Ca to P ratio is likely most important to this phenotype given GB diets such as the NIH-07 or NIH-31M (Ca to P ratio ¼ 0.9) were found to cause mild KC in young, female rats (Rao, 2002). When the AIN committee met to formulate the AIN93 series diets, increasing the Ca to P ratio above 1 was at the top of their list (Reeves et al., 1993a). The AIN-93 diets contain a Ca to P ratio of 1.3:1 and that, with a lower level of sucrose (10% vs. 50%) was able to “fix” the KC problem, but at the expense of having a mineral mix that is deficient in phosphorus and relying on casein (0.7% phosphorus) to fill the phosphorus void. Even still, a previous report suggested that some rats still have a mild degree of KC when fed the AIN-93G diet, suggesting this “fix” was not enough (Cockell and Belonje, 2004). Pubertal Onset Given what was discussed above regarding the influence of phytoestrogens on pubertal onset, one might speculate that a phytoestrogen-free diet would prevent precocious pubertal onset in rodents. However, a phytoestrogen-free diet such as the AIN-76A or AIN93G diet can also reduce the timing of VO and increase

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uterine weight, even in some cases when compared with phytoestrogen-containing GB diets, depending on the animal model (Thigpen et al., 2002, 2007). This is thought to be due to the higher metabolizable energy (or caloric density) content of purified diets (3.9e4 kcal/g diet in AIN-76A and AIN-93G, respectively) compared with GB diets (3e3.5 kcal/g) (Thigpen et al., 2002, 2007). GB diets typically contain 15%e25% fiber (both insoluble and soluble) and around 3%e5% soluble fiber (Pellizzon and Ricci, unpublished observations), whereas the AIN diets contain 5% of it (only insoluble fiber). Therefore, although it is currently unknown what particular dietary factor(s) in purified diets is “estrogenic,” it is possible that a reduced fiber content (and therefore higher metabolizable energy level) and perhaps even lack of soluble fiber are responsible and can easily be addressed by simply adding more fiber in purified diets. Metabolic Effects Aside from KC, the metabolic phenotype, including plasma and liver lipids, glucose tolerance, and blood pressure, can be significantly altered by purified diets and in some cases, not on purpose. For example, the AIN-76A and AIN-93G can have adverse effects on metabolic phenotypes in rodents, including increased body weight, blood and liver lipids, and blood pressure, compared to GB diets (Fullerton et al., 1992; Reeves et al., 1993b; Lien et al., 2001; Mattson et al., 2004). These diets contain sucrose in two concentrations (50% and 10% in the AIN-76A and AIN-93G diets, respectively), and high sucrose has been found to reduce glucose tolerance in C57BL/6 mice (Sumiyoshi et al., 2006) and induce IR, hyperTG, hepatic steatosis, and hypertension in rats (Hwang et al., 1987; Pagliassotti and Prach, 1995; Pagliassotti et al., 1996), even at lower concentrations, at least in rats (Thresher et al., 2000). As mentioned above, fiber levels are also very low in purified diets compared with GB diets. Furthermore, purified diets typically have only insoluble fiber (cellulose), whereas GB diets have both insoluble and soluble fiber sources from cereal grains. Crude fiber levels of GB diets are typically listed at 5%e6%, but these diets typically contain four times more total dietary fiber than the crude fiber analyses indicate (Wise and Gilburt, 1980) (w18% insoluble and w2e5% soluble). In comparison, the AIN-76A and AIN-93G contain 5% fiber by weight (50 g per 3902 kcals and 50 g per 4000 kcals for AIN-76A and AIN-93G, respectively) as cellulose (100% insoluble fiber). Modification of total fiber and fiber type in purified diets to be similar in composition to GB diets may lead to a healthier rodent phenotype. For example, addition of soluble fibers such as inulin can also reduce body weight, adiposity, and

Purified Diet

Grain-Based Diet

“Improved” Purified Diet

Purified Cellulose

Mix of Grain Fibers Fermentable Sources?

NO

YES

Inulin, Pectin Fermentable Sources?

Fermentable Sources?

YES

Microbial Fermentation

Gut health*

Overall Health

* Increased morphology, improved mucosal defense

FIGURE 40.3 Current purified diets may be improved by adding soluble fiber sources.

blood and liver lipids and improve glucose tolerance of rodents, and these changes are likely due to increases in short-chain fatty acids produced by fermentation of inulin by gut microbiota (Delzenne et al., 2002, 2007). Other mechanisms likely exist, including more direct effects of microbiota to reduce inflammation, and increase epithelial cell formation and mucosal layer thickness for improved barrier function (Chassaing et al., 2017; Zou et al., 2017). Additional fiber (both nonfermentable and fermentable) can also influence risk for other chronic diseases including cancer (Jacobs, 1986; Taper and Roberfroid, 2002) and may improve life span in rodents fed purified diets, which is usually shorter than those fed GB diets (Fullerton et al., 1992). Therefore, an increase in total fiber level and addition of soluble fiber are warranted in purified diets for normal growth and health maintenance of rodents (Fig. 40.3).

CONCLUDING REMARKS AND FUTURE DIRECTIONS The use of animals in research has provided us with an important means to understand more about our biology in general and the many toxicological factors in our environment that can affect our health. When designing any study using rodent models, diet needs to be considered, and one should ask three questions before making a decision: Can I report the diet? Can I repeat the diet? Can I revise the diet? Purified diets allow for each of these questions to be answered as “yes” and such diets are required in toxicological studies to minimize background contaminants.

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